JPC SYSTEMIC PATHOLOGY
ENDOCRINE SYSTEM
February 2022
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; reported in the gallbladder of 3 dogs
• 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
• Generally considered malignant, slow growing neoplasms that 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
• 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: cytokeratin 13, synaptophysin, chromogranin A, protein gene product 9.5, neuron-specific enolase, , calcitonin gene-related polypeptide, serotonin, and Leu-7; +/- pancytokeratin
  • Negative: S-100, GFAP, vasoactive intestinal peptide, galanin, methionine-enkephalin, vimentin, alpha-smooth muscle actin, somatostatin, glucagon, and gastrin
• 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
• Cattle: One recent report in an adult Holstein cow (rectal carcinoid)
• Sprague-Dawley rat, cynomolgus monkey: One report each
• Humans: “Carcinoid syndrome” is due to release of vasoactive amines resulting in flushing, diarrhea, bronchospasm, valvular heart lesions, and edema

REFERENCES:

1. Albers TM, Alroy J, McDonnell JJ, Moore AS. A poorly differentiated gastric carcinoid in a dog. J Vet Diagn Invest. 1998;10:116-118.
2. Brown DL, Van Wettere AJ, Cullen JM. Hepatobiliary system and exocrine pancreas. In: McGavin MD, Zachary JF, eds. Pathologic Basis of Veterinary Disease. 6th ed. St. Louis, MO: Elsevier; 2017: 445.
3. 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.
4. 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.
5. Lippo NJ, Williams JE, Brawer RS, Sobel KE. Acute hemobilia and hemocholecyst in 2 dogs with gallbladder carcinoid. J Vet Intern Med. 2008;22:1249-1252.
6. Majka JA, Sher S. Spontaneous gastric carcinoid tumor in an aged Sprague-Dawley rat. Vet Pathol. 1989;26:88-90.
7. Meuten DJ, ed. Tumors in Domestic Animals, 5th ed. Ames, IA: John Wiley & Sons, Inc.; 2017:473, 489, 508, 559, 568-569, 624-626.
8. Michishita M, Takahashi K, Moriya H, Nakamura S, Koyama H, Sako T. Poorly differentiated rectal carcinoid in a cow. Vet Pathol. 2007;44:414-417.
9. Morrell CN, Volk MV, Mankowski JL. A carcinoid tumor in the gallbladder of a dog. Vet Pathol. 2002;39:756-758.
10. Ritter JM, Garner MM, Chilton JA. Gastric Neuroendocrine Carcinomas in Bearded Dragons (Pogona vitticeps). Vet Pathol. 2009;46(6): 1109-16.
11. Sako T, et al. Immunohistochemical evaluation of a malignant intestinal carcinoid in a dog. Vet Pathol. 2003;40:212-215.
12. Sykes GP, Cooper BJ. Canine intestinal carcinoids. Vet Pathol. 1982;19:120-131.
13. van Maanen C, Klein WR, Dik KJ, van den Ingh TSGAM. Three cases of carcinoid in the equine nasal cavity and maxillary sinuses: Histologic and immunohistochemical features. Vet Pathol. 1996;33:92-95.

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