JPC SYSTEMIC PATHOLOGY

DIGESTIVE SYSTEM

October 2024

D-N07

 

Signalment (JPC #2368962): 11-year-old bichon frise

 

HISTORY: This dog presented with a sudden onset of profuse, hemorrhagic diarrhea. A cecal mass was removed during surgery.

 

HISTOPATHOLOGIC DESCRIPTION: Cecum (per contributor): Originating in the tunica muscularis, expanding the muscular layers, and compressing the cecal lumen of the cecum, is an unencapsulated, well demarcated, multilobular, 13mm diameter, densely cellular neoplasm composed of polygonal cells arranged in small, closely packed nests and packets separated by fine, fibrovascular stroma. Neoplastic cells have distinct borders and abundant lightly eosinophilic to clear and occasionally granular cytoplasm. Nuclei are round with finely stippled chromatin and 1-2 indistinct nucleoli. Mitotic figures average 2 per 2.37mm². Multifocally, neoplastic cells are widely separated by variably sized aggregates of clear, acicular clefts (cholesterol) that are surrounded by low numbers of macrophages, multinucleated giant cells, lymphocytes, and plasma cells, and are further separated by clear space and ectatic lymphatics (edema), fibrin, minimal hemorrhage, and occasional hemosiderin-laden macrophages. Neoplastic lobules are separated by multifocal to focally extensive areas of edema, fibrosis, and hemorrhage, as well as numerous large, dilated (congested) vessels.

 

MORPHOLOGIC DIAGNOSIS: Cecum: Gastrointestinal neuroendocrine carcinoma (carcinoid), bichon frise, canine.

 

GENERAL DISCUSSION: 

• Enteroendocrine cells: Heterogenous population of amine- or peptide-secreting endocrine/paracrine cells; make up 1% of the gastrointestinal epithelial population 
  1. Classified based on contents of secretory vesicles: Serotonin, somatostatin, cholecystokinin, peptide YY, glucagon-like peptides, and secretin
  2. Physiologic actions include regulation of intestinal motility and peristalsis, secretions, visceral sensations, and appetite 
• Arise from neuroendocrine cells in a variety of organs, including the stomach, intestines, liver, and gallbladder
  1. In the liver arise from the neuroendocrine cells that lie within the intra- and extrahepatic biliary epithelium and hepatic parenchyma 
• Rare tumor of domestic animals; mainly in old dogs; rare in cats, cows, and horses
• Can be behaviorally benign (carcinoids) or can be malignant, slow growing neoplasms that metastasize through hematogenous and lymphatic routes (neuroendocrine carcinoma, carcinomatosis) 

 

PATHOGENESIS: 

• Hypersecretion of functional polypeptide hormones > diarrhea 
• Limited data on biologic behavior; extensive invasion of the gut wall and veins > metastasis to the liver 
• Liver: Most likely originate from among biliary epithelium or hepatic parenchyma
• Lung: Most likely arises from the neuroendocrine cells in the airway epithelium 
• Norwegian lundehund dogs with chronic atrophic gastritis: mild chronic inflammation with fundic gland atrophy may be associated with subsequent development of gastric neuroendocrine carcinoma (carcinoid)

 

TYPICAL CLINICAL FINDINGS:

• Intestinal obstruction 
• Ulceration and hemorrhage > anemia 
• Intermittent diarrhea 
• Intestinal bleeding
• Has been associated with hyperglycemia
• Abdominal pain
• Emaciation
• Carcinoids secreting gastrin are responsible for Zollinger-Ellison syndrome, 

characterized by severe gastric hypersecretion and ulceration

 

TYPICAL GROSS FINDINGS:

• Usually lobulated, firm, dark-red to cream colored masses a few millimeters to 2 cm in diameter
  1. May protrude from the anus
• Liver: Disseminated masses within multiple liver lobes; portal veins draining the affected region may be distended and contain thrombi
• Serosa: Adhesions; neoplasms may extend through the serosa 
• Lung: Multiple, large, firm pulmonary masses close to the mainstem bronchi
• Nasal cavity of horses
• Dogs: Duodenum, colon, and rectum, rarely in stomach and lower small intestine 
• Metastatic sites:
  1. Canine: Lung, pleura, liver, pancreas, and local lymph nodes
  2. Cats: Mesentery, omentum, lymph nodes, bile duct, gallbladder, skin, colon, trachea, esophagus, liver, and pancreas
  3. Carcinomatosis – Metastasis to the abdomen any location

 

TYPICAL LIGHT MICROSCOPIC FINDINGS:

• Arise deep in the mucosa, often forming submucosal or subserosal nodules with ulceration of overlying mucosa, and infiltrating transmurally and into the mesentery
• Distinct endocrine appearance 
  1. Round or oval to polyhedral cells with abundant finely eosinophilic granular or vacuolated cytoplasm containing argyrophilic granules; fine fibrous stroma divides the tumor masses into pseudoalveolar arrays
  2. Vesiculate nuclei which are often antibasilar with prominent nucleoli; uninuclear megalocytes and multinucleated giant cells are occasionally present
• 3 distinct histologic patterns:
  1. Solid groups or nests of cells forming pseudolobular pattern with palisading of peripheral cells along the fine fibrovascular stroma
  2. Groups of rosettes or acinar-like structures 
  3. Anastomosing rows of cells forming ribbons 
• Occasional amyloid in intercellular and perivascular spaces

 

ULTRASTRUCTURAL FINDINGS:

• Dense core neurosecretory granules: Numerous cytoplasmic, round-to-oval, membrane-bound, 75 to 300 nm diameter granules that are surrounded by a clear halo; uniform density 
• Abundant rough endoplasmic reticulum and plasma membrane forms interdigitating processes

 

ADDITIONAL DIAGNOSTIC TESTS:

• Definitive diagnosis is based on the endocrine histologic pattern, cytoplasmic argentaffinic and argyrophilic granularity, immunohistochemical identification of specific secretory products, and the typical ultrastructural appearance

• Positive immunohistochemically for synaptophysin, neuron specific enolase (NSE), and chromogranin A (CgA), immune probes related to the peptides being produced
  1. Rectal tumors or those that undergo prolonged formalin fixation may lose their histochemical and immunohistochemical immunoreactivity

• Churukian-Schenk and Grimelius silver techniques demonstrate argyrophilic    cytoplasmic granules
• The Sevier-Munger silver technique may demonstrate both argentaffinic and argyrophilic granules
• Increase concentration of specific secretory products may be detected in circulation 
• Cytology: High yield with many lysed cells (bare nuclei) or partially disrupted, in sheets with indistinct cell borders and overlapping nuclei; nuclei are relatively uniform with mild anisokaryosis despite high-grade behavior
  1. Differentiation of a carcinoid from metastatic neuroendocrine tumors to the liver is not possible with cytology

 

DIFFERENTIAL DIAGNOSIS: 

For histologic findings:

• Adenoma/Carcinoma: May contain argyrophilic cells (exclude with neurendocrine markers, i.e. NSE, chromogranin, synaptophysin) 
• Lymphoma: Round cells positive for lymphocyte markers i.e. CD3, CD79a  
• Plasma cell tumor: Round cells with plasmacytoid appearance i.e. eccentric nuclei with perinuclear hoff, variation in chromatin pattern (i.e. “clockface” or “cartwheel” chromatin pattern), exclude with silver stains i.e. Churukian-Schenk
• Gastrointestinal mast cell tumor: Round cells, granules stain with Toluidine Blue; C-kit immunoreactive
• Leiomyoma/leiomyosarcoma: Spindle-shaped cells; positive for desmin, muscle specific actin and smooth muscle actin 

 

COMPARATIVE PATHOLOGY:

• In captivity, the multimammate rat (Praomys (Mastomys) natalensis) has a high prevalence of carcinoids of the gastric epithelium
• There is one report of a spontaneous gastric carcinoid in a Sprague-Dawley rat
• Other reports in laboratory animals have been only after long-term treatment with various chemical agents
• Carcinoid tumors have also been reported in a mare with chronic colic, the colon and rectum of a cow, the foregut in a domestic cat, three cases in the maxillary sinuses of horses, in a cynomolgus monkey, and in an elephant
• Neuroendocrine tumors are reported in the stomach of bearded dragons
• Goblet cell carcinoids in humans have features of both carcinoids and adenocarcinomas; single report in a dog 

 

REFERENCES:

1. 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. 
2. 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; 2016:349.
3. 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.
4.  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.
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. Origgi FC. Lacertilia. In: Terio K, McAloose D, Leger J, eds. Pathology of Wildlife and Zoo Animals, San Diego, CA: Elsevier 2018:889.
7. 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.
8. 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. 
9. 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.
10. 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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