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RENAL ADENOCARCINOMA, HEPATOCELLULAR CARCINOMA, ANDPANCREATIC ISLET CELL CARCINOMA IN A BINTURONG (ARCTICTISBINTURONG)Author(s): Eric KlaphakeD.V.M., Ahmed ShoiebD.V.M., Ph.D., Ed RamsayD.V.M., Dipl. A.C.Z.M.,Juergen SchumacherD.V.M., Dipl. A.C.Z.M., and Linden CraigD.V.M., Ph.D., Dipl. A.C.V.P.Source: Journal of Zoo and Wildlife Medicine, 36(1):127-130. 2005.Published By: American Association of Zoo VeterinariansDOI: http://dx.doi.org/10.1638/03-084URL: http://www.bioone.org/doi/full/10.1638/03-084

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Journal of Zoo and Wildlife Medicine 36(1): 127–130, 2005Copyright 2005 by American Association of Zoo Veterinarians

RENAL ADENOCARCINOMA, HEPATOCELLULAR CARCINOMA,AND PANCREATIC ISLET CELL CARCINOMA IN A BINTURONG(ARCTICTIS BINTURONG)

Eric Klaphake, D.V.M., Ahmed Shoieb, D.V.M., Ph.D., Ed Ramsay, D.V.M., Dipl. A.C.Z.M.,Juergen Schumacher, D.V.M., Dipl. A.C.Z.M., and Linden Craig, D.V.M., Ph.D., Dipl. A.C.V.P.

Abstract: A 19-yr-old binturong (Arctictis binturong) with acute upper respiratory disease was euthanized. Post-mortem findings included hepatocellular carcinoma, pancreatic islet cell carcinoma, and renal adenocarcinoma withmetastasis to the spleen, pleura, and pericardium. A link between primary hepatic and renal neoplasms has been notedin older humans.

Key words: Binturong, Arctictis binturong, renal adenocarcinoma, hepatocellular carcinoma, pancreatic islet cellcarcinoma, neoplasia.

BRIEF COMMUNICATION

A 20-kg, 19-yr-old, male binturong (Arctictisbinturong) from the Knoxville Zoological Gardenswas immobilized with medetomidine (Dormitor,Pfizer Animal Health, Exton, Pennsylvania 19341,USA; 0.06 mg/kg, i.m.), ketamine (Ketaset, FortDodge Animal Health, Fort Dodge, Iowa 50501,USA; 3 mg/kg, i.m.), and butorphanol (Torbugesic,Fort Dodge Animal Health, Fort Dodge, Iowa50505, USA; 0.5 mg/kg, i.m.) and was intubatedand maintained on oxygen and isoflurane (IsoFlo,Abbott Laboratories, North Chicago, Illinois 60064,USA) in March 2003 because of a recent historyof coughing, wheezing, bilateral clear nasal dis-charge, and watery eyes. The only abnormalitiesnoted on the skull, thoracic, and abdominal radio-graphs were several collapsed intervertebral discspaces with spondylosis. The complete blood countand select serum chemistries were within referenceintervals except for packed cell volume (PCV)(58.8% vs. 37–54%), and blood urea nitrogen(BUN) (15.0 mmol/L [42 mg/dl], vs. 5.7–20.0mmol/L [8–28 mg/dl]).4

After 1 wk of amoxicillin and clavulanic acidtherapy (Clavamox, Pfizer Animal Health, NewYork City, New York 10017, USA; 250 mg/kg,p.o., b.i.d.) with no improvement, the binturongwas reimmobilized with medetomidine (0.06 mg/kg, i.m.), ketamine (3 mg/kg, i.m.), and butorpha-nol (0.5 mg/kg, i.m.) and was intubated and main-tained on oxygen and isoflurane for examination. Itwas dehydrated, was not properly grooming itself,

From the Departments of Small Animal Clinical Sci-ences (Klaphake, Ramsay, Schumacher) and Pathobiology(Shoieb, Craig), The University of Tennessee College ofVeterinary Medicine, Knoxville, Tennessee 37996, USA.Correspondence should be directed to Dr. Klaphake.

and the left kidney was palpably enlarged and ir-regular. The PCV (57%) and BUN (12.9 mmol/L[36 mg/dl]) values were mildly increased, as wasthe creatinine level (186 mmol/L [2.1 mg/dl] vs.80–150 mmol/L [0.9–1.7 mg/dl]).4

Radiography revealed an atypical left kidney out-line, diffuse hepatomegaly, probably with an asso-ciated mass, splenomegaly, and a suspected focalcentral abdominal mass, severe pleural effusion,and pulmonary nodules. Approximately 0.5 L ofserosanguineous fluid was removed by thoracocen-tesis at the left seventh intercostal space and alsoat the right seventh intercostal space. These fluidsamples were cellular and contained dark blue clus-ters of epithelial cells, each with round to oval nu-clei containing densely clumped chromatin and oneto two prominent nucleoli of varying size andshape. Occasional cells were either multinucleate(up to eight nuclei), contained small nuclear frag-ments, or displayed bizarre mitotic figures. Thecells exhibited moderate to marked anisokaryosisand anisocytosis and variable nuclear–cytoplasmicratios. The blue cytoplasm typically contained nu-merous small discrete vacuoles. Cohesive aggre-gates of cells occasionally had amorphous red ma-terial between or within the cells. Cytology of thefluid was consistent with a carcinoma, although amesothelioma could not be ruled out. The prognosiswas poor and the animal was euthanized.

Necropsy revealed additional serosanguineousfluid (0.52 L) in the thoracic cavity. The pericar-dium was thickened and covered with numerouscoalescing, 2- to 5-mm-diameter, firm, white nod-ules. A fibrous adhesion connected the parietal peri-cardium and the right ventricular epicardium nearthe interventricular septum. The lungs were darkred, spongy, and had multifocal to coalescing pleu-ral and parenchymal nodules. The liver had a prom-

128 JOURNAL OF ZOO AND WILDLIFE MEDICINE

Figure 1. Renal cell carcinoma in a binturong (Arctictis binturong). The carcinoma (on the right) is characterizedby irregular tubule formation and large bizarre nuclei. Interstitial fibrosis is present in the adjacent compressed renalparenchyma. H&E. Bar 5 50 mm.

inent reticular pattern with multiple 1- to 2-mm-diameter tan nodules within the parenchyma. Theright medial hepatic lobe had a 2.0- by 1.5- by 1.5-cm, soft, dark red nodule with focal, adjacent, ir-regular capsular fibrosis. The right kidney had a 5-cm-diameter, firm, white-tan mass in the cranialthird. A 6- by 4- by 2-cm, enlarged, gelatinous mes-enteric lymph node was present. The spleen hadround margins, and there were two 13- by 11- by4-mm and 3-mm white nodules. Representative tis-sues from most organs were fixed in 10% neutralbuffered formalin, processed routinely for paraffinembedding, sectioned at 5 mm, and stained withhematoxylin and eosin.

Histologic evaluation revealed effacement of therenal tissue by a pleomorphic population of polyg-onal to columnar cells arranged in nests, papillae,or tubules (Fig. 1). There was marked cellular atyp-ia, moderate anisocytosis, and anisokaryosis. Themitotic index was 0–4 at 3400 magnification. Ir-regular areas of desmoplasia were present. The tu-bules were often irregular, lined by one or more

layers of columnar epithelium, and contained largenumbers of exfoliated and necrotic cells. Occasion-al multinucleate cells and areas of necrosis wereseen. Some tubular epithelial cells contained yel-low-green to golden cytoplasmic pigment. Multiplemetastases were composed of similar neoplasticcell populations that extend to variable distances inthe parietal pleura, lung, muscle of the thoracicwall, pericardium, spleen, and a splenic blood ves-sel.

The liver had compressive ill-defined nonencap-sulated masses composed of cords of well-differ-entiated hepatocytes 3–12 cells thick. Marked dif-fuse congestion, mild to moderate portal fibrosis,and small numbers of hemosiderin-laden macro-phages were present. Many hepatocytes containedyellow-green to brown cytoplasmic pigment, andthere were rare necrotic hepatocytes. Scattered,large vacuolated cells (Ito cells) and hemosiderin-laden Kupffer cells were present. Frequent bile can-aliculi were distended with bile.

The pancreas contained multiple variably sized,

129KLAPHAKE ET AL.—MULTIPLE NEOPLASMS BINTURONG

Figure 2. Pancreatic islet cell carcinoma in a binturong (Arctictis binturong). The neoplastic cells are arranged inpackets and cords and have only mild nuclear pleomorphism. H&E. Bar 5 100 mm.

partially encapsulated, compressive nodules con-sisting of irregular nests and cords of monomorphicpolygonal cells with a fine fibrovascular stroma(Fig. 2). In some nodules, single layers of palisad-ing polygonal cells formed blood-filled cysts andtubules. The cells had eccentric, medium-sized,uniform, round nuclei with stippled chromatin andabundant finely granular pale eosinophilic cyto-plasm. Mitotic figures were uncommon. The stromawas variably expanded by globular to amorphouspale pink material with extensive mineralizationand deposits of yellow-orange pigment. PositiveCongo red stain and Hall bile stain results indicatedthat these were amyloid and biliverdin, respective-ly. Adjacent to the large nodules were multiple, ir-regular to ovoid nodules of poorly organized duc-tular tissue (atrophic exocrine pancreas) with mildlymphocytic infiltrates.

The final diagnoses in the binturong were renaladenocarcinoma (with metastasis to the pleura,pericardium, and spleen), hepatocellular carcinoma,and pancreatic islet cell carcinoma. One study ofneoplasia in viverrids reported three neoplasms

(two hepatic and one thyroid) in 11 necropsies,6

another retrospective study of 85 viverrid necrop-sies revealed no neoplastic disease,1 whereas a thirdretrospective study of captive wild mammals duringa 5-yr period found two cases of hepatic neoplasiain viverrids (chloangiocarcinoma and a hepatocel-lular carcinoma).10 In binturongs, only a metastaticpulmonary carcinoma, a metastatic mammary ade-nocarcinoma, and a mammary carcinoma havebeen reported.2,6

The number of etiologies responsible for thethree neoplasms in the binturong studied is un-known. In humans .70 yr of age, primary hepaticand renal neoplasms may occur in parallel, andthere may be a common unknown etiology.8 Syn-chronous multiple primary neoplasias are relativelyunusual in humans (1.2–1.9% of all primary can-cers).3 This case fits the criteria for multiple pri-mary malignant neoplasia because each neoplasmpresented a definite picture of malignancy; eachwas physically separate and distinct, and the like-lihood of one representing a metastasis from anoth-er was excluded.3 The etiology of multiple primary

130 JOURNAL OF ZOO AND WILDLIFE MEDICINE

neoplasia in humans is unknown, although geneticalterations has been proposed.3

Renal cell carcinoma is the most common pri-mary renal neoplasia in cats and dogs and is usuallymalignant.5 Polycythemia can occur because of in-appropriate production of erythropoietin,5 and azo-temia may be noted with bilateral carcinoma.5 Poly-cythemia and azotemia occurred on both serumchemistries of the binturong although one kidneywas normal. Renal neoplasia has not been describedin other viverrids.

About 70% of hepatocellular carcinomas in hu-mans are associated with liver cirrhosis.8 Chronicliver disease, viral hepatitis, hemochromatosis, he-patic carcinogens, and mycotoxins may also con-tribute.8 Cirrhosis may lead to reduced hepaticfunction with impaired or altered metabolism ofvarious substances that may result in oncogenicproducts.8 Primary hepatic tumors are rare in dogsand cats, although hepatocellular carcinoma is themost common primary hepatic tumor in older maledogs.7 Diagnostics are often nonspecific, indicatingelevated liver enzymes and radiographic or ultra-sonic evidence of hepatomegaly,7 as was observedin the binturong. The four previously reported casesof viverrid hepatic neoplasia suggest that it may becommon in this family.6,10

Pancreatic islet cell carcinomas can occur in old-er dogs and are rare in cats.9 Insulinomas are mostcommon, although gastrinomas and glucagonomasmay also occur. In dogs, hypoglycemia with hy-perinsulinemia may help with antemortem diagno-sis.9 Only glucose levels were assessed in the bin-turong, and they were within normal limits. Viver-rid pancreatic islet cell carcinoma has not been de-scribed previously. Further investigation intocausative factors for neoplasms in binturongs iswarranted.

Acknowledgments: We thank Drs. David Ed-

wards and Robert Cole for assisting in the ante-mortem diagnosis.

LITERATURE CITED1. Appleby, E. C. 1987. Pathological findings in cap-

tive wild mammals—a survey based on the ‘‘V.R.Z.A.’’data recording programme. Zool. Gart. 57: 325–342.

2. Bjornson, A. P., J. C. M. Lewis, and E. C. Appleby.1999. Mammary neoplasia in a binturong (Arctictis bin-turong). Vet. Rec. 144: 421–422.

3. Chang, Y., C. Tsai, T. Yang, C. Shih, M. Wu, and J.Lin. 2002. Synchronous triple cancers at middle and loweresophagus and stomach with different histological featuresand genetic alterations. J. Gastroenterol. Hepatol. 17:724–727.

4. Denver, M. 2003. Procyonidae and Viverridae. In:Fowler, M. E., and R. E. Miller (eds.). Zoo and Wild An-imal Medicine, 5th ed. Elsevier Science, St. Louis, Mis-souri. Pp. 516–522.

5. Forrester S. D. 2000. Diseases of the kidney andureter. In: Birchard S. J., and R. G. Sherding (eds.). Saun-ders Manual of Small Animal Practice, 2nd ed. W. B.Saunders Co., Philadelphia, Pennsylvania. Pp. 913–937.

6. Ippen, R. 1987. The occurrence of tumors in non-domesticated wild carnivorous animals (Fissipedia).Dtsch. Tierarztl. Wochenschr. 94: 61–63.

7. Johnson S. E., and R. G. Sherding. 2000. Diseasesof the liver and biliary tract. In: Birchard S. J., and R. G.Sherding (eds.). Saunders Manual of Small Animal Prac-tice, 2nd ed. W. B. Saunders Co., Philadelphia, Pennsyl-vania. Pp. 824–873.

8. Kaczynski, J., E. Holmberg, A. Oden, and S. Wal-lerstedt. 2002. Remarkable association between liver andkidney cancer. Gastrointest. Cancer: Int. J. Gastrointest.Oncol. 4: 45–47.

9. Nelson R. W., and S. K. Salisbury. 2000. Pancreaticbeta cell neoplasia. In: Birchard S.J. and R.G. Sherding(eds.). Saunders Manual of Small Animal Practice, 2nded. W. B. Saunders Co., Philadelphia, Pennsylvania. Pp.288–294.

10. Wadsworth, P. F., D. M. Jones, and S. L. Pugsley.1982. Primary hepatic neoplasia in some captive wildmammals. J. Zoo Anim. Med. 13: 29–32.

Received for publication 16 September 2003