Signalment:  

Aged male common marmoset, Callithrix jacchus, non-human primate.This colony marmoset was housed at the U.S. Army Medical Research Institute of Infectious Diseases. The marmoset was euthanized because of chronic weight loss and lethargy.

Gross Description:  

The wall of the proximal jejunum was circumferentially thickened and firm for a length of approximately 0.5 cm with marked narrowing of the lumen (napkin-ring appearance/stricture). Other necropsy findings included: minimal subcutaneous and visceral adipose tissue; several missing and worn incisor teeth; mild splenomegaly; a moderately enlarged, pale tan liver with patchy white to pale yellow coalescing areas that bulged on cut surface; and few, approximately 0.5 mm diameter, white, slightly raised foci on the capsular surface of the right liver lobe.

Histopathologic Description:

Jejunum: Expanding and infiltrating the mucosa, submucosa, and tunica muscularis is an unencapsulated, poorly circumscribed, moderately cellular neoplasm composed of polygonal cells (epithelial origin) arranged in disorganized acini and nests often separated and surrounded by an abundant amphophilic finely fibrillar material (mucin). Neoplastic cells have generally distinct cell borders, small to moderate amount of eosinophilic cytoplasm, round nuclei with finely stippled chromatin, and 1-2 distinct, occasionally prominent, nucleoli. A subpopulation of neoplastic cells is rounded with amphophilic cytoplasm that peripheralizes the nucleus (signet-ring appearance). There is moderate anisokaryosis with occasional multinucleate neoplastic cells. Mitotic figures are not observed. The tunica muscularis is markedly expanded (up to 5x normal) by fibrosis and reactive fibrous tissue (desmoplasia). There are moderate numbers of lymphocytes and plasma cells with fewer macrophages, neutrophils, and eosinophils scattered within the neoplasm. Multifocally, moderately expanding the basement membrane of vessels and adjacent connective tissue within the lamina propria is a pale eosinophilic amorphous material (consistent with amyloid). Other findings in some sections include: villous fusion and blunting (atrophy); erosion/ulceration; crypt abscesses; serositis with reactive mesothelium; and lymphoid follicular aggregates in the deep tunica muscularis.

Morphologic Diagnosis:  

1. Jejunum: Adenocarcinoma, mucinous. 
2. Jejunum, lamina propria: Amyloidosis, multifocal, mild.

Condition:  

Jejunal adenocarcinoma

Contributor Comment:  

Small intestinal adenocarcinomas are generally uncommon in human and nonhuman primates. The most commonly reported intestinal carcinomas in nonhuman primates are ileocecal adenocarcinomas in aged rhesus macaques (Macaca mulatta) and colorectal adenocarcinoma in cotton-top tamarins (Saguinus oedipus).(5) In humans, most small intestinal malignant tumors are metastases from tumors arising in other locations with colorectal adenocarcinomas much more commonly reported.(1) The association of chronic-active colitis with development of colorectal adenocarcinomas in cotton-top tamarins and humans is also generally well-accepted.(3,5,6,8)

A recent report suggests that small intestinal adenocarcinoma may be a relatively common neoplasm in aged common marmosets (Callithrix jacchus).(5) In this report, tumors were usually located within the proximal small intestine, immediately distal to the duodenum, with grossly observed thickening and stricture at the tumor site often present. Signet-ring cell differentiation, lymphatic infiltration, and metastatic spread to the regional lymph nodes were other common findings. Carcinomatosis was not observed. An association between presence of callitrichine herpesvirus 3 (marmoset lymphocryptovirus) or Helicobacter sp. and tumor development was not found.(5) This case shares similar features to those reported; however, evidence of metastasis was not observed in histologically examined tissues. 

The reason for the predisposition of development of small intestinal adenocarcinoma at the duodenal-jejunal interface is unknown; however, there is a belief among some pathologists that components of biliary or pancreatic secretions that enter the intestine at this location may result in cell damage and subsequent tumorigenesis.(1) Even though the small intestine has a high cell turnover and large epithelial surface, adenocarcinomas develop much less frequently than in the large intestine. Several hypotheses have been postulated to explain this disparity in occurrence and these include: dilution of potential carcinogens due to the more liquid nature of small intestinal contents allows decreased mucosal contact; rapid transit time in the small intestine allows decreased mucosal contact of potential luminal carcinogens; presence of Paneth cells in the small intestine aids in antibacterial activity; lack of anaerobic bacteria in the small intestine that are able to convert bile salts to potential carcinogens; large amounts of lymphoid tissue (lamina propria and Peyers patches) that provide increased immunosurveillance against tumor cells; large amounts of mucosal enzymes that can detoxify luminal contents; less mechanical trauma to the mucosa due to more liquid luminal contents; and crypt stem cells are further away from contact with potential luminal carcinogens.(1)

Intestinal adenocarcinomas can often be further described based on their predominant morphologic appearance into acinar, papillary, mucinous, signet-ring cell, undifferentiated, or adenosquamous subtypes. In general, small intestinal adenocarcinomas are uncommon in domestic animals. However, in some countries, small intestinal adenocarcinoma can be common in cattle and is associated with ingestion of bracken fern and bovine papillomavirus type 4 infection.(2) Tumors are usually multiple and vary from adenoma to carcinoma affecting all levels of the small intestine. In sheep, there has also been an association with bracken fern ingestion and herbicide use.(2) Unlike in cattle, these tumors are usually mid-jejunal and solitary.

An additional finding in this marmoset was the presence of a pale eosinophilic amorphous material in widespread tissues (gastrointestinal tract, spleen, liver, kidney, adrenal gland, and thyroid gland). Congo red stain of a replicate section of kidney from this marmoset confirmed that the eosinophilic material is amyloid. Systemic AA or reactive secondary amyloidosis has been reported in common marmosets, usually related to a chronic inflammatory process that results in elevated serum amyloid A (SAA) protein levels. A genetic factor may also play a role in the common marmoset.(4) In addition to the small intestinal adenocarcinoma, this marmoset exhibited marked to severe granulomatous and eosinophilic cholangitis with intralesional degenerate parasitic remnants suggesting that this chronic inflammatory process likely contributed to elevated SAA levels with resulting widespread amyloid deposition.

Note: Opinions, interpretations, conclusions, and recommendations are those of the author and are not necessarily endorsed by the U.S. Army. 

Research involving this marmoset was conducted in compliance with the Animal Welfare Act and other federal statutes and regulations relating to animals and experiments involving animals and adheres to principles stated in the Guide for the Care and Use of Laboratory Animals, National Research Council, 2011. This research was conducted under an Institutional Animal Care and Use Committee (IACUC) approved protocol. The facility where this research was conducted is fully accredited by the Association for Assessment and Accreditation of Laboratory Animal Care International. 

JPC Diagnosis:  

1. Jejunum: Adenocarcinoma, mucinous type.
2. Jejunum, lamina propria: Amyloidosis, multifocal, moderate. 
3. Jejunum: Ulcer, focal. 

Conference Comment:  

The contributor provides an excellent discussion of intestinal adenocarcinomas in non-human primates, as well as the association between inflammation, cell damage and tumorigenesis. Conference participants discussed the pathogenesis of colorectal cancer in humans and nonhuman primates, noting that similar pathogeneses are proposed for both colorectal and small intestinal adenocarcinomas.(5) Colorectal adenocarcinomas account for 15% of all human cancer-related deaths in the United States, making it the second leading cause of cancer-related deaths, behind lung cancer.(7) While numerous infectious, genetic and environmental factors contribute to the development of gastrointestinal tumors, two distinct genetic pathways have been implicated with playing major roles in the development of intestinal adenocarcinomas: the Wnt signaling pathway (involving APC and β-catenin ) and the microsatellite instability pathway.(5,7) Wnt is a signaling pathway that regulates β-catenin. The APC (adenomatous polyposis coli gene) is a potent tumor suppressor that, under normal conditions, complexes with and phosphorylates β-catenin, marking it for ubiquitination and ultimately destruction. When Wnt is activated, the destruction complex between APC and β-catenin is deactivated, resulting in increased cytoplasmic β-catenin levels. As levels rise, β-catenin translocates into the nucleus, where it binds to TCF, a transcription factor that activates genes such as MYC and cyclin D1 that promote proliferation and increase cell cycle progression. Loss or mutation of APC can likewise lead to increased levels of β-catenin and cell cycle promotion and growth. This is followed by other mutations, such as activating mutations in KRAS, SMAD2 and SMAD4, which further promote cell proliferation and inhibit apoptosis. SMAD2 and SMAD4 are effectors of TGF-β signaling. TGF-β normally inhibits the cell cycle; hence, loss of these genes can allow unregulated cell proliferation. Additionally, mutations (chromosome deletions) in the tumor suppressor gene p53 also occur in later stages of tumor progression. Mutations such as these are due to chromosomal instability, which is a hallmark of APC/β-catenin pathway.(7) Another pathway implicated in the development of intestinal adenocarcinomas is microsatellite instability, which occurs when DNA mismatch repair is deficient, allowing mutations to accumulate in microsatellite repeats. Generally, microsatellites are in noncoding regions, but some microsatellite sequences are located in coding or promoter regions in genes that regulate cell growth (i.e. genes encoding type II TGF-β receptor and the proapoptotic protein Bax). Type II TGF-β mutations can contribute to uncontrolled cell growth, whereas loss of Bax may enhance the survival of neoplastic cells.(5,7)

In addition to playing a role in the Wnt signaling pathway, β-catenin activity also has effects on cell-cell organization. β-catenin normally binds to the cytoplasmic domain of type I cadherins, facilitating linkage to the actin cytoskeleton and contributing to normal cellular structure and organization. Perturbed interactions between β-catenin and type I cadherins destabilize cell-cell interactions and thus promote the loss of cell cohesion which may contribute to metastatic spread of neoplastic cells.(7)

References:

1. Fenoglio-Preiser CM, Noffsinger AE, Stemmermann GN, Latz PE, Isaacson PG. Gastrointestinal Pathology: An Atlas and Text. 3rd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2008:471-494.
2. Head KW, Cullen JM, Dubielzig RR, Else RW, Misdorp W, Patnaik AK, et al. In: Schulman Y, ed. Histological Classification of Tumors of the Alimentary System of Domestic Animals, 2nd series, Vol. X. Washington, DC: Armed Forces Institute of Pathology/ American Registry of Pathology; 2003:89-94.
3. Johnson LD, Ausman LM, Sehgal PK, King, Jr. NW. A prospective study of the epidemiology of colitis and colon cancer in cotton-top tamarins (Saguinus oedipus). Gastroenterology. 1996:110:102-115.
4. Ludlage E, Murphy CL, Davern SM, Solomon A, Weiss DT, Glenn-Smith D, et al. Systemic AA amyloidosis in the common marmoset. Vet Pathol. 2005;42(2):117-124.
5. Miller AD, Kramer JA, Lin KC, Knight H, Martinot A, Mansfield KG. Small intestinal adenocarcinoma in common marmosets (Callithrix jacchus). Vet Pathol. 2010;47(5):969-976.
6. Riddell RH, Petras RE, Williams GT, Sobin LH. In: Rosai J, ed. Atlas of Tumor Pathology: Tumors of the Intestines, 3rd series, Fascicle 32. Washington, DC. Armed Forces Institute of Pathology/ American Registry of Pathology. 2002:189-194.
7. Turner JR. The gastrointestinal tract. In: Kumar V, Abbas AK, Fausto N, Aster JC, eds. Robbins and Cotran Pathologic Basis of Disease. 8th ed. Philadelphia, PA: Elsevier/Saunders; 2010:822-825.
8. Valverde CR, Tarara RP, Griffey SM, Roberts JA. Spontaneous intestinal adenocarcinoma in geriatric macaques (Macaca sp.). Comp Med. 2000;50(5):540-544.

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4-1. Small intestine

4-2. Small intestine

4-3. Small intestine

4-4. Small intestine

4-5. Small intestine

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