Cytologic Diagnosis of Transitional Cell Carcinoma in Dogs and Cats

W. Jerry Frost, DVM; Pauline M. Rakich, DVM, PhD; and Kenneth S. Latimer, DVM, PhD

Class of 2001 (Frost), Athens Diagnostic Laboratory (Rakich), and Department of Pathology (Latimer), College of Veterinary Medicine, The University of Georgia, Athens, GA 30602-7388

Introduction

Although lower urinary tract tumors comprise less than 1% of all canine neoplasms, the most frequent urinary neoplasm is transitional cell carcinoma.^1-4 From a comparative standpoint, transitional cell carcinoma is the second most common malignant neoplasm of the genitourinary system in human beings.⁵ In one study of 115 dogs, transitional cell carcinoma accounted for 87% of all bladder and urethral tumors.¹ In cats, bladder neoplasms account for less than 0.8% of all neoplasms.³ The mean age for development of transitional cell carcinoma in dogs is approximately 9 years.^1,2 The most common site of tumor development is the trigone area of the bladder. Less commonly, these neoplasms originate in the urethra and may involve the prostate gland of males or the vaginal vault of females. The pattern of neoplastic cell growth may be papillary, non-papillary, or invasive.⁶ Metastasis occurs approximately 50% of the time.^1-3 The most common sites for metastasis include regional lymph nodes, surrounding soft tissues, bones of the hindquarters, and lung. ^1-3 In one study, 37% of dogs had metastasis by the time of initial clinical diagnosis.¹

Diagnosis

Dysuria, hematuria, and pollakuria are very pertinent historical facts as in one study 101/115 dogs presented with these three clinical signs of disease.¹ Changes such as hematuria, pyuria, proteinuria, or bacteruria are common on urinalysis (Fig. 1).¹ Cytology may used to evaluate urine sediment or fine-needle aspirations of discrete masses or suspicious lesions. Fine-needle aspiration may be assisted by abdominal palpation or ultrasonographic location of the mass. Ultrasound and contrast cystography are useful imaging tools to define the presence and extent of a neoplasm or suspicious lesion.

Figure 1. Transitional cell carcinoma, urine sediment, dog, Wright-Leishman stain. Bacteria and purulent inflammation are present in conjunction with neoplastic epithelial cells.

Cytologic Features

Normal urine may contain a few transitional epithelial cells, crystals (including amorphous crystal), hyaline casts, and fat droplets (especially in cats). Other contaminants may be observed in voided urine specimens. These contaminants may include squamous epithelial cells from the distal urethra, vagina, or prepuce and bacteria.³ Transitional cell carcinomas usually exfoliate large numbers of neoplastic cells. The cells may be scattered individually or arranged in variably-sized aggregates (Fig. 2).^3,6 Frequently, the cells are markedly pleomorphic with pronounced anisocytosis, anisokaryosis, and variations in tinctorial characteristics (Fig. 3).^3,6,7 The cytoplasm may be decreased to a thin rim in some cells⁷ or may be abundant in other cells (Fig. 4).^3,7 Overall, the cells are reported to have a high nuclear to cytoplasm ratio,^6,7 but this cannot be appreciated in all cytology preparations. Also, the cytoplasm may contain small to large pale vacuoles^3,6,7 which may compress the nucleus.⁷ Occasionally, the vacuoles may be filled with a granular, magenta material, presumably of mucoid or glycoprotein origin (Fig. 5).⁶ Anisokaryosis^6,7 is a key cytologic feature; some affected nuclei may be extremely large (5-10 times normal, Fig. 6).⁷ Nuclear chromatin may be finely or coarsely reticulated.³ Some nuclei may be light colored and vacuolated or have condensed chromatin along the nuclear membrane.⁷ The nuclei may lack visible nucleoli or may contain subtle to prominent nucleoli (Fig. 7).^3,6,7 Mitotic figures may or may not be observed.^3,6,7 Squamous metaplasia also may be apparent, especially in urine sediments.^3,6 However, mild anisokaryosis and hyperchromatic nuclei may be observed in both neoplastic and hyperplastic transitional epithelial cells.⁶

Figure 2. Transitional cell carcinoma, dog, Wright-Leishman stain. Neoplastic cells are scattered singly or arranged in variably-sized clusters.	Figure 3. Transitional cell carcinoma, dog, Wright-Leishman stain. Anisocytosis, anisokaryosis, and tinctorial variation are present within the neoplastic epithelial cells.

Figure 4. Transitional cell carcinoma, dog, Wright-Leishman stain. Variation in the abundance of cytoplasm among neoplastic transitional cells.	Figure 5. Transitional cell carcinoma, dog, Wright-Leishman stain. Cytoplasmic vacuoles are filled with granular, magenta material.

Cytologic preparations of 31 transitional cell carcinomas from 29 dogs and 2 cats presented to The University of Georgia Veterinary Medical Teaching Hospital were reviewed microscopically. Anisocytosis and anisokaryosis were prominent cytologic features (Figs. 3 & 6). An average score of 2.9 on a 0-4 scale was given for anisocytosis and anisokaryosis. Large, granular, magenta staining, cytoplasmic vacuoles were found in neoplastic cells from 15 of 31 transitional cell carcinomas (Fig. 5). An overall estimate of N:C ratio on a scale of 1-4 was slightly increased at 1.8. Epithelial cells from 27 of the neoplasms had blue as opposed to gray cytoplasm. Mitotic figures were observed in cytologic preparations from 10 neoplasms. Other cytologic findings included binucleate and multinucleate neoplastic cells (Fig. 8), individual cell necrosis (Fig. 9), and purulent inflammation (Figs. 1 & 10). Nucleoli were single or multiple and ranged from indistinct to prominent.

Cytologic features alone may not distinguish transitional cell carcinoma from transitional cell hyperplasia in all fine-needle aspirates or urine sediments. In dogs, the diagnosis of transitional cell carcinoma may be improved with the use of a commercially available bladder tumor antigen detection test (V-BTA test, POLYMEDCO Inc., 510 Furnace Dock Rd., Cortlandt Manor, NY 10567). This test uses a latex agglutination system to detect a unique tumor-associated glycoprotein in urine. The sensitivity and specificity of this test is 90% and 78%, respectively.⁸ The test works reliably in most instances; however, false positive tests may be associated with marked glucosuria (4+), heavy proteinuria (4+), and pyuria or hematuria (>30-40 WBC or RBC per microscopic hpf of view).

Figure 6. Transitional cell carcinoma, dog, Wright-Leishman stain. Marked anisokaryosis is present.	Figure 7. Transitional cell carcinoma, dog, Wright-Leishman stain. Nucleoli and nucleolar rings are present.

Figure 8. Transitional cell carcinoma, dog, Wright-Leishman stain. Multinucleated neoplastic transitional epithelial cell (right side of image).	Figure 9. Transitional cell carcinoma, dog, Wright-Leishman stain. Scattered necrotic cells stain light gray and lack discernable nuclei. Degenerative neutrophils, bacteria, and Bilirubin crystals also are present.

Figure 10. Transitional cell carcinoma, dog, Wright-Leishman stain. Purulent inflammation is present in addition to neoplastic transitional cells.

Treatment

In dogs and cats, surgery is the only treatment that offers a potential cure, provided the neoplasm can be completely excised and metastasis has not occurred. In a study of 11 dogs, 10 of which had transitional cell carcinoma, the median survival time was 365 days following surgical excision in the absence of detectable nodal or distant metastasis.¹ Six additional dogs with incomplete surgical excision of the transitional cell carcinoma and no evidence of metastasis at the time of surgery had a reduction in median survival time to 120 days.¹ If the tumor was located in bladder or urethra, the median survival times following surgery were 290 days and 277 days, respectively. If the bladder and urethra were involved concurrently, the median survival time was reduced to 90 days.¹ In studies evaluating the use of carboplatin⁸ and cisplatin⁹ in the treatment of transitional cell carcinoma, neither drug was found to be of great benefit. However, peroxicam (a nonsteroidal antiinflammatory drug) may have had some effect against neoplastic cells in 3 of 10 dogs with TCC.¹⁰ This drug currently is being used as palliative treatment for transitional cell carcinoma in dogs.

References

1. Norris, A.M. Laing, E.J., Valli, V.E., et al. Canine bladder and urethral tumors: a retrospective study of 115 cases (1980-1985). J Vet Intern Med 6:145-153, 1992.

2. Osborne, C.A., Low, D.G., Perman, V., et al. Neoplasms of the canine and feline urinary bladder: incidence, etiologic factors, occurrence and pathologic features. Am J Vet Res 29:2041-2053, 1968.

3. Baker, R., Lumsden, J.H. The urinary tract. Color Atlas of Cytology of the Dog and Cat. Baker, R., Lumsden, J.H. (eds). Mosby, St Louis, 2000.

4. Hanika, C., Rebar, A.H. Ureteral transitional cell carcinoma in the dog. Vet Pathol 17:643-6, 1980.

5. Koenig, F., Jung, K., Schnorr, D., Loenig, S.A. Urinary markers of malignancy. Clin Chim Acta 297:191-205, 2000.

6. Zinkl, J.G. Urinary sediment and cytology of the urinary tract. In Diagnostic Cytology of the Dog and Cat. R.D. Cowell, R.D. Tyler, and J.H. Meinkoth (eds). Mosby, St Louris, 1999.

7. Rozengurt, N., Hyman, W.J., Berry, A., et al. Urinary cytology of a canine bladder carcinoma. J Comp Pathol 96:581-585, 1986.

8. Borjesson, D.L., Christopher, M.M., Ling, G.V. Detection of canine transitional cell carcinoma using a bladder tumor antigen urine dipstick test. Vet Clin Pathol 28:33- 38, 1999.

9. Knapp, C.R., Widmer, W.R., De Nicola, D.B., et al. Phase II clinical trial of carboplatin in canine transitional cell carcinoma of the urinary bladder. J Vet Intern Med 11:279-83, 1997.

10. Knapp, C.R., Widmer, W.R., Glickman, N.W., et al. Cisplatin treatment of transitional cell carcinoma of the urinary bladder in dog cases (1983-1993). J Am Vet Med Assoc 209:1588-91, 1996.

11. Knapp, C.R., Richardson, R.C., Bottoms, G.D. Phase I trial of piroxicam in 62 dogs bearing naturally occurring tumors. Cancer Chemother Pharmacol 29:214-218, 1992.

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