Small bowel adenocarcinomas (SBAs) are rare tumors, but their incidence is increasing. The most common primary location is the duodenum. Even though SBAs are more often sporadic, some diseases are risk factors. Early diagnosis of small bowel adenocarcinoma remains difficult, despite significant radiologic and endoscopic progress. After R0 surgical resection, the main prognostic factor is lymph node invasion. An international randomized trial (BALLAD [Benefit of Adjuvant Chemotherapy For Small Bowel Adenocarcinoma] study) will evaluate the benefit of adjuvant chemotherapy. For metastatic disease, retrospectives studies suggest that platinum-based chemotherapy is the most effective treatment. Phase II studies are ongoing to evaluate targeted therapy in metastatic SBA.
Key points
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The most frequent location of small bowel adenocarcinoma is duodenum.
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Small bowel adenocarcinoma occurs in around 20% in a context of predisposing disease.
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Small bowel adenocarcinoma molecular phenotype is close to that of colorectal adenocarcinoma.
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After an R0 resection, lymph node invasion is the main prognostic factor.
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The benefit of adjuvant chemotherapy should be demonstrated by a prospective clinical trial.
Introduction
Small bowel adenocarcinoma (SBA) is a rare cancer, but there is a growing impetus to perform multicenter or collaborative studies to answer key questions in patient management. Large biological studies are now possible to potentially exploit the molecular and cellular basis of SBA development and progression to develop novel therapies. Collaboration through the International Rare Cancer Initiative has led to an adjuvant therapy trial, which is ongoing. Other important information will be obtained from large prospective cohorts.
Introduction
Small bowel adenocarcinoma (SBA) is a rare cancer, but there is a growing impetus to perform multicenter or collaborative studies to answer key questions in patient management. Large biological studies are now possible to potentially exploit the molecular and cellular basis of SBA development and progression to develop novel therapies. Collaboration through the International Rare Cancer Initiative has led to an adjuvant therapy trial, which is ongoing. Other important information will be obtained from large prospective cohorts.
Epidemiology
Small Intestine Cancer
Despite the fact that the small intestine makes up 75% of the length of the digestive tract and 90% of its mucosal surface area, small bowel cancer is rare, accounting for less than 5% of gastrointestinal cancers. According to the National Cancer Data Base (NCDB, 1985-2005) and the Surveillance Epidemiology and End Results (SEER, 1973-2004) database, the incidence of all small bowel cancers in the United States increased from 11.8 cases/million persons in 1973 to 22.7 cases/million persons in 2004. Four histologic types of cancer predominate in the small bowel: adenocarcinomas, neuroendocrine tumors, gastrointestinal stromal tumors and lymphomas.
Small Bowel Adenocarcinoma
SBA accounts for around 30% to 40% of all cancers of the small intestine. The incidence of SBA varies according to geographic location, with higher rates in North America and Western Europe, and lower rates in Asian countries. In the United States, the estimated annual incidence of SBA is about 5300 new cases, with 1100 deaths per year. The median age at diagnosis is in the sixth decade of life, with a sex ratio close to 1. In Europe, the annual incidence is about 5.7 cases per million inhabitants resulting from an estimated number of annual new cases of SBA of 3600 according to the EUROCARE database.
Duodenum Adenocarcinoma
Duodenum adenocarcinoma is the most common tumor site, as it is seen in more than half of SBA cases, followed by the jejunum and ileum. The increasing incidence of SBA is mainly owing to the increase in duodenum tumors.
Tumor phenotyping
Many of the main molecular aberrations that are implicated in the pathogenesis of colorectal cancer have been investigated in SBA ( Table 1 ).
| Study | N | Abnormal TP53 (%) | Abnormal β−CATENIN (%) | HER2 Overexpression or Mutation (%) | APC Mutation (%) | KRAS Mutation (%) | dMMR Phenotype (%) |
|---|---|---|---|---|---|---|---|
| Laforest et al, 2014 | 83 | 41 | — | 12 | 13 | 43 | 21 |
| Aparicio et al, 2013 | 63 | 42 | 20 | 3.2 | — | 43 | 23 |
| Overman et al, 2010 | 54 | — | — | 1.7 | — | — | 35 |
| Blaker et al, 2004 | 21 | — | 24 | — | 10 | 57 | — |
| Svrcek et al, 2003 | 27 | 52 | 7.4 | — | — | — | 7 |
| Planck et al, 2003 | 89 | — | — | — | — | — | 18 |
| Wheeler et al, 2002 | 21 | 24 | 48 | — | 0 | — | 5 |
| Blaker et al, 2002 | 17 | — | — | — | 18 | — | 12 |
| Nishiyama et al, 2002 | 35 | 40 | — | — | — | 9 | — |
| Arai et al, 1997 | 15 | 27 | — | — | 8 | 53 | — |
| Rashid & Hamilton, 1997 | 22 | — | — | — | — | 40 | 13 |
Wnt/Adenomatous polyposis coli /β-Catenin Signaling Pathway
Adenomatous polyposis coli
The adenomatous polyposis coli ( APC ) gene causes a loss of the regulation of β-catenin, which accumulates in the cytoplasm and then in the nucleus and acts as a transcription factor that stimulates the expression of genes involved in cellular proliferation. This mutation is considered one of the main trigger events in colorectal carcinogenesis. The prevalence of the APC gene mutation in SBA is about 10% to 18% contrasting to the prevalence of 80% of APC gene mutation observed in colorectal cancer.
Nuclear accumulation of β-catenin
Nuclear accumulation of β-catenin, probably caused by a gain-of-function mutation in the β-CATENIN gene, is observed in 20% to 50% of cases. Moreover, aberrant activation of the Wnt/β-catenin pathway has been correlated with poor prognosis. Thus, Wnt/β-catenin pathway, even if less common than in colorectal cancer, remains an important pathway for SBA pathogenesis.
Other Tumor Phenotyping
Vascular endothelial growth factor and epidermal growth factor receptor
Abnormal expression of vascular endothelial growth factor-A (VEGF-A) and of the epidermal growth factor receptor (EGFR) was found in 50 of 54 (92%) and 36 of 54 (66%) cases, respectively, suggesting that this cancer could benefit from therapies targeting the EGFR and VEGF pathways.
RAS
The mutation rate of KRAS in SBA is comparable to that observed in colorectal cancers (9%–57%). Other RAS mutations occur in less than 5% of the tumor.
HER2
HER2 protein is rarely overexpressed in contrast to gastric cancer. Nevertheless, HER2 gene mutation or amplification is observed in 12% of SBAs.
TP53
TP53 gene mutation or overexpression of its protein is observed in 24% to 52% of SBAs, suggesting that TP53 plays a major role in this disease.
Mismatch Repair Alteration
Inactivation of the DNA mismatch repair (MMR) system is involved in around 15% of colorectal cancers. Deficient MMR (dMMR) can be caused by a germline mutation of one of the 4 MMR genes (usually MSH2 , or MLH1 , and more rarely MSH6 and PMS2 ) as part of Lynch syndrome or to methylation of the MLH1 promoter in sporadic tumors, especially those occurring in elderly patients in colorectal cancer. In SBA, the frequency of the dMMR phenotype is variable, ranging from 5% to 35% of cases. Methylation of the MLH1 promoter seems less frequent in dMMR SBA than in dMMR colorectal cancer except in SBA found in association with celiac disease, suggesting that the proportion of Lynch syndrome among dMMR tumors is higher in SBA than in colorectal cancer. The dMMR phenotype was more frequently observed in duodenum and jejunum tumors than in ileum tumors.
Risk factors for small bowel adenocarcinoma
Genetic Predisposition
Familial adenomatous polyposis
Familial adenomatous polyposis (FAP) is a consequence of a germinal mutation of the APC gene. In patient with FAP, SBA is the second most common primary cancer after colorectal cancer. Duodenal adenomas are present in 80% of cases and develop into adenocarcinoma in 4% of cases requiring intensive screening. FAP is present in less than 5% of SBAs. In cases of FAP, SBA occurred mainly in duodenum (71%) or in jejunum (29%).
Lynch syndrome
Lynch syndrome is caused by a germline mutation of an MMR gene. In patients with Lynch syndrome, the lifetime cumulative risk for SBA is around 1%. However, an MMR phenotype is systematically recommended in SBA, because it could reveal Lynch syndrome. The most common site of SBA in Lynch syndrome is the duodenum (60%), whereas jejunal and ileal locations were reported in 35% and 5% of cases, respectively. The proportion of SBA related to Lynch syndrome is estimated around 6%.
Peutz-Jeghers syndrome
Peutz-Jeghers syndrome is an autosomal dominant disorder caused by the STK11 suppressor gene mutation that predisposes to hamartomatous gastrointestinal tract polyposis. The estimated cumulative risk of SBA is 13%. The Peutz-Jeghers syndrome is the predisposing disease for less than 1% of SBA.
Intestinal Diseases
Crohn’s disease
Crohn’s disease induces chronic inflammation in the digestive tract. The distal ileum is the site most frequently involved. The chronic inflammation releases cytokines that interact with cell surface receptors and target genes that can promote carcinogenesis. The risk of SBA is correlated with the duration and location of the inflammatory damage. The standardized relative risk compared with the general population is 34 in Crohn’s disease affecting the small intestine and 46 for disease duration greater than 8 years. In contrast to SBA in sporadic cases, SBA in Crohn’s disease appears in younger patients (fourth decade of life). The cumulative risk is estimated around 0.2% after 10 years and 2.2% after 25 years of Crohn’s disease. Crohn’s disease is involved in around 8% of SBAs, mostly in ileum.
Celiac disease
Celiac disease increases the relative risk of SBA from 10 to 30 compared to the general population. Celiac disease is associated with SBA in around 2% of cases, the main location is in the jejunum.
Environmental Factors
In contrast to colorectal cancer, studies of the pathogenesis in SBA are constrained by the rarity of the disease. Alcohol consumption confers a relative risk of around 1.5. Other factors including smoking and consumption of certain foods, such as red meat, sugar, and starchy foods, have been reported to increase the risk of cancer of the small intestine, whereas the consumption of fiber, fruits, vegetables, and fish reduces this risk.
Diagnosis of small bowel adenocarcinoma
SBA is usually diagnosed in the context of an emergency involving intestinal obstruction or gastrointestinal bleeding. If no source of bleeding has been identified after normal upper and lower endoscopy, several investigations could be considered.
Computed Tomography with Enteroclysis
Computed tomography with enteroclysis has a sensitivity of between 85% and 95% for the diagnosis of small bowel tumor and a specificity of 90% to 96%.
Video Capsule Endoscopy
Video capsule endoscopy had also a high sensitivity and specificity to detect a small bowel tumor in case of obscure bleeding but should not be used in a context of subacute obstruction. A systematic screening for SBA in patients with Lynch syndrome with video capsule endoscopy does not seem to be efficient.
Double Balloon Enteroscopy
Double balloon enteroscopy can be used to obtain histologic diagnosis.
Prognosis
SBA carries a poor prognosis. The 5-year overall survival (OS) rate is correlated to the tumor stage: 50% to 60% for stage I, 39% to 55% for stage II, 10% to 40% for stage III, and 3% to 5% for stage IV. SBAs are diagnosed with synchronous metastasis in around 30% of cases, stage III in 30%, stage II in 18% to 27%, and stage I in 5% to 10%.
Lymph Node
Lymph node invasion is the main prognostic factor after resection of localized SBA. In stage III tumor, involvement of ≥3 lymph nodes confers a worse 5-year disease-free survival. For jejuno-ileal tumors, multivariate analysis identified advanced age, advanced stage, an ileal location, the recovery of less than 10 lymph nodes, and the number of positive nodes as significant for poor OS. Thus, a curative resection should systematically include a regional lymphadenectomy.
Duodenal Primary Tumors
Duodenal primary tumors are associated with worse prognosis in comparison with jejunum and ileum locations. Other factors have been associated with poor prognosis as advanced age, pT4 tumor stage, poorly differentiated tumor, and positive resection margins.
Biologic Factors
Some biological factors are suggested to have prognostic value. A dMMR phenotype is associated with a better disease-fee survival after curative resection. Surprisingly, KRAS mutation is associated with a better survival for patients with metastatic SBA in one study. Mutation of TP53 is associated with poor survival in another study.
Metastatic Small Bowel Adenocarcinoma
In metastatic SBA treated with chemotherapy, impaired World Health Organization performance status and an above-normal value of carcinoembryonic antigen and carbohydrate antigen 19-9 are prognostic factors for poor survival.
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