JPC SYSTEMIC PATHOLOGY

ENDOCRINE SYSTEM

January 2025

E-N10

 

Signalment (JPC #1754878): Military Working Dog

 

HISTORY: None

 

SLIDE A: HISTOPATHOLOGIC DESCRIPTION: Pancreas: Effacing 50% of the section, 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 lobules are separated and surrounded by moderate, discontinuous bands of fibrous connective tissue. 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 squared. There are multifocal areas of scant hemorrhage and few hemosiderin laden macrophages. Multifocally, neoplastic cells surround and separate preexisting exocrine pancreatic acini and compress adjacent exocrine pancreatic lobules that are occasionally shrunken and 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 
• Microscopic metastasis is commonly present at the time of surgical diagnosis; common sites are 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 > 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; monomorphic neuroendocrine appearance and requires histology for definitive diagnosis 
• 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
• Insulinoma-associated protein I (INSM1) is a neuroendocrine marker that reliably labels neuroendocrine tumors except parathyroid neoplasms; should be used as part of an immunohistochemical panel (Yang, Vet Pathol, 2024)

 

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
• Dogs and humans: Canine pancreatic neuroendocrine tumors (PanNETs) share well-differentiated histomorphology, SSTR2A expression, and absence of nuclear p53 immunolabeling with human PanNETs (de Vries, J Comp Pathol, 2020)
• 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
• Sheep: Case report of a sheep diagnosed with an insulinoma, adrenocortical carcinoma, and a thyroid C-cell carcinoma; report indicates that multiple endocrine neoplasms can occur in sheep as in other animals (Tanaka, J Vet Diagn Invest, 2023)
• Guinea pig: One case report of functional insulinoma
• Komodo dragon: three reports of islet cell carcinoma
• Rhesus macaque, pig tailed macaque, baboons, chimpanzees, and mantled howler monkey: Islet cell adenomas and carcinomas; carcinomas are rare in rhesus macaques
• Rhesus macaque: Majority of pancreatic neuroendocrine tumors are non-functional; recent report of a functional insulinoma in a rhesus macaque that was immunoreactive for chromogranin A, synaptophysin, insulin, gastrin, and/or pancreatic polypeptide > consistent with a functional insulinoma (Saied, J Comp Pathol, 2022)
• Other animals with reports of islet cell tumors: Coquerel’s giant mouse lemur, Atlantic hagfish, fat-tailed dwarf lemur, Coquerel’s sifaka, dwarf galago, greater bushbaby 

 

REFERENCES: 

1. Allen J. Chapter 8: Pancreas (Exocrine and Endocrine). In: Raskin RE, Meyer DJ, & Boes KM eds. Canine and Feline Cytopathology: A Color Atlas and Interpretation Guide. 4th ed. St. Louis, MO: Elsevier; 2022:332-338.
2. Bell RRW, Latouche JS, Borjesson DL. The Pancreas. In: Valenciano AC, Cowell RL, eds. Diagnostic Cytology and Hematology of the Dog and Cat. 5th ed. St. Louis, MO: Elsevier Mosby; 2014:322-324.
3. de Vries C, Konukiewitz B, Weichert W, Klöppel G, Aupperle-Lellbach H, Steiger K. Do Canine Pancreatic Neuroendocrine Neoplasms Resemble Human Pancreatic Neuroendocrine Tumours? A Comparative Morphological and Immunohistochemical Investigation. J Comp Pathol. 2020;181:73-85.
4. Jubb KVF, Stent AW. Pancreas. In: Maxie MG. ed. Jubb, Kennedy and Palmer’s Pathology of Domestic Animals. Vol 2. 6^th ed. St. Louis, MO: Elsevier; 2016:372-376. 
5. McAloose D, Stalis IH. Prosimians. In: Terio KA, McAloose D, St. Leger J, eds. Pathology of Wildlife and Zoo Animals. London, UK: Academic Press; 2018:339.
6. Miller AD. Neoplasia and Proliferative Disorders of Nonhuman Primates. In: Abee CR, Mansfield K, Tardif S, Morris T eds. Nonhuman Primates in Biomedical Research: Volume 2: Diseases. 2nd ed. San Diego, CA: Elsevier; 2012.
7. Miller MA. Endocrine system. In: Zachary JF ed. Pathologic Basis of Veterinary Disease. 6^th ed. St. Louis, MO: Elsevier; 2017:690,694,711-713.
8. 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.
9. Peters LM, Meyer DJ. Chapter 9: Hepatobiliary System. In: Raskin RE, Meyer DJ, & Boes KM eds. Canine and Feline Cytopathology: A Color Atlas and Interpretation Guide. 4th ed. St. Louis, MO: Elsevier; 2022:367-376.
10. Saied AA, Shroyer MN, Taylor JM, Midkiff CC. Functional Insulinomas in a Rhesus Macaque (Macaca mulatta). J Comp Pathol. 2022;198:1-5.
11. Stockham SL, Scott MA. Fundamentals of Veterinary Clinical Pathology. 2nd ed., Ames, IA: Blackwell Publishing Professional;2008:719-722.
12. Tanaka Y, Watanabe K, Morita Y, Kobayashi Y. Multiple endocrine neoplasia in a sheep: insulinoma, adrenocortical carcinoma with myxoid differentiation, and thyroid C-cell carcinoma. J Vet Diagn Invest. 2023;35(4):433-437.
13. Williams BH, Burek-Huntington KA, Miller M. Mustelids. In: Terio KA, McAloose D, St. Leger J, eds. Pathology of Wildlife and Zoo Animals. London, UK: Academic Press; 2018:294.
14. Yang FH, Chang YP, Chang YC, Chang HW, Jeng CR, Jiang JW, Tsao WT, Luo IC, Huang WH. Insulinoma-associated protein 1 (INSM1) immunohistochemical expression in normal, hyperplastic, and neoplastic canine neuroendocrine tissues. Vet Pathol. 2024.

 

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