Small intestine & ampulla
Carcinoma
Adenocarcinoma-small intestine
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Last author update: 15 March 2021
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PubMed Search: Adenocarcinoma small intestine
See also: Ampullary adenocarcinoma
Table of Contents
Definition / general | Essential features | ICD coding | Epidemiology | Sites | Etiology | Clinical features | Diagnosis | Laboratory | Radiology description | Prognostic factors | Case reports | Treatment | Clinical images | Gross description | Gross images | Frozen section description | Frozen section images | Microscopic (histologic) description | Microscopic (histologic) images | Cytology description | Cytology images | Positive stains | Negative stains | Molecular / cytogenetics description | Sample pathology report | Differential diagnosis | Additional references | Board review style question #1 | Board review style answer #1 | Board review style question #2 | Board review style answer #2Cite this page: Patel KS, Windon AL. Adenocarcinoma-small intestine. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/smallboweladenocarcinoma.html. Accessed April 18th, 2024.
Definition / general
- Nonampullary primary malignant epithelial neoplasm of the small intestine showing glandular differentiation
Essential features
- Small bowel adenocarcinomas are histologically very similar to colorectal adenocarcinomas, with complex glandular formations
- Gross identification of the tumor epicenter is essential in duodenal tumors that involve the ampulla to exclude a primary ampullary adenocarcinoma or extension from pancreatic or bile duct malignancies
- Adenocarcinomas can arise in a variety of inflammatory, autoimmune and familial conditions
ICD coding
Epidemiology
- 30 - 40% of small intestinal cancers are adenocarcinoma and 3.3% of gastrointestinal cancers were from the small intestines in 2020 (CA Cancer J Clin 2020;70:7)
- More frequently seen in men, African Americans and patients in their early to mid 60s (Cancer Causes Control 2005;16:781)
Sites
- Most common locations include the periampullary region of the duodenum (50 - 64%) followed by the jejunum (18 - 20%) and finally the ileum (15%) (Ann Surg 2009;249:63, Cancer 1999;86:2693)
- Patients with Crohn's disease have adenocarcinomas in a predominantly ileal location
Etiology
- Inflammatory, autoimmune, genetic and familial diseases have been recognized as common risk factors:
- Crohn's disease: the cumulative risk increases after 10 years of disease and there is an absolute risk of 2.2% at 25 years
- Risk increases with longstanding ileal inflammation, younger than average age of onset, previous immunosuppressant use, male sex and stricture and fistula formation (Dis Colon Rectum 2007;50:839, Am J Gastroenterol 2005;100:2724, Am Surg 2007;73:1181, J Crohns Colitis 2014;8:19)
- Celiac disease: there is an increased relative risk of 10 to 80 times compared with the general population in longstanding, untreated disease (QJM 2003;96:345)
- Most adenocarcinomas occur in the jejunum
- Familial adenomatous polyposis (FAP): there is a 3 - 5% lifetime risk
- Most tumors occur in the duodenum and periampullary regions
- Risk increases with a higher number of polyps, larger polyps and those with poorer histologic features (Lancet 1989;2:783)
- Peutz-Jeghers syndrome: there is a 1.7 - 13% lifetime risk (Gastroenterology 2000;119:1447, Clin Cancer Res 2006;12:3209)
- Adenocarcinomas most commonly occur in the jejunum and ileum and can arise from hamartomatous or adenomatous polyps
- Lynch syndrome: there is a 4% lifetime risk (Cancer 1998;83:240)
- Adenocarcinomas most commonly occur in the duodenum and jejunum
- Crohn's disease: the cumulative risk increases after 10 years of disease and there is an absolute risk of 2.2% at 25 years
- Other associations and risk factors include:
- Ileal conduits / reservoirs which expose the small intestine to its nonnative milieu (Oncol Rep 2012;27:371)
- Exposure to acid and bile, especially in the vicinity of ampulla and pylorus (Int J Cancer 1997;70:512)
- Smoking, alcohol and dietary factors (low fiber, high red meat consumption, sugary drinks) (Int J Cancer 1997;70:512, Cancer Epidemiol 2015;39:265)
- Congenital bowel duplication, ileostomy, duodenal or jejunal bypass surgery (Radiographics 1998;18:379)
Clinical features
- Patients are typically asymptomatic or exhibit nonspecific symptoms in the early stages of disease
- Some symptoms include abdominal pain, anemia, GI bleeding, weight loss, nausea and vomiting
- Intestinal obstruction may develop in ileal and jejunal cancers as the disease progresses, necessitating surgical intervention (Cancer 2004;101:518)
Diagnosis
- Initial workup for primarily duodenal adenocarcinomas includes esophagogastroduodenoscopy (EGD) with endoscopic ultrasound (EUS) and biopsy for diagnosis and staging (J Natl Compr Canc Netw 2019;17:1109)
- CT or MRI can be used to evaluate local tumor invasion and assess for metastatic disease
- Balloon assisted and video capsule endoscopy allow for a detailed examination of entire small bowel if nonobstructed (J Natl Compr Canc Netw 2019;17:1109)
Laboratory
- Complete blood count (CBC), chemistry profile, carbohydrate antigen 19-9 (CA19-9), carcinoembryonic antigen (CEA) (J Natl Compr Canc Netw 2019;17:1109)
Radiology description
- Distal adenocarcinomas may manifest as annular narrowing with abrupt concentric or irregular overhanging edges, a discrete tumor mass or an ulcerative lesion, while duodenal adenocarcinomas tend to be papillary or polypoid on CT scan (Radiographics 1998;18:379)
Prognostic factors
- Prognosis is related to the stage of disease at diagnosis, resectability, margin status, differentiation and lymph node status (Langenbecks Arch Surg 2019;404:439, Dis Colon Rectum 2002;45:1496, Am J Surg Pathol 2014;38:1484)
- Special morphologic variants (e.g. mucinous, adenosquamous) and tumor size are not strong predictors of outcome (Dis Colon Rectum 2002;45:1496)
- Duodenal tumors have a worse prognosis compared with tumors occurring in the remainder of small bowel (Cancer 2004;101:518)
- Mismatch repair deficient adenocarcinomas of the small bowel may present at an earlier stage of disease with lower recurrence rates (Clin Cancer Res 2021;27:1429)
Case reports
- 7 year old boy with Peutz-Jeghers syndrome (BMJ Case Rep 2018;11:e225076)
- 37 year old woman with bilateral ovarian metastasis (Gastroenterology Res 2017;10:366)
- 38 year old woman with coexisting ileal diverticulosis, Crohn’s disease and small bowel adenocarcinoma (In Vivo 2018;32:191)
- 47 year old man with adenocarcinoma arising in jejunal adenomyoma (Pathol Int 2019;69:556)
- 49 year old morbidly obese man with recurrent adenocarcinoma (BMJ Case Rep 2018;2018:bcr2018225273)
Treatment
- Surgery is the mainstay of treatment with regional lymph node removal for stage I - III disease (J Natl Compr Canc Netw 2019;17:1109)
- Segmental resection is usually performed for jejunal, ileal and some duodenal primaries; pancreaticoduodenectomy may be indicted for some duodenal tumors that invade the pancreas or ampulla
- Adjuvant chemotherapy and radiation have mixed, limited results and are still being evaluated
Clinical images
Images hosted on other servers:
Suspicious growth with jejunal stricture
Near obstructing mass distal to duodenal bulb
Irregular and ulcerated jejunal lesion (capsule endoscopy)
Gross description
- A substantial number of duodenal adenocarcinomas show plaque-like growth but they can also present with polypoid growth in approximately 33% of cases (Mod Pathol 2017;30:255)
- Jejunal and ileal adenocarcinomas present as large, annular, constricting apple core lesions with circumferential bowel wall involvement (Cancer 1975;36:1876)
- Gross appearance can also be influenced by background mucosa in adenocarcinomas that arise in inflammatory conditions (Crohn's disease), polyposis syndromes or intestinal duplications (Virchows Arch 2018;473:265)
- Frequent serosal involvement or extension into other organs is not uncommon
Gross images
Images hosted on other servers:
Jejunal
submucosal tumor
with overlying
normal mucosa
Jejunal tumor invading adherent transverse colon
Ileal tumor with ulceration
Frozen section description
- Intraoperative consultation (gross or microscopic) may be requested to evaluate margin status for pancreaticoduodenectomy or segmental resection specimens
- In patients undergoing surgery for inflammatory bowel disease, intraoperative findings concerning for malignancy (i.e. abscess formation, strictures, fistula tracts, perforation) may prompt a frozen section analysis
- Microscopic features compatible with malignancy include complex glandular architecture, invasion, desmoplastic reaction, cellular and nuclear pleomorphism, loss of epithelial polarity and luminal necrosis
Frozen section images
Contributed by Krutika S. Patel, M.B.B.S., M.D. and Annika L. Windon, M.D.
Invasive jejunal adenocarcinoma
Microscopic (histologic) description
- Adenocarcinomas, not otherwise specified, are characterized by columnar epithelial cells with elongated, pseudostratified nuclei forming complex glandular architecture with nuclear pleomorphism, loss of epithelial polarity and luminal dirty necrosis
- Histologic grading system, based on the extent of glandular formation in the tumor, is recommended; grading is done as well differentiated (with more than 95% of tumor composed of glands), moderately differentiated (with 50% to 95% of tumor composed of glands) and poorly differentiated (with less than 50% of tumor composed of glands)
- Additional histologic characterizations include mucinous adenocarcinoma (> 50% mucin), poorly cohesive cell carcinoma (with or without signet ring cells), medullary carcinoma, adenosquamous carcinoma (squamous and adenocarcinoma components), undifferentiated carcinoma or mixed neuroendocrine nonneuroendocrine neoplasm (MiNEN)
- Signet ring cell / poorly differentiated carcinomas, presenting as late stage disease, are more common in Crohn's disease than as de novo small intestinal carcinomas (Inflamm Bowel Dis 2005;11:828)
- Lynch syndrome associated small intestinal adenocarcinomas show similar features to their colorectal counterparts; tumors often show a high number of intratumoral lymphocytes and Crohn's-like lymphoid reaction (Gastroenterology 2005;128:590)
- Preexisting adenoma is present in the majority of proximal tumors but sometimes cannot be identified in large distal small intestinal adenocarcinomas due to tumor overgrowth
- Determining a background of Crohn's disease can sometimes be difficult because the histologic characteristics of Crohn's disease such as transmural inflammation can be caused by the tumor; oftentimes patients present without an established diagnosis of inflammatory bowel disease (J Crohns Colitis 2014;8:19)
Microscopic (histologic) images
Contributed by Krutika S. Patel, M.B.B.S., M.D. and Annika L. Windon, M.D.
Well differentiated adenocarcinoma
Moderately and poorly differentiated adenocarcinoma
Mucinous adenocarcinoma
Lymph node metastasis
Higher stage carcinomas
Ileal adenocarcinoma arising in Crohn's disease
Signet ring adenocarcinoma
Adenocarcinoma arising in a tubulovillous adenoma
Lymphovascular invasion
Perineural invasion
Cytokeratin 7
Cytokeratin 20
Cytology description
- Cytopathologic analysis (FNA or brushing) is rarely used in the small intestine, except for occasionally diagnosing duodenal tumors in the ampullary or pyloric region
- Malignant cells are arranged in loose 3 dimensional clusters of crowded epithelial cells without goblet cells
- Alternatively, many single atypical cells with mitoses, increased nuclear to cytoplasmic ratio and marked nuclear pleomorphism are present
- Reference: J Gastrointest Oncol 2012;3:285
Cytology images
Images hosted on other servers:
Duodenal adenocarcinoma and normal mucosa
Positive stains
- CK7, CK20 (variable) (Am J Surg Pathol 2004;28:1352)
- CDX2 in up to 70% of cases (Arch Pathol Lab Med 2017;141:1155)
- SATB2 in up to 46% of cases, with patchy and weak staining in most cases, strong and diffuse staining in < 10% of cases (Arch Pathol Lab Med 2017;141:1155)
- MUC1 (EMA): positive in up to 53% of cases (Am J Clin Pathol 2007;128:808)
- MUC2: positive in up to 57% of cases
- Villin: positive in up to 67% of cases (can be focal)
- Small intestinal mucin antigen (SIMA): variably positive in up to 50% of cases
- p53: strong, diffuse overexpression or completely negative (mutated phenotype) in a subset of mutated tumors
- MUC5AC: focally in up to 40% of cases
- MUC6: focally in up to 30% of cases
Negative stains
- AMACR: usually negative (Am J Surg Pathol 2005;29:890)
- CDH17 (Arch Pathol Lab Med 2017;141:1155)
Molecular / cytogenetics description
- 2 well defined molecular pathways are reported in small bowel adenocarcinomas, similar to colorectal adenocarcinoma tumorigenesis
- First pathway includes APC, KRAS, TP53 (Int J Cancer 1997;70:390)
- Prevalence of mutations in KRAS is similar between colorectal and small bowel adenocarcinomas, typically 30 - 60%
- Prevalence of TP53 mutations is also comparable, 20 - 50%
- Fewer than 20% of small bowel adenocarcinomas have mutations in APC, in contrast to 80% of colorectal carcinomas
- Second pathway includes inactivation of mismatch repair (MMR) genes, either by germline mutations (Lynch syndrome) or promoter hypermethylation (sporadic), which occurs in up to 38.5% of small bowel adenocarcinomas (Clin Cancer Res 2021;27:1429)
- A number of other genetic alterations have been reported in small bowel adenocarcinomas, including mutations in CTNNB1, SMAD4, IDH1, CDH1, KIT, FGFR2, FLT3, NPM1, PTEN, MET, AKT, RET, ERBB2 (HER2), NOTCH1 and ERBB4 (Gut 2002;50:218, Scand J Gastroenterol 2004;39:748, Int J Cancer 1997;70:390, Am J Gastroenterol 2000;95:1576, Oncotarget 2015;6:20863)
Sample pathology report
- Small bowel, duodenum, biopsy:
- Invasive moderately differentiated adenocarcinoma arising in a tubular adenoma; lymphovascular invasion is present (see comment)
- Comment: Mucosal colonization from an ampullary, biliary or pancreatic origin must be excluded. Clinical and radiographic correlation is recommended. Immunohistochemical testing for mismatch repair (MMR) proteins shows intact nuclear expression of MLH1, PMS2, MSH2, MSH6 in the tumor cells. Background nonneoplastic tissue / internal control shows intact nuclear expression. Based on these results, there is low probability of MSI-H (MSI = microsatellite instability; H = high).
Differential diagnosis
- Metastatic adenocarcinoma (e.g. colon, breast, ovary, lung):
- Adenoma with high grade dysplasia:
- Differentiating prolapse from invasion around ampulla can be challenging
- Presence of desmoplasia and single cells supports invasion
- Ectopic pancreas:
- Presence of only ducts in a small biopsy specimen may be misinterpreted as neoplasm
- Endometriosis:
- Presence of endometrial stroma and ciliated epithelium helps to make this diagnosis
- Ampullary adenocarcinoma:
- Advanced duodenal carcinoma may extend to involve the ampulla but only those centered on or circumferentially surrounding the ampulla are regarded as ampullary carcinomas
- Careful gross examination to assess the tumor epicenter helps in distinguishing ampullary / periampullary primary from duodenal primary
Additional references
Board review style question #1
Which of the following syndromes is most associated with this tumor, arising in the small bowel?
- Budd-Chiari syndrome
- Cronkhite-Canada syndrome
- Hereditary mixed polyposis syndrome
- Juvenile polyposis syndrome
- Peutz-Jeghers syndrome
Board review style answer #1
E. Peutz-Jeghers syndrome. This image illustrates a well differentiated adenocarcinoma of the small bowel. Patients with Peutz-Jeghers syndrome have a 1.7 - 13% lifetime risk of developing small bowel adenocarcinoma. It arises most commonly in jejunum and ileum and can arise from hamartomatous or adenomatous polyps.
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Board review style question #2
Which of the following statements is true regarding development of small bowel carcinoma in patients with Crohn's disease?
- Carcinoma that develops in Crohn's disease is usually seen in older individuals in their 80s
- Carcinoma that presents in Crohn's disease tends to present as early stage disease
- Carcinomas in Crohn's disease usually are well differentiated
- Risk of developing carcinoma is related to duration of disease
- There is no increased risk when compared to the general population
Board review style answer #2
D. Risk of developing carcinoma is related to duration of disease. The cumulative risk of small carcinoma increases after 10 years, with an absolute risk of 2.2% at 25 years in Crohn's disease. Risk increases with longstanding ileal inflammation, younger than average age of onset, previous immunosuppressant use, male sex, strictures and fistula formation. Signet ring cell / poorly differentiated carcinomas, presenting as late stage disease, are more common in Crohn's disease than as de novo small intestinal carcinomas.
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