Neoplasitic Diseases in Ferrets in Japan: A Questionnaire Study for 2000 to 2005

FULL PAPER Internal Medicine Neoplasitic Diseases in Ferrets in Japan: A Questionnaire Study for 2000 to 2005 Yasutsugu MIWA 1), Asuka KUROSAWA 2), Hiroyuki OGAWA 1), Hiroyuki NAKAYAMA 3), Hiroshi SASAI 4) and Nobuo SASAKI 2) * 1) Laboratories of Veterinary Emergency Medicine, 2) Veterinary Surgery and 3) Veterinary Pathology, Graduate School of Agricultural and Life Sciences, The University of Tokyo, 1 1 1 Yayoi, Bunkyo-ku, Tokyo 113 8657 and 4) Kitasuma Animal Hospital, 9 5 8 Yokoo Suma, Kobe, Hyogo, 654 0131, Japan (Received 15 August 2008/Accepted 1 November 2008) ABSTRACT. The objective of this study was to collect epidemiological data on neoplasms in pet ferrets in Japan. A questionnaire to collect information was made available to Japanese veterinary practitioners through the web site of the Japanese Society of Exotic Pet Medicine. Completed questionnaires were returned from 29 practices, and 945 neoplasms met the criteria for inclusion in the study. Neoplasms were found in every organ system except the respiratory system; the endocrine (418; 44.2%), integumentary (196; 20.7%) and hemolymphatic (184; 19.5%) systems were most commonly affected. The most common tumor types were pancreatic islet cell tumor (211: 22.3%), adrenal gland tumor (207; 21.9%) and lymphoma (152; 16.1%). The age of the affected ferrets ranged from less than 3 months to more than 7 years of age. Tumor incidence was highest in ferrets between 4 and 6 years of age. No sex predilection was found. These results were similar to those recently published in North America. Most Japanese pet ferrets are imported from North America, and their husbandry including diets is similar to that in North America, which may explain the similar tendencies in the incidence of neoplasms in this study and those of findings in North America. KEY WORDS: epidemiology, ferret, Japan, neoplasm. J. Vet. Med. Sci. 71(4): 397 402, 2009 The ferret (Mustela putorius furo) belongs to the order Carnivora and to the family Mustelidae and has been a domestic animal since 4 BC [3]. However, it was not until the late 1990s that ferrets began to be routinely brought to veterinary practices for veterinary care by their owners [3]. Spontaneous neoplasms were not reported in the ferret until the 1950s [19]; by 1980, only 20 tumor cases of ferrets had appeared in the literature. Additionally, early experimental studies using certain chemical carcinogens and viral agents failed to induce neoplasms in ferrets [9, 12]. Hence, the early literature suggested that the incidence of neoplasms in ferrets was low [2, 5]. However, increased numbers of neoplasms have been reported since the 1990s [1, 2, 11 13, 20] due to the increased population of ferrets as pets and laboratory animals in North America. Currently, there is a large number of reports concerning ferret neoplasms, including epidemiological data, and the fact that neoplasms are much more common in this species than previously indicated has been established. Furthermore, particularly high incidences of specific neoplasms, such as adrenal gland tumor, insulinoma and lymphoma, have been recognized in North America [1, 4, 11, 13, 18, 20]. In Japan, use of ferrets as companion animals has been increasing, and neoplasms are recognized as a major clinical disease in ferrets. Although there have been some case reports concerning ferret neoplasms in Japan [14 16], to the best of our knowledge, no epidemiologic data has been reported in regard to *CORRESPONDENCE TO: SASAKI, N., Department of Veterinary Surgery, Graduate School of Agricultural and Life Sciences, The University of Tokyo, 1 1 1 Yayoi, Bunkyo-ku, Tokyo 113 8657, Japan. e-mail:miwayasutsugu@hotmail.com neoplasms in Japanese ferrets. The aim of this study was to collect epidemiological data on neoplasms in Japanese ferrets by sending questionnaires to practitioners and to compare the results to those reported in other countries. MATERIALS AND METHODS This study was conducted to investigate neoplastic diseases in ferrets that were diagnosed between 2000 and 2005 at animal practices in various areas in Japan. In order to gather the information needed for this study, a questionnaire was sent to practitioners to ask about the number of cases of neoplastic disease in ferrets in their practices. Only cases histologically or cytologically confirmed by commercial or university veterinary pathology laboratories to be neoplasms and tumor-like lesions were used for this analysis. Other information was requested for each case, including sex, age, body weight, type of neoplasm, diagnostic methods and concurrent diseases. Sex was categorized into male, female, castrated male, spayed female or unknown. Age was categorized into less than 1 month, 1 3 months, 4 6 months, 6 12 months, 1 2 years, 2 3 years, 3 4 years, 4 5 years, 5 6 years, 6 7 years, more than 7 years or unknown. Body weight was recorded at first admission for the neoplastic disease. Tumor types were categorized according to the standard terminology [13] and grouped by the affected organ or system. Diagnostic methods refers to whether the case was diagnosed using histopathology or cytopathology. Concurrent diseases were categorized as neoplastic disease or non-neoplastic disease, and a concurrent neoplasm in the same ferret was recorded as an independent neoplasm using

398 Y. MIWA ET AL. the same ID number for the ferret. Data concerning the total number of ferrets seen at the practice, clinical signs, treatments, outcome and name of the ferret farm from which the ferret was purchased were also supplied. The questionnaire in this study was introduced to the members of the Japanese Society of Exotic Pet Medicine at the annual conference of the society. The questionnaire was also placed on the web site of this society and was available to any practitioner. The practitioners wrote their answers into a Microsoft Excel file and emailed the file to the authors to facilitate analysis. All answers to questionnaires were evaluated, and only cases that met the inclusion criteria were included in this study. RESULTS Questionnaires were recovered from 29 animal practices in districts of Japan ranging from Hokkaido down to Kyushu. The number of ferret cases reported by practitioners ranged from 1 to 661 per animal practice. All questionnaires recovered were evaluated, and ferrets fulfilling the requirements of this study were used for further analysis. Insufficient amounts of body weight, concurrent disease and optionally provided information, such as clinical signs, treatments and outcome, were received in the questionnaires, so all these data were omitted from further analysis. Nine-hundred and forty-five cases were further analyzed in this study. Nine out of 29 responding animal practices (31.0%) answered with the total number of ferrets that had been brought to their practices during the research period. In these 9 practices, the total number of ferret patients during the six-year research period was 6640, and the number of neoplasm cases was 345. In these 9 practices, the mean incidence of the ferret neoplasm was 5.2%. The types of neoplasm were summarized according to the organ systems and are shown in Table 1. Various neoplastic types were found in every organ system except the respiratory system. Neoplasms of the endocrine system (44.2%) were the most common, followed by the integumentary (20.7%) and hemolymphatic (19.5%) systems. In the endocrine system, pancreatic islet tumors (211 cases) and adrenal gland tumors, including adrenal hyperplasia (207 cases), were most common. The total number of neoplasms of these two cell origins accounted for 100% of endocrine neoplasms and 44.2% of all neoplasms in the present study. Neoplasms of the integument system (20.7%) were the second most common, but their types were various. The most common integument neoplastic type was the sebaceous gland tumor, including cases with hyperplasia (74 cases), followed by mast cell tumor (42 cases) and apocrine gland tumor, including cysts (20 cases). The remaining neoplastic types in the integument system are shown in Table 1. The third most commonly found neoplasm was lymphoma (152 cases), which accounted for 82.6% of neoplasms of hemolymphatic systems and 16.1% of all neoplasms. Neoplasms of the skeletal system included 45 cases, accounting for 4.8% of all neoplasms, and chordoma (38 cases) was the most common type, among which 24 cases (63.2%) were found on the tail. The remaining neoplasms of this system included osteosarcoma and chondrosarcoma. In the digestive system (39 cases, 4.1% of all neoplasias), the bile duct (11 cases) and liver (7 cases) were the most commonly affected organs, while other neoplasms were found in the gastrointestinal tract, oral cavity and salivary gland. Hemangiosarcoma (15 cases) was the most common neoplasm in the cardiovascular system (22 cases, 2.3% of all tumors), and the vessels of the skin were the most commonly affected site. On the other hand, the respiratory system (no cases) appeared to be the least common organ, followed by the urinary system (2 cases, 0.2% of all tumors) and the nervous system (4 cases, 0.4% of all tumors). Neoplasms of other organ systems included mesotheliomas (10 cases) and abdominal tumors (2 cases). A few neoplasms in this study, such as nephroblastoma, salivary gland adenoma and adenocarcinoma of the paranasal sinuses, had not been previously reported in ferrets. Among the patients, 24 were males (2.5%), 19 were females (2.0%), 508 were castrated males (53.8%), 377 were spayed females (39.9%) and 17 were of unknown sex (1.8%), respectively. The incidence of males and castrated males (57.3%) was slightly higher than females and spayed females (42.7%), but there was no significant difference. Most cases (887 cases, 93.9%) were neutered (castrated or spayed) ferrets. The age of the affected ferret was confirmed in 889 out of 945 cases (94.1%), and Fig. 1 shows the age distribution of the ferret patients. There were no tumor cases in ferrets less than one month old, but there was one case less than three month old and 11 cases (1.2%) less than one year old. In ferrets less than 1 year old, the tumor types included lymphoma (4), chordoma (1), epulis (1), mesothelioma (1), liposarcoma (1), hemangiosarcoma (1), adrenocortical hyperplasia (1) and sebaceous adenocarcinoma (1). Tumor incidence increased with age and peaked at 5 6 years of age (Fig. 1). DISCUSSION The population of pet ferrets in Japan has been increasing, and various neoplasms have been reported over the past decade [14 16]. However, most previous reports have described individual case details; there have been no data reported concerning the prevalence of ferret neoplastic diseases in Japan. Early literature suggested that the incidence of neoplasm in ferrets was low [2, 5], but recent studies from North America have shown an increased incidence of neoplastic disease in ferrets [1, 6, 12, 13, 20]. The present study revealed a high incidence of neoplastic diseases of various tumor types in Japanese ferrets. The incidence of ferret neoplasm in the United States has been reported to be 12% based on a large-scale study [13]. In the present study, 9 responding practices reported the total number of ferret patients in their practices during the research period; the incidence of neoplastic diseases in these prac-

NEOPLASTIC DISEASES IN FERRETS 399 Table 1. Distribution by organ system and histologic diagnosis of 945 tumors in ferrets Total Number of Organ System Number Affected organ Histologic diagnosis ferrets Hemolymphatic 184 Lymphoid tissues (152) Lymphoma 152 Spleen (20) Extramedullary hemopoiesis 19 Lipoma 1 Others (12) Leukemia 8 Myeloma 3 Hematopoietic tumor, unspecified 1 Integument 196 Sebaceous gland (74) Adenoma 52 Adenocarcinoma 20 Hyperplasia 1 Apocrine gland (20) Cyst 9 Adenocarcinoma 7 Adenoma 4 Mammary gland (6) Adenoma 3 Adenocarcinoma 3 Foreskin (6) Adenocarcinoma 4 Adenoma 1 Anal sac gland (1) Carcinosarcoma 1 Integument epithelial origin (17) Squamous cell carcinoma 7 Trichoblastoma 6 Hamartoma 2 Inverted papiloma 1 Benign adnexal tumor 1 Integument soft tissue origin (72) Mast cell tumor 42 Leiomyosarcoma 11 Leiomyoma 2 Lipoma 2 Liposarcoma 2 Lipoma or liposarcoma 1 Histiocytoma 2 Fibrosarcoma 1 Fibroma 1 Mucoid fibroma 1 Mesenchymal tumor, unspecified 1 Histiocytic malignant tumor 1 Carcinoma, NOS 5 Endocrine 418 Adrenal gland (207) Adrenocortical adenocarcinoma 87 Adrenocortical adenoma 41 Adrenocortical hyperplasia 41 Adrenal gland tumor, unspecified 34 Pheochromocytoma 2 Leiomyosarcoma 2 Pancreatic islet (211) Islet cell tumor 201 Tumor, unspecified 7 Hyperplasia 3 Digestive 39 Liver (7) Hepatocellular carcinoma 3 Hepatocellular adenoma 3 Hepatoblastoma 1 Bile duct (8) Cholangioma 5 Cholangiocarcinoma 3 Hyperplasia 3 Small intestine (3) Adenocarcinoma 3 Intestine, site unspecified (2) Adenocarcinoma 2 Stomach (2) Adenocarcinoma 2 Gingiva (4) Epulis 2 Carcinoma, NOS 2 Pancreatic exocrine (6) Hyperplasia 5 Rectum (1) Adenoma 1 Salivary gland (1) Adenoma 1 Oral cavity (2) Odontogenic tumor 2

400 Y. MIWA ET AL. Table 1. continue Total Number of Organ System Number Affected organ Histologic diagnosis ferrets Nervous 4 Peripheral nervous (3) Schwannoma 3 Barin (1) Meningioma 1 Skeletal 45 Vertebra (38) Chordoma 38 Bone (7) Osteosarcoma 3 Chondrosarcoma 2 Tumor, unspecified 2 Reproductive 6 Ovary (6) Granulosa cell tumor 5 Urinary 2 Kidney (2) Nephroblastoma 1 Fibroma 1 Cardiovascular 22 Skin (5) Hemangiosarcoma 5 Gastrointestine (2) Hemangiosarcoma 2 Liver (1) Hemangiosarcoma 1 Abdominal cavity (1) Hemangiosarcoma 1 Site unspecified (6) Hemangiosarcoma 6 Skin (1) Hemangioma 1 Site unspecified (4) Hemangioma 4 Site unspecified (1) Hemangioma or hemangiosarcoma 1 Liver (1) Lymphangiosarcoma 1 Respiratory 0 0 Special sensory 2 Ear canal (1) Ceruminous adenocarcinoma 1 Paranasal sinuses (1) Adenocarcinoma 1 Others 27 Thoracic cavity (6) Mesothelioma 6 Abdominal cavity (4) Mesothelioma 1 Leiomyosarcoma 1 Tumor, unspecified 2 Site unspecified (17) Leiomyosarcoma 9 Mesothelioma 3 Lipoma 2 Liposarcoma 1 Lipoma or liposarcoma 1 Carcinoma, NOS 1 Total 945 NOS=Not origin specified. tices was 5.2%. This may be considered the estimated incidence of neoplasms in pet ferrets in Japan, though a more reliable incidence must be calculated in future research undertaken on a larger scale. Most of the previous epidemiological data on ferret tumors has been reported from North American countries, and the tendencies in the data are different before and after Beach s report [2]. In the early 1990s, Beach et al. reported that the most common neoplasm was genital tumors, followed by lymphoma. But from the late 1990s on wards, most ferrets were neutered at an early age (4 6 weeks of age) before being shipped to pet stores, and the incidence of genital tumors drastically decreased. Subsequently, endocrine tumors, such as insulinoma or adrenal tumors, became the most common neoplasm in ferrets [1, 2, 11 13, 20]. In the present study, tumor types and their incidences correlated well with recent reports from North American countries [1, 11 13, 20], and endocrine tumors were the most common neoplasm, followed by lymphoma. The three most common tumors in ferrets were adrenal tumors, insulinoma and lymphoma, accounting for 60.3% (570 cases) of all ferret tumors in the present study. Previous reports suggest that the higher incidence of endocrine-system tumors might be related to neutering at an early age based on a report in mice [12, 13, 18, 20]. In that report, gonadectomy at an early age led to adrenocortical nodular hyperplasia or formation of tumors that hypersecrete sex steroid hormones. Ovaries and adrenal glands develop in close anatomic relation to one another during embryologic development in the urogenital ridge. It is speculated that small nests of gonadal cells may be present in the adrenal glands during migration and that these cells may be transformed into neoplastic cells. In regard to the organ systems, the second most commonly affected organ system was the integumentary system, which had a similar incidence to that of the hemolympatic system, though various tumor types were included in this

NEOPLASTIC DISEASES IN FERRETS 401 Fig. 1. Age distribution of the affected ferrets. system. In the integumentary system, sebaceous gland tumors (37.8%) and mast cell tumors (21.4%), followed by apocrine gland tumors (10.2%), had higher incidences than the other types. According to the report of Parker et al. [17], basal cell tumors (trichoblastoma) were the most common tumor (58%) among 57 cutaneous tumors in their study, while in the present study, they constituted only 6 cases out of 196 cutaneous neoplasms (3%). Mast cell tumors had the second-highest incidence in both Parker s report and our study, accounting for 16% and 21% of cutaneous neoplasms, respectively. This may suggest there are various types of tumors in the integument system and that their incidences may differ according to country. The hemolympatic system was the third most commonly affected organ system, and among these cases, lymphoma had the highest incidence (82.7%). This tendency was similar to that in previous reports, which showed that lymphoma was the second or third most common neoplasm in ferrets [1, 11 13, 20]. The fourth most commonly affected organ system in this study was the skeletal system, and among these cases, chordoma had the highest incidence (84.4%). In ferrets, chordoma has usually been found on the caudal vertebrae [1, 12, 20], while in the present study, tumors were found on the tail in 24 out of 38 chordoma cases (63.2 %); in the remaining 14 cases, the site was unspecified. The cases with nephroblastoma in the present study had salivary gland adenoma and adenocarcinoma of the paranasal sinuses; this is the first report of these tumors in ferrets. The incidence of tumors was apparently higher in neutered ferrets, since pet ferrets are commonly neutered at an early age (4 6 weeks of age) before being shipped to pet shops. The age with the highest tumor incidence was between 4 and 6 years of age, which is similar to results from other reports [11 13, 20]. Neoplasms have been known to appear in very young ferrets less than 1 month of age [12, 13, 20]. In this study, there were no cases less than 1 month old, but there were a small number of cases less than 1 year old, including 1 case less than 3 months old, 3 cases less than 6 months old and 11 cases (1.2%) less than 1 year old, respectively. Among these cases, lymphoma was the most common tumor, accounting for about 36.4% of tumor cases in ferrets younger than 1 year of age. These results are similar to those in previous reports [1, 6, 8, 13, 20]. In conclusion, the epidemiological data on the incidence of various neoplasms in Japanese ferrets were similar to those reported in the U.S. This may be due to the fact that most Japanese pet ferrets are imported from North America, and their husbandry including diet is very similar to that of North American pet ferrets. The incidence of ferret tumors is reportedly lower in Australia [11] and European countries [7] than that in North American countries. Factors such as genetic background or husbandry in North American countries may relate to the higher incidence of neoplasms there. In fact, there are several hypotheses [11 13, 20] regarding human activities (spaying and castration, etc.), genetic factors and husbandry in regard to the cause of the high incidence of tumors in ferrets; however, the causes have not yet been confirmed. Further research is necessary to clarify the causes of the high incidence of neoplasm in ferrets in Japan and North American countries. ACKNOWLEDGMENTS. The present research was completed thanks to the efforts of a large number of cooperating Japanese practitioners and their staff. The authors gratefully acknowledge them for the time they took to investigate their extensive medical records. This work was supported in part by the Japanese Society of Exotic Pet Medicine.

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