Development of renal adenocarcinoma in a ferret with renal cortical cysts (Mustela putorius furo)

Amanda D. Wong From the Department of Veterinary Clinical Medicine, College of Veterinary Medicine, University of Illinois, Urbana, IL 61802.

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Delphine Laniesse From the Eläinsairaala Evidensia Tammisto, 01510 Vantaa, Finland.

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Alex zur Linden From the Department of Clinical Studies, Ontario Veterinary College, University of Guelph, Guelph, ON N1G 2W1, Canada.

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Ameet Singh From the Department of Clinical Studies, Ontario Veterinary College, University of Guelph, Guelph, ON N1G 2W1, Canada.

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Leonardo Susta From the Department of Pathobiology, Ontario Veterinary College, University of Guelph, Guelph, ON N1G 2W1, Canada.

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Hugues Beaufrère From the Department of Clinical Studies, Ontario Veterinary College, University of Guelph, Guelph, ON N1G 2W1, Canada.

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Abstract

CASE DESCRIPTION

A 5.5-year-old 0.929-kg spayed female domestic ferret (Mustela putorius furo) underwent serial abdominal ultrasonographic and clinicopathologic examinations after multiple renal cysts were detected bilaterally during a routine examination.

CLINICAL FINDINGS

The ferret was apparently healthy at the start of the monitoring period and had no clinical signs for > 20 months. Four months after the initial examination, the largest cyst became increasingly mineralized; 17 months after detection, it had increased in size and become amorphous, and the ferret’s plasma BUN concentration was mildly high. Within 21 months after the first visit, a nodule was detectable, and hydronephrosis developed in the kidney with the largest cyst. Findings for fine-needle aspirates from the nodule were consistent with renal carcinoma.

TREATMENT AND OUTCOME

Contrast-enhanced CT revealed severe unilateral nephromegaly with no contrast uptake in the affected ureter. Following surgical removal of the affected kidney, histologic examination identified renal adenocarcinoma replacing the entire renal cortex and medulla. The ferret was euthanized postoperatively because of declining condition. On necropsy, metastasis to a mesenteric lymph node was identified; comorbidities included 2 other neoplasms and acute, severe injury of the contralateral kidney.

CLINICAL RELEVANCE

Neoplastic transformation of a renal cyst was suspected in the ferret of this report on the basis of observed ultrasonographic changes over time and extensive infiltration of the neoplasm throughout the affected kidney. Renal cysts are linked to renal neoplasia in other species, and the findings for this patient supported the need for periodic monitoring of renal cysts in ferrets.

Abstract

CASE DESCRIPTION

A 5.5-year-old 0.929-kg spayed female domestic ferret (Mustela putorius furo) underwent serial abdominal ultrasonographic and clinicopathologic examinations after multiple renal cysts were detected bilaterally during a routine examination.

CLINICAL FINDINGS

The ferret was apparently healthy at the start of the monitoring period and had no clinical signs for > 20 months. Four months after the initial examination, the largest cyst became increasingly mineralized; 17 months after detection, it had increased in size and become amorphous, and the ferret’s plasma BUN concentration was mildly high. Within 21 months after the first visit, a nodule was detectable, and hydronephrosis developed in the kidney with the largest cyst. Findings for fine-needle aspirates from the nodule were consistent with renal carcinoma.

TREATMENT AND OUTCOME

Contrast-enhanced CT revealed severe unilateral nephromegaly with no contrast uptake in the affected ureter. Following surgical removal of the affected kidney, histologic examination identified renal adenocarcinoma replacing the entire renal cortex and medulla. The ferret was euthanized postoperatively because of declining condition. On necropsy, metastasis to a mesenteric lymph node was identified; comorbidities included 2 other neoplasms and acute, severe injury of the contralateral kidney.

CLINICAL RELEVANCE

Neoplastic transformation of a renal cyst was suspected in the ferret of this report on the basis of observed ultrasonographic changes over time and extensive infiltration of the neoplasm throughout the affected kidney. Renal cysts are linked to renal neoplasia in other species, and the findings for this patient supported the need for periodic monitoring of renal cysts in ferrets.

Introduction

A 5.5-year-old 0.929-kg spayed female domestic ferret (Mustela putorius furo) was presented for a routine health examination at the Ontario Veterinary College Health Sciences Centre. The owner did not report any abnormal clinical signs or behaviors at home. The ferret reportedly had a good appetite and was fed a mixture of commercial kitten kibble and ferret kibble. Its water intake was unremarkable. No abnormalities were noted on physical examination. The ferret was sedated with midazolam (0.2 mg/kg, IM, once) and butorphanol (0.2 mg/kg, IM, once) for routine abdominal ultrasonographic examination, which revealed multiple bilateral renal cortical cysts (Figure 1). The largest cyst in the right kidney was 1.9 × 0.9 cm, and the largest cyst in the left kidney was 3.2 mm in diameter. Mild mineralization in the right kidney was noted. Analysis of a urine sample obtained by means of ultrasound-guided cystocentesis revealed hypersthenuria (urine specific gravity, 1.042) and pyuria with occasional granular cysts. There was no overt proteinuria, and the protein-to-creatinine ratio was not assessed. A CBC for a sample collected by venipuncture of the cranial vena cava revealed a WBC concentration within the reference interval and neutrophils with mild toxic changes, and the remainder of the CBC was within the reference interval.1 The sample volume was insufficient for biochemical analysis. Both the urinalysis and hematologic analysis were performed at the facility’s clinical pathology laboratory. Sedation was reversed with flumazenil (0.03 mg/kg, SC, once), and empirical treatment for a suspected urinary tract infection was initiated with a 3-week course of amoxicillin–clavulanic acid (20 mg/kg, PO, q 12 h).

Figure 1
Figure 1

Ultrasonographic images of the right kidney of a spayed female domestic ferret (Mustela putorius furo) at the time of a routine examination when multiple renal cortical cysts were detected bilaterally and at follow-up visits over the next 21 months (A through H). The largest cyst in the right kidney is shown. A—Image obtained at the time of initial examination for the 5.5-year-old ferret. B—One month after the initial examination, no substantial changes are present. C—Four months after the lesions were first detected, mineralization of the ventral aspect of the cyst is evident. D—At a 17-month follow-up visit, the cyst is increased in size with an amorphous shape. E and F—At a 20.75-month follow-up visit, the right kidney is distended by a large amount of echogenic fluid, and a solitary, 1.2-cm-diameter nodule is present in the caudodorsal region of the cortex. G—After removal of a large amount of the fluid shown in panels E and F by ultrasound-guided fine-needle aspiration during the same visit, the cyst size is reduced. H—Image depicting ultrasound-guided fine-needle aspiration of the renal nodule in panel F 3 days after fluid aspiration was performed. The ventral aspect of the abdomen is at the top of the images. The fluid-filled cystic cavity (asterisk), mineralization of part of the cyst (white arrows), corticol nodule (red arrows), and positioning of the needle (arrowheads) for aspiration of the nodule are indicated.

Citation: Journal of the American Veterinary Medical Association 259, 12; 10.2460/javma.20.09.0520

One month after the initial examination, the ferret had a recheck examination and was sedated as previously described for abdominal ultrasonography, which revealed no morphological changes to the renal cysts (Figure 1). Analysis of a urine sample collected as previously described revealed no abnormalities, with a urine specific gravity of 1.036. Results of a CBC and plasma biochemical analysis for a blood sample obtained from the cranial vena cava were within the respective reference intervals.1 Three months after the initial examination, the ferret was examined because of minimal fur regrowth after the previous ultrasonographic examinations. The ferret had no other clinical signs, but the owner was concerned about hyperadrenocorticism and was interested in having hematologic screening performed. The ferret was sedated as previously described, a blood sample was collected from the cranial vena cava, and serum was submitted to the University of Tennessee College of Veterinary Medicine Endocrinology Laboratory for adrenocortical disease screening. The results revealed hyperestrogenism (estradiol concentration, 206 pmol/L [reference interval, 30 to 180 pmol/L]).

On follow-up examination 4 months after the initial visit, the ferret was again sedated for abdominal ultrasonography, which revealed increased mineralization at the ventral aspect of the largest right renal cyst causing a hyperechoic interface that cast an acoustic shadow (Figure 1). The adrenal glands appeared ultrasonographically normal. In the absence of an ultrasonographically identified ovarian remnant, a diagnosis of hyperadrenocorticism was made.2 Medical management was initiated with leuprolide acetate for depot suspension (AbbVie Inc; 30-day formulation) at a dosage of 0.35 mg/kg, IM, every 30 days. Fur regrowth was noted by the owner after 2 months of treatment and confirmed at follow-up visits, and the treatment regimen was continued.

Seventeen months after renal lesions were first observed, the ferret continued to show no clinical signs of illness. Abdominal ultrasonography and collection of a blood sample from the cranial vena cava were performed with the ferret under sedation; the mineralized right renal cyst was found to have increased in size and was amorphous in shape (Figure 1). The multiple small cortical cysts in the left kidney were unchanged. There was mild bilateral pyelectasia, and the renal pelvises measured up to 0.24 cm wide. Results of a CBC were within respective reference intervals, and plasma biochemical analysis revealed mildly increased BUN concentration and creatinine concentration within the reference interval (Table 1). These findings persisted in follow-up plasma biochemical tests that were performed on blood samples collected by the same methods 18 and 19 months after the initial evaluation. Owing to concerns about potential dehydration or early renal dysfunction, the owner began administering a multiple-electrolyte solution (Baxter Corp; 30 mL/kg, SC, q 24 h)3 at home, and reevaluation was performed after 1 month of daily SC fluid administration (20.5 months after the initial examination). The owner reported that the ferret had increased lethargy with a normal appetite, and a 3- to 4-cm-diameter mass was palpated in the right cranial aspect of the abdomen. A blood sample was collected from the sedated ferret as previously described, and plasma biochemical analysis for indicators of renal function revealed BUN concentration at the upper limit of the reference interval and a mildly high creatinine concentration. The plasma glucose concentration was 63 mg/dL (reference interval, 85 to 207 mg/dL), and a possible insulinoma was suspected. The owner was advised to monitor for clinical signs of an insulinoma until the ferret’s circulating blood glucose concentration after food withholding was rechecked.4 The owner continued SC fluid administration at the same dosage and began administering a probiotic to support renal health (Vetoquinol N-A Inc).

Table 1

Serial measurements of plasma BUN, creatinine, and phosphorous concentrations obtained during follow-up examinations after multiple renal cortical cysts were detected bilaterally during a routine abdominal ultrasonographic examination for a spayed female domestic ferret (Mustela putorius furo).

Analyte Reference interval1 Time after initial examination (mo)
1 4 17 18 19 20.5* 21
BUN (mg/dL) 10–45 33 24 47 47 52 45 83
Creatinine (mg/dL) 0.2–1.0 0.4 0.3 0.9 1.0 1.0 1.4 3.3
Phosphorus (mg/dL) 4.2–10.1 5.2 4.6 4.6 5.5 5.3 6.1 9.5

At the time of the initial examination, the ferret was 5.5 years old and the owner had noted no abnormal clinical signs or behaviors.

Values were obtained after 1 month of fluid administration (30 mL/kg, SC, q 24 h) for supportive care.

Values were obtained when the ferret declined clinically after right nephrectomy was performed.

The following week (20.75 months after the initial examination), the ferret was sedated for abdominal ultrasonography as previously described. The right kidney was markedly enlarged (2.8 × 3.5 × 4.8 cm) and distended by a large volume of centrally located echogenic fluid (Figure 1). No obstruction of the renal pelvis or ureter was identified. A new solitary 1.2-cm-diameter nodule was also noted within the caudodorsal cortex of the right kidney. The mesentery in the cranioventral abdominal region surrounding the right kidney was diffusely hyperechoic and contained multiple small to moderately sized, relatively hypoechoic lymph nodes that measured up to 0.65 cm wide. The multiple small, anechoic cystic lesions in the left renal cortex appeared unchanged, compared with previous findings.

The right ventral abdominal region was prepared with an aseptic technique, and a 1.5-inch, 21-gauge needle was used to perform ultrasound-guided fine-needle aspiration of the echogenic fluid in the kidney for diagnostic and therapeutic purposes. This yielded a turbid, brown fluid and reduction in cyst size (Figure 1). Cytologic evaluation of the fluid revealed a poorly cellular (18.7 × 109 cells/L), proteinaceous (total solids concentration, 3.5 g/dL) sample on a mildly hemorrhagic background that contained rare renal epithelial cells as well as occasional neutrophils and macrophages. No microorganisms were observed, and results of bacterial culture of the fluid were negative. The fluid creatinine concentration was 0.9 mg/dL and much lower than the plasma creatinine concentration (1.4 mg/dL), indicating the aspirated fluid was unlikely to be urine and that its source was the renal cyst rather than a dilated renal pelvis.5

Following the fine-needle aspiration and food withholding for approximately 2 hours, the ferret’s plasma glucose concentration was rechecked and revealed marked hypoglycemia (36 mg/dL). A serum sample was submitted for paired testing of insulin and glucose concentrations, and the results (insulin, 41.5 µU/mL [reference interval, 6.4 to 17.6 µU/mL]; glucose, 66 mg/dL) led to a presumptive diagnosis of insulinoma.6 Aside from lethargy, the owner did not report any additional clinical signs of insulinoma and was instructed to begin feeding frequent, small meals.2

Because examination of the cystic fluid did not yield a diagnosis, the ferret was sedated again 3 days later for ultrasound-guided fine-needle aspiration of the right renal nodule. Results of a CBC for a sample obtained from the cranial vena cava were within respective reference intervals. The right ventral abdominal region was prepared aseptically, and a 1.5-inch, 21-gauge needle was used to sample the nodule. The previously aspirated right renal cyst was found to have refilled to approximately 50% of its original size (Figure 1).

Cytologic examination of the right renal nodule sample revealed individual round-to-polygonal cells that had a marked degree of anisocytosis (up to 10-fold differences) with basophilic cytoplasm and occasional small punctate vacuoles. Most cells had a single, round-to-oval, eccentric nucleus, and multinucleated cells were rarely seen. There was a marked degree of anisokaryosis (up to 7-fold differences) and 1 or more prominent, irregular nucleoli with anisonucleosis. The nuclear chromatin was reticular. Occasional abnormal mitotic figures and macrophages, frequently associated with cytophagy, were observed. Malignant neoplasia cytologically consistent with renal carcinoma with nonsuppurative inflammation was suspected.

A right nephrectomy was recommended, and the owner was advised of an overall poor prognosis given the ferret’s high plasma BUN and creatinine concentrations, as well as concurrent adrenal gland disease and insulinoma. The owner elected for surgical treatment with a preoperative whole-body CT scan to screen for metastatic disease.

The ferret was sedated as previously described, a 24-gauge IV catheter was placed in the right cephalic vein, and CT scanning was performed before and after administration of contrast medium (Omnipaque 240; GE Healthcare Canada Inc; 2 mL/kg, IV, once). A helical scan was performed with a 16-slice scanner (Brightspeed; GE Healthcare) according to a standardized protocol (slice thickness, 0.625 mm; voltage peak, 120 kVp; current, 140 mAs; pitch, 0.938:1; and rotation time, 1 second). The images were reformatted to 1.25-mm slice thickness. The right kidney was severely enlarged (3.8 × 3.9 × 5.4 cm; approx 4 times the size of the left kidney) and contained a large volume of centrally located fluid-attenuating material. The cranial, medial, and caudal aspects of the right kidney had a soft tissue density with multiple punctate mineralized features and moderate contrast enhancement (Figure 2). A portion of the soft tissue–attenuating mass was present at the ureteral exit of the renal hilus, and no contrast medium was identified in the right ureter. The right renal vein was moderately distended, compared with the contralateral structure, and it had a central region of decreased attenuation in the postcontrast sequences. The left kidney was 2.4 cm long and had a mildly undulant contour. It contained multiple fluid-attenuating ovoid features, the largest of which was 4 mm in diameter. Contrast medium was filtered through the left kidney and entered the left ureter and the urinary bladder. Other findings included 2 cystic hepatic nodules (likely benign degenerative lesions), mild gastric lymphadenopathy, and a small (1-mm-diameter) pulmonary nodule in the periphery of the right caudal lung lobe compatible with a metastatic focus or a small osteoma. The left kidney was suspected to be the only functional kidney because contrast medium was not appreciated in the right ureter. Despite the pulmonary nodule detected on CT, the owner elected to proceed with a right nephrectomy.

Figure 2
Figure 2

Reconstructed dorsal- and transverse-plane contrast-enhanced CT images of the ferret in Figure 1 obtained prior to surgery and viewed in soft tissue (A and B) and lung (C) windows. A—The right kidney is severely enlarged, with a large, fluid-density center (asterisk) and a thick craniomedial wall with heterogenous contrast enhancement (arrowhead). The gastric lymph node is mildly enlarged with smooth, round margins (arrow). B—An image obtained at the level of the enlarged right kidney (asterisk) shows mild evidence of central mineralization (arrow). C—An image obtained at the level of the caudal lung lobes reveals a small (1-mm-diameter) pulmonary nodule with soft tissue density (arrowhead) in the right caudal lung lobe.

Citation: Journal of the American Veterinary Medical Association 259, 12; 10.2460/javma.20.09.0520

The ferret was hospitalized overnight for IV administration of fluids (Baxter Corp; 50 mL/kg/d, IV) containing 2.5% dextrose. The following day, the ferret was premedicated with midazolam (0.2 mg/kg, IV, once) and fentanyl (3 µg/kg, IV, once), and anesthesia was induced with propofol (6.3 mg/kg, IV, once). Following intubation with a 2.5-mm uncuffed endotracheal tube, anesthesia was maintained with isoflurane in oxygen. The IV fluid administration was maintained at 10 mL/kg/h, IV, throughout the procedure, and intraoperative analgesia was provided with a continuous rate infusion of fentanyl (5 µg/kg/h, IV). Anesthetic monitoring equipment included an ultrasonic Doppler flow detector, an electrocardiograph, an arterial catheter placed in the ventral tail artery, a rectal thermometer probe, and a capnograph. A routine ventral midline laparotomy was performed. Abdominal exploration revealed a small hepatic nodule, a large gastric lymph node, and an enlarged, deformed right kidney. The peritoneal membrane over the right kidney was sharply incised, and blunt dissection was performed to mobilize the kidney from its retroperitoneal attachments. Hemostasis was achieved with bipolar electrocautery forceps. The right kidney was adhered to the vena cava, and meticulous dissection was performed until the renal vein was observed and occluded with a vascular clip (Hemoclip; Teleflex Medical Canada Inc). Dissection was continued in search of the renal artery, and the aorta, which appeared to be mispositioned on the right side of the abdomen and adherent to the right kidney, was inadvertently punctured during this process. Hemorrhage was limited with vascular clamp placement on the aorta while a transfusion of homologous whole blood (12 mL, IV) that had been obtained from a donor ferret prior to surgery was administered. Norepinephrine (0.5 μg/kg/min, IV) was administered to increase arterial blood pressure. The defect in the aorta was repaired with a vascular clip (Hemoclip; Teleflex Medical Canada Inc) and resulted in an approximately 50% decrease in aortic diameter. The renal artery was identified and occluded with a vascular clip (Hemoclip; Teleflex Medical Canada Inc). The right kidney was removed and submitted for histologic examination, and the incision was closed without additional complications. The ferret’s body weight was reduced from 0.875 kg before the procedure to 0.75 kg afterward (a 14.3% weight loss).

The ferret was monitored during recovery from anesthesia and hospitalized in the intensive care unit. Because blood pressure could not be measured with the ultrasonic Doppler flow detector and the arterial line lost patency, the ferret was presumed to be hypotensive, and IV fluid (Baxter Corp) administration was maintained at the intraoperative rate for several hours. A continuous rate IV infusion of fentanyl (2 µg/kg/h) was administered for analgesia. A blood sample was obtained from the cranial vena cava without additional sedation for PCV determination and analysis of blood gases and electrolytes later that evening. The results revealed anemia (PCV, 30% [reference interval, 34.6% to 55%]) compatible with blood loss, mild hyperlactatemia (lactate concentration, 2.3 mmol/L [reference interval, 0.5 to 2 mmol/L]) compatible with tissue hypoperfusion associated with the surgery, hyperglycemia (glucose concentration, 259 mg/dL), and mild hypocalcemia (Ca2+ concentration, 0.93 mmol/L [reference interval, 1.1 to 1.4 mmol/L]).7 The PCV subsequently decreased to 23%, but blood glucose, lactate, and ionized calcium concentrations were within the reference intervals. Intravenous administration of fluids (Baxter Corp; 10 mL/kg/h) with 2.5% dextrose and fentanyl (2 µg/kg/h, IV) was continued overnight. The ferret was offered frequent meals and had a variable appetite, remaining sedate overnight and showing little movement of the pelvic limbs.

Despite intensive care, the ferret clinically declined over the next 2 days and became anuric, dyspneic, and hypotensive, with fluid overload evidenced by ascites and pleural effusion. Urine production ceased 2 days postoperatively. Clinical and clinicopathologic end points suggested the development of acute kidney injury, likely secondary to the iatrogenic abdominal aortic stenosis. Fentanyl administration was discontinued, but the ferret remained sedate and did not require additional sedation to facilitate diagnostic imaging and venipuncture. Abdominal ultrasonographic evaluation of blood flow in the abdominal aorta was challenging, and only a mild pulsatile color flow was visualized at the aortic bifurcation into the external iliac arteries. Blood gas and electrolyte analysis of a sample from the cranial vena cava revealed marked hyponatremia and hypochloridemia (sodium and chloride concentrations below the lower limits of detection) and metabolic acidosis (pH, 7.172; Pco2, 39 mm Hg). The ferret’s plasma BUN and creatinine concentrations increased to 83 and 3.3 mg/dL, respectively (Table 1), despite treatment with furosemide (1 to 2 mg/kg, SC or IV, q 4 to 6 h, then 0.5 mg/kg/h, IV), a reduced IV fluid rate (0.5 mL/kg/h), and therapeutic thoraco- and abdominocenteses. A continuous rate infusion of dopamine (1 μg/kg/min, IV) was instituted to promote renal blood flow and reestablishment of glomerular filtration but did not resolve the anuria. Abdominal ultrasonography was performed, and blood flow to the left kidney was not detected. The owner elected euthanasia, and a necropsy was performed.

Gross evaluation of the excised right kidney (submitted as a biopsy sample) revealed a severely dilated and distended renal pelvis that left a variably thin (2- to 7-mm) layer of renal cortex, medulla, or capsule alone (Figure 3). At 1 pole of the kidney, a 1.5 × 1.5-cm, poorly demarcated, white to tan, soft nodule was present that extended within the renal parenchyma toward the renal pelvis and included the ureter. Histologically, a multilobular, unencapsulated, densely cellular, infiltrative neoplasm effaced the renal cortex and medulla, occasionally extending to the perirenal fat and often compressing segments of cortical parenchyma. The cortical tissue had severe atrophy and fibrosis, with only a few remaining glomeruli or glomerular outlines (Figure 4). The neoplasm was composed of polygonal epithelial cells arranged to form irregular tubules (often ectatic), acini, and, rarely, compact sheets, variably supported by a fibrous or scirrhous stroma. The neoplastic cells had poorly distinct cell borders, moderate amounts of eosinophilic fibrillar to granular cytoplasm, and round nuclei with finely stippled chromatin and occasionally prominent single or multiple magenta nucleoli. There was marked anisocytosis and anisokaryosis (5- to 7-fold differences) with frequent bi- and multinucleation, as well as occasional karyomegaly. There were frequent mitotic figures (in total, 32/10 hpf [400X]; maximum value, 9/hpf). Encompassing approximately 30% of the neoplasm on cut section were multifocal areas of necrosis associated with marked neutrophilic infiltration and hemorrhage. Clusters of lymphocytes were scattered throughout the adjacent areas of atrophic kidney, particularly close to the capsule, which was thickened 3-fold by mature connective tissue. On the basis of these findings, a histologic diagnosis of renal adenocarcinoma was made, confirming the clinical suspicion.

Figure 3
Figure 3

Representative photomicrograph of a section from the right kidney in a region distant from the renal nodule. The cortex is diffusely thinned and replaced by large amounts of fibrous tissue (hydronephrosis). The remaining tubules are haphazardly arranged and often ectatic and contain cellular debris. H&E stain; bar = 1 mm.

Citation: Journal of the American Veterinary Medical Association 259, 12; 10.2460/javma.20.09.0520

Figure 4
Figure 4

Representative photomicrographs of sections of the nodule identified in the right kidney. A—The renal cortex is effaced by a multinodular tumor, and the adjacent cortex is severely compressed and fibrotic. H&E stain; bar = 1 mm. B—The neoplastic cells are often arranged in tubules containing small micropapillary projections and cellular debris. The cells are often surrounded by increased amounts of fibrous tissue. H&E stain; bar = 100 µm. C—The neoplastic cells are occasionally arranged in dense sheets. H&E stain; bar = 100 µm. D—The neoplastic tubules are lined by multiple layers of disorganized cells (dysplasia), which show marked anisocytosis and anisokaryosis (atypia). H&E stain; bar = 25 µm.

Citation: Journal of the American Veterinary Medical Association 259, 12; 10.2460/javma.20.09.0520

On postmortem examination, the most severe lesion consisted of massive left renal cortical necrosis, histologically characterized by full-thickness hypereosinophilia and loss of differential staining of the entire cortex. This finding was consistent with the clinical diagnosis of anuric renal failure. Additionally, 1 mesenteric lymph node had neoplastic epithelial cells present that formed tubules and small nests, often associated with a severe scirrhous response, in the subcapsular and medullary sinuses and perinodal adipose tissue. Owing to the cytologic characteristics and prominent tubular formation, this was interpreted as a metastatic lesion from the renal adenocarcinoma.

Two other neoplasms were identified on necropsy: lymphoma (present in multiple mesenteric lymph nodes) and an adrenocortical tumor. Other lesions included multifocal cardiac fibrosis and mineralization that affected < 10% of the myocardium at the level of the papillary muscles and interventricular septum (interpreted as scarring from previous infarcts) and pancreatic nodular hyperplasia and fibrosis, which was associated with mild neutrophilic and necrotizing pancreatitis and saponification of the peripancreatic fat. Incidental findings included multifocal ectasia of the tubular glands in the fundic portion of the stomach, a single focus of heterotopic bone formation in the right caudal lung lobe, and splenic extramedullary hematopoiesis. No lesions compatible with an insulinoma were identified by microscopic examination of available sections of the pancreas.

Discussion

Renal cysts are commonly identified in domestic ferrets,3,8,9,10 with a reported prevalence of 69% (37/54) in 1 study.10 Although they can be incidental findings during routine diagnostic examinations or necropsy, renal cysts can also be associated with clinical disease if there is substantial disruption of the normal renal architecture or if polycystic kidney disease is present.3,8,9,11,12 In contrast, renal neoplasia is rare in ferrets,11,13,14,15 and 1 retrospective multicenter study16 found it accounts for < 1% (6/639) of tumors in ferrets with neoplastic diseases. Reported renal neoplasms in ferrets include transitional cell carcinoma, adenoma, carcinoma, adenocarcinoma, nephroblastoma, fibroma, lymphoma, and unspecified sarcoma.14,16,17,18,19,20 A clinical report18 describes renal adenocarcinoma that was identified in a ferret on necropsy but was not associated with antemortem signs of renal failure.

In the ferret of the present report, renal adenocarcinoma was associated with temporal morphological changes in a renal cortical cyst and mild increases in plasma biochemical indicators of renal function. The biochemical changes in this ferret were suspected to be secondary to the nodule that extended from within the renal parenchyma toward the renal pelvis and incorporated the ureter, resulting in acute obstructive hydronephrosis. Kawagushi et al18 also noted the presence of a renal cyst ipsilateral to the renal adenocarcinoma in their reported necropsy findings, but the cyst was suspected to have resulted from chronic hydronephrosis related to the solid neoplasm, rather than developing prior to that lesion. In addition, gross metastasis to a single mesenteric lymph node was identified in our patient, whereas there was a substantial number of multifocal nodules affecting the lungs in the ferret of the report by Kawagushi et al.18

Renal failure in domestic ferrets has been described in association with intrinsic renal and postrenal pathological changes.9 Intrinsic renal causes include toxic insults and neoplasia affecting the renal pelvis, and postrenal causes include ureteral stenosis, adrenal gland–associated prostatomegaly, and urolithiasis.17,21,22 Hydronephrosis has been occasionally reported secondary to ureteral obstruction, congenital defects, or iatrogenic causes.23,24,25,26 In the ferret of the present report, mildly increased plasma BUN concentration was not detected until 17 months after the renal cysts were first detected. Whereas the BUN concentration normalized after the initiation of regular subcutaneous fluid therapy, the ferret’s plasma creatinine concentration concurrently increased. This may have been secondary to the neoplastic nodule’s extension toward the renal pelvis and subsequent development of hydronephrosis. Although increases in circulating BUN and creatinine concentration may be attributed to early renal failure, these findings can also result from other causes including dehydration, gastrointestinal bleeding, or consumption of raw diets.9,12 Early renal failure was considered the most likely reason for the biochemical changes in our patient, as the changes developed despite ongoing SC fluid administration and no history of gastrointestinal signs or a raw diet was noted.

Renal cysts have been linked to renal neoplasia in people, transgenic mice, dogs, cats, and cattle.27,28,29,30,31,32,33,34 In people, cystic renal cell carcinomas are frequently misdiagnosed as benign renal cysts.35 Additionally, patients with acquired cystic kidney disease undergoing long-term hemodialysis, defined as a pretransplantation dialysis interval > 4.6 years, have a greater incidence of renal cell carcinoma than patients with acquired cystic kidney disease undergoing a shorter pretransplantation dialysis interval.36 In the ferret of the present report, it is unknown whether the renal cyst underwent neoplastic transformation into renal adenocarcinoma or it originated as a slow-growing adenocarcinoma or a precancerous lesion. If neoplastic transformation occurred, this may have been indicated by the increased mineralization that was noted 4 months after the renal cysts were first detected.

The ferret described in the present report was suspected to have hypoglycemic episodes due to an insulinoma on the basis of blood glucose and insulin measurements, but no microscopic evidence of insulinoma was found on necropsy. Lethargy, which was presumed secondary to the hypoglycemia, was the primary clinical sign observed. However, renal adenocarcinoma, lymphoma, and the adrenocortical tumor could have contributed to this. The hypoglycemia could have resulted from lymphoma, a microscopic insulinoma not detected on histologic examination, or a potential paraneoplastic syndrome.2,37 In human medicine, a paraneoplastic syndrome termed non–islet cell tumor hypoglycemia (NICTH) is described.37,38,39 This type of hypoglycemia develops secondary to tumor production of insulin-like growth factor 2, which can cause hypoglycemia because its structure and function are similar to those of insulin.37,38,39 The hypoglycemia is resolved upon complete surgical resection of the tumor.37 The presence of NICTH has been reported for a variety of neoplasms, including the 3 types identified in the ferret of this report, and it is also rarely reported in association with renal cell carcinoma in people.37,38,39 Insulin-like growth factor 2 concentrations were not measured for the ferret of this report, so it was unknown whether NICTH occurred. However, we considered it more likely that the ferret had an insulinoma that was not detectable on the histologic sections obtained.

The ferret described here and the ferret of the report by Kawagushi et al18 were geriatric ferrets with concurrent neoplasias found on necropsy. Neoplasia is a common occurrence in North American ferrets, and most domestic ferrets in Japan also originate from North America.13,19 The definitive causes of frequent neoplasia in domestic ferrets are unknown, but proposed causes include familial predisposition, early neutering, and infectious agents.13 Although renal neoplasms are rare in domestic ferrets, the prevalence of renal tubular cell neoplasms in black-footed ferrets (Mustela nigripes) at 1 institution was found to be 20.7% (38/184).40 Regardless of the frequencies of renal neoplasia in these species, is it not unusual for geriatric ferrets to develop multiple neoplastic processes and comorbid conditions,8 as seen in the ferret of the present report.

Several limitations related to the case may have affected the clinical outcome for this ferret. Serial urinalyses were not performed, and evaluation of urine specific gravity may have provided earlier detection of renal insufficiency and resulted in earlier therapeutic intervention.41 Preoperative evaluation of the left kidney’s glomerular filtration rate during the contrast-enhanced CT scan would have provided more information about the ferret’s prognosis.42 The inadvertent puncture of the aorta and subsequent repair resulting in decreased aortic diameter contributed to the infarction and development of anuric renal failure of the left kidney. Unfortunately, deviation of the aorta on the right side of the abdomen was not appreciated on the preoperative CT scan, and the information that this case may have provided about the outcome of surgical treatment for this uncommonly reported neoplasm in ferrets remained unknown.

In the ferret of this report, we identified a renal cyst that may have undergone neoplastic transformation into a renal adenocarcinoma. The case also highlighted the importance of considering differential diagnoses for hypoglycemia other than insulinoma, such as a paraneoplastic syndrome. Although renal cysts are frequently considered incidental findings, it is important for practitioners to closely monitor these cysts for possible progression that may cause renal failure and clinical compromise that necessitates medical and surgical intervention.

Acknowledgments

The authors declare that there were no conflicts of interest.

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