Pathogenesis. In people, the pathogenesis of the skin disease is thought to be an indirect result of chronically elevated plasma glucagon
concentrations. The high glucagon concentrations promote amino acid mobilization in tissues because of the need for substrate
in prolonged gluconeogenesis.3 Glucagon's subsequent activation of the urea cycle enzymes carbamoyl-phosphate synthase and argininosuccinate synthase promotes
the catabolism of amino acids. These pathways of protein degradation are hypothesized to cause hypoaminoacidemia, which causes
cellular necrosis in the epidermis by depleting epidermal proteins.2 Liver disease along with fatty acid and zinc deficiencies may also contribute to the pathogenesis of the skin lesions in
A similar pathogenesis may exist for superficial necrolytic dermatitis in dogs. Serum amino acid concentrations were determined
in three of the eight reported cases, and 20 of 24, 13 of 18, and four of five amino acids tested were found to be decreased.5 Amino acid concentrations were not determined in this case.
Diabetes mellitus and nonspecific clinical signs
Hyperglycemia or glucose intolerance in association with diabetes mellitus has been reported in people with glucagon syndrome
and in some dogs with glucagonomas.2,5,15 Diabetes mellitus is hypothesized to be due to glucagon's diabetogenic actions.2 However, the development of diabetes mellitus most likely depends on the glucagon:insulin ratio, the relative proportion
of other hyperglycemic hormones, and the pre-existing genetic tendency toward glucose intolerance.2 In this case report, the patient had no evidence of concurrent diabetes mellitus.
Other nonspecific clinical signs associated with glucagonomas in dogs include normocytic normochromic nonregenerative anemia
and weight loss.2 When present, anemia can be explained by the suppression of bone marrow erythropoiesis (i.e. anemia of chronic disease) induced by the neoplasm, and the weight loss is a result of glucagon's catabolic effects.4
Elevated serum glucagon concentration
The hallmark laboratory finding in people with glucagonomas is elevated fasting serum glucagon concentrations. High metastatic
rates are also commonly associated with glucagonomas in people.2
As in this case report, glucagon concentrations were markedly elevated in seven of nine previously reported cases in dogs.5,8 A pancreatic mass was identified in seven of the nine canine glucagonoma cases; however, in two dogs, a primary pancreatic
tumor was not identified. The diagnosis of glucagonoma in those two dogs was reached by demonstrating glucagon immunoreactivity
in hepatic metastases.5,10 Metastases were identified in five of the nine cases, most frequently involving the liver and the mesenteric or hepatic
lymph nodes. In this dog, at the time of euthanasia, no metastatic disease was found despite the plasma glucagon concentration's
being above the published canine reference interval, suggesting local or metastatic tumor growth.
Similar to this case and to cases in people, all previously reported cases of canine glucagonoma were immunoreactive for glucagon,
either singly or in combination with insulin, somatostatin, islet amyloid pancreatic polypeptide, or pancreatic polypeptide.
This finding underscores the importance of plasma glucagon concentrations in reaching a definitive diagnosis of glucagonoma
and glucagonoma-associated paraneoplastic skin disease.
Although glucagonomas are uncommon tumors in veterinary medicine, they should be considered as a differential diagnosis in
any patient exhibiting clinical and histologic changes consistent with superficial necrolytic dermatitis. A diagnosis of glucagonoma
should be based on elevated plasma glucagon concentrations and a confirmed neuroendocrine pancreatic tumor. In addition, the
characteristic cutaneous changes are strongly suggestive of the disease. Immunohistochemical analysis of tumor tissue is a
helpful diagnostic tool; however, it is limited by the ability of many islet cell tumors to produce multiple hormones. Thus,
plasma glucagon concentrations are necessary for a definitive diagnosis. As demonstrated by this case and from previous reports,
the prognosis for patients with and without surgical excision of their neoplasm remains poor to guarded.