Treatment of Renal Nephroblastoma in an Adult Dog

Introduction

Nephroblastoma is a rare tumor of juvenile and adult dogs that has been previously associated with hypertrophic osteopathy.^1–6 In children, nephroblastomas are the fifth most common pediatric malignancy. They are treated with a combination of nephrectomy, chemotherapy, and radiation therapy determined by tumor stage and histopathology.⁷ Reported cases of renal nephroblastoma in dogs have not described successful therapy with surgery, chemotherapy, radiation, or a combination of the above. This study describes treatment of a Stage I, unfavorable histopathological renal nephroblastoma with nephrectomy followed by vincristine and doxorubicin in an adult dog that resulted in a disease-free interval of >25 months.

Case Report

An 8-year-old, neutered male Labrador retriever was referred to the University of Tennessee College of Veterinary Medicine Teaching Hospital because of bilateral symmetrical swelling of the carpi and hematuria of 3 months’ duration that was unresponsive to trimethoprim/sulfadiazine, doxycycline, and enrofloxacin. On presentation, the dog was bright and alert. There were bilaterally symmetrical, firm swellings proximal and medial to the carpi and slight thickening over the tarsi. The dog was not lame, and the swellings were not painful on palpation. The overlying skin was normal and there was no joint effusion. The popliteal lymph nodes were slightly and symmetrically enlarged.

A complete blood count (CBC), serum biochemical analysis, urinalysis, urine culture, coagulation panel, and fine-needle aspirates of the popliteal lymph nodes were performed. Abnormalities included a mature neutrophilia (19.8 × 10³/μL; reference range, 3.0 to 11.5 × 10³/μL), hypoglycemia (64 mg/dL; reference range, 70 to 117 mg/dL), increased alkaline phosphatase activity (197 IU/L; reference range, 12 to 72 IU/L), and microscopic hematuria (3 to 5 red blood cells per high-power field; 1+ occult blood). The lymph nodes were cytologically reactive. On radiography, hypertrophic osteopathy of the left carpus, tarsus, metacarpus, and metatarsus was identified [Figure 1]. Thoracic radiographs were unremarkable. On abdominal radiographs, an irregular, soft-tissue opacity in the area of the right kidney was identified. On ultrasonographic evaluation of the abdomen, the right kidney was effaced by a mixed-echogenicity mass; all normal renal architecture was obliterated. Prothrombin and partial thromboplastin times were within reference ranges. The hypoglycemia was not repeatable (glucose, 74 mg/dL; reference range, 70 to 117 mg/dL).

Renal neoplasia was suspected. An abdominal exploratory celiotomy identified an enlarged, firm, tan, irregular right kidney. There was no gross evidence of metastatic disease. Mesenteric lymph nodes were not biopsied. A nephrectomy of the diseased right kidney was done. Surgical recovery was unremarkable, and the dog was discharged 2 days later.

On gross evaluation, one pole of the kidney contained an irregular, off-white, 5 × 4.2 × 2-cm mass within the cortex and medulla and partially ulcerated pelvic transitional epithelium. Histopathological examination revealed the epithelial component to be benign, but the mesenchymal component was sarcomatous [Figure 2]. The tumor was designated as Stage I with unfavorable histopathology [see Table].

A combination chemotherapy protocol was begun 17 days after surgery. Vincristine (0.5 mg/m² of body surface, intravenously [IV]) and doxorubicin (30 mg/m² of body surface, IV) were given every 3 weeks for a total of five treatments. Diphenhydramine (2 mg/kg body weight, intramuscularly, once) was given 20 minutes prior to each chemotherapy treatment. A CBC was evaluated and found to be within reference ranges prior to each therapy. An intermittent arrhythmia was ausculted prior to the second doses of vincristine and doxorubicin; an electrocardiogram identified occasional unifocal, ventricular, premature contractions. An echocardiogram was unremarkable. The arrhythmia was not treated and did not recur. Ten days after the second doses of vincristine and doxorubicin, the dog became febrile and depressed with a neutropenia (160/μL; reference range, 3.0 to 11.5 × 10³/μL) and thrombocytopenia (73 × 10³/μL; reference range, 200 to 500 × 10³/μL). He received IV fluids, enrofloxacin (5 mg/kg body weight, IV, q 12 hours), and ampicillin (20 mg/kg body weight, IV, q 8 hours) for presumptive chemotherapy-induced immunosuppression and subsequent sepsis. The pyrexia, neutropenia, and thrombocytopenia resolved after 2 days of treatment, and he was discharged on enrofloxacin (5 mg/kg body weight, per os [PO], q 12 hours for 7 days) and amoxicillin (20 mg/kg body weight, PO, q 12 hours for 7 days).

The hypertrophic osteopathy lesions began resolving 5 weeks after the nephrectomy, as determined by measurement of limb circumference, and were no longer detectable 7 months after surgery. Thoracic radiographs and abdominal ultrasonography were unremarkable prior to the first, third, fourth, and fifth doses of chemotherapy and 7, 12, 18, and 24 months after the initial diagnosis. Follow-up CBCs, serum biochemistries, and urinalyses were normal except for isosthenuria and mild azotemia (creatinine, 2.0 mg/dL; reference range, 0.9 to 1.8 mg/dL) at the 7-, 12-, 18-, and 24-month rechecks. At the 12-month recheck, he was placed on a low-salt and protein-restricted diet^a for management of chronic renal failure.

Discussion

Hypertrophic osteopathy usually occurs with intrathoracic diseases such as primary or metastatic lung tumors, pneumonia, heartworm disease, and lung atelectasis. Additionally, nephroblastomas, renal adenocarcinoma, and rhabdomyosarcoma of the bladder have been associated with hypertrophic osteopathy.^1–3 The periosteal reaction of hypertrophic osteopathy is attributed to increased blood flow to the distal limbs due to a neural reflex.¹ Hypertrophic osteopathy is initially characterized by fibrous, vascularized, collagenous connective tissue, then by fibrochondroid metaplasia and new bone production subperiosteally. The treatment of choice is removal of the underlying disease.¹³

Renal neoplasia is rare in dogs, constituting 0.6% to 1.7% of neoplasms.^4–6 The majority are carcinomas.^4–6 Nephroblastoma is a rare tumor usually seen in young dogs but reported in dogs up to 8 years of age. Nephroblastomas can be benign but are usually malignant. There is no sex or breed predilection, and they are usually unilateral.^4–6

Nephroblastomas may also occur in extrarenal locations. There are several reports of primary spinal cord nephroblastomas in the dog, arising from embryonic remnants, usually occurring as intradural extramedullary masses dorsolateral to the spinal cord. The renal and spinal variants of nephroblastoma are similar histopathologically.^8–14 There are several reports of long-term survival after surgical excision of spinal nephroblastoma.⁸¹⁰ Metastasis can occur from the primary tumor to bone marrow and vertebrae.¹²

Nephroblastomas in humans are the fifth most common pediatric malignancy. Classification of these tumors is based on stage of the tumor and histopathology [see Table]. In humans, 90% of children have favorable histopathology, and only 10% have unfavorable (i.e., anaplastic or sarcomatous) histopathology. Treatment recommendations for humans are determined by a combination of tumor stage and histopathology. Nephrectomy is indicated unless the tumors are bilateral. Vincristine and actinomycin D are used unless the tumor is Stage I with favorable histopathology, in which case postoperative chemotherapy is not indicated. Intra-abdominal radiation is recommended if the tumor is Stage III or higher or if it is Stage II and anaplastic. With these guidelines, 90% of children survive 2 years and are considered cured.⁷¹⁵ Doxorubicin was used instead of actinomycin D in this dog because of the greater familiarity with doxorubicin in veterinary oncology, the drugs’ similar mechanisms of action to actinomycin D, and the greater efficacy of doxorubicin over actinomycin D in the treatment of lymphoma in dogs.¹⁶

Three reports were found in the literature regarding treatment of canine renal nephroblastoma.²¹⁷¹⁸ One dog had Stage II tumor with unfavorable histopathology and was treated with surgery alone; she had metastasis within 6 weeks.¹⁷ The second dog had Stage II tumor with unfavorable histopathology and was treated with nephrectomy, vincristine, doxorubicin, and intra-abdominal radiation; she had metastasis within 8 months and was euthanized at 15 months.² The third dog had Stage III tumor with favorable histopathology and was treated with nephrectomy, vincristine, and actinomycin D for one treatment and then doxorubicin beginning 3 weeks after the first dose of actinomycin D. This dog developed metastasis at 15 weeks and was euthanized at 16 weeks.¹⁸ The authors report a Stage I tumor with unfavorable histopathology in a dog treated with nephrectomy, doxorubicin, and vincristine that survived >24 months. Too few dogs with nephroblastoma have been treated to make definitive treatment recommendations. Given the metastatic pattern identified in previous cases, staging using thoracic and abdominal radiographs and abdominal ultrasonography is recommended. Although the paucity of reported cases makes it difficult to make broad conclusions, this case demonstrates that it is possible for dogs with Stage I renal nephroblastoma with unfavorable histopathology to survive over 2 years with treatment.