JPC SYSTEMIC PATHOLOGY
ENDOCRINE SYSTEM
February 2022
E-N10

Signalment (JPC #1754878):  Military Working Dog

HISTORY:  None

SLIDE A: HISTOPATHOLOGIC DESCRIPTION:  Pancreas: Effacing 50 % of the section of pancreas, extending to a cut margin, and compressing and multifocally infiltrating the adjacent exocrine pancreas is a moderately cellular, multilobulated, partially encapsulated, infiltrative neoplasm composed of polygonal cells arranged in nests and packets separated by and often palisading along a moderate fibrovascular stroma. Neoplastic cells have distinct cell borders, a moderate amount of eosinophilic, granular to flocculant cytoplasm, and a round to oval, often-antibasilar nucleus with finely stippled chromatin and one prominent nucleolus. There is mild anisocytosis and anisokaryosis. The mitotic count averages 2 per 2.37 mm^2. Multifocally scattered throughout the neoplasm are areas of hemorrhage, fibrin, edema, hemosiderin laden macrophages, and there are rare areas of cellular loss (necrosis).  Multifocally, neoplastic cells surround and separate preexisting exocrine pancreatic acini.  Adjacent exocrine pancreatic lobules are compressed and rarely have shrunken acini that lack zymogen granules (atrophy). At the periphery of the neoplasm in the fibroadipose tissue, there are few small perivascular aggregates of lymphocytes and plasma cells.

Tonsils, salivary gland, and lymph node:  Essentially normal tissue.

Slide B:  Pancreas (insulin immunohistochemistry):  There is strong cytoplasmic immunoreactivity of islet beta cells within the islets of the normal pancreas (internal control).  Multifocally neoplastic cells exhibit strong cytoplasmic immunoreactivity.

MORPHOLOGIC DIAGNOSIS:  Pancreas:  Islet b-cell tumor, breed unspecified, canine.

SYNONYMS:  Islet cell adenoma (insulinoma), islet cell carcinoma

GENERAL DISCUSSION:

• Insulinoma is the most common neoplasm arising from pancreatic islets
• Most insulinomas are endocrinologically active producing hypoglycemia
• Functional islet tumors often produce multiple hormones, not just insulin
• Overview: Islets of Langerhans are composed of several cell types:
• Alpha (α) cells secrete glucagon, cholecystokinin, gastric inhibitory peptides, and ACTH-endorphin
• Beta (β) cells secrete insulin and amylin (IAPP)
• Delta (δ) cells secrete somatostatin and vasoactive intestinal peptide (VIP)
• F cells (PP cells) secrete pancreatic polypeptide (and secreted by the stomach/duodenum)
• Epsilon cells secrete ghrelin
• Difficult to distinguish between benign or malignant islet cell tumors; based on cell morphology, presence of well-demarcated and encapsulated nodules, not invading adjacent tissue
• Almost all islet cell tumors in dogs are malignant
• Generally microscopic metastasis has occurred by the time of surgical diagnosis
• Metastasis common to the liver, mesentery/omentum, and regional lymph nodes
• Boxers, fox terriers, standard poodles, and German shepherd dogs are over represented

PATHOGENESIS:

• Insulin is overproduced by beta cells, causing hyperinsulinemia > excessive insulin causes glucose to leave the bloodstream (hypoglycemia)
• Effects of hypoglycemia on the central nervous system
• Glucose is the primary fuel used by the CNS (scant carbohydrate reserves)
• Glucose enters neurons by passive diffusion; independent of insulin
• Decreased supply of glucose for intraneuronal oxidative processes > decline in neuronal adenosine triphosphate (ATP) > lack of energy > typical neural signs of stupor, seizures, and tremors
• Prolonged hypoglycemia can cause permanent neuronal damage and cortical laminar necrosis

TYPICAL CLINICAL FINDINGS:

• Most common in middle-aged or older dogs
• Recurrent disorientation or seizures associated with exercise, stress, or fasting
• Hypoglycemia, especially when combined with high insulin levels
• Animals recover with administration of glucose

TYPICAL GROSS FINDINGS:

• Adenoma: <2 cm spherical nodule; solitary, but can be multiple nodules; yellow to dark red; surrounded by a thin fibrous capsule
• Carcinoma: Usually larger than adenomas; multilobular; invades surrounding tissue; may metastasize to the liver, mesentery, omentum, and regional lymph nodes
• The right (duodenal) lobe is more frequently involved than the left (splenic) lobe

TYPICAL LIGHT MICROSCOPIC FINDINGS:

• Amyloid has been seen in tumors from dogs and cats but not cattle
• Adenoma
• Well differentiated round to polygonal cells
• Distinct cell borders and pale eosinophilic finely granular cytoplasm
• Arranged in small nests and packets
• Mitotic figures are rare
• Carcinoma
• Can be difficult to distinguish between benign and malignant tumors
• Look for peripheral infiltration, +/- large areas of necrosis, frequent mitoses, and marked cellular atypia
• Often hepatic metastases are microscopic

ULTRASTRUCTURAL FINDINGS:

• A variety of membrane bound secretory granules may be present
• Mature secretory granules contain internal cores that are circular or “V” shaped and often surrounded by a wide halo

ADDITIONAL DIAGNOSTIC TESTS:

• Cytology: Canine pancreatic FNAs have good diagnostic yield; high correlation to histopathology
• Hypoglycemia with concurrent, inappropriately elevated insulin levels
• Beta cell tumors are immunoreactive to insulin
• Histochemical and immunohistochemical stains for neuroendocrine tissue
• Cherukian-Schenk: Argyrophilic secretory granules
• Chromogranin A and/or B, synaptophysin, neuron-specific enolase, Lue-7

DIFFERENTIAL DIAGNOSIS:

• Islet cell neoplasms can be differentiated based on clinical signs/pathology or immunohistochemical stains:
• Gastrinoma (rare)
• Produce excess amounts of the hormone gastrin > gastric acid hypersecretion > gastric antral mucosal hypertrophy and gastroduodenal ulceration (Zollinger-Ellison syndrome)
• Prognosis is guarded to poor
• Glucagonoma (rare)
• Persistant, mild hyperglycemia (Type S diabetes mellitus) secondary to increased hepatic gluconeogenesis and glycogenolysis
• Diffuse vacuolar hepatopathy, hypoaminoacidemia, and superficial necrolytic dermatitis (I-M16)
• Somatostatinoma reported rarely in dogs and associated with multiple endocrine neoplasia
• VIPomas (Vasoactive Intestinal Peptide-oma) have not been reported in domestic animals
• Differentials for pancreatic masses
• Exocrine pancreatic adenoma/ adenocarcinoma
• Masson’s trichrome will stain zymogen granules bright pink to red
• Nesidioblastosis: Non-neoplastic proliferation of islet cells and ductular tissue; uncommon and results in enlarged appearance to islets; majority of cells are β cells but other cell types may also be present; usually incidental and the cause is unclear
• Islet hyperplasia my also occur as a sequela to other conditions, possibly as a compensatory condition; islets may appear very large and compress adjacent parenchyma; may be associated with fibrosis, particularly in aged rats
• Differentials for hypoglycemia in dogs:
• Non-islet cell tumors causing hypoglycemia due to secretion of insulin-like substances, excessive glucose utilization by neoplastic cells, and/or decreased hepatic function
• Case report: Pulmonary adenocarcinoma with aberrant production of Insulin-like Growth Factor 2 (Noguchi, Vet Pathol. 2020)
• Others reported include leiomyomas, leiomyosarcomas, hepatocellular carcinomas, and renal carcinomas
• Puppies: Starvation, portal hepatic shunt, sepsis
• Young adult dogs: Liver insufficiency, hypoadrenocorticism, sepsis, growth hormone deficiency, hypopituitarism, exertional hypoglycemia (hunting dogs)
• Older dogs: Liver insufficiency, extrapancreatic neoplasia, hypoadrenocorticism, sepsis
• Spurious: error in sample handling; delayed separation of serum (in vitro glycolysis in leukocytes, erythrocytes, platelets, possibly bacteria)
• Glycogen storage diseases (rare)
• Xylitol toxicosis

COMPARATIVE PATHOLOGY:

• Ferrets: Insulinomas are the most common neoplasms; especially males; may have a long disease-free period after surgical removal; less malignant than in dogs
• Horses and cattle: May occur with unilateral pheochromocytoma as part of multiple endocrine neoplasia (MEN) syndrome
• F344/N rat: Spontaneously arising islet cell tumors, 8.55% (males), 2.01% (females)
• Cat: One case report of multiple endocrine neoplasia (MEN) syndrome
• Goat: One case report of cholecystic adenocarcinoma and insulinomas
• Guinea pig: One case report of functional insulinoma
• Komodo dragon: three reports of islet cell carcinoma

REFERENCES:

1. Bakthavatchalu V, Muthupalani S, Marini RP, Fox JG. Endocrinopathy and Aging in Ferrets. Vet Pathol. 2016; 53(2):349-365.
2. Eustace R, Garner MM, Cook K, et al. Multihormonal islet cell carcinomas in three komodo dragons (Varanus komodoensis). J Zoo Wildl Med. 2017; 48(1):241-244.
3. Head KW, et al. Histological classification of tumors of the alimentary system of domestic animals. In: Schulman FY, ed.  World Health Organization, International Histological Classification of Tumors of Domestic Animals.  Vol 10. 2^nd  Washington, DC:  American Registry of Pathology; 2003:114-115.
4. Jubb KVF, Stent AW. Pancreas. In: Maxie MG. ed.  Jubb, Kennedy and Palmer’s Pathology of Domestic Animals.  Vol 2. 6^th St. Louis, MO: Elsevier; 2016:372-376.
5. Miller MA. Endocrine system. In: Zachary JF Pathologic Basis of Veterinary Disease. 6^th ed. St. Louis, MO: Elsevier; 2017:690,694,711-713.
6. Noguchi S, Kubo Y, Araki M, et. al. Big Insulin-like Growth Factor 2-Producing Tumor in a Hypoglycemic Dog. Vet Pathol. 2020;57(3):432-436.
7. Stockham SL, Scott MA. Fundamentals of Veterinary Clinical Pathology. 2nd ed., Ames, IA: Blackwell Publishing Professional;2008:719-722.
8. Struthers JD, Robl N, Wong VM, Kuipel M. Gastrinoma and Zollinger-Ellison syndrome in canids: a literature review and a case in a Mexican gray wolf. J Vet Diagn Invest. 2018; 30(4):584-588.

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