Treatment of a Malignant Pheochromocytoma in a Dog Using ¹³¹I Metaiodobenzylguanidine

Introduction

Pheochromocytomas are neuroendocrine tumors that arise from chromaffin cells of the sympathetic nervous system and are primarily found in the adrenal glands. Chromaffin cells store and secrete catecholamines such as norepinephrine and epinephrine. Clinical signs of pheochromocytomas include weakness, polyuria/polydipsia, collapse, tachyarrhythmias, and vomiting.¹ In people, approximately 10% of pheochromocytomas are malignant, but in dogs, approximately 50% are malignant.^1–3 Malignant pheochromocytomas invade through the capsule of the tumor, contain areas of coagulation necrosis or hemorrhage, and may metastasize to distant sites.⁴ Surgery is the only definitive curative treatment of local pheochromocytomas in both humans and dogs.^2,5 In dogs, perioperative mortality is high, ranging from 20% to 40%, even when the surgery is performed by highly skilled surgeons.^1,3,5 Surgical debulking may only be palliative in controlling clinical signs when the dog has either an extensive tumor burden or metastatic disease, and very few other treatment options are available.

Metaiodobenzylguanidine (MIBG) is an alkyl-guanidine derivative with a molecular structure that is very similar to that of norepinephrine, and can be taken up by pheochromocytomas.⁶ This compound has been successfully radiolabeled and is used as an imaging agent in human medicine. MIBG has also been used to image other tumors of neural crest origin such as medullary thyroid tumors and gastrinomas.^7,8 When labeled with a β emitter such as iodine 131 (¹³¹I), MIBG can be used for therapeutic purposes. In humans with pheochromocytomas or other neural crest tumors having measureable local or metastatic disease, remissions have occurred in 33–60% of treated patients, although complete remissions are rare.^9–11

Canine pheochromocytomas have also been successfully imaged using [¹²³I]MIBG, and more recently, with a related compound p-flurobenzylguanidine labeled with fluorine 18.^12,13 These two reports demonstrate that MIBG is selectively concentrated by canine pheochromocytomas. To the author's knowledge, [¹³¹I]MIBG has not been evaluated as a therapeutic agent for any canine neuroendocrine tumor. This report documents a case of canine pheochromocytoma treated with [¹³¹I]MIBG.

Case Report

A 12 yr old castrated male Yorkshire terrier was presented to the referring veterinarian's practice for evaluation of a midabdominal mass palpated incidentally by the owner (who was a board-certified veterinary surgeon). Because the dog was handled frequently by the owner, the sudden detection of an obvious mass suggested that the mass had grown rapidly. No clinical signs were present, and blood work at that time revealed a mildly elevated blood urea nitrogen (BUN) level, a normal creatinine level, and mild anemia (Table 1). An ultrasound demonstrated a large, right-sided abdominal mass of undetermined origin. An exploratory celiotomy revealed that the mass encompassed multiple organs, including the right kidney and the caudal vena cava. Surgical excision was not possible, but a biopsy was performed. Histopathology and immunohistochemistry results were consistent with a pheochromocytoma. The dog was treated with 0.5 mg/kg of phenoxybenzamine q 12 hr per os (PO) postoperatively starting the day after surgery for any undocumented hypertension.

TABLE 1 Patient Complete Blood Count and Serum Chemistry Profile

*

Reference ranges for 06/02/07, 08/25/07, and 12/19/07 (i.e., samples taken at Garden State Veterinary Specialists)

†

Reference ranges for 07/02/07, 12/10/07, 12/14/07, and 12/15/07 (i.e., samples taken at the University of Missouri-Columbia Veterinary Medical Teaching Hospital)

fT4, free thyroxine; T4, thyroxine; USG, urine specific gravity.

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The dog was presented to the University of Missouri-Columbia Veterinary Medical Teaching Hospital 1 mo later for evaluation and to discuss potential treatment options. The owner reported that the dog had developed mild lethargy and anorexia since the time of the original diagnosis. A physical examination revealed a grade 3/6 left basilar systolic heart murmur, a large, firm mass in the right caudal abdomen, and caudal epigastric venous distention. A neurologic exam was unremarkable. Systolic and diastolic blood pressures were within normal limits as determined by repeated oscillometric measurements. Hematologic evaluation revealed a mild, normocytic, normochromic, nonregenerative anemia and a mild increase in band neutrophils. The leukogram was otherwise unremarkable. A mild increase in BUN with normal serum creatinine levels and mild hypocholesterolemia were noted on the serum chemistry profile. Thoracic radiographs revealed a moderate, generalized cardiomegaly that was most compatible with mitral and tricuspid valvular endocardiosis. There was no evidence of thoracic tumor metastasis. An abdominal computed tomography (CT) scan with a low osmolarity iodinated contrast agent^a demonstrated a large, heterogeneously attenuating mass displacing the abdominal viscera and engulfing the right kidney. The right adrenal gland could not be delineated. Severe hydronephrosis of the right kidney was also seen (Figure 1). Due to the extremely aggressive nature of this tumor, surgery was deemed impossible, and radioisotope therapy was elected. Four days prior to radionuclide therapy, the dog was started on oral sodium iodide^b (100 mg PO q 24 hr) in an attempt to inhibit uptake of the radioisotope by the thyroid glands. On the fifth day after presentation to the authors’ hospital, 370 megabecquerels (MBq, equivalent to 10 millicuries [mCi]) of [¹³¹I]MIBG^c was administered through the right cephalic vein. Scintigraphy performed 2 days after the injection showed that the mass had moderately concentrated the [¹³¹I]MIBG (Figure 2). The dog was released from radiation isolation after 6 days and returned home with his owner.

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The dog improved clinically, with increased energy and appetite (according to the owner). Follow-up blood work and a thyroid panel performed 7 wk post-treatment revealed no significant changes from baseline (Table 1). A CT scan was performed, which demonstrated that the tumor had not enlarged, and contrast-enhanced imaging showed additional areas of hypoattenuation compared with the previous CT scan (Figure 3). The tumor response was determined to constitute stable disease for a minimum of 6 wk based on imaging, and 4 mo based on clinical response.

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The dog was re-presented to the University of Missouri-Columbia Veterinary Medical Teaching Hospital 5 mo after initial treatment for anorexia and vomiting. The only medication the dog was receiving at that time was phenoxybenzamine (0.5 mg/kg PO q 12 hr). The physical examination remained unchanged, except that the abdominal mass was subjectively larger on palpation. Neurologic exam was unremarkable, and the blood pressure remained within normal limits on repeated measurements. Hematologic evaluation revealed a severe, normocytic, normochromic, nonregenerative anemia with no other remarkable abnormalities. Biochemical evaluation results were characterized by an increased BUN, low creatinine, low cholesterol, and electrolyte abnormalities consistent with mild dehydration. The urinalysis revealed moderately concentrated urine (Table 1). Thoracic radiographs revealed no abnormalities, and an abdominal CT scan documented tumor progression to a size 1.3 times the initial measurements, compared using three-dimensional reconstruction volumes from the previous scans (215 cm³ versus 280 cm³ (Figure 4). Given the lack of other feasible therapeutic options and considering the clinical response noted from the previous therapy, the dog was treated again with [¹³¹I]MIBG using the same dosing protocol as before except that no follow-up scintigraphy was performed.

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During the second day in radiation isolation, the dog became lethargic, completely anorexic, and developed dark, tarry diarrhea. Laboratory evaluation the following day showed a worsening anemia, thrombocytopenia, neutropenia with mild toxicity, lymphopenia, and eosinopenia. The patient was also severely hypoglycemic, had an increasing BUN, normal creatinine, normal electrolytes, and hypoalbuminemia (Table 1). The dog was moved to the small animal intensive care unit where he was treated with IV 0.9% sodium chloride^d with 5% dextrose^e at a rate of 13 mL/hr. A whole blood transfusion was also initiated, and fluid therapy was continued. The dog also received cefazolin^f (22 mg/kg IV), sucralfate^g (250 mg PO q 8 hr), and famotidine^h (0.5 mg/kg PO q 12 hr). A physiologic dose of dexamethasoneⁱ (0.025 mg/kg) was administered subcutaneously as well.

The next day, the hypoglycemia resolved, there was a significant drop in the BUN, and a slight increase in albumin. The dog's hematocrit had increased to 21% after the transfusion (Table 1). The dog had improved clinically and had an improved attitude and appetite. Radioactivity counts were equivalent to background readings, allowing him to be cleared by Missouri University radiation safety officers. He was then discharged to the owner with oral antibiotics and gastrointestinal protectants.

The dog was presented to the Garden State Veterinary Specialists a few days later for a follow-up examination. He had an improved appetite, better energy level, and normal stool (according to the owner). Blood work on that day revealed a normal leukogram with moderate neutrophil toxicity, a normal platelet count, a stable hematocrit with no signs of regeneration, and low and normal thyroxine (T4) and free T4 (fT4) levels, respectively (Table 1). The dog was discharged, but 3 days later the dog was returned to the Garden State Veterinary Specialists with complete anorexia, lethargy, and melena. The packed cell volume had dropped to 12%. The dog received two more transfusions of whole blood and was discharged when his appetite and activity level had rebounded. The dog was continued on famotidine, sucralfate, and cephalexin, but developed worsening melena at home. He was returned to the clinic 8 days later with a packed cell volume of 10%. The dog died before therapy could be instituted.

A complete necropsy was not performed, but the adrenal tumor and surrounding structures were obtained and submitted for histopathologic examination. Grossly, the right kidney, the enlarged left kidney, and the pancreas were adhered to the mass, but could be demarcated from the tumor. Several enlarged mesenteric lymph nodes were also noted. Representative areas of the tumor, kidneys, lymph nodes, and pancreas were evaluated histopathologically. Microscopically, the tumor was composed of dense cellular packets and sheets of polyhedral cells separated by minimum fibrovascular stroma (Figure 5). Wide bands of dense, mature fibrous tissue subdivided and surrounded the mass. Lymphatic and vascular tumor emboli were noted in several locations in the tumor capsule (Figure 5). Large patches of necrosis and hemorrhage were obvious in the center of the mass. The cortices of several distant lymph nodes were effaced by tumor growth, and a tumor embolus was noted in the right kidney. Individual neoplastic cells displayed moderate variation in cell and nuclear size (Figure 6). Homogenous, finely granular chromatin was present, and mitoses were uncommon in the primary tumor, but were more common in lymph node metastases. Additional sections were examined for chromogranin A and synaptophysin. The neoplastic cells had cytoplasmic granules that stained with variable intensity, which were positive for synaptophysin and chromogranin expression, confirming that the mass was a malignant pheochromocytoma.

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Discussion

Patients with unresectable or metastatic pheochromocytomas have relatively few treatment options available to them. Medical management with α and β adrenergic antagonists can help to control the clinical signs associated with catecholamine release, but these drugs do not to reduce the tumor burden.¹⁴ Partial remissions have been reported in the human literature with [¹³¹I]MIBG.^9,10,15 In the case described here, [¹³¹I]MIBG localized to the pheochromocytoma, and administration resulted in clinically stable disease for 4 mo despite the extremely aggressive nature of the tumor.

Several factors may have prevented a better response in this dog, including irregular concentration of the ¹³¹I within the tumor. Localization of MIBG to neuroendocrine tissues is thought to occur by two separate uptake mechanisms. Both are active transport processes, but one is neuron-specific (uptake-1) and the other occurs in extraneuronal tissues (uptake-2).¹⁶ Localization requires that the tumor cells actively absorb norepinephrine by an uptake-1 process, which is mimicked by MIBG, and that the tumor retains the compound after MIBG enters intracytoplasmic storage vesicles.^17,18 In a series of 400 people, the uptake of [¹³¹I]MIBG in pheochromocytomas varied significantly between adrenal medullary tumors from no detectable concentration to intense uptake. No pattern of anatomic location, histologic tumor grade, or serum/urine catecholamine levels explained the variations observed. Although appreciable uptake was noted in almost all of the adrenal pheochromocytomas, high variation in the absence of a predictable pattern makes prescintigraphy case selection impossible.¹⁹ Another study reported that less than half of malignant pheochromocytomas concentrate high levels of [¹³¹I]MIBG, indicating that many patients are suboptimal candidates for therapy.¹⁰

In the case reported here, nuclear scintigraphy was performed 2 days after a therapeutic dose of [131]MIBG had been given. The scan revealed that [¹³¹I]MIBG had moderately concentrated within the tumor, but it was impossible to determine the magnitude or uniformity of the radiation dose received. Ideally, a diagnostic tracer [¹³¹I]MIBG scan or a [¹²³I]MIBG scan would have been performed prior to treatment to document high uptake-1 capability of the tumor. This was not done due to the relatively high cost of the [¹³¹I]MIBG, which resulted in the treatment of a dog that was a suboptimal candidate.

A second factor that may have hampered the response was the large size of the tumor. On the original CT scan, the tumor occupied a large portion of the abdomen and had very heterogeneous iodinated contrast uptake (Figure 2). On the postmortem exam, the tumor accounted for one-third of the patient's total body weight and had engulfed many of the nearby organs. In general, tumor vasculature tends to be malformed, which can create large areas of increased interstitial pressure, hypoxia, and large diffusion distances for intravascular molecules.²⁰ In this case, poor blood supply and hypoxia were also indicated by the large areas of hypoattenuating tumor tissue on the CT scan and by the necrosis seen microscopically. Poor tumor circulation could prevent homogenous distribution of the radioisotope, and tumor hypoxia would create an intrinsic resistance to lower linear energy transfer radiation.²¹ A smaller tumor without such large hypoxic areas may have been more amenable to intravenous radiopharmaceuticals. Surgical debulking of the tumor might have mitigated some of these complicating factors; however, the risks of surgery were substantial.⁵ Nonetheless, 4 mo of clinical stability in a dog with such a large mass suggests that there was some efficacy to the first therapy.

A third factor that may have reduced efficacy was delay of the second treatment. Human patients receive multiple doses of [¹³¹I]MIBG at 3-mo intervals in an effort to improve the efficacy of the treatment.^10,22 After a partial remission, repeat administration may allow for the [¹³¹I]MIBG to reach tumor cells previously too far from the blood supply to be affected. Reoxygenation may also occur between the doses, increasing the number of tumor cells susceptible to radiation. A second dose of [¹³¹I]MIBG was administered to this dog 5 mo after the original therapy. The delay may have allowed for excessive repopulation of the tumor. Earlier readministration of [¹³¹I]MIBG 3 mo after the original therapy may have been more effective by taking advantage of reoxygenation and recruitment of previously hypoxic, noncycling cells, and prevention of repopulation of the tumor cells.

The toxicity of therapeutic doses of [¹³¹I]MIBG in dogs is unknown. Toxicity of [¹³¹I]MIBG in humans has generally been limited to minor hematologic abnormalities.^10,11 Greater myelosuppression has been seen with concurrent chemotherapy and higher doses of [¹³¹I]MIBG.^15,23 The dog treated here may have experienced hematologic toxicity; however, comorbid conditions complicated the authors’ assessment. The anemia and elevated BUN were consistent findings even prior to therapy, suggesting gastrointestinal bleeding, potentially from ischemic damage caused by the mass. The dog did not experience any other adverse clinical or clinicopathologic events after the first treatment, and had normal thyroid values. After the second treatment, the dog became completely anorexic and dehydrated. These factors, as well as the continued bleeding from the gastrointestinal tract, could explain the hypoglycemia, hypoalbuminemia, severe anemia, and thrombocytopenia. The hypoglycemia could have also been related to sepsis from neutropenia and bacterial translocation in the gastrointestinal tract. Myelosuppression from radioiodine is a potential sequela, and leukopenia was noted in the treated dog. The decrease in WBCs was noted 3 days after radioiodine administration, but they returned to normal by 6 days after therapy, which does not fit the expected timeline of myelosuppression from ¹³¹I. In humans treated with a high dose [¹³¹I]MIBG (18 mCi/kg), platelet nadirs were noted at a median of 24 days (range, 18–47 days), and neutrophil nadirs were reported at 42 days (range, 10–66).²³ In a canine study using ¹³¹I, three dogs became myelosuppressed and died at days 26, 37, and 124.²⁴ The early onset and resolution of leukopenia in this patient suggests that the leukopenia was caused by something other than the radioiodine, such as a degenerative left shift associated with sepsis. The continuing anemia after the patient was sent home may have been in part due to the [¹³¹I]MIBG, but given the dog was having persistent and progressively worse melena, the radioisotope was at best just a contributing factor. Although it appears that the second dose of [¹³¹I]MIBG did not improve the dog's clinical status, it is unlikely that the patient's rapid decline was due to the therapy described here. In retrospect, the patient may have not been clinically well enough for the treatment, but no other realistic treatment options were available.

Conclusion

In summary, MIBG has previously been shown to localize to canine pheochromocytomas. To the authors’ knowledge, this is the first report of [¹³¹I]MIBG to treat an inoperable malignant pheochromocytoma in a dog. Although measureable tumor response was not documented, the treatment was clinically well tolerated, and improvement in clinical signs was noted after the first therapy. It is unclear what effects (if any) the second dose of [¹³¹I]MIBG had on the tumor or the patient, but given the timing of the events, it is unlikely that the radiopharmaceutical was related to any leukopenia, and, most likely, it was only a minor contributor to the anemia. Additional prospective assessment of tumor response, survival data, and toxicity needs to be collected in dogs to better determine the clinical utility of this treatment option. Further investigation of [¹³¹I]MIBG in dogs with inoperable pheochromocytomas, and potentially other neuroendocrine tumors, is warranted.