History: An 8-year-old castrated male domestic shorthair cat was presented to Purdue University Veterinary Teaching Hospital following a three week history of anorexia, weight loss, intermittent hematuria, and urinating outside of the litter box.  Physical exam findings included muscle wasting, tachycardia (240 bpm), and hepatomegaly.  Mildly increased liver enzymes (ALT and ALP) and markedly elevated lipase levels were noted on serum biochemistry.  Complete blood count results showed a mild anemia and lymphopenia.  Radiographs demonstrated urinary calculi and an enlarged liver with irregular margins.  Several masses were identified in the liver and pancreas on abdominal ultrasound, along with enlarged gastric lymph nodes and mild peritoneal effusion.  Cytology of liver mass aspirates was interpreted as adenocarcinoma with hepatic lipidosis.  The cat was euthanized due to poor prognosis and submitted for necropsy examination to the Animal Disease Diagnostic Laboratory.

Gross examination:  Subcutaneous tissue and visceral organs were icteric.  The pancreas, liver, and gastric/pancreatic lymph nodes contained multifocal to coalescing masses, characterized by pale tan, firm, often umbilicated, nodules measuring up to 6 cm in diameter.  The masses extended into the parenchyma of affected organs and, occasionally, had brown, friable, central necrosis on cut section.

Histopathologic examination:  Masses in the pancreas, liver, and lymph nodes effaced normal tissue parenchyma and were composed of solid packets or nests of neoplastic cells separated by moderate fibrovascular stroma.  The cells occasionally organized around central lumina, forming irregular acini or ductules.  Features of the tumor cells included polygonal to columnar cell shape, moderate amphophilic cytoplasm, round to oval nuclei with stippled chromatin, and single distinct nucleoli.  Mitotic figures were common with an index of 44 per ten high power fields (400X magnification).  Hemorrhage, necrosis, and mixed inflammation were present multifocally in the masses.  Portal veins contained tumor emboli, and micrometastases were identified in lung and adrenal cortex.

Immunohistochemistry:   Tissue of origin could not be determined based on morphology alone in this tumor.  Differential diagnoses included carcinoma (pancreatic or biliary) or malignant neuroendocrine tumor (pancreatic islet cell carcinoma).  Immunohistochemical (IHC) tests utilized in this case consisted of antibodies against neuron-specific enolase, PGP 9.5, and insulin.  Neuron-specific enolase and PGP 9l5 were both positive in tumor cells, supporting a diagnosis of neuroendocrine tumor, likely of islet cell origin.  Insulin IHC was also positive, indicating the production of insulin in tumor cells and confirming the diagnosis as beta-cell carcinoma (insulinoma).

Comment:  Insulinoma is a tumor derived from pancreatic beta-cells, which are the insulin-producing cells in the islets of Langerhans.  Insulinoma is rarely documented in cats, with only five reports identified in the literature, and is uncommon in dogs.  Interestingly, three of the five cats reported with insulinoma were Siamese.

  In this type of tumor, neoplastic beta-cells produce insulin and can autonomously secrete the hormone, resulting in hyperinsulinemia.  Excess insulin causes hypoglycemia, which is the most consistent hematologic or serum biochemical abnormality in animals with insulinoma.  The classical manifestation, best characterized in the dog, is episodic neurological signs such as weakness, ataxia, syncope, or seizures during fasting or exercise when hypoglycemia becomes most severe.  After eliminating other causes of hypoglycemia, demonstration of inappropriate levels of insulin (i.e. normal or increased in the face of hypoglycemia) can help confirm the diagnosis of insulin-secreting neoplasia.  Ultrasound of the pancreas can assist in identification of the mass, although the tumors are commonly small (<3 cm) at the time of diagnosis, and can be difficult to detect.  Exploratory laparotomy may be warranted for definitive diagnosis

Treatment for insulinoma can include surgery, medical management, or both.  Surgery is rarely curative, and can create new challenges by inciting pancreatitis, the most common post-operative complication.  Medical management consists of feeding frequent small meals, supplementing with glucocorticoids to counteract the hyperinsulinemia, and limiting excitement and exercise.  The goal is to keep glucose levels from falling dangerously low, rather than maintaining normal levels at all times.  Prognosis is poor due to challenging case management and high incidence of metastasis of this tumor.

  The interesting features in this case include the absence of neurological signs and the inability to document hypoglycemia (cat was euglycemic on presentation).  One plausible explanation may be that , although the neoplastic cells produced insulin as indicated by positive insulin IHC staining, the hormone was either non-functional or not secreted from the tumor cells.  It is also possible that hyperinsulinemia and hypoglycemia did occur, but glycose failed to reach levels low enough to manifest as

-by Dr. Pamela Mouser, ADDL Graduate Student

References:

1. Feldman EC, Nelson RW: 2004.  Beta-cell neoplasia: insulinoma.  In: Canine and feline endocrinology and reproduction, 3rd ed. Saunders, St. Louis, MO.  pp 642-643.

2. Krajhe AC: 2003.  Hypoglycemia and irreversible neurologic complications in a cat with insulinoma.  JAVMA 223:812-814.

3. Lurye JC, Behrend EN: 2001.  Endocrine tumors.  Vet Clin North Am Small Anim Prac 31_ 1083-1110