Renal Transitional Cell and Choristoma in a Degu (Octodon degus)

PATRICK A. LESTER, RPH, DVM, MS,1,* HOWARD G. RUSH, DVM, DIPLOMATE, ACLAM,1 and ROBERT E. SIGLER, DVM, PHD, DIPLOMATE, ACVP2

A 4.5-year-old female degu (Octodon degus) was minimally responsive with a poor body condition, a rough haircoat, and moderate dehydration. Blood was present around its urethral orifi ce and on the cage bedding. Laboratory analyses revealed leukocytosis with neutro- philia and anemia; hypoproteinemia and hypoalbuminemia; hyperglycemia, hyperphosphatemia, and elevated alanine aminotransferase, blood urea nitrogen, and creatinine; and hematuria and pyuria with occasional squamous and transitional epithelial cells. A urine culture was positive for coagulase-negative Staphylococcus sp. On gross necropsy, the right kidney was enlarged, cystic, and greenish-brown, with a 10-mm, hemorrhagic, granular mass extending from the renal pelvis into the cranial cortex. Only a small amount of renal cortex appeared normal. Th e urinary bladder had focal areas of hemorrhage and contained frank blood. Histologically, the papillary mass in the right renal pelvis comprised basophilic, moderately anaplastic, clustered epithelial transition cells consistent with a transitional cell carcinoma. Internally, the tumor showed squamous metaplasia and moderate multifocal interstitial fi brosis. Th e right kidney cortex contained a choristoma comprising trabecular bone, mature adipocytes, and cellular infi ltrates suggestive of osteocytes, lymphocytes, and plasma cells. Th e urinary bladder had mild to moderate, focal, hemorrhage with neutrophilic infl ammation and contained focal areas of mild transitional cell epithelial ; these changes may have been secondary to irritation by hemorrhage in the renal pelvis. Th ere was no evidence of . Renal transitional cell tumors are rare in rodents. Th is is the fi rst report of both a renal transitional cell carcinoma and a renal choristoma in a degu.

Octodon degus, commonly called the degu, is a hystricomorph Table 1. Hematology profi le of the presented degu rodent native to South America. Degus inhabit Chile and Peru over Animal Normal reference a wide variety of altitudes, ranging from the coastal regions to the presented range for degus western slopes of the Andes (2000 m) (24). Th e average adult degu × 9 a weighs approximately 200 g and has a lifespan of 3 to 5 years. Degus Total white blood cells, 10 /L 16.8 2.4–11.36 × 9 a are very social animals and typically live in small groups (7). Th ey Neutrophils, 10 /L 14.0 1.34–6.32 Lymphocytes, × 109/L 2.64 0.27–5.36 produce a unique vocal distress call to warn of danger and possess tails Monocytes, × 109/L 0.12 0.12–1.87 that tear off to prevent capture. Th e tail does not grow back. Unlike Eosinophils, × 109/L 0.09 0.0–0.34 most rodents, the degu has a diurnal behavior pattern (15). Degus Basophils, × 109/L 0.01 0.0–0.07 are active during the day and rest at night. In addition, degus show Red blood cells, total, × 1012/L 3.29a 7.07–12.64 a circadian rise in body temperature in the morning associated with Hemoglobin, g/ dL 5.1a 11.20–20.40 peak activity in the early afternoon (27). Th ese properties make the Hematocrit, % 14.2a 32.2–55.4 degu a unique animal model for studying sleep biology, chronophar- Mean corpuscular volume, fL 43.2 41.5–52.2 macology, and circadian physiology (12, 15, 27). Mean corpuscular hemoglobin, pg 15.5 14.0–18.5 Mean corpuscular hemoglobin 35.9 33.0–38.8

concentration, g/dL Case History Red cell distribution width, % 18.2 17.2–24.6 A 4.5 year-old female degu was reported to the veterinary staff for Platelet count × 109/L 250 141–448 red-stained bedding, depression, and an unkempt appearance. Th e Mean platelet volume, fL 4.1 3.6–7.6 degu came from a conventional colony that was monitored for stan- aAbnormal value. dard rodent pathogens. Th e degu was singly housed in a polycarbonate solid-bottom rat cage (Allentown Caging Equipment, Allentown, the Association for the Assessment and Accreditation of Laboratory N.J.) with corn-cob bedding (Th e Andersons, Maumee, Ohio) and Animal Care, International. was fed commercial guinea pig chow (Purina Lab Diet 5025, PMI Physical exam revealed a depressed degu in poor body condition International, Brentwood, Mo.) as a maintenance diet with ad libi- with a rough hair coat and moderate dehydration (approximately 5 tum access to water. Th e room was maintained on a 12:12-h light: to 7%). Moderate, red-orange semi-viscous vulvar–urethral discharge dark cycle and within an average ambient temperature of 22°C. Th e resembling blood was present. Auscultation of the thoracic and ab- degu was maintained in accordance with the University Committee dominal cavities was unremarkable. In light of the animal’s advanced on the Use and Care of Animals at the University of Michigan, Ani- age and the absence of physical trauma, a preliminary diagnosis of mal Welfare Act regulations, and the Guide for the Care and Use of neoplasia was made. Th e degu was sedated with 2% isofl urane, and Laboratory Animals (21). Th e University of Michigan is accredited by blood was collected via the right brachiocephalic trunk for a complete blood count and serum biochemistry analysis (Tables 1 and 2). In ad- Unit for Laboratory Animal Medicine, University of Michigan, 018 Animal Research dition urine was collected via cystocentesis. Euthanasia was performed Facility, 1150 W. Medical Center Dr., Ann Arbor, Michigan 48109-06141; Esperion with intraperitoneal pentobarbital (200 mg/kg; Beuthanasia-D, Th erapeutics, Division of Pfi zer Global Research, 3621 S. State St. 695 KMS Place, Ann Arbor, Michigan 481082 Shering-Plough Animal Health, Kenilworth, N.J.). *Corresponding author Th e complete blood count results included a leukocytosis with neu-

Volume 44, No. 3 / May 2005 CONTEMPORARY TOPICS © 2005 by the American Association for Laboratory Animal Science 41 Table 2. Serum biochemical profi le of the presented degu Animal Normal reference presented range for degus Glucose, mg/dL 276a 60–125 Alanine aminotransferase, IU/L 126a 31.7–51.3 Aspartate aminotransferase, IU/L 232a 37.5–58.3 Alkaline phosphatase, IU/L 86a 60.3–81.3 Blood urea nitrogen, mg/dL 110a 9.0–31.5 Creatinine, mg/dL 0.8 0.6–2.2 Albumin, g/dL 1.8a 2.1–3.9 Protein, g/dL 3.2a 4.6–6.2 Total bilirubin, mg/dL 0.2 0.1–1.1 Calcium, mg/dL 7.9a 9.6–10.7 Phosphorous, mg/dL 10.1a 0.0–5.3 Sodium, mmol/L 146 146–152 Potassium, mmol/L 4.4a 6.8–8.9 Chloride, mmol/L 110 99–111 aAbnormal value.

Figure 2. Photomicrograph of the right kidney. Transitional cell carcinoma of renal pelvis (arrowheads). A papillary mass is present in the renal pelvis with associated hemorrhage. Presence or lack of infi ltration cannot be determined. H&E stain; magnifi cation, ×10.

Figure 1. Cross section of aff ected right kidney. A granular, hemorrhagic mass was found extending from the renal pelvis into the cranial cortex. trophilia and a normocytic normochromic anemia (Table 1). Serum biochemistry results (Table 2) included hypoproteinemia and hypo- albuminemia, consistent with blood loss anemia. Other noteworthy biochemical abnormalities included hyperglycemia, hyperphospha- temia, hypocalcemia, elevated liver enzymes (alanine and aspartate aminotransferases), elevated alkaline phosphatase, and increased blood Figure 3. Photomicrograph of the right kidney. Transitional cell carcinoma of urea nitrogen. Th e remaining biochemistry values were within normal the renal pelvis. Th ere is marked squamous metaplasia and moderate multifo- × limits. Th e urinalysis revealed hematuria and pyuria with occasional cal interstitial fi brosis within the tumor. H&E stain; magnifi cation, 40. squamous and transitional epithelial cells. Urine culture results were positive for coagulase-negative Staphylococcus sp. neutrophilic infl ammation, and hemorrhage of urinary transitional On gross necropsy examination, the right kidney was moderately cell epithelium and lamina propria with mild, focal, urothelial hy- enlarged (20 by 15 by 10 mm), was greenish-brown in color, and perplasia (Fig. 5). appeared cystic. Th e left kidney appeared normal and measured 15 by 10 by 10 mm. Upon cross-sectioning of the right kidney, a 10- Discussion mm, granular, hemorrhagic mass was found extending from the renal Th is is the fi rst report of both a renal transitional cell carcinoma pelvis into the cranial cortex (Fig. 1). No evidence of gross metastasis and a renal choristoma in a degu. Renal transitional cell was observed. have been reported to occur in other species, and their occurrence is Histologic evaluation revealed a papillary mass with associated noted to be rare (2, 9, 17). In rodents, spontaneous occurring renal hemorrhage comprised of basophilic, moderately anaplastic, clustered transitional cell carcinomas occur at very low frequencies. Chandra epithelial transition cells in the right renal pelvis, consistent with a and colleagues reported a prevelance of 0.07% in Sprague-Dawley transitional cell carcinoma (Fig. 2). Within the tumor, there was (1340 male and 1329 female) and 0.09% in F-344 (530 male and marked squamous metaplasia and moderate multifocal interstitial 530 female) rats used as controls for carcinogenicity studies (4). In fi brosis (Fig. 3). In addition, a choristoma (normal cells or tissues humans, upper urinary tract transitional cell carcinomas comprise in abnormal locations) comprising trabecular bone, mature adipo- 5 to 7% of urothelial tumors and mainly arise from the renal pelvis cytes, and cellular infi ltrates suggestive of osteocytes, lymphocytes, (16). and plasma cells, was located within the right renal cortex (Fig. 4). Unlike spontaneously occurring renal transitional cell carcinomas, Microscopic evaluation of the left kidney appeared normal. Histo- urinary bladder transitional cell carcinomas occur more frequently logical examination of the urinary bladder showed moderate, focal, in rats and mice used in toxicology studies. In rats, the frequency

42 CONTEMPORARY TOPICS © 2005 by the American Association for Laboratory Animal Science Volume 44, No. 3 / May 2005 Figure 4. Photomicrograph of the right kidney. A renal cortical choristoma. Trabecular bone, mature adipocytes, and cellular infi ltrates suggestive of osteocytes, lymphocytes, or plasma cells are present. H&E stain; magnifi ca- tion, ×10. and grade of urinary papillary transitional cell carcinoma depends upon the dose and duration of the administered . In rats, the stages of urinary bladder tumor progression include hyperplasia, papillary or nodular hyperplasia, , and carcinoma. In mice, the process can be similar to that for rats or proceed from to eventually to invasive carcinoma. For more detailed discussion of rodent urinary bladder tumors, see reviews by Oyasu and Cohen (5, 25). Th e etiology of renal transitional cell tumors remains unclear. In humans, renal transitional cell carcinomas are linked to age, gender, exposure to cigarette smoke, occupational , toxins from vegetable, fungal or viral sources, and chemotherapeutic agents such as cyclophosphamide (3, 13, 18). Other factors include long-term Figure 5. Photomicrograph of the urinary bladder shows moderate, focal, ingestion of analgesics such as phenacetin, exposure to human papil- neutrophilic infl ammation and hemorrhage of the urinary transitional cell epithelium and lamina propria with mild focal urothelial hyperplasia (ar- loma virus, and or treatment of prior urinary bladder transitional cell rowheads). H&E stain; magnifi cation, ×10. carcinoma via cystectomy (10, 23, 26). Currently, there are few studies directly linking molecular or ments is particularly unique and rare. In humans, this anomaly is chromosomal instability to the development of renal transitional cell uncommon, and only a couple of reported renal related cases have carcinomas. Hayashi and coauthors reported an infrequent association been published (19-20). Osseous choristomas generally are embedded of a single-base mutation in the human p53R2 gene, which encodes within the stroma of fi brovascular connective tissue and often lack a a protein with a p53 binding site that may possess tumor-suppressor true capsule or are pseudoencapsulated. Bone maturation can occur functions (8). In addition, mutations of the p53 gene were reported within choristomas resulting in lamellar bone with fatty marrow or in 33% (29 of 89) of renal transitional cell tumors analyzed by direct hematopoietic elements. In the case we present, there is probably no DNA sequencing (3). Transitional cell carcinoma tumor grade was association between the choristoma and the tumor. found to be associated with apoptosis, which may be involved in renal Another diff erential diagnosis to consider for a choristomatous tumor progression (14). Comparative genomic hybridization studies lesion in the kidney is myelolipoma, which is often an incidental fi nd- have shown recurrent loss of 9q, which may be a region responsible ing. Myelolipomas are rare of the adrenal gland and consist for the development of renal transitional cell carcinoma, whereas other of mature adipose tissue mixed with variable amounts of hematopoi- chromosomal abnormalities were similar to those found in bladder etic elements. Th e tumor is not known to undergo metastasis, yet it transitional cell carcinomas (6, 28). can be found in extra-adrenal locations (1, 11, 29). In a human case Transitional cell carcinomas tend to grow in sheets of neoplastic report, an adrenal myelolipoma was found along with an infi ltrating cells and usually form papillary lesions with a broad base and branch- urinary bladder transition cell carcinoma (22). Histopathology of both ing fi brovascular core. Some tumors are not papillary and infi ltration adrenals in the degu revealed no noteworthy fi ndings. is variable. Th ey also can form carcinoma in situ. Th e majority of Transitional cell carcinoma of the renal pelvis causes symptoms upper uroepithelial tumors are of transitional cell consistency, with primarily due to partial obstruction of the urinary tract, secondary squamous cell comprising a smaller percentage. Th e grade of infection and infl ammation of the tumor. Hematuria is the most transitional cell carcinomas tends to correlate with its stage. Superfi cial common presenting clinical sign which agrees with presenting signs tumors are graded I or II, whereas infi ltrative tumors are graded III in this case (13). Spontaneous urinary extravasation due to tumor or IV. Metastasis generally occurs through the lymphatic system and infi ltration and rupture may result in an acute abdomen situation. not hematologically. Diagnosis of the presented tumor occurred postmortem. If necessary, Th e fi nding of a renal transitional cell carcinoma associated with a nephrectomy could be performed and the aff ected kidney should a cortical choristoma comprised of trabecular bone and marrow ele- be submitted for histopathology. In humans, intravenous urography

Volume 44, No. 3 / May 2005 CONTEMPORARY TOPICS © 2005 by the American Association for Laboratory Animal Science 43 is most commonly performed to initially detect fi lling defects associ- 12. Kas, M. J. and D. M. Edgar. 1999. Circadian-timed wakefulness at ated with transitional cell carcinomas. Ultrasound evaluation of the dawn opposes compensatory sleep responses after sleep deprivation in aff ected kidney or ultrasound-guided biopsy also are options to aid Octodon degus. Sleep 22(8):1045-1053. diagnosis. In addition, brush biopsy or ureteroscopy can be performed 13. Kirkali, Z. and E. Tuzel. 2003. Transitional cell carcinoma of the ureter and renal pelvis. Crit. Rev. Oncol. Hematol. 47:155-169. to obtain specimens in larger species. Urinalysis may not be defi nitive 14. Kong, C., X. Zhang, and I. Takenaka. 2001. Apoptotic cell death and for renal tumor diagnosis, as transitional cell carcinomas of the urinary Smad4 expression in transitional cell carcinoma of the renal pelvis and bladder may shed neoplastic cells into the urine (17). ureter. Int. J. Urol. 8(7):386-390. 15. Lee, T. M. 2004. Octodon degus: a diurnal, social, and long-lived rodent. Acknowledgments ILAR J. 45(1):14-24. We thank Anna Colvig, BA, for her assistance during postmortem process- 16. Melamed, M. R. and V. E. Reuter. 1993. and staging of ing and examination. We also thank Kay-Ann Schuck, BS, MT (ASCP), for urothelial tumors of the kidney and ureter. Urol. Clin. North Am. performing hematological and biochemical analyses. Th is work was supported 20(2):333-347. by grant number T32 RR07008 from the National Center for Research 17. Militerno, G., R. Bazzo, D. Bevilacqua, G. Bettini, and P. S.Marcato. Resources, National Institutes of Health. 2003. Transitional cell carcinoma of the renal pelvis in two dogs. J. Vet. Med. 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