JPC SYSTEMIC PATHOLOGY
DIGESTIVE SYSTEM
September 2021
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 10 HPF (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:
- Arise from neuroendocrine cells in a variety of organs, including the stomach, intestines, liver, and gallbladder
- Rare tumor of domestic animals
- Reported 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)
TYPICAL CLINICAL FINDINGS:
- Intermittent diarrhea
- Intestinal bleeding
- Has been associated with hyperglycemia
- Abdominal pain
- Emaciation
- Anemia and thrombocytopenia
- Partial or complete obstruction of the gastrointestinal tract may occur
- 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
- Pale gray to tan masses in liver
- Arise deep in the mucosa, often forming submucosal or subserosal nodules, with ulceration of the overlying mucosa, and infiltrating transmurally and into the mesentery
- May extend through the serosal surface and form adhesions
- In dogs, the duodenum, colon, and rectum are the most frequent sites
- Metastatic sites:
- Canine: Lung, pleura, liver, pancreas, and local lymph nodes
- Cats: Mesentery, omentum, lymph nodes, bile duct, gallbladder, skin, colon, trachea, esophagus, liver, and pancreas
- Carcinomatosis – metastasis to the abdomen any location
- Portal veins draining the affected region may be distended and contain thrombi
- In liver most likely originate from among biliary epithelium or hepatic parenchyma
TYPICAL LIGHT MICROSCOPIC FINDINGS:
- Have a distinct endocrine appearance
- 3 distinct histologic patterns:
- Solid groups or nests of cells forming pseudolobular pattern with palisading of peripheral cells along the fine fibrovascular stroma
- Groups of rosettes or acinar-like structures
- Anastomosing rows of cells forming ribbons
- All three patterns separated by fine fibrovascular stroma
- Round or oval to polyhedral cells with abundant finely eosinophilic granular or vacuolated cytoplasm containing argyrophilic granules
- Vesiculate nuclei which are often antibasilar with prominent nucleoli
- Occasional amyloid in intercellular and perivascular spaces
- Uninuclear megalocytes and multinucleated giant cells are occasionally present
- Can look histologically similar to gastrointestinal mast cell tumors
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
- Cytoplasm contains abundant rough endoplasmic reticulum
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)
- Churukian-Schenk and Grimelius silver techniques demonstrate argyrophilic
cytoplasmic granules
- The Sevier-Munger silver technique may demonstrate both argentaffinic and
argyrophilic granules
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
- 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
- There is one report of a primary carcinoid arising from the mammary gland of a dog (Nakahira, J Comp Pathol. 2015),
- There is one report of a malignant carcinoid in the spleen of an African Pygmy Hedgehog (Atelerix albiventris) (Lowden, J Comp Pathol. 2016)
- 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; there is one report in a dog
References:
- 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.
- Head KW, Cullen JM, Dubielzig RR, Else RW, Misdorp W, Patnaik AK, Tateyama S, van der Gaag I. Tumors of the Alimentary System of Domestic Animals, 2nd series.Washington D.C.: Armed Forces Institute of Pathology; 2003:33, 79, 94-96,127-128.
- Lowden LR, Davies JL. Malignant Neuroendocrine Tumor (Carcinoid) of the Spleen in an African Pygmy Hedgehog (Atelerix albiventris). J Comp. Path. 2016:155:88-91.
- Michishita M, Takagi M, Kishimoto TE, et al. Pancreatic neuroendocrine carcinoma with exocrine differentiation in a young cat. J Vet Diagn Invest. 2017:29(3):325-330.
- 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.
- Munday JS, Lohr CV, Kiupel M. Tumors of the Alimentary Tract. In: Meuten J, ed. Tumors in Domestic Animals. 5th ed. Ames, Iowa: John Wiley & Soncs, Inc; 2017:559,568.
- Nakahira R, Michishita M, Yoshimura H, Hatakeyama H, Takahashi K. Neuroendocrine carcinoma of the mammary gland in a dog. J Comp. Path. 2015:152:188-191.
- Origgi FC. In: Terio K, McAloose D, Leger J, eds. Pathology of Wildlife and Zoo Animals, San Diego, CA: Elsevier 2018:889.e7.
- 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; 2016:105-106.