JPC SYSTEMIC PATHOLOGY
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 (D-N05a): 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 cells arranged in tubules and acini supported by a moderately dense desmoplastic stroma. Neoplastic cells have indistinct borders, moderate amounts of granular eosinophilic cytoplasm, 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. Tubules are often filled with sloughed neoplastic cells, necrotic debris, and occasionally degenerate and non-degenerate 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 (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.
- 1. Duodenum: Adenocarcinoma, tubular, Rhesus macaque (Macaca mulatta), nonhuman primate.
- Pancreas: Atrophy, acinar, focally extensive, moderate, with tubular complexes (regeneration)
Signalment (JPC #2460108): Ten-year-old cotton top tamarin (Saguinus oedipus)
HISTORY: Presented thin and dehydrated and had been treated numerous times for colitis beginning at 6.5 years of age.
HISTOPATHOLOGIC DESCRIPTION (D-N05b): Colon: Multifocally effacing the mucosa, submucosa, and subjacent gut associated lymphoid tissue is a moderately cellular, unencapsulated, infiltrative, poorly circumscribed neoplasm composed of cuboidal to columnar cells arranged in disorganized cords and tubules supported by a fine fibrous stroma. Neoplastic cells have indistinct cell borders, moderate amounts of lightly basophilic, granular to vacuolated cytoplasm, and oval nuclei with finely stippled chromatin and 1 to 2 variably distinct nucleoli. Mitoses average 2 per HPF, and there is moderate anisocytosis and anisokaryosis. Neoplastic cells often pile up to 4 cell layers thick. Multifocally, occasional neoplastic cells are rounded with a single clear cytoplasmic vacuole that peripheralizes the nucleus (signet ring cells). Neoplastic tubules are often dilated and contain a mixture of neutrophils, mucin, sloughed epithelial cells, and cellular debris. Subjacent lymphatics are ectatic (edema). Multifocally, scattered throughout the neoplasm and expanding adjacent lamina propria are plasma cells, lymphocytes, and fewer neutrophils. Diffusely within adjacent tissue, the mucosal epithelium is uneven with papillary hyperplasia. Crypts are multifocally mildly ectatic and contain crypt abscesses.
- 1. Colon: Adenocarcinoma, cotton-top tamarin (Saguinus oedipus), nonhuman primate.
- Colon: Colitis, proliferative, chronic-active, diffuse, moderate, with crypt hyperplasia and crypt abscesses.
CONDITION: Intestinal/colonic adenocarcinoma
- 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: by far the most common spontaneous gastrointestinal neoplasms in NHPs are ileocecal/colonic adenocarcinomas in rhesus macaques (cause up to 50% of tumors identified in rhesus macaques over 20 years old) 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 have been reported to spontaneously occur in rhesus macaques and those 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
- Cotton-top tamarins: up to 60% of animals spontaneously develop ulcerative colitis and 25-40% of those progress to develop colonic adenocarcinoma
- Colonic adenocarcinoma in these NHPs typically is 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
- Scirrous, 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 scirrous
- Anaplastic, individualized: Less common, accompanied by a great deal of 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
- PAS: Gastrointestinal adenocarcinomas often produce mucin which is PAS positive
- IHC: In a recent study (Harbison 2015), all rhesus macaque intestinal adenocarcinomas displayed altered expression of 1 or more of: CD10, β-catenin, sirtuin I, cytokeratin 17 (CK17), and p53 as compared to age-matched controls; the most common pattern was concurrent increased p53, decreased SIRT1, and decreased β-catenin staining; there was no noted difference in MMP2 or MMP9 expression
- 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
- 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
- Gastric carcinomas predominate, more commonly in male dogs, and more commonly in the pyloric region but also in the antrum; there is breed predisposition of multiple breeds (Tervuren, Bouvier des Flandres, Groenendael, Collie, Standard Poodle, Norwegian Elkhound; possibly associated with chronic gastritis in Lundehund); grossly, nonulcerating firm thickenings with loss of rugal folds or localized plaque-like thickenings with central ulceration (more than 50% of canine gastric carcinomas ulcerate); early metastasis is common
- Small intestinal and colonic carcinomas are relatively uncommon, occur most frequently in the proximal small intestine or colon, and may be accompanied by anemia if ulcerated; there is evidence of progression from benign adenomatous lesions to malignancy in some colonic carcinomas and the adenomatous polyposis coli (APC) tumor suppressor gene is frequently altered in canine colonic adenoma and adenocarcinoma
- 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 2016), display increased TLR2 and TLR4 expression of inflammatory cells as well as the colonic epithelium (Yokoyama 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 2018)
- Small intestinal and colonic adenocarcinomas are relatively common (less common than intestinal lymphoma), with the ileum most commonly affected; intestinal carcinoma is more prevalent in Siamese cats than other breeds, and a higher prevalence has been reported in males; 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
- Intestinal adenocarcinoma is relatively common in certain geographic locations (New Zealand, the United Kingdom, Scotland, Iceland, Norway, and southeastern Australia) due to an undetermined predisposing factor (one resource states these are virally induced, one resource proposes herbicide 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 infections of foals and pigs may result in polypoid lesions that should be differentiated from adenomatous neoplasia
- Gastric carcinoma is exceptionally uncommon in cattle
- Intestinal adenocarcinoma and upper alimentary tract neoplasms are usually associated with bracken fern ingestion in association with bovine papillomavirus; this intestinal neoplasia is 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 are often incidental findings
- Gastric adenocarcinomas are occasionally reported, and have been associated with Helicobacter mustelae infection (see D-B18)
- Intestinal and colonic adenocarcinomas are occasionally seen
- Sika deer: Intestinal adenocarcinomas have been reported at a high incidence in an inbred herd, associated with bracken fern toxicity (ptaquiloside) (Kelly 2015), morphologically resembles human hereditary non-polyposis colorectal cancer including multiple de novo sites of tumorigenesis, sessile and non-polyposis mucosal changes, frequent mucinous type adenocarcinoma, lymphocytic infiltration in neoplastic tubules, and lymphoid follicles at the deep margin of the tumor, but sika deer neoplasms did not display genetic mutations of mismatch repair genes (MMR) as occurs in humans (Jahns 2015)
- Snakes: Recent report of gastric adenocarcinoma in a California king snake (Hseuh 2018), although the majority of gastric neoplasms are of mesenchymal origin
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- Gelberg HB. Alimentary system and the Peritoneum, Omentum, Mesentery, and Peritoneal Cavity. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 6th ed. St. Louis, MO: Elsevier; 2017: 365-366, 385.
- Harbison CE, Taheri F, Knight H, Miller AD. Immunohistochemical characterization of large intestinal adenocarcinoma in the rhesus macaque (Macaca mulatta). Pathol. 2015;52(4):732-740.
- 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). Comp. Pathol. 2018;160:10-14.
- Jahns H, Browne JA. Mismatch repair mRNA and protein expression in intestinal adenocarcinoma in sika deer (Cervus nippon) resembling heritable non-polyposis colorectal cancer in man. Comp. Pathol. 2015;152:131-137.
- Kelly PA, Toolan D, Jahns H. Intestinal adenocarcinoma in a herd of farmed sika deer (Cervus Nippon): a novel syndrome. Vet Pathol. 2015;52(1):193-200.
- Miller AD. Neoplasia and proliferative disorders of nonhuman primates. In: Abee CR, Mansfield K, Tardiff S, Morris T, eds. Nonhuman Primates in Biomedical Research: Diseases, Vol. 2. 2nd ed. Waltham, MA: Academic Press; 2012:333-335.
- Saito T, Chambers JK, Nakashima K, Uchida E, Ohno K, Tsujimoto H, Uchida K, Nakayama H. Histopathologic features of colorectal adenoma and adenocarcinoma developing within inflammatory polyps in miniature Dachshunds. Pathol. 2018;55(5): 654-662.
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- Uchida E, Chambers JK, Nakashima K, Saito T, Ohno K, Tsujimoto H, Nakayama H, Uchida K. Pathologic features of colorectal inflammatory polyps in miniature Dachshunds. Pathol. 2016;53(4):833-839.
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- Yokoyama N, Ohta H, Yamazaki J, Kagawa Y, Ichii O, Khoirun N, Morita T, Osuga T, Lim SY, Sasaki N, Morishita K, Nakamura K, Takiguchi M. Localization of Toll-like Receptor (TLR) 2 and TLR4 mRNA in the colorectal mucosa of miniature Dachshunds with inflammatory colorectal polyps. Comp. Pathol. 2017;156:183-190.