JPC SYSTEMIC PATHOLOGY
DIGESTIVE SYSTEM
September 2021
D-N05

SLIDE A: Signalment (JPC #2423644):  30-year-old male rhesus macaque

 

HISTORY:  Exposed to whole body penetrating proton radiation 28 years previously. Severe progressive weight loss was noted (3.4 kg over 6 months) before death.

 

HISTOPATHOLOGIC DESCRIPTION:  Duodenum: Transmurally infiltrating and effacing the mucosa, lamina propria, submucosa, tunica muscularis, and serosa, projecting into the duodenal lumen, and compressing the adjacent exocrine pancreas, is an unencapsulated, infiltrative, poorly demarcated, moderately cellular neoplasm composed of cuboidal to columnar epithelial cells arranged in tubules and acini supported by a moderately dense desmoplastic stroma.  Neoplastic cells have indistinct borders, moderate amounts of granular eosinophilic cytoplasm, and irregularly round to oval nuclei with finely stippled chromatin and 1 to 2 distinct nucleoli.  Neoplastic cells often lack polarity, and pile up to 4 cell layers thick.  The mitotic rate is regionally variable, between 2 to 6 per individual HPF (0.237mm²).  Tubules are often filled with sloughed neoplastic cells, necrotic debris, and occasionally degenerate and viable neutrophils. Multifocally throughout the fibrous stroma, the lamina propria, and the pancreas, there are aggregates of lymphocytes and plasma cells and fewer macrophages, as well as ectatic lymphatics (edema).  Within a focally extensive area of the exocrine pancreas, there is loss of acinar cells (exocrine pancreatic atrophy), a marked decrease in the zymogen granules of remaining acinar cells (degeneration), and increased numbers of small pancreatic ducts (tubular complexes). Multifocally, pancreatic ducts are ectatic.

 

MORPHOLOGIC DIAGNOSIS:  

1. Duodenum:  Adenocarcinoma, tubular, Rhesus macaque (Macaca mulatta), nonhuman primate.

2. Pancreas: Atrophy, acinar, focally extensive, moderate, with tubular complexes (regeneration)

 

SLIDE B: Signalment (JPC #2892538):  Seven-year-old cotton top tamarin (Saguinus oedipus)

 

HISTORY:  For a couple of weeks, this monkey had hemorrhagic diarrhea and weight loss. Antibiotic therapy did not improve the condition and the animal was humanely euthanized due to poor prognosis.

 

HISTOPATHOLOGIC DESCRIPTION:  Colon: Diffusely and transmurally infiltrating and variably expanding and replacing all colonic layers and focally extending into the mesentery is a moderately cellular, poorly demarcated, unencapsulated neoplasm composed of polygonal cells arranged in disorganized islands and occasional tubules supported by abundant mucinous matrix and pre-existing fibrovascular stroma. Neoplastic cells have either abundant eosinophilic cytoplasm or contain pale gray-blue granular material (mucin) which peripheralizes the nucleus. Nuclei are oval with finely stippled chromatin and one prominent nucleolus. Mitoses average 2 per 10 high power fields (2.37mm²). Anisocytosis and anisokaryosis are moderate. Neoplastic cells are often surrounded by large lakes of mucin up to 1mm in diameter. Within the mucosa, the neoplasm is infiltrated by low to moderate numbers of neutrophils, and within the submucosa and tunica muscularis the neoplasm is infiltrated by clusters of lymphocytes and plasma cells. Multifocally, there are clusters of macrophages that contain intracytoplasmic brown pigment (secretory product or hemosiderin). The serosa is expanded by neoplastic cells, fibrous connective tissue, dilated lymphatics, and lymphocytes and plasma cells. Within the areas of less affected mucosa, the lamina propria is expanded by moderate numbers of lymphocytes, plasma cells, and rare neutrophils that separate colonic glands.

 

MORPHOLOGIC DIAGNOSIS:  Colon: Adenocarcinoma, mucinous, cotton-top tamarin (Saguinus oedipus), nonhuman primate.

 

CONDITION:  Intestinal/colonic adenocarcinoma

 

GENERAL DISCUSSION:

• The presence and distribution of gastrointestinal adenocarcinomas varies among species; microscopic appearance is similar regardless of species or location
• Full thickness biopsy is best for diagnosis to assess degree of infiltration; the submucosal and transmural portions of the tumor are routinely larger and more readily identified, and the mucosal surface may simply contain necrosis, inflammation, and/or fibrosis
• Neoplasia of the digestive system is very common in many species of nonhuman primates (NHP):
  • Colonic adenocarcinoma: The most common spontaneous gastrointestinal neoplasms in NHPs are ileocecal/colonic adenocarcinomas in rhesus macaques and colonic adenocarcinomas in cotton-top tamarins; cecal adenocarcinomas are reported with increased frequency in aged baboons
  • Small intestinal adenocarcinoma: reported to be common in one colony of common marmosets with site predilection for the proximal jejunum with frequent metastasis to the mesenteric lymph node; rarely reported in rhesus macaques and several species of prosimians
  • Gastric carcinomas are uncommon, but spontaneously occur in rhesus macaques and NHPs dosed with a specific carcinogen
• Intestinal adenocarcinoma is uncommon in most animal species, except for cotton-top tamarins, rhesus macaques, and sheep from New Zealand, Australia, and Europe

 

PATHOGENESIS:

• Cotton-top tamarins: commonly develop ulcerative colitis, 25-40% of those progress to develop colonic adenocarcinoma
• Colonic adenocarcinoma is typically multifocal, not preceded by polypoid adenomas, and lacks pre-invasive dysplastic lesions
• The endangered status of this species limits use as a model of human disease
• In rhesus macaques, progression from polyps and/or adenomas to carcinomas has not been recognized, and there is no association with colitis
• Gastrointestinal adenocarcinomas metastasize early and widely (surgical excision is rarely curative), mainly to the draining lymph nodes (e.g. mesenteric, colonic, iliac, and other pelvic lymph nodes and less commonly to liver, spleen, and lungs); tumor explantation along serosal surfaces (carcinomatosis) may result in obstruction of omental and diaphragmatic lymphatics leading to ascites

           

TYPICAL CLINICAL FINDINGS:  

• Clinical signs are associated with intestinal strictures and/or with mucosal ulceration: weight loss, vomiting, anorexia, abdominal distension, diarrhea, tenesmus, hematochezia, hypoproteinemia, fecal occult blood positive

 

TYPICAL GROSS FINDINGS:

• Nodular or annular, sclerosing, firm, gray-white, often transmural neoplasm that often does not ulcerate or project into the lumen
• Intestinal dilation or muscular hypertrophy proximal to stenosis or tumor obstruction
• Gastrointestinal adenocarcinomas have the capability to produce carcinomatosis

 

TYPICAL LIGHT MICROSCOPIC FINDINGS:

• Often transmural local effacement or obstruction by proliferating polygonal mucus-producing epithelial cells that infiltrate the lamina propria then invade sequentially through the submucosa, tunica muscularis, and into lymphatics and sometimes veins, and may penetrate the serosa and exfoliate into the peritoneal cavity to establish neoplastic implants on the omentum and mesentery, and may metastasize early via venous and/or lymphatic routes
• There is usually more than one histologic subtype present within the same neoplasm, and there is no proven significance to the different patterns
  • Scirrhous, mucus-producing carcinomas: most common form in domestic animals and in rhesus macaques; create mucus-filled lakes throughout the intestinal wall
  • Tubular/acinar pattern: Less common in domestic animals, tends to be less scirrhous
  • Anaplastic, individualized: Less common, accompanied by abundant desmoplastic tissue (differentiating from a stromal malignancy or reactive fibrosis may be challenging)
• Formation of signet ring cells (an epithelial cell with a large, clear cytoplasmic vacuole that peripheralizes the nucleus) is relatively common

 ADDITIONAL DIAGNOSTICS:

• PAS: Gastrointestinal adenocarcinomas often produce mucin which is PAS positive
• IHC: In a recent study (Harbison, Vet Pathol. 2015), all rhesus macaque intestinal adenocarcinomas displayed altered expression of 1 or more of:  CD10, β-catenin, sirtuin I, CK17, and p53; the most common pattern was concurrent increased p53 with decreased SIRT1 and β-catenin staining; no noted difference in MMP2 or MMP9 expression

 

DIFFERENTIAL DIAGNOSIS:

• Hyperplastic polyp: Tubular or papillary proliferation resembling normal adjacent tissue that does not invade into the lamina propria, submucosa, or tunica muscularis (as opposed to the papillary form of gastrointestinal adenocarcinoma); most common in dogs and cattle
• Adenoma: Similar pattern, but lacks malignant features (invasiveness, marked nuclear atypia, etc.) and desmoplasia; rectal papillary adenomas are very common and can be impossible to distinguish from an invasive papillary adenocarcinoma with endoscopic biopsy samples; submucosal herniation of glandular structures still surrounded by lamina propria in adenomas (pseudoinvasion) can lead to erroneous diagnosis of malignancy
• Carcinoid (tumors of neuroendocrine origin): Nests, ribbons, and rosettes divided by a fine fibrovascular stroma; granular to vacuolated cytoplasm; vesiculate, antibasilar nuclei with prominent nucleoli
• Undifferentiated carcinoma (solid carcinoma, medullary carcinoma): Nests of epithelial cells without glandular and papillary formation
• Mesothelioma may resemble carcinomatosis

 

COMPARATIVE PATHOLOGY:

• Gastric and intestinal epithelial neoplasms (adenomas, adenocarcinomas) are rare in domestic animals; they occur in all species but are most often seen in dogs and cats (possibly due to longer life span) and sheep
• Dogs:
  • Gastric carcinomas predominate, predominantly males, and more common in the pylorus, but also in the antrum; multiple breeds predisposed (Tervuren, Bouvier des Flandres, Groenendael, Collie, Standard Poodle, Norwegian Elkhound; possibly associated with chronic gastritis in Lundehund); grossly, non-ulcerating firm thickenings with loss of rugal folds or localized plaque-like thickenings with central ulceration; early metastasis is common
  • Small intestinal and colonic carcinomas are uncommon, most frequently in the proximal small intestine or colon, and may be accompanied by anemia if ulcerated; males and many breeds most common (Boxers, Collies, Poodles, German shepherd dogs); progression from benign to malignant possible; adenomatous polyposis coli (APC) tumor suppressor gene is frequently altered; ß-catenin and COX-2 sometimes overexpressed; EGFR (Cho, Vet Pathol. 2021) and p53 (Cho, J Comp Pathol. 2020) expression highest in adenocarcinomas (over non-neoplastic, adenoma and in situ lesions), versus decreased CDX-2 expression (Cho,Vet Pathol. 2021)
  • Rectal adenomatous polyps: also known as rectal papillary adenoma, adenomatous hyperplasia, papillotubular adenoma, colorectal polyp or adenoma, and polypoid carcinoma in situ; usually a single nodule, sessile to pedunculated, often with ulcerated surface, may have predominant tubular or papillary growth pattern; excision is often curative
  • Inflammatory polyps of miniature Dachshunds: inflammatory polyps are uncommon in the canine colorectum but are often seen in miniature Dachshunds in Japan (Uchida, Vet Pahtol. 2016), display increased TLR2 and TLR4 expression of inflammatory cells as well as the colonic epithelium (Yokoyama, J Comp Pathol. 2017), and have been shown to progress from inflammation to neoplasia (adenoma and/or adenocarcinoma), with tumor development likely related to aberrations of APC and β-catenin expression (Saito, Vet Pathol. 2018)
• Cats:
  • Small intestinal and colonic adenocarcinomas are relatively common (less common than intestinal lymphoma), with the ileum most commonly affected; Siamese cats and males overrepresented; histologic appearance is typical except stromal osteochondroid metaplasia may be a feature; papillary form is most commonly seen in feline colonic carcinoma
  • Gastric carcinoma is rare
  • Benign adenomatous polyps are reported in the stomach and duodenum, often middle-aged male Asian breeds
• Sheep:
  • Intestinal adenocarcinoma is relatively common in certain geographic locations (New Zealand, the United Kingdom, Scotland, Iceland, Norway, and southeastern Australia), especially those used for fat lamb production, this may be due to an undetermined predisposing factor (possibly bracken fern or carcinogen exposure); often incidental but may cause weight loss and ascites; mineralization and osseous metaplasia may develop in the stroma
  • Intestinal polyps: adenomatous polyps occur in sheep with intestinal adenocarcinoma, hyperplastic polyps occur in the small intestine of lambs with chronic coccidiosis
• Goats, horses, swine: Gastrointestinal adenocarcinomas are rare, usually arise in small intestine, frequently scirrhous
  • Hyperplastic polyps occur in the small intestine of goats with chronic coccidiosis
  • Lawsonia intracellularis (D-B15) infections of foals and pigs may result in polypoid lesions that should be differentiated from adenomatous neoplasia
• Cattle:
  • Gastric carcinoma is exceptionally uncommon in cattle
  • Associated with bracken fern ingestion, bovine papillomavirus, and upper alimentary cancer; usually an adenoma of one of three recognized types: sessile plaque, adenomatous polyp, or proliferative adenoma of the ampullae (bile and pancreatic duct opening into the duodenum); usually incidental finding at meat inspection
  • Intestinal polyps often incidental findings
• Ferret:
  • Gastric adenocarcinomas are occasionally reported, and have been associated with Helicobacter mustelae infection (D-B18)
  • Intestinal and colonic adenocarcinomas are occasionally seen
• Sika deer: Intestinal adenocarcinomas reported at a high incidence in an inbred herd, associated with bracken fern toxicity (ptaquiloside) (Kelly, Vet Pathol. 2015), morphologically resembles human hereditary non-polyposis colorectal cancer.
• Snakes: Diffuse mucinous and signet ring cell gastric adenocarcinoma reported in a California king snake (Hseuh, J Comp Pathol. 2018) and mucinous rectal adenocarcinoma in a Urutu snake (Santos, J Comp Pathol. 2021), although the majority of gastric neoplasms are of mesenchymal origin; intestinal adenocarcinoma common in colubrids
• Cetaceans: Belugas in the St. Lawrence Estuary have high rate of neoplasia, the most common of which is gastrointestinal adenocarcinoma

 

REFERENCES:

1. Cho SH, Seung BJ, Kim SH, et. al. CDX-2 protein and mRNA expression in canine intestinal adenocarcinoma. J Comp Pathol. 2020;184:24-30.
2. Cho SH, Seung BJ, Kim SH, et. al. EGFR overexpression and sequence analysis of KRAS, BRAF, and EGFR mutation hot spots in canine intestinal adenocarcinoma. Vet Pathol. 2021;58(4):674-682.
3. Cho SH, Seung BJ, Kim SH, et. al. Overexpression and mutation of p53 Exons 4-8 in canine intestinal adenocarcinoma. J Comp Pathol. 2020;175:79-84.
4. Fox JG, Muthupalani S, Kiupel M, Williams B. Neoplastic diseases.  In: Fox JG, Marini RP. Biology and Diseases of the Ferret.  3rd ed.  Ames, IA: Wiley; 2014: 604-606.
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6. Harbison CE, Taheri F, Knight H, Miller AD. Immunohistochemical characterization of large intestinal adenocarcinoma in the rhesus macaque (Macaca mulatta).  Vet Pathol. 2015;52(4):732-740.
7. Hseuh CS, Li WT, Jeng CR, Pang VF, Chang HW. Diffuse-type gastric mucinous and signet ring cell adenocarcinoma in a captive California king snake (Lampropeltis getula californiae).  J Comp Pathol. 2018;160:10-14.
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