Oral malignancy is rare in chimpanzees. A 34-year-old female chimpanzee (Pan troglodytes) at Kumamoto Sanctuary, Japan, had developed it. Treatment is technically difficult for chimpanzees while malignant neoplasm is seemingly rising in captive populations. Widespread expert discussion, guidelines for treatment, especially for great apes in terminal stages is urgently needed

Fujisawa, M

Hirata, S

Hirosawa, M

Idani, G

Matsubayashi, K

Mori, Y

Morimura, N

Nagano, K

Nasu, K

Nogami, E

Saito, A

Seres, M

Teramoto, M

Tomonaga, M

Tsuruyama, T

Udono, T

Uesaka, H

Journal of Medical Primatology

Kyoto University Research Information Repository

TitleA case of maxillary sarcoma in a chimpanzee (Pantroglodytes).Author(s)Fujisawa, M; Udono, T; Nogami, E; Hirosawa, M; Morimura,N; Saito, A; Seres, M; Teramoto, M; Nagano, K; Mori, Y;Uesaka, H; Nasu, K; Tomonaga, M; Idani, G; Hirata, S;Tsuruyama, T; Matsubayashi, KCitationJ urnal of medical primatology (2014), 43(2): 111-114Issue Date2014-04URL http://hdl.handle.net/2433/199614RightThis is the peer reviewed version of the following article:Fujisawa, M., Udono, T., Nogami, E., Hirosawa, M.,Morimura, N., Saito, A., Seres, M., Teramoto, M., Nagano, K.,Mori, Y., Uesaka, H., Nasu, K., Tomonaga, M., Idani, G.,Hirata, S., Tsuruyama, T. and Matsubayashi, K. (2014), A caseof maxillary sarcoma in a chimpanzee (Pan troglodytes).Journal of Medical Primatology, 43: 111‒114, which has beenpublished in final form at http://dx.doi.org/10.1111/jmp.12086.This article may be used for non-commercial purposes inaccordance with Wiley Terms and Conditions for Self-Archiving.Type Journal ArticleTextversionauthorKyoto University Page 1 of 8  A case of maxillary sarcoma in a chimpanzee (Pan troglodytes) 1 Michiko Fujisawa1,2, Toshifumi Udono1, Etsuko Nogami1, Mari Hirosawa1, Naruki Morimura1, 2 Aya Saito1, Michael Seres3, Migaku Teramoto1, Kunitoshi Nagano1, Yusuke Mori1, Hirosuke 3 Uesaka1, Kazuyo Nasu1, Masaki Tomonaga3, Gen’ichi Idani1, Satoshi Hirata3, Tatsuaki 4 Tsuruyama4, Kozo Matsubayashi2 5  6 1. Kumamoto Sanctuary, Wildlife Research Center, Kyoto University, Uki, Kumamoto, 7 Japan 8 2. Center for Southeast Asian Studies, Kyoto University, Kyoto, Kyoto, Japan 9 3. Primate Research Institute, Kyoto University, Inuyama, Aichi, Japan 10 4. Department of Diagnostic Pathology, Kyoto University Hospital, Kyoto, Kyoto, Japan 11  12 Acknowledgments of funding 13 This study was financially supported by MEXT (20002001, 20040001, 22659141) and WISH Grant and 14 Human Evolution Grant to the Primate Research Institute, Kyoto University. 15  16 Corresponding author: Michiko Fujisawa 17 Center for Southeast Asian Studies, Kyoto University 18 46, Shimoadachi-cho, Yosida, Sakyo-ku, Kyoto-shi, Kyoto 606-8501, Japan 19  Page 2 of 8  Tel: 075-753-7302, 20 Fax: 075-753-7350, 21 E-mail: mfujisaw@cseas.kyoto-u.ac.jp 22  23 Running Title 24 A case of maxillary sarcoma in a chimpanzee. 25  26 Total numbers of figure 27 2 28  29 Key Words 30 ape, malignant neoplasm, aging, care 31  32  33 Abstract 34 Oral malignancy is rare in chimpanzees. A 34-year-old female chimpanzee (Pan troglodytes) at Kumamoto 35 Sanctuary, Japan had had developed it. Treatment is technically difficult for chimpanzees while malignant 36 neoplasm is seemingly rising in captive populations. Widespread expert discussion, guidelines for 37 treatment, especially for great apes in terminal stages is urgently needed. 38  Page 3 of 8   39 Case Report 40 Genetically chimpanzees are the closest living relatives of human. We were diverged almost 7 millions 41 years ago, and the changes in disease conditions could have occurred in conjunction with evolutionary 42 changes. As our life expectancies increased, the later-onset diseases such as malignant neoplasm, 43 arteriosclerotic diseases, and dementia have also increased, thus, becoming a serious issue. These diseases 44 are dependent on the lifestyle and aging; they could be referred to as age-dependent diseases. 45 In contrast, very little is known about the nature of age-dependent diseases in chimpanzees. The 46 question remains whether the age-dependent diseases are exclusively human, or simply undiagnosed in 47 chimpanzees. For example, malignancy is extremely rare in chimpanzees [4]. Previous studies have shown 48 only few examples of such diseases in chimpanzees [2, 5]. 49 This is the first report of oral sarcoma in a chimpanzee. The case occurred in an estimated 34-year-old 50 wild born female. She was utilized in hepatitis C virus (HCV) infection research at another facility 51 between 1979 and 1987. Persistent HCV infection was observed without other specific notations. 52 The subject's right cheek had started swelling in February 2011. We suspected bacterial infection of the 53 dental root. Antibiotics were administered; however, no improvement was observed (Figure 1). Blood 54 analysis showed slight increases in white-blood-cell, C-reactive protein, and γ-glutamyl 55 transpeptidase levels and decrease in albumin level. No other noteworthy observations were made. Her 56 weight was 43 kg. 57  Page 4 of 8  Figure 2 shows histopathological image of the lesion. Abnormal undifferentiated cells including 58 spindle cells and adipose-like cells proliferated papillary or focally. Increased N/C ratio and multiple 59 images of mitosis showed this tumor was highly malignant. By immunohistological stain, vimantin was 60 positive, cytokeratine was partially slightly positive. On X-ray examination maxilla invasion was identified, 61 however, no pulmonary metastasis could be observed. Cervical lymph nodes were not swollen. 62 The common treatment for sarcoma in humans is mainly surgical resection with radiation or 63 chemotherapy. In this case, because extensive resection was required, the reconstruction of the oral cavity 64 must be considered. Surgical resection and radiation could not be options due to technical difficulties. 65 Chemotherapy was avoided as the side effects were thought to be too severe in proportion to the potential 66 results. It was also difficult to give her injection due to risking anesthesia on a daily basis. A conservative 67 palliative treatment was chosen instead during the remaining progression of the disease.  68 The tumor reached the end of hard palate, began to construct the pharynx. However, food intake was 69 still achieved by altering the texture of food. A timetable was created incorporating contact time with other 70 chimpanzees, with staffs, and time spent alone. Gradually, the time spent being recumbent increased, 71 however, she would still rise to interact with staff. Breathing difficulty appeared except when lying on her 72 right side. On August 15, she had eventually attempted to roll over and reached with her arms and legs out 73 to staff. She died at 9:30 am on August 17. Euthanasia was debated during the course, but was not 74 performed because she was still able to ingest food and did not appear to be in great distress. 75 When she died her weight was 26 kg. Pathological autopsy showed that the tumor had already invaded 76  Page 5 of 8  her maxilla. The mass had protruded into the oral cavity, and it was largely necrotic and ulcerated but the 77 tumor had not yet progressed into the orbital cavity. Despite the tumor extended almost to cover the entire 78 palate it did not reach the pharynx. The mandible and cervical lymph nodes were largely swollen and the 79 right cervical lymph nodes entwined the carotid artery. Multiple metastatic lesions were identified in 80 lymph nodes of the pulmonary hilum and of posterior mediastinum, in lungs, and in diaphragm. The right 81 lung showed poor aeration with the lower lung atelectasis. No pleural effusion was observed. No 82 intraperitoneal spread was detected. 83 Pathological diagnosis: (1) maxillary sarcoma with multiple metastases, (2) respiratory failure due to 84 metastases. 85 There are very few reports of malignant tumors in chimpanzees. Till recently, a number of hypotheses 86 have been raised, including claims that malignant tumors are simply remain undiagnosed [5] or that 87 because apoptosis suppression difference between human and chimpanzees, there is a known relationship 88 between suppression of apoptosis and increased risk of the onset of malignancy [3][12]. Recent studies 89 also have shown multiple genetic differences associated with malignancies [1, 8, 14, 15]. From these 90 findings, it is now understood that currently, there are very few identified genetic predispositions for 91 malignant neoplasm in chimpanzees. 92 The ratio that of chimpanzees actually reaches an advanced age is low [9]. Although the frequency of 93 occurrence of malignancy because of gene restoration anomalies increases with aging, the frequency of 94 malignancy remains low in chimpanzees due to the shorter lifespan. This can be a possible explanation for 95  Page 6 of 8  the minimal number of age-related diseases that are observed in chimpanzees. 96 The case subject had persistent HCV infection. In humans, oral squamous-cell carcinoma is considered 97 as a complication of HCV infection [7, 10, 11, 13]. Chimpanzees with a history of being utilized in 98 hepatitis research are numerous in Japan and in several countries, including USA. Although cases of 99 hepatic carcinoma have been reported, thus far there have been no reports of oral malignancy. 100 As outlined above, the possibility is that HCV infection is partially responsible for the oral sarcoma.  101 Since the subject was not young, the potential for gene restoration mistakes to occur at a higher rate along 102 with advancement in age must also be taken into consideration. 103 Noteworthy, that the subject was able to ingest food orally till the end; further, pain did not seem to 104 appear. The subject was able to live out the remainder of her life in relative comfort during the terminal 105 phase of the disease due to devoted staff until her very last day. The actual treatment of a chimpanzee 106 during the terminal phase of disease may be decided on a case-to-case basis. The number of aging 107 chimpanzees in captivity is increasing, and so we have to consider the need for terminal care cases will 108 also increase. Therefore, we think the necessity for a widespread discussion, regarding these issues is 109 inevitable among other chimpanzee holding facilities. 110  111 ACKNOWLEDGMENTS 112 We thank Drs Yasunori Sumi and Zenzo Isogai of National Center for Geriatrics and 113 Gerontology Hospital for providing valuable suggestion on treating malignanct tumor in oral 114  Page 7 of 8  cavity and skin. This study was financially supported by the following grants: MEXT 115 20002001, 20040001, 22659141, and WISH Grant and Human Evolution Grant to the Primate Research 116 Institute, Kyoto University. 117  118 References 119 1) Ahmed J, Günther S, Möller F, Preissner R. A structural genomics approach to the regulation of 120 apoptosis: chimp vs. human. Genome Inform 2007; 18: 22-34. 121 2) Amyx HL, Salazar AM, Newsome DA, Gibbs CJ Jr, Gajdusek DC: Nasopharyngeal carcinoma with 122 intracranial extension in a chimpanzee. J Am Vet Med Assoc 1982; 181: 1425-1426. 123 3) Arora G, Polavarapu N, McDonald JF. Did natural selection for increased cognitive ability in humans 124 lead to an elevated risk of cancer? Med Hypotheses 2009; 73: 453-456. 125 4) Bailey J: An examination of chimpanzee use in human cancer research. Alter Lab Anim 2009; 37: 126 399-416. 127 5) Brown SL, Anderson DC, Edward J. Dick Jr., Rodolfo G-M, AnaPatricia G, Gene BH. Neoplasia in the 128 Chimpanzee. (Pan spp.)J Med Primatol. 2009; 38: 137-144. 129 6) Carrozzo M. Oral diseases associated with hepatitis C virus infection. Part 1: sialadenitis and salivary 130 glands lymphoma. Oral Dis 2008; 14: 123-130. 131 7) Carrozzo M. Oral diseases associated with hepatitis C virus infection. Part 2: lichen planus and other 132 diseases. Oral Dis 2008; 14: 217-228. 133  Page 8 of 8  8) Calarco JA, Xing Y, Cáceres M, Clarco JP, Xiao X, Pan Q, Lee C, Preuss TM, Blencowe BJ. Global 134 analysis of alternative splicing differences between humans and chimpanzees. Genes dev 2007; 21: 135 2963-2975. 136 9) Finch CE. Evolution of the human lifespan and disease of aging: role of infection, inflammation, and 137 nutrition. Proc Natl Acad Sci 2010; 107: 1718-1724. 138 10) Gandolfo S, Richiardi L, Carrozzo M, Broccoletti R, Carbone M, Pagano M, Vestita C, Rosso S, 139 Merletti F. Risk of oral squamous cell carcinoma in 402 patients with oral lichen planus: a follow-up 140 study in an Italian population. Oral Oncol 2004; 40: 77-83. 141 11) Grossmann SM, Teixeira R, de Aguiar MC, de Moura MD, do Carmo MA. Oral mucosal conditions in 142 chronic hepatitis C Brazilian patients: a cross-sectional study. J Public Health Dent 2009; 69: 168-175. 143 12) Lowe SW, Lin AW. Apoptosis in cancer. Carcinogenesis 2000; 21: 485-495. 144 13) Nagao Y, Sata M, Noguchi S, Seno’o T, Kinoshita M, Kameyama T, Ueno T: Detection of hepatitis C 145 virus RNA in oral lichen planus and oral cancer tissues. J Oral Pathol Med 2000; 29: 259-266. 146 14) Wallace DC, Brown MD, Lott MT. Mitochondrial DNA variation in human evolution and disease. 147 Gene 1999; 238: 211-230. 148 15) Wallace DC. A mitochondrial paradigm of metabolic and degenerative diseases, aging, and cancer: A 149 dawn for evolutionary medicine. Annual Rev Genet 2005; 39: 359-407. 150 Figure 1a.b.c.d.e.f.Figure 2

A case of maxillary sarcoma in a chimpanzee (Pan troglodytes).

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A case of maxillary sarcoma in a chimpanzee (Pan troglodytes).

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