UROTHELIAL CARCINOMA IN THE URINARY BLADDER OF A JAPANESE MACAQUE (Macaca fuscata)

Abstract

Tumors of urinary origin are infrequently reported in nonhuman primates. Urothelial carcinoma involving the urinary bladder was diagnosed in an adult female Japanese macaque that extended transmurally to the uterus and cervix. To our knowledge, this is the first report of a primary cystic urothelial carcinoma in a Japanese macaque.

INTRODUCTION

Tumors originating in the urinary system are infrequently reported in nonhuman primates; when diagnosed, are often malignant and of urothelial origin. These tumors are typically associated with schistosomiasis; administration of carcinogenic agents, or in a rhesus receiving experimental whole body irradiation.^1–6 Few spontaneous urinary bladder tumors have been described in the rhesus macaque and include a leiomyoma and urothelial cell (UC) or transitional cell carcinomas.^7–8 To our knowledge, this is the first report of a primary urinary bladder urothelial carcinoma in the Japanese macaque.

CASE REPORT

A 16 year-old female Japanese macaque was born at the ONPRC and housed primarily in a group setting in an indoor/outdoor facility. All experimental procedures were approved by the Institutional Animal Care and Use Committee (IACUC) at the ONPRC, which is fully accredited by the Association for Assessment and Accreditation of Laboratory Animal Care International.^9–10 At the time of necropsy, this animal was assigned to a research project monitoring for the development of retinal degeneration.

At clinical presentation, this macaque was quiet, alert and responsive following a fall from a perch while in social housing. Physical examination revealed renomegaly, confirmed by transabdominal ultrasonography, along with bilateral hydronephrosis and hydroureter. A CBC revealed normocytic hypochromic nonregenerative anemia (HCT 25.42% (29–42.2%), MCV 78.03 fL (74–84), MCHC 32.26 g/dL (32.7–34.2), reticulocyte 0.5%). Serum chemistry results demonstrated azotemia (BUN 199.7 mg/dL (9–22mg/dL), creatinine 13.9 mg/dL (0.6–1mg/dL)) and hyperkalemia (7.8 mEq/L (3.3–5.6 mEq/L)). Euthanasia was elected due to the poor prognosis.

At necropsy, gross findings included bilateral renomegaly, hydronephrosis, hydroureter, and chronic colitis. The kidneys were markedly enlarged with swollen, pale tan cortices, capsular fibrosis, and a 3mm brown cyst in the right kidney. The renal pelvis was dilated ~1–1.5cm diameter bilaterally and the renal papillae were friable, with multifocal hemorrhage. The ureters were dilated ~1cm in diameter and the ureteral serosa was edematous and hemorrhagic. Within the trigone of the urinary bladder, a 1.5cm diameter of mucosa was rough, irregular, and red-tan. The subjacent serosal surface was adhered to the ventral aspect of the cervix. There was frank hemorrhage into the cervical lumen and vagina.

Primary microscopic findings included a large transmural, unencapsulated, poorly demarcated, infiltrative neoplasm that arose from the cystic urothelium with features of hyperplasia and dysplasia. Islands and cords of neoplastic polygonal cells had variably distinct cell borders and a modest amount of eosinophilic cytoplasm. Nuclei were irregularly round, with stippled chromatin and 1–2 magenta nucleoli. Anisocytosis and anisokaryosis were marked and mitotic figures averaged 50 in ten fields (400X). Multifocally, neoplastic cells exhibited squamous differentiation characterized by prominent intercellular bridges, intracellular keratin, and the formation of keratin pearls. Neoplastic cells infiltrated the cervix and uterus, and were rarely observed within blood vessels. Pan-cytokeratin (AE1 (CK10, 14–16, 19)/AE3 (CK1–8)) (panCK) immunohistochemistry (IHC) revealed diffuse reactivity throughout the normal urothelium, a predominantly basilar cytoplasmic immunoreactivity in the majority of neoplastic cells, as well as strong diffuse cytoplasmic immunoreactivity throughout the areas of squamous differentiation. Uroplakin III IHC exhibited strong superficial membranous reactivity within the normal urothelium; however hyperplastic, dysplastic, and neoplastic cells were rarely positive. The histologic features combined with the IHC findings are consistent with the diagnosis of urothelial carcinoma, with squamous differentiation (UCSD).

DISCUSSION

In humans, most malignant neoplasms of the urinary bladder are urothelial carcinomas (UC). Squamous differentiation is the most commonly identified variant and is associated with a poorer prognosis.^11–12 Characteristic features of squamous differentiation include prominent intercellular bridges, intracellular keratin, or keratin pearls, which were observed in this case.¹²

Differential diagnosis included metastatic carcinoma, cervical or uterine carcinoma and squamous cell carcinoma (SCC). Metastatic disease was excluded, as there was no evidence of a primary neoplasm elsewhere in the body. The diagnosis of UC was favored over a cervical or uterine carcinoma due to the clear morphologic transition in the urothelium from hyperplasia to dysplasia to neoplasia. SCC was considered less likely as squamous differentiation was not a predominant feature of this neoplasm and was not present in all sections examined.

Discrimination of UCSD from SCC may present a challenge on HE examination. Ideally, an immunohistochemical panel utilizing high molecular weight cytokeratins and uroplakin III would aid in the differentiation of UC, UCSD and SCC.¹³ According to Gaisa et al, high molecular weight cytokeratins CK5/6 and CK5/14 were positive in 76.6% and 95.8% of primary urinary bladder SCCs respectively, whereas 33% and 57.1% of pure UCs were positive for CK5/6 and CK5/14, respectively.¹³ They also reported variations in the pattern of immunoreactivity, with UCs predominantly exhibiting a basilar pattern of immunoreactivity and SCCs demonstrating diffuse immunoreactivity.¹³ This pattern held true for UCDSs, in that squamous foci demonstrated diffuse reactivity and areas of UC exhibited a basilar pattern.¹³ In this case, the immunohistochemical staining pattern of panCK revealed similar patterns as described for UCSDs by Gaisa et al. It is not possible to make a direct comparison between the results of the pan-cytokeratin in the tumor presented and the conclusions drawn by Gaisa et al, who employed specific high molecular weight cytokeratins. However, as the panCK cocktail used in this case contained CK 5, 6, and 14 and a comparable pattern of immunohistochemical reactivity was noted which supported a diagnosis of UCSD. The tumor presented was rarely positive for uroplakin III, however, in one study only 22% of pure UCs, 8% of UCSDs, and 0% of primary SCC express uroplakin III.¹³ Uroplakins are a specific marker for terminal differentiation of urothelium; it is likely that neoplastic transformation with extensive tissue invasion and cellular atypia resulted in the loss of terminal differentiation and consequently immunoreactivity.

A urothelial carcinoma of the urinary bladder with squamous differentiation that exhibited vascular invasion and direct extension into the cervix and uterus is described. Obstructive nephropathy developed secondary to impaired urinary outflow due to the presence of the neoplasm in the trigone of the urinary bladder. This is an uncommon tumor in nonhuman primates and to our knowledge not previously reported in the Japanese macaque.

Figure 1.

Urinary tract of rhesus macaque with urothelial carcinoma. A, Kidneys and ureters. The renal pelvises and ureters are dilated (hydronephrosis and hydroureter). There is renal cortical pallor and papillary hemorrhage. B, Trigone of urinary bladder, cystic mucosa is focally thickened, irregular and discolored red-tan.

Figure 2.

Urothelial carcinoma with squamous differentiation, urinary bladder. A, An infiltrative neoplasm arises from the proliferative and dysplastic urothelium (HE, 6.5X). B, Neoplastic polygonal cells are arranged in islands and cords with multifocal squamous differentiation (arrowhead) (HE, 10X). C, Cells exhibit marked anisocytosis and anisokaryosis. Those with squamous differentiation often have deeply eosinophilic, keratinized cytoplasm (arrowhead). (HE, 40X). D, Pattern of immunoreactivity with pan-cytokeratin IHC reveals primarily a basilar cytoplasmic immunoreactivity in the neoplastic urothelial cells (arrowhead) and strong, diffuse cytoplasmic immunoreactivity throughout the areas of squamous differentiation (arrow) (10X). Inset: Low numbers of neoplastic cells show immunohistochemical reactivity to uroplakin III (20X).