Tumors of the Small Intestine

Descriptive Epidemiology

The histology and epidemiology of SI tumors differs geographically and ethnically. An average age-adjusted incidence of primary SI cancers of 1.9% per 100,000 men and 1.4 per 100,000 women has been reported in the USA. The incidence rates for all histologic types of SI neoplasia are higher in men than in women. The male-to-female ratio of incidence rates for SI carcinoids, adenocarcinomas and stromal tumors ranges from 1.1 to 1.5, and from 1.2 to 2.0 for SI lymphomas. ^, Globally, incidence rates of SI tumors differ inter- and intra-continentally, with the highest rates being observed in North America, Northern Europe, and Oceania, ^, and the lowest rates in Asian/Pacific Islanders and Hispanics. In the USA, the incidence rate of all SI cancers is higher in African Americans than in Caucasians ^, and race-based differences in histologic subtypes of SI tumors have been noted. Incidence rates for SI adenocarcinomas and malignant carcinoids are higher in African Americans than in whites, whereas incidence rates of stromal tumors and lymphomas are higher in whites. The incidence of SI cancers rises with age, beginning at 30 years, with a median age at diagnosis of 66 years. ^, The age-specific increase in incidence rates differs among histologic subtypes: there is a steep, continuous increase for adenocarcinomas up to the 9th decade; the increase in incidence rates plateaus at approximately 60 to 70 years of age for carcinoid tumors, stromal tumors and lymphomas; after age 70 years, the incidence of carcinoid tumors decreases.

Metastases to the SI from adenocarcinomas and sarcomas account for approximately 50% of all SI tumors. Among primary SI tumors, adenocarcinoma (24% to 52%), malignant carcinoid (17% to 41%), lymphoma (12% to 29%), and sarcomas (11% to 20%) are most common. ^{, ,} In 2000, carcinoid tumors surpassed adenocarcinoma as the most common SI tumor. Over the last 3 decades, overall incidence rates of SI tumors have increased at an annual rate of 2.1% and 2.6% for men and women, respectively. The increase was highest for GIST tumors with an annual increase of 11%. SI lymphomas and neuroendocrine tumors increased at an annual rate of 4% to 5%, whereas sarcomas and adenocarcinomas only increased at an annual rate of 1% to 2%. ^, In contrast, incidence rates of leiomyosarcomas and unspecific SI cancers decreased over time.

Tumor location in the SI is dependent on the histologic type of tumor. Of SI adenocarcinomas, 49% are found in the duodenum, 21% in the jejunum, and 15% in the ileum. In the setting of Crohn disease, adenocarcinomas more commonly occur distally in the ileum. Fifty-two percent and 30% of carcinoids and primary lymphomas are located in the ileum, whereas sarcomas are more evenly distributed throughout the SI. Interestingly, a relative increase in duodenal primary SI tumors has been noted with a parallel decrease in jejunal and ileal SI tumors.

Several hypotheses have been proposed to explain why SI tumors are relatively rare, but objective data are mostly lacking. Hypotheses include the following: (1) Rapid transit time and liquid luminal contents reduce mucosal contact with putative carcinogens, while mucosal enzymes, for example, benzpyrene hydroxylase, detoxify them. (2) Bacterial enzymes have been postulated to play a role in colonic carcinogenesis. When the intestinal microbiota is altered, as in SIBO, SI carcinomas develop with a higher frequency than expected. The SI, however, has relatively low bacterial counts (the upper two thirds of the SI contains low concentrations of aerophilic Gram-positive bacteria such as lactobacill and enterococci ), with an absence of anaerobes under normal conditions. (3) Stem cells located at the crypt base lie deeper in the SI than in the colon, perhaps reducing contact with luminal carcinogens. The rapid differentiation of stem cells into mature, non-proliferating enterocytes and goblet cells may also protect against factors that deregulate cell growth and promote cancer development. (4) Apoptosis involving damaged cells and potentially tumorigenic clones differs between the SI and colon. (5) Lymphoid tissue in the lamina propria and Peyer patches of the ileum may provide immune surveillance against neoplastic cells through IgA-rich secretions.

There is evidence of geographic correlation between SI and colon incidence rates for neoplasia, and shared dietary risk factors have been suggested. ^, It also has been noted that patients with colorectal cancer (CRC) are at increased incidence for SI tumors and vice-versa. Although these data suggest shared risk factors, the increasing rates of SI bowel tumors but decreasing rates of CRCs suggest yet unrecognized factors in the pathogenesis of primary SI malignancies.

Biology and Biochemical Changes

In comparison with CRC, relatively little is known about the molecular genetic events associated with the evolution of SI tumors. Human RAS genes encode guanine nucleotide-binding proteins that regulate intracellular signaling pathways. In a small but representative study, KRAS mutations were common in sporadic and Crohn disease-associated adenocarcinomas of the SI. KRAS mutations were present in all 4 sporadic carcinomas with contiguous adenomas, in 2 of 11 (18%) carcinomas without adenomas, and in 4 of 7 (43%) of Crohn disease-associated carcinomas. In the same study, alterations in the p53 gene product and allelic loss of chromosome 17p were present in 47% of sporadic SI adenocarcinomas, 33% of contiguous adenomas, and 71% of Crohn disease-associated carcinomas. Deletions of chromosome 17p involve the p53 tumor-suppressor gene, the product of which normally prevents cells with damaged DNA from progressing from the G ₁ phase to the S phase in the cell cycle and regulates apoptosis. In recent years, next-generation sequencing studies with larger sample sizes in the range of 28 to 317 samples, and the development of transgenic animal models, have confirmed the role of the abovementioned genes in SI carcinogensis and provided additional insights in the molecular profile of SI tumors. In SI adenocarcinoma, the most commonly mutated genes are KRAS (43% to 47%) and TP53 (41% to 48%); mutations in both of these genes is mutually exclusive. The rate of mutations in these genes also is influenced by location, with an increasing mutation rate of KRAS from duodenum to jejunum and ileum; the opposite was noted for TP53 mutation rates. In a transgenic mouse model for tumor-suppressor APC -inactivation and oncogenic KRAS -activation (KRAS ^V12G /Apc ^+/1638N ), mice developed duodenal adenomas and adenocarcinomas. Other genes that are commonly mutated in SI adenocarcinomas include APC (13% to 27%), SMAD4 (10% to 17%), ^, PIK3CA (9.6%), and ERBB2 and BRAF (6% to 9%) ; BRAFV600E mutations, however, are less common in SI adenocarcinoma than in colon carcinoma. ^, The role of APC in the molecular pathogenesis of SI adenocarcinomas is supported by its alterations in conditions known to put patients at risk for the development of SI adenocarcinomas and by animal models. The APC gene on the long arm of chromosome 5 (5q21) is mutated in the germ-line of persons with familial adenomatous polyposis (FAP) and these individuals frequently develop SI and periampullary adenomas and carcinomas. Genetic silencing of APC in mice results in SI adenoma formation, and compound heterozygote APC/SMAD4 knockout mice develop large numbers of adenomas, with malignant SI tumors found in more than half of the mice and periampullary adenocarcinomas found in 20%. ^,

Microsatellite instability can be found in 5% to 35% of SI adenocarcinomas. ^, These tumors arise in the setting of defective mismatch repair (MMR) and, therefore, a high mutation burden. Alterations in MMR genes are characteristic of patients with Lynch syndrome (see Chapter 126 ). MMR gene mutations in hMLH1 and hMSH2 were present in 15 of 42 (36%) Lynch syndrome-associated SI carcinomas in one series. Pathogenic germ-line mutations in genes including MLH1, MSH2, and MSH6 were identified in 81% of individuals with Lynch syndrome and SI tumors with loss of MMR protein expression in 89% of cases in another large series. DNA replication errors characterized by microsatellite instability have also been reported in 13% of sporadic SI adenocarcinomas. More recently, loss of MMR proteins was reported in 13% to 35% of patients with primary SI adenocarcinomas. ^,

SI neuroendocrine tumors (SI-NETs) are now the most common primary malignancies of the SI. In SI-NETs, loss of heterozygosity in chromosome 18 is frequent (78%) but focal point mutations are relatively rare. The most commonly mutated gene in SI-NET is the cell-cycle regulator CDKN1B , which is mutated in 10% of tumors. In 2 recent sequencing studies in which 48 and 55 tumor samples were examined, mutations of several cancer-related and therapeutically relevant genes were identified (i.e., in SRC , SMAD , AURKA , EGFR , HSP90, and PDGFR genes), although common mutations were present in only 1% to 10% of samples within and between the studies. ^, Data on the concordance between genetic alterations in the primary tumor and metastases are inconsistent. Concordance rates of 40% to 85% have been reported for somatic copy number alterations and somatic single nucleotide variants in paired primary and metastatic tumor samples. ^, A common mechanism of aberrant gene expression in SI-NETs is epigenetic dysregulation (i.e., methylation, chromatin modification). Recently, genome-wide DNA methylation and gene expression were evaluated in 97 tumor samples—including primary tumors and hepatic metastases of SI-NETs—from 85 patients. Analysis of differentially methylated genes demonstrated enrichment in cancer-relevant pathways such as EGF receptor (EGFR), mammalian target for rapamycin (mTOR), and vascular endothelial growth factor (VEGF) pathways. Subsequent integrated methylation and gene expression analysis identified 21 epigenetically dysregulated genes. In 65% of the tumor samples, aberrant methylation was found in at least 10 of these 21 genes, suggesting epigenetic dysregulation as a frequent event in the carcinogenesis and/or tumor progression of SI-NETs. This methylation signature was specific to SI-NETs when compared with the Cancer Genome Atlas (TCGA) data from normal tissue and other GI malignancies. The most frequent differentially methylated genes included CDX1 , FBP1 , TMEM171 , GDAP1L1 , and CELSR3, with 82% of tumors demonstrating altered methylation in at least 4 of these 5 genes. Hypermethylation of the gastric inhibitory polypeptide receptor gene was noted in 74% of samples and its aberrant methylation and overexpression was positively correlated with the development of hepatic metastases.

GISTs contain gain-of-function mutations that affect 2 receptor tyrosine kinase genes, KIT and PDGFRA. KIT mutations are detected in 63% to 85% and PDGFRA mutations in 10% to 15% of GISTs. ^, KIT mutations are most frequent in exon 11 (70% to 75%), followed by exons 9 and 17, whereas PDGFRA mutations are most frequent in exon 18, followed by exon 12, and, rarely, exon 14. KIT activation is a crucial oncogenic mechanism in sporadic and familial GISTs. Mutations in KIT or PDGFRA predict prognosis and response to therapy with tyrosine kinase inhibitors (see later and Chapter 33 ). GISTs that carry KIT exon 11 mutations, for example, respond better to targeted treatment than tumors with wildtype KIT and PDFGRA , whereas both primary and secondary (acquired) mutations affecting the tyrosine kinase domain do not generally respond to imatinib. In multivariate analysis, KIT exon 11 mutations was found to be an independent prognostic factor, with patients harboring KIT exon 11 mutations having significantly longer overall survival than patients with wildtype KIT/PDGFRA . BRAF mutations are rare in GIST tumors but have been associated with imatinib resistance. Wildtype KIT/PDGFRA GIST can be stratified based on their levels of succinate dehydrogenase. In a large immunohistochemical study evaluating 1078 GIST tumors, 89% of succinate dehydrogenase-deficient KIT/PDGFRA wildtype GIST tumors were found to overexpress IGF1R.

Risk Factors and Associated Conditions

Numerous risk factors and associated conditions have been described with relation to tumors of the SI ( Box 125.2 ) and approximately 12% of SI adenocarcinomas develop in the setting of such predisposing factors. A recent prospective study of risk factors for adenocarcinomas and malignant carcinoids of the SI (the 2 most common tumor types) indicated that age ≥65 years was the only significant risk factor for adenocarcinomas, whereas male gender, BMI, and current menopausal hormone therapy use were positively associated with malignant carcinoids. Race, education, diabetes, smoking history, physical activity and alcohol intake were not associated with either histologic type. These findings differ, to some extent, from previous reports in which modestly increased odds ratios for cigarette smoking and for heavy alcohol intake were reported for adenocarcinomas and carcinoids in some, but not all, studies ; this is further supported by a recent meta-analysis that showed odds ratios of 1.51 and 1.24 for alcohol and smoking, respectively, as risk factors for small bowel adenocarcinomas. Several studies report a link between obesity and SI cancer, but this is not universal. A meta-analysis from Asia including data from 500,000 patients found a trend for increased SI cancers in patients with a BMI of greater than 27.6, but this did not reach statistical significance. Studies based on retrospective medical record review do not often take into account the amount and duration of exposures, and dose-response trends, or adjust for other influences that may explain these differences. Weekly or more frequent consumption of red meat or salt-cured foods, frequent intake of foods rich in heterocyclic amines (fried bacon, ham, barbecued or smoked meat and fish), high sugar intake, intake of bread, pasta, and rice have all been associated with an increased risk of SI adenocarcinoma in small older studies, with reports of an inverse relationship with coffee, fish, vegetables and fruit.

FAP patients have a lifetime risk of 90% to 100% for duodenal adenomas. A relative risk (RR) for duodenal adenocarcinoma of 331 and a RR of 124 for ampullary carcinoma has been reported in patients with FAP compared with the general population. Mean ages of diagnosis were 53 years for duodenal carcinoma and 49 years for ampullary carcinoma. A prospective study in 5 Nordic countries and the Netherlands demonstrated that at first endoscopy, 65% of individuals with FAP had duodenal adenomas at a median age of 38 years. The cumulative incidence of adenomatosis at 70 years was 90%. The cumulative incidence of cancer was 4.5% at age 57 years. SI adenomas and adenocarcinomas elsewhere in the bowel have also been reported in recent studies using capsule endoscopy and single balloon enteroscopy. Inactivation of one of the base excision repair (BER) genes ( MYH or MUTYH ) is a cause of an autosomal recessive form of FAP (MUTYH-associated polyposis or MAP). Duodenal polyposis is found in up to 18% of MAP patients and SI cancers also have been reported in MAP. Periodic screening of the proximal SI in this setting is recommended in a manner similar to FAP (see later). ^, Lynch syndrome is an inherited disease in which colon cancers arise in discrete adenomas, but polyposis (i.e., hundreds of polyps) does not occur. SI cancer is part of the tumor spectrum of Lynch syndrome, with a prevalence of SI neoplasias of 1.8% and an estimated life-time risk for the development of SI adenocarcinoma of 4%. ^, In a report from a Swedish registry, the RRs of SI cancer in families that fulfilled the Amsterdam II and Bethesda criteria were 36.1 and 5.75, respectively. Data from the Colon Cancer Family Registry for 764 carriers of MMR gene mutations who had previous CRC demonstrated a primary SI cancer rate of 2.2% with a cumulative 20-year risk of 4%. The standardized incidence ratio of SI cancers was 73, consistent with an elevated risk for SI cancers in patients with MMR gene mutations and a prior history of CRC malignancies. Patients with Lynch syndrome generally present with SI cancer 10 to 20 years earlier (reported median age 39 to 55 years) than the general population and SI cancer may be the first manifestation of Lynch syndrome. Tumors in Lynch syndrome may be distributed throughout the SI but are most commonly found in the duodenum (47% to 65%). ^,

Hamartomatous polyposis syndromes are a group of disorders marked by the finding of multiple hamartomatous polyps in the GI tract. One of the better known of the hamartomatous syndromes is Peutz-Jeghers syndrome, an autosomal-dominant disease, which, in most families, has been mapped to chromosome 19p13.3 and the STK11 (serine threonine kinase 11) gene. Extracolonic cancers are common in Peutz-Jeghers syndrome, occurring in 50% to 90% of patients (SI, stomach, pancreas, esophagus, ovary, lung, uterus, breast); the RR for all cancers is 15.2 compared with the general population. The SI represents the most frequent site of cancer development, with an RR of development of adenocarcinoma of 520 compared with the general population. Patients often present with obstructive symptoms and may develop SI intussusception.

Juvenile polyposis syndrome is an autosomal-dominant disease in which hamartomatous polyps may be limited to the colon or the stomach, or occur throughout the GI tract. Mixed juvenile and adenomatous polyps have also been reported. The RR for SI cancer is unclear, but cancers of the duodenum have been reported. Patients may present with bleeding, intussusception, and obstruction. A life-threatening protein-losing enteropathy has been reported in some patients. Germ-line mutations in the SMAD4 (chromosome 18q21.1) and PTEN (chromosome 10q23) genes have been reported in juvenile polyposis syndrome.

Patients with Crohn disease are at increased risk for primary SI malignancies, with an overall standardized incidence ratio of 8.3. Although adenocarcinomas are the most common type of primary SI malignancy, with standardized incidence ratios of up to 46, the overall risk of SI adenocarcinoma is relatively low, with a cumulative risk of 0.2% and 2.2% after 10 and 20 years of Crohn disease. ^, Other primary SI cancers reported in patients with Crohn disease include lymphomas and neuroendocrine carcinomas, although both are rare. A recent longitudinal study (241,620 person-years) following 23 patients reported a standardized incidence ratio of 6.8 for SI-NETs. The standardized incidence ratio for the development of SI lymphoma in the absence of immunotherapy was 1.37 in a recent retrospective analysis of 1420 cases. A dysplasia-carcinoma sequence occurs in the SI in Crohn disease similar to that of the colon and rectum. Crohn disease–associated SI carcinomas and dysplasias are accompanied by frequent genetic alterations in K- ras and p53 . SI adenocarcinomas in Crohn disease are mostly located in the ileum.

Diversion of bile to the lower SI either surgically or by feeding cholestyramine increases the yield of SI carcinomas in carcinogen-treated animals. Therefore, cholecystectomy, which increases delivery of bile to the proximal bowel, could theoretically lead to an increased risk of both small and large bowel cancer. Indeed, a large retrospective analysis of 278,460 patients who had undergone cholecystectomy suggested that patients who underwent cholecystectomy had an increased risk of SI adenocarcinoma and carcinoid, with standardized incidence ratios of 1.77 and 1.16. The risk of SI tumors decreased with increasing distance from the common bile duct providing support for the association of bile acids with the development of small bowel malignancies.

An increased risk of both SI adenocarcinoma and non-Hodgkin lymphoma has been associated with celiac disease. The standardized incidence ratio for lymphoproliferative disease of patients with celiac disease compared with the general population is 2.8 and in the setting of persistent villus atrophy is 3.8. Lymphomas in the setting of celiac disease are usually of T-cell origin (enteropathy-associated T-cell lymphomas, EATLs). Adenocarcinoma may arise in focal areas of dysplasia.

Other conditions also carry an increased RR for SI neoplasia (see Box 125.2 ), but they are relatively rare. Patients with urinary diversion to the SI (e.g., ileal loop conduits) appear to have an increased risk of carcinoma. Adenocarcinomas arise in the mucosa of ileostomies and ileal pouches in patients with IBD and FAP, although this event is probably rare. Type 1 neurofibromatosis has been associated with development of SI GISTs.

Clinical Features

SI neoplasms may have some common clinical features but, for the most part, signs and symptoms vary with individual tumor type ( Table 125.1 ). Abdominal pain may result from partial or complete SBO, intussusception, or ischemia. Obstruction may be the result of the physical bulk of the tumor, wall infiltration, or annular constriction. Carcinoid tumors may cause an intense desmoplastic reaction, which, in turn, may result in intestinal buckling or kinking. Intussusception may occur with benign polypoid lesions, accounting for half of adult intussusception, and is common in patients with GISTs. Occult GI blood loss is another common feature of benign and malignant SI tumors. With ulcerated GISTs, however, bleeding may be acute and brisk. Weight loss is especially common and pronounced in patients with SI lymphoma.

Adenocarcinoma

Adenocarcinoma is the second most common primary malignant disease of the SI (24% to 52% of SI malignancies) behind neuroendocrine malignancy, with the majority of tumors outside the setting of IBD occurring in the duodenum. The epidemiology of SI adenocarcinoma is discussed earlier. Adenocarcinomas arise from adenomas or dysplastic changes of the SI (see section “Pathology, Natural History, and Staging”). Adenomas and adenocarcinomas of the SI, and especially of the duodenum and ampulla of Vater, are most frequently encountered in the setting of FAP. There is no clear association between the site of mutation in the APC gene and the severity of duodenal polyposis. A number of classifications describe the severity of duodenal polyposis; the most commonly used is the Spigelman Classification, which takes into account number, size, histology and severity of dysplasia of polyps. A 10-year prospective study of 114 patients found that Spigelman stages II, III and IV are correlated with the risk of duodenal cancer at a rate of 2%, 2%, and 36%, respectively. Most FAP patients present with stage II and III disease. Age at presentation appears to increase 4 to 11 years with advancing stages. ^{, ,}