Functional Islet Cell Tumors
The most frequent pancreatic islet tumor is an islet cell carcinoma derived from insulin-secreting β cells. These neoplasms frequently are hormonally active and secrete excessive amounts of insulin, which causes hypoglycemia. Endocrine pancreatic tissue appears to be derived from multipotential ductal epithelial cells, which differentiate into one of the several cell types present within the islets. Gastrin, somatostatin, pancreatic polypeptide, and vasoactive intestinal peptide may also be produced in excess in islet cell tumors. β-cell neoplasms of the pancreatic islets (insulinomas) are seen most frequently in dogs 5–12 yr old. They are common in ferrets and have also been less frequently reported in cats and in older cattle.
The clinical signs seen with insulinomas result from excessive insulin secretion, which leads to an increased rate of transfer of glucose from the extracellular fluid to body tissues and thus to severe hypoglycemia. The clinical signs are a reflection of the hypoglycemia and are not specific for hyperinsulinism associated with β-cell neoplasms. Initial signs include posterior weakness, fatigue after exercise, generalized muscular twitching and weakness, ataxia, mental confusion, and changes of temperament. Dogs are easily agitated, and there are intermittent periods of excitability and restlessness. Periodic seizures may occur, and episodes of collapse resembling syncope have also been reported.
Clinical signs are characteristically episodic and occur initially at widely spaced intervals but become more frequent and prolonged as the disease progresses. Hypoglycemic attacks may be precipitated by physical exercise (increased use of glucose) or fasting (decreased availability of glucose), as well as by ingestion of food (stimulation of insulin release). Administration of glucose rapidly alleviates the signs.
The predominance of clinical signs relating to the CNS demonstrates the primary dependence of the brain on the metabolism of glucose for energy. When the brain is not supplied with glucose, cerebral oxidation decreases and manifestations of anoxia appear. Because clinical signs are compatible with primary disease of the CNS, functional islet cell tumors may be misdiagnosed as idiopathic epilepsy, brain tumors, or other organic neurologic disease. Repeated episodes of prolonged and severe hypoglycemia may result in irreversible neuronal degeneration throughout the brain. Permanent neurologic disability probably accounts for the terminal coma, unresponsiveness to glucose, and eventual death of some dogs.
Insulinomas usually appear as single, yellow to dark red, spherical, small (1–3 cm) nodules visible from the serosal surface. They occur as single or occasionally multiple nodules in the same or different lobes of the pancreas. They are of similar consistency to or slightly firmer than the surrounding pancreatic parenchyma. A thin layer of fibrous connective tissue separates the neoplasm from the adjacent parenchyma. Insulinomas frequently metastasize to regional lymph nodes or the liver (or both) before diagnosis. True benign adenomas of islet cells are rare.
A blood glucose determination should be done on all older dogs with a history of periodic weakness, collapse, or seizures. Fasting hypoglycemia (≤60 mg/dL) in a middle-aged to older dog is strong support for an insulinoma. Serum insulin concentrations taken at the time of hypoglycemia are normal to increased in animals with an insulinoma. Differential diagnoses for hypoglycemia include hypoadrenocorticism, hepatic failure, large extrapancreatic neoplasms, sepsis, polycythemia, insulin overdosage, and laboratory error.
Although insulinomas are usually solitary in dogs, the entire pancreas should be examined carefully for multiple tumors. Complete excision of the tumor ameliorates the hypoglycemia and associated neurologic signs, unless there have been irreversible changes in the CNS. If there are nonvisible metastases, hypoglycemia may persist after surgery. Even though the potential for malignancy of insulinomas is high, many dogs live >1 yr with acceptable quality of life if all visible tumors are debulked at surgery. Dogs with inoperable tumors may be managed fairly well with multiple feedings per day and glucocorticoid administration (0.5–1 mg/kg/day). Diazoxide (20–80 mg/kg/day, divided into three equal doses) may also alleviate clinical signs in some dogs, although problems with availability have limited its use. The chemotherapeutic agent streptozotocin has been investigated for the treatment of islet cell tumors in dogs and may be considered after surgical resection.