JPC SYSTEMIC PATHOLOGY

ENDOCRINE SYSTEM

January 2025

E-N12 (NP)

 

SIGNALMENT (JPC #2017861): 8-year-old male Irish setter

 

HISTORY: This dog had a well-vascularized, deeply orange-brown mass at the ileocecal junction.

 

HISTOPATHOLOGIC DESCRIPTION: Ileocecal junction: Multifocally infiltrating the submucosa and muscular tunics and extending to cut margins is a multilobulated, unencapsulated, poorly circumscribed, well-demarcated, 1.5 x 2.5 cm neoplasm composed of polygonal cells arranged in cords, nests, packets, and solidly cellular areas on a fine fibrovascular stroma, while neoplastic lobules are separated by dense collagenous septa and/or preexisting tissue. Neoplastic cells have indistinct cell borders, a moderate amount of eosinophilic, finely granular cytoplasm, and a round to oval nucleus that is vesiculate or contains coarsely clumped chromatin and one variably distinct nucleolus. Anisocytosis and anisokaryosis are mild, and mitoses average 1 per 2.37 sq. mm. There is occasional single cell necrosis. Multifocally, neoplastic cells infiltrate the muscular tunics and fill vessel lumina (vascular invasion). Multifocally, fibrovascular septa are expanded by increased clear space (edema). Within the submucosa are low numbers of lymphocytes and hemosiderin-laden macrophages, and lymphatics are multifocally ectatic. There are multifocal areas with hemorrhage, fibrin, edema, and clear acicular clefts (cholesterol clefts).

 

MORPHOLOGIC DIAGNOSIS: Ileocecal junction: Neuroendocrine carcinoma, Irish setter, canine.

 

SYNONYM: Carcinoid, neuroendocrine tumor 

 

GENERAL DISCUSSION:

• Neuroendocrine tumors are also known as carcinoids because they histologically closely resemble carcinomas of intestinal epithelial origin but have a different histogenesis; the term “neuroendocrine tumor” or “neuroendocrine carcinoma” is preferred by some pathologists
• Neuroendocrine tumors are uncommon neoplasms that arise from endocrine or paraendocrine cells in a variety of organs (e.g. gastrointestinal tract, urogenital tract, nasal cavity, tracheobronchial tree, liver and pancreas)
  • Dogs: Primarily reported in duodenum, colon, and rectum, but also occasionally in the stomach and liver
• Gastrointestinal neuroendocrine tumors are rare in domestic animals; most are reported in aged dogs; they are rare in cats, cows, and horses, and very rare in other species
• Hepatic neuroendocrine tumors occur in the extrahepatic and intrahepatic biliary system
• Can be benign or malignant; slow growing neoplasms that can metastasize similar to adenocarcinomas, via lymphatics and hematogenous routes; metastasis occurs to liver, spleen, kidney, lungs, regional lymph nodes, and brain

 

PATHOGENESIS:

• May secrete vasoactive amines including serotonin, kallikrein, insulin, gastrin, substance P, bombesin, and calcitonin; these excessive amines usually cause no functional derangements in domestic animals
• Hypersecretion of functional polypeptide hormones can cause diarrhea 
• Neuroendocrine tumors that secrete gastrin (G cell tumors) are responsible for Zollinger-Ellison syndrome (gastric hypersecretion, ulcers, and diarrhea) and have been reported in cats and dogs; these are usually non-beta cell tumors of pancreatic origin rather than gastrointestinal tumors

 

TYPICAL CLINICAL FINDINGS:

• Intestinal obstruction, hemorrhagic diarrhea, abdominal pain, emaciation, anemia, thrombocytopenia
• Zollinger-Ellison syndrome (gastric hypersecretion, ulcers and diarrhea) from a non-beta cell tumor of pancreatic origin
• Horses: Nonspecific, chronic colic; if the nasal and maxillary sinus or retrobulbar space is involved, can see epistaxis and exophthalmos
• Cattle: Bloating, diarrhea, and weight loss

 

TYPICAL GROSS FINDINGS:

• Tan-yellow tumors that range from annular stenosing thickenings to nodular masses in the intestinal wall
• Rectal neuroendocrine tumors may protrude from the anus
• Large tumors can cause submucosal or subserosal nodule formation and ulceration of the overlying mucosa
• There may be extensive invasion of the gut wall and vasculature

 

TYPICAL LIGHT MICROSCOPIC FINDINGS:

• Typical neuroendocrine appearance: Polygonal cells arranged in nests, packets, cords, ribbons, rosettes, or diffuse sheets; small, uniform, round to oval cells separated by thin fibrous trabeculae or vascular channels
• May form a pseudoalveolar arrangement or palisade along stroma
• Variable distribution of mitotic figures, necrosis, or mineralization
• Occasional multinucleate giant cells
• +/- Amyloid in intercellular and perivascular spaces (especially canine rectal neuroendocrine tumors ); amyloid is derived from polypeptides of prohormones secreted by the neoplastic cells
• May have extensive invasion of gut wall and veins with metastasis

 

ULTRASTRUCTURE:

• Numerous membrane-bound neurosecretory granules
• Plasma membrane with interdigitating processes
• Cells contain abundant rough endoplasmic reticulum

 

ADDITIONAL DIAGNOSTIC TESTS:

• Histochemical stains: Tumor cells have an affinity for silver stains; many neuroendocrine tumors are positive with both argentaffin and argyrophilic procedures
  • Argentaffinic stain: Modified Fontana-Masson
  • Argyrophilic stains: Churukian-Shenk, Grimelius
• Immunohistochemistry:
  • Positive: Pancytokeratin, synaptophysin, chromogranin A+B, protein gene product 9.5, neuron-specific enolase
• Serum serotonin levels may be elevated

 

DIFFERENTIAL DIAGNOSIS:

For histologic findings: 

• Lymphoma: CD3 or CD20 and CD79a positive
• Carcinoma: Cytokeratin positive
• Intestinal mast cell tumor (D-N04): Mainly aged cats, rare in dogs; eosinophils, metachromatic granules evident with Giemsa and/or toludine blue stains
• Plasma cell tumor (D-N10): MUM1, +/- CD 79a, light chain positive
• Pheochromocytoma (E-N06): Ultrastructurally, norepinephrine (eccentrically placed electron dense core surrounded by a wide submembranous space) or epinephrine (coarsely granular internal core and a narrow submembranous space) granules; catecholamine IHC positive
• Adenomatous polyp (for rectal carcinoid)

 

COMPARATIVE PATHOLOGY:

• African rodent (Praomys (Mastomys) natalensis): Extremely high incidence of spontaneous gastric carcinoids (up to 50% of aged animals); animal model
• Horses: Several reports of nasal and maxillary sinus and retrobulbar carcinoids; locally malignant and expansile, with destruction of bony structures causing exophthalmos or epistaxis
• Cats: Rare
• Bearded dragon: Report of 5 “young” bearded dragons with gastric neuroendocrine carcinomas that secreted somatostatin and readily metastasized to many different organs 
• Humans: “Carcinoid syndrome” is due to release of vasoactive amines resulting in flushing, diarrhea, bronchospasm, valvular heart lesions, and edema

 

REFERENCES:

1. Caswell JL, Williams KJ. Respiratory system. In: Maxie MG, ed. Jubb, Kennedy, and Palmer’s Pathology of Domestic Animals. Vol 2. 6th ed. St. Louis, MO: Elsevier Limited; 2016: 497-498.
2. Choi U, Arndt T. Endocrine and Neuroendocrine Systems. In: Raskin RE, Meyer DJ, Boes KM, eds. Canine and Feline Cytology: A Color Atlas and Interpretation Guide. 4th ed. St. Louis, MO: Elsevier; 2023:614-617. 
3. Cullen JM, Stalker MJ. Liver and biliary system. In: Maxie MG, ed. Jubb, Kennedy, and Palmer’s Pathology of Domestic Animals. Vol 2. 6th ed. St. Louis, MO: Elsevier Limited; 2016: 349.
4. Haddad JL, Marks Stowe DA, Neel JA. The Gastrointestinal Tract. In: Valenciano AC, Cowell RL, eds. Diagnostic Cytology and Hematology of the Dog and Cat. 5th ed. St. Louis, MO: Elsevier Mosby; 2020:301.
5. Lopez A, Martinson SA. Respiratory System, Thoracic Cavities, Mediastinum, and Pleurae. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 7th ed. St. Louis, MO: Elsevier; 2022:594.
6. Lowenstine LJ, Osborn KG. Respiratory System Diseases 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; 2012:442.
7. Meuten DJ, ed. Tumors in Domestic Animals, 5th ed. Ames, IA: John Wiley & Sons, Inc.; 2017:491, 568-569.
8. Origgi FC. Lacertilia. In: Terio K, McAloose D, Leger J, eds. Pathology of Wildlife and Zoo Animals, San Diego, CA: Elsevier 2018:889.
9. Peters LM, Meyer DJ. Hepatobiliary System. In: Raskin RE, Meyer DJ, Boes KM, eds. Canine and Feline Cytology: A Color Atlas and Interpretation Guide. 4th ed. St. Louis, MO: Elsevier; 2023:367-369.
10. Ritter JM, Garner MM, Chilton JA. Gastric Neuroendocrine Carcinomas in Bearded Dragons (Pogona vitticeps). Vet Pathol. 2009;46(6): 1109-16.
11. Siegel A, Wiseman MD. The Liver. In: Valenciano AC, Cowell RL, eds. Diagnostic Cytology and Hematology of the Dog and Cat. 5th ed. St. Louis, MO: Elsevier Mosby; 2020:340-341. 
12. Uzal FA, Plattner BL, Hostetter JM. Alimentary system. In: Maxie MG, ed. Jubb, Kennedy and Palmer’s Pathology of Domestic Animals. Vol 2. 6th ed. St. Louis, MO: Elsevier; 2016:60, 105-106.
13. Van Wettere AJ, Brown DL. Hepatobiliary System and Exocrine. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 7th ed. St. Louis, MO: Elsevier; 2022:527. 

 

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