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Cholangiocarcinoma in a cat infected with domestic cat hepatitis B virus

##article.authors##

  • Haruka Dosaka University of Miyazaki, Department of Veterinary Pathology, Faculty of Agriculture
  • Nanami X Kato University of Miyazaki, Laboratory of Veterinary Microbiology, Department of Veterinary Science, Faculty of Agriculture
  • Kei Taga Tokyo Cat Specialists
  • Soshin Yamamoto Tokyo Cat Specialists
  • Kaito Kondo University of Miyazaki, Department of Veterinary Pathology, Faculty of Agriculture
  • Rissar Siringo Ringo University of Miyazaki, Laboratory of Veterinary Microbiology, Department of Veterinary Science
  • Yasuyuki Kaneko University of Miyazaki, Veterinary Teaching Hospital, Faculty of Agriculture
  • Takuya Hirai University of Miyazaki, Department of Veterinary Pathology, Faculty of Agriculture
  • Akatsuki Saito University of Miyazaki, Laboratory of Veterinary Microbiology, Department of Veterinary Science
  • Fuke, Naoyuki University of Miyazaki, Department of Veterinary Pathology, Faculty of Agriculture

DOI:

https://doi.org/10.51094/jxiv.1376

キーワード:

cat、 cholangiocarcinoma、 domestic cat hepadnavirus、 immunohistochemistory、 in situ hybridization

抄録

Cholangiocarcinoma is a rare hepatic malignancy in domestic cats, and its etiology remains largely undefined. Domestic cat hepadnavirus (DCHBV), a recently discovered member of the Orthohepadnavirus genus, shares similarities with human hepatitis B virus (HBV), which is associated with liver cancers, including cholangiocarcinoma. Here, we report a case of cholangiocarcinoma in a feline immunodeficiency virus-positive, 17-year-old spayed female cat infected with DCHBV. The patient presented with persistent vomiting, anorexia, and an elevated globulin level. Ultrasound revealed multiple hypoechoic hepatic lesions, and histopathology confirmed cholangiocarcinoma. Using quantitative PCR, DCHBV was detected in the spleen and ascitic fluid, and full-genome sequencing identified a unique 12-base deletion in both the polymerase and surface protein genes. Immunohistochemistry and RNA in situ hybridization demonstrated DCHBV core protein and mRNA expression in both tumor and non-tumor liver tissues, though signals were more prominent in non-neoplastic hepatocytes. The tumor exhibited CK7 positivity and HepPar-1 negativity, confirming biliary origin. While the causal relationship between DCHBV and cholangiocarcinoma remains to be clarified, the presence of a viral antigen and mRNA in neoplastic tissue suggests a potential role for DCHBV in hepatobiliary carcinogenesis. This is the first report describing cholangiocarcinoma in a cat with DCHBV infection, raising the possibility that DCHBV may have broader pathogenic potential beyond hepatitis and hepatocellular carcinoma.

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The authors declare no conflict of interest.

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引用文献

Adıgüzel E, Erdem-Şahinkesen E, Koç BT, Demirden C, Oğuzoğlu TÇ. The detection and full genomic characterization of domestic cat Orthohepadnaviruses from Türkiye. Vet Med Sci. 2023;9(5):1965–1972.

Aghazadeh M, Shi M, Barrs VR, et al. A Novel Hepadnavirus Identified in an Immunocompromised Domestic Cat in Australia. Viruses. 2018;10(5):269.

Anderson LJ, Sandison AT. Tumors of the liver in cattle, sheep and pigs. Cancer. 1968;21(2):289–301.

Andrade RLFS, Dantas AFM, Pimentel LA, et al. Platynosomum fastosum-induced cholangiocarcinomas in cats. Vet Parasitol. 2012;190(1–2):277–280.

Anpuanandam K, Selvarajah GT, Choy MMK, et al. Molecular detection and characterisation of Domestic Cat Hepadnavirus (DCH) from blood and liver tissues of cats in Malaysia. BMC veterinary research.2021;17(1):9.

Barrantes Murillo DF, Cattley RC, Cullen JM, et al. Intrahepatic mucinous cholangiocarcinoma with recurrent colic in a horse case report and literature review of cholangiocarcinoma in horses. J Vet Diagn Invest. 2024;36(4):547–553.y

Bartenschlager R, Junker-Niepmann M, Schaller H. The P gene product of hepatitis B virus is required as a structural component for genomic RNA encapsidation. J Virol. 1990;64(11):5324–5332.

Bartenschlager R, Schaller H. The amino-terminal domain of the hepadnaviral P-gene encodes the terminal protein (genome-linked protein) believed to prime reverse transcription. EMBO j. 1998;7(13):4185–4192.

Bastianello SS. A survey on neoplasia in domestic species over a 40-year period from 1935 to 1974 in the Republic of South Africa. I. Tumours occurring in cattle. Onderstepoort J Vet Res. 1982;49(4):195–204.

Bastianello SS. A survey of neoplasia in domestic species over a 40-year period from 1935 to 1974 in the Republic of South Africa. V. Tumours occurring in the cat. Onderstepoort J Vet Res. 1983;50(2):105–110.

Bastianello SS. A survey on neoplasia in domestic species over a 40-year period from 1935 to 1974 in the Republic of South Africa. VI. Tumours occurring in dogs. Onderstepoort J Vet Res. 1983;50(3):199–220.

Beasley RP, Hwang LY, Lin CC, et al. Hepatocellular carcinoma and hepatitis B virus. A prospective study of 22 707 men in Taiwan. Lancet. 1981;2(8256):1129–1133.

Berto AN, Lemos GAA, Navolar FMN, Di Santis GW, Zanutto MS. Metastatic pancreatic carcinoma with neuroendocrine differentiation in a cat. JFMS Open Rep. 2024;10(1):20551169231213504.

Bettini G, Marcato PS. Primary hepatic tumours in cattle. A classification of 66 cases. J Comp Pathol. 1992;107(1):19–34.

Brechot C, Pourcel C, Louise A, et al. Presence of integrated hepatitis B virus DNA sequences in cellular DNA of human hepatocellular carcinoma. Nature. 1980;286(5772):533–535.

Brindley PJ, Melinda Bachini, Sumera I. Ilyas, et al. Cholangiocarcinoma. Nat Rev Dis Primers. 2021;7(1):65.

Capozza P, Maura Carrai, Yan Ru Choi, et al. Domestic Cat Hepadnavirus: Molecular Epidemiology and Phylogeny in Cats in Hong Kong. Viruses. 2023;15(1):150.

Carpenter JL, Andrews IK. Tumors and tumor-like lesions. In: Holzworth J, ed. Diseases of the Cat. Saunders; 1987:406–AD.

Chang HP. HEPATIC CLONORCHIASIS AND CARCINOMA OF THE BILE DUCT IN A DOG. J Pathol Bacteriol. 1965;89:365–367.

Chang HP. PATHOLOGICAL CHANGES IN THE INTRAHEPATIC BILE DUCTS OF CATS (FELIS CATUS) INFESTED WITH CLONORCHIS SINENSIS. J Pathol Bacteriol. 1965;89:357–364.

Conti MB, Marchesi MC, Zappulla F, et al. Clinical findings and diagnosis in a case of cholangiocellular carcinoma in a horse. Vet Res Commun. 2008;32(Suppl 1):S271-273.

Cullen JM. Tumors of the liver and gallbladder. In: Meuten DJ, ed. Tumors in Domestic Animals. 5th ed. John Wiley & Sons; 2017:617–621.

Diakoudi G, Capozza P, Lanave G, et al. A novel hepadnavirus in domestic dogs. Sci Rep. 2022;12(1):2864.

Domínguez MC, Chávez G, Trigo FJ, Rosales ML. Concurrent cholangiocarcinoma, peritonitis, paratuberculosis, and aspergillosis in a goat. Can Vet J. 2001;42(11):884–885.

Fujimoto A, Furuta M, Totoki Y, et al. Whole-genome mutational landscape and characterization of noncoding and structural mutations in liver cancer. Nat Genet. 2016;48(5):500–509.

Hayashi Y, Tajiri K, Ozawa T, et al. Impact of preS1 Evaluation in the Management of Chronic Hepatitis B Virus Infection. Medicina (Kaunas). 2024;60(8):1334.

Hayes HM, Morin MM, Rubenstein DA. Canine biliary carcinoma: epidemiological comparisons with man. J Comp Pathol. 1983;93(1):99–107.

Head KW, Else RW, Dubielzig RR. Tumors of the liver. In: Head KW, Else RW, Dubielzig RR, eds. Histological Classification of Tumors of the Alimentary System of Domestic Animals. 2nd ed. Armed Forces Institute of Pathology; 2003:121–126.

Hirao K, Matsumura K, Imagawa A, Enomoto Y, Hosogi Y. Primary neoplasms in dog liver induced by diethylnitrosamine. Cancer Res. 1974;34(8):1870–1882.

Hirose N, Uchida K, Kanemoto H, Ohno K, Chambers JK, Nakayama H. A retrospective histopathological survey on canine and feline liver diseases at the University of Tokyo between 2006 and 2012. Journal Vet Med Sci. 2014;76(7):1015–1020.

Hou PC. PRIMARY CARCINOMA OF BILE DUCT OF THE LIVER OF THE CAT (FELIS CATUS) INFESTED WITH CLONORCHIS SINENSIS. J Pathol Bacteriol, 1964;87:239–244.

Hu J, Flores D, Toft D, Wang X, Nguyen D. Requirement of heat shock protein 90 for human hepatitis B virus reverse transcriptase function. J Virol. 2004;78(23):13122–13131.

Imazeki F, Yaginuma K, Omata M, Okuda K, Kobayashi M, Koike K. Integrated structures of duck hepatitis B virus DNA in hepatocellular carcinoma. J Virol. 1988;62(3):861–865.

Jakab Cs, Kiss A, Schaff Zs, et al. Claudin-7 protein differentiates canine cholangiocarcinoma from hepatocellular carcinoma. Histol Histopathol. 2010;25(7):857–864.

Jeanes EC, Wegg ML, Mitchell JA, Priestnall SL, Fleming L, Dawson C. Comparison of the prevalence of Domestic Cat Hepadnavirus in a population of cats with uveitis and in a healthy blood donor cat population in the United Kingdom. Vet Ophthalmol. 2022;25(2):165–172.

Jones SA, Clark DN, Cao F, Tavis JE, Hu J. Comparative analysis of hepatitis B virus polymerase sequences required for viral RNA binding, RNA packaging, and protein priming. J Virol. 2014;88(3):1564–1572.

Kim S, Lee J, Ryu W-S. Four conserved cysteine residues of the hepatitis B virus polymerase are critical for RNA pregenome encapsidation. J Virol, 2009;83(16):8032–8040.

Kim Y, Hong YB, Jung G. Hepatitis B virus: DNA polymerase activity of deletion mutants. Biochem Mol Biol Int, 1999;47(2):301–308.

Lanave G, Capozza P, Diakoudi G, et al. Identification of hepadnavirus in the sera of cats. Sci Rep. 2019;9(1): 10668.

Lanford RE, Chavez D, Brasky KM, R B Burns 3rd, R Rico-Hesse. Isolation of a hepadnavirus from the woolly monkey, a New World primate. Proc Natl Acad Sci U S A. 1998;95(10):5757–5761.

Lanford RE, Kim YH, Lee H, Notvall L, Beames B. Mapping of the hepatitis B virus reverse transcriptase TP and RT domains by transcomplementation for nucleotide priming and by protein-protein interaction. J Virol, 1999;73(3):1885–1893.

Lawrence HJ, Erb HN, Harvey HJ. Nonlymphomatous hepatobiliary masses in cats: 41 cases (1972 to 1991). Vet Surg. 1994;23(5):365–368.

Lin B, He Q, Lu Y, Zhang W, Jin J, Pan H. Viral hepatitis increases the risk of cholangiocarcinoma: a systematic review and meta-analysis. Transl Cancer Res. 2023;12(6):1602–1616.

Lourenço J, McNaughton AL, Pley C, Obolski U, Gupta S, Matthews PC. Polymorphisms predicting phylogeny in hepatitis B virus. Virus Evol. 2022;9(1):veac116.

MacVean DW, Monlux AW, Anderson PS Jr, Silberg SL, Roszel JF. Frequency of canine and feline tumors in a defined population. Vet Pathol. 1978;15(6):700–715.

Madsen T, Arnal A, Vittecoq M, et al. Cancer prevalence and etiology in wild and captive animals. In: Aktipis CA, Maley CC, eds. Ecology and Evolution of Cancer. Academic Press; 2017:11–46.

Magnius L, Mason WS, Taylor J, et al. ICTV Virus Taxonomy Profile: Hepadnaviridae. J Gen Virol. 2020;101(6):571–572.

Maronpot RR, Giles HD, Dykes DJ, Irwin RD. Furan-induced hepatic cholangiocarcinomas in Fischer 344 rats. Toxicol Pathol. 1991;19(4 Pt 2):561–570.

Niwa H, Yamamura K, Miyazaki J. Efficient selection for high-expression transfectants with a novel eukaryotic vector. Gene. 1991;108(2):193–199.

Nomoto K, Tsuneyama K, Cheng C, et al. Intrahepatic cholangiocarcinoma arising in cirrhotic liver frequently expressed p63-positive basal/stem-cell phenotype. Pathol Res Pract. 2006;202(2):71–76.

Pandolfo GW, Teixeira MBS, de Cristo TG, Gaspar T, Carniel F, Casagrande RA. Metastatic gallbladder adenocarcinoma in a cat. Brazilian Journal of Veterinary Pathology, 2023;16(2):117–121.

Patnaik AK, Liu SK, Hurvitz AI, McClelland AJ. Nonhematopoietic neoplasms in cats. J Natl Cancer Inst. 1975;54(4):855–860.

Patnaik AK, Hurvitz AI, Lieberman PH, Johnson GF. Canine bile duct carcinoma. Vet Pathol. 1981;18(4):439–444.

Patnaik, A.K. A morphologic and immunocytochemical study of hepatic neoplasms in cats. Vet Pathol. 1992;29(5):405–415.

Pesavento PA, Jackson K, Hampson TSTTB, Munday JS, Barrs VR, Beatty JA. A Novel Hepadnavirus is Associated with Chronic Hepatitis and Hepatocellular Carcinoma in Cats. Viruses. 2019;11(10):969.

Piewbang C, Wardhani SW, Chaiyasak S, et al. Insights into the genetic diversity, recombination, and systemic infections with evidence of intracellular maturation of hepadnavirus in cats. PloS One. 2020;15(10):e0241212.

Pley C, Lourenço J, McNaughton AL, Matthews PC. Spacer Domain in Hepatitis B Virus Polymerase: Plugging a Hole or Performing a Role?. J Virol. 2022;96(9):e0005122.

Radziwill G, Tucker W, Schaller H. Mutational analysis of the hepatitis B virus P gene product: domain structure and RNase H activity. J Virol. 1990;64(2):613–620.

Ramos JA, Vara, Borst LB. Immunohistochemistry: fundamentals and applications in oncology. In: Meuten DJ, ed. Tumors in Domestic Animals. 5th ed. John Wiley & Sons; 2017:44–87.

Roy S, Glaser S, Chakraborty S. Inflammation and Progression of Cholangiocarcinoma: Role of Angiogenic and Lymphangiogenic Mechanisms. Front Med (Lausanne). 2019;6:293.

Shofa M, Ohkawa A, Okabayashi T, Kaneko Y, Saito A. Development of a direct duplex real-time PCR assay for rapid detection of domestic cat hepadnavirus. J Vet Diagn Invest Official Publication of the American Association of Veterinary Laboratory Diagn Invest. 2023;35(2):139–144.

Silva BB, Chen JY, Villanueva BH, et al. Genetic Diversity of Domestic Cat Hepadnavirus in Southern Taiwan. Viruses. 2023;15(10):2128.

Sivanand A, Talati D, Kalariya Y, Patel P, Gandhi SK. Associations of Liver Fluke Infection and Cholangiocarcinoma: A Scoping Review. Cureus. 2023;15(10):e46400.

Song Z, Lin S, Wu X, et al. Hepatitis B virus-related intrahepatic cholangiocarcinoma originates from hepatocytes. Hepatol Int. 2023;17(5):1300–1317.

Sripa B, Kaewkes S, Sithithaworn P, et al. Liver fluke induces cholangiocarcinoma. PLoS Med. 2007;4(7):e201.

Sternberg SS, Popper H, Oser BL, Oser M. Gallbladder and bile duct adenocarcinomas in dogs after long term feeding of aramite. Cancer. 1960;13:780–789.

Stone C, Petch R, Gagne RB, et al. Prevalence and Genomic Sequence Analysis of Domestic Cat Hepadnavirus in the United States. Viruses. 2022;14(10):2091.

Strafuss AC. Bile duct carcinoma in dogs. J Am Vet Med Assoc. 1976;169(4):429.

Summers J, Smolec JM, Snyder R. A virus similar to human hepatitis B virus associated with hepatitis and hepatoma in woodchucks. Proc Natl Acad Sci U S A. 1978;75(9):4533–4537.

Takahashi K, Kaneko Y, Shibanai A, et al. Identification of domestic cat hepadnavirus from a cat blood sample in Japan. J Vet Med Sci. 2022;84(5):648–652.

Taylor GN, Lloyd RD, Mays CW, et al. Plutonium- or americium-induced liver tumors and lesions in beagles. Health Phys. 1991;61(3):337–347.

Tessmann A, Sumienski J, Sita A, et al. Domestic cat hepadnavirus genotype B is present in Southern Brazil. Virus Genes. 2025;61(1):81–86.

Trigo FJ, Thompson H, Breeze RG, Nash AS, et al. The pathology of liver tumours in the dog. J Comp Pathol. 1982;92(1):21–39.

Tsuchiya J, Miyoshi M, Kakinuma S, et al. Hepatitis B Virus-KMT2B Integration Drives Hepatic Oncogenic Processes in a Human Gene-edited Induced Pluripotent Stem Cells-derived Model. Cell Mol Gastroenterol Hepatol. 2025;19(2):101422.

Wang C, Wang MD, Cheng P, et al. Hepatitis B virus X protein promotes the stem-like properties of OV6+ cancer cells in hepatocellular carcinoma. Cell Death Dis. 2017;8(1): e2560.

Whitehead JE. Neoplasia in the cat. Vet Med Small Anim Clin. 1967;62(1):44–45.

公開済


投稿日時: 2025-07-10 05:46:40 UTC

公開日時: 2025-07-14 09:59:36 UTC
研究分野
生物学・生命科学・基礎医学