Version May 2024
INTRODUCTION — The diagnosis of small bowel tumors is often difficult due to the rarity of these lesions and the nonspecific and variable nature of the presenting signs and symptoms. Thus, delay in diagnosis is common, which may result in the discovery of disease at a late stage and a poor treatment outcome.
Several tumors can arise within the small bowel, both malignant (adenocarcinomas, neuroendocrine tumors, lymphomas, and sarcomas) and benign (adenomas, leiomyomas, lipomas). Epidemiology, clinical manifestations, and specific tumor types will be reviewed here. Diagnosis, staging, and management of small bowel tumors are discussed separately. (See "Diagnosis and staging of small bowel neoplasms" and "Treatment of small bowel neoplasms".)
TYPES OF TUMORS — A variety of tumors, both malignant and benign, may arise within the small intestine.
Malignant tumors — The distribution of histologic types of small bowel malignant tumors is changing, largely because of the increasing incidence of neuroendocrine (carcinoid) tumors (NETs). In 1987, the most common histologic types of malignant tumors of the small intestine in population-based registry data from the Surveillance, Epidemiology and End Results (SEER) program of the National Cancer Institute (NCI) were adenocarcinoma 45 percent, NET 29 percent, lymphoma 16 percent, and sarcoma 10 percent [1].
In the year 2000, NETs surpassed adenocarcinomas as the most common small bowel tumor reported to the National Cancer Database (NCDB) [2]. Between 1985 and 2005, the proportion of patients with NETs increased from 28 to 44 percent, while the proportion of adenocarcinoma decreased from 42 to 33 percent. The proportion of patients with stromal tumors and lymphoma remained essentially stable (17 and 8 percent, respectively).
Although these malignancies may be found throughout the different regions of the intestine, certain subtypes have a predilection for specific regions [1,3]. Adenocarcinoma is the most common malignancy affecting the duodenum, and NET is the most common tumor in the ileum, while sarcomas and lymphomas can develop throughout the entire small bowel [2,4]. The distribution of tumor subtypes according to small bowel location in a combined analysis of data from three registry-based series (the NCDB [1985 to 2005] and United States SEER [1973 to 2005] cohorts, and the Connecticut Tumor Registry [1980 to 2000] [5-7]) is depicted in the figure (figure 1) [8].
Largely as a result of these differences in distribution, the reported relative incidence of each histology varies considerably with the patient population under study [5,9,10].
Benign lesions — Benign lesions that may arise in the small bowel include adenomas, hamartomas, leiomyomas, fibromas, and lipomas [11].
EPIDEMIOLOGY — The following sections will discuss general aspects of the epidemiology of small bowel tumors. Specific epidemiologic aspects of the individual tumor types are discussed below.
Malignancies involving the small intestine are rare. In the United States, there are approximately 12,000 new cases and 2000 deaths from small bowel cancer annually [12]. Although the small intestine represents approximately 75 percent of the length and over 90 percent of the surface area of the alimentary tract, small bowel malignancies account for approximately 3 percent of all gastrointestinal tract neoplasms [12,13].
By contrast, over 150,000 new cases of large bowel cancer are diagnosed each year in the United States [12]. Several theories, based upon the unique microenvironment of the small intestine, have been proposed to explain the low rate of small bowel neoplasms relative to large bowel cancer [1,14]:
●The more dilute and liquid contents of the small bowel may cause less mucosal irritation than the more solid contents of the colon.
●The relatively rapid transit of intestinal contents through the small bowel may provide for a shorter exposure to carcinogens.
●The much lower bacterial load (particularly anaerobic bacteria) in the small bowel may result in less conversion of bile acids into potential carcinogens by anaerobic organisms.
●Benzpyrene, a known carcinogen present in food, is converted to less toxic metabolites by benzpyrene hydroxylase, which is present in higher concentrations in the small intestine compared with the stomach and colon.
●The increased lymphoid tissue and secretory immunoglobulin A (IgA), found in large quantities in the small bowel, may be protective.
While rates of large bowel cancer have been stable or decreasing over time, the incidence of small bowel cancer appears to be increasing, at least in the United States [2,5,6,15-17]. In older studies, reported age-adjusted incidence rates of small bowel cancer ranged from 1 to 3 per 100,000 population [4,9,16]. However, in a study analyzing the Connecticut Tumor Registry, a marked rise in the incidence of small bowel tumors over time was noted, with an incidence in the most recent time interval (1994 to 2000) of 14.8 cases per 100,000 population [5].
The degree to which the increased incidence is related to advances in diagnostic imaging is not known. However, much of the increase appears to be driven by a rising incidence of small bowel neuroendocrine tumors (NETs) [2]. (See "Clinical characteristics of well-differentiated neuroendocrine (carcinoid) tumors arising in the gastrointestinal and genitourinary tracts", section on 'Epidemiology' and 'Malignant tumors' above.)
The mean age at diagnosis of a small bowel neoplasm is 65 years old, with sarcoma and lymphoma presenting at a slightly younger age (60 to 62) than adenocarcinoma and NETs (67 to 68) [5,10]. There is a slight male predominance (male to female ratio of 1.5:1 [16]), and a number of studies report a higher incidence in Black than in White patients [1,16].
As a general rule, patients with small bowel adenocarcinoma have a higher incidence of secondary malignancies involving the colon, rectum, ampulla of Vater, endometrium, and ovary [18,19]. Conversely, patients with colon adenocarcinoma have an increased risk of small bowel adenocarcinoma [20]. These findings suggest that similar underlying genetic or environmental factors are involved in the carcinogenesis of adenocarcinomas arising in both the small and large intestine. A number of known heritable cancer syndromes are associated with adenocarcinoma of both the large and small bowel, including hereditary nonpolyposis colorectal cancer (HNPCC), familial adenomatous polyposis (FAP), and Peutz-Jeghers syndrome. (See 'Pathogenesis, risk factors, and predisposing conditions' below.)
PATHOGENESIS, RISK FACTORS, AND PREDISPOSING CONDITIONS — The etiology of most small bowel tumors is unknown, although a number of risk factors and predisposing conditions have been described.
Adenocarcinoma
The adenoma-carcinoma sequence — Most small bowel adenocarcinomas arise from adenomas, and the available data suggest an adenoma-carcinoma sequence driven by a multistep process of specific genetic changes similar to that described for colorectal cancers, but less well documented or understood (figure 2) [8,21]. Single, specific germline mutations underlie some common inherited syndromes (eg, familial adenomatous polyposis [FAP], hereditary nonpolyposis colorectal cancer [HNPCC]), while sporadic cancers result from the stepwise accumulation of multiple somatic mutations, possibly acquired as a result of exposure to carcinogens within the intestinal lumen. (See "Molecular genetics of colorectal cancer".)
As is seen in colon cancer, the increasing size of adenomas and the presence of villous features are both risk factors for the development of invasive carcinoma within an adenoma [22]. (See "Overview of colon polyps".)
Molecular profiling — Increasingly, biomarker expression is driving therapeutic decision making in patients with advanced refractory cancer. Small bowel adenocarcinomas have a different genomic profile compared with colorectal and gastric adenocarcinomas, including variations in the frequency and types of alterations of KRAS, adenomatosis polyposis coli (APC), BRAF, human epidermal growth factor receptor 2 (ERBB2/HER2), ERBB3, and other genes [23,24]. These variations might be contributing to the disparities in outcomes among these tumor types, and they also might provide some opportunity for targeted therapeutics in this disease. (See "Treatment of small bowel neoplasms", section on 'Molecular profiling and targeted therapies'.)
In one report, a total of 7559 patients (317 small bowel adenocarcinomas, 889 gastric carcinomas, and 6353 colorectal cancers) were analyzed on either a 236 or 315 cancer-related gene panel by Foundation Medicine, and alterations were compared across these three tumor types.
●The main differences in the frequency of genomic alterations between small bowel adenocarcinoma and colorectal cancer were in the APC (26.8 percent in small bowel versus 75.9 percent in colorectal cancer, p<0.001) and cyclin-dependent kinase inhibitor 2A (CDKN2A; 14.5 percent in small bowel versus 2.6 percent in colorectal cancer, p<0.001) genes.
●The main differences between small bowel adenocarcinoma and gastric cancer were in KRAS (53.6 percent in small bowel versus 14.2 percent in gastric cancer, p<0.001), APC (26.8 versus 7.8 percent, p<0.001), and mothers against decapentaplegic homolog 4 (SMAD4; 17.4 versus 5.2 percent, p<0.001).
●Molecular differences between small bowel subsites (duodenum, jejunum, ileum) were minimal, suggesting common genomic features across the small bowel.
In a separate report, exome sequencing performed on 106 primary small bowel adenocarcinomas demonstrated four mutational signatures: signature 6, associated with mismatch repair (MMR) deficiency; signature 1A, associated with older age; and signatures 17 and U2, two signatures of unknown cause [24].
These efforts demonstrate small bowel adenocarcinomas to have their own molecular profile differing from other neighboring gastrointestinal tract cancers.
Hereditary cancer syndromes — An increased risk of adenocarcinoma is seen in a number of familial cancer syndromes, many of which are linked to specific inherited genetic abnormalities:
●HNPCC is an inherited condition characterized by loss of DNA MMR, which is caused by a germline mutation in one allele of a MMR gene and inactivation of the second allele by mutation, loss of heterozygosity, or epigenetic silencing by promoter hypermethylation. The biologic footprint of deficient DNA MMR is high levels of microsatellite instability (MSI-H). Affected individuals are at risk for colorectal cancer and for several extracolonic cancers, including adenocarcinomas of the small bowel and endometrium. As with colorectal cancer, HNPCC is thought to be responsible for approximately 5 to 10 percent of small bowel adenocarcinomas [25,26]. (See "Lynch syndrome (hereditary nonpolyposis colorectal cancer): Clinical manifestations and diagnosis".)
●The Peutz-Jeghers syndrome is an autosomal dominant polyposis disorder characterized by multiple hamartomatous polyps throughout the intestinal tract and a marked increase risk for adenocarcinoma of both the large and small bowel [27]. (See "Peutz-Jeghers syndrome: Clinical manifestations, diagnosis, and management".)
●FAP is associated with a germline mutation in the APC gene that promotes tumor formation in primarily the large intestine but also the duodenum. These patients have multiple duodenal polyps (with a predilection for the ampullary region), which can undergo malignant transformation into an adenocarcinoma. In addition, patients with FAP are predisposed to the development of desmoid tumors, which develop within the small bowel or its mesentery and are often multiple in number (image 1) [28,29]. (See "Desmoid tumors: Epidemiology, molecular pathogenesis, clinical presentation, diagnosis, and local therapy" and "Clinical manifestations and diagnosis of familial adenomatous polyposis" and "Ampullary adenomas: Clinical manifestations and diagnosis".)
Dietary factors, tobacco, and obesity — A number of dietary factors have been associated with an increased risk of a small bowel cancer in case-control studies, including intake of alcohol, refined sugar, red meat, and salt-cured and smoked foods [14,17,30,31]. Tobacco use was associated with cancer risk in two studies, while others suggest no increased risk in smokers [30,32,33]. Studies on the relationship between obesity and small bowel malignancy are conflicting, with some showing an increased risk in obese patients [34-36], some a decreased risk [33], and others no effect [14].
Cystic fibrosis — Patients with cystic fibrosis have an elevated risk of small bowel cancer. In a meta-analysis, the pooled standardized incidence ratio was 18.94, 95% CI 9.37-38.27, and it was two- to fivefold higher following lung transplantation [37]. (See "Cystic fibrosis: Overview of gastrointestinal disease", section on 'Gastrointestinal cancer'.)
Chronic inflammation — A role for chronic inflammation in the etiology of both adenocarcinoma and lymphoma is suggested by the fact that small bowel disorders characterized by chronic mucosal inflammation predispose to malignancy. Inflammatory bowel disease, in particular Crohn disease, predisposes to adenocarcinoma within the involved area of the small intestine. The risk increases with both the extent and duration of small bowel involvement [38-40]. (See "Clinical manifestations, diagnosis, and prognosis of Crohn disease in adults".)
An increased risk of small bowel lymphoma is seen in patients with chronic immunodeficiency states and autoimmune disorders, including celiac disease [41,42]. Patients with celiac disease also have a higher risk for small bowel adenocarcinoma [43]. (See "Clinical presentation and diagnosis of primary gastrointestinal lymphomas" and "Epidemiology, pathogenesis, and clinical manifestations of celiac disease in adults".)
Neuroendocrine tumors — The pathogenesis and risk factors for neuroendocrine tumors arising in the small bowel are almost entirely unknown, apart from an association with multiple endocrine neoplasia type I (MEN-I) in rare cases [44,45]. (See "Multiple endocrine neoplasia type 1: Clinical manifestations and diagnosis".)
CLINICAL PRESENTATION — The general aspects of the clinical presentation of benign and malignant small bowel tumors are discussed here. Specific symptoms associated with individual tumor types are discussed below. (See 'Types of tumors' above.)
The most common presenting symptom of a small bowel tumor is abdominal pain, which is present in 44 to 90 percent of patients [46-49]. Pain is typically intermittent and crampy in nature. Weight loss occurs in 24 to 44 percent, nausea and vomiting in 17 to 64 percent, and gastrointestinal bleeding in 23 to 41 percent. Intestinal obstruction is more common than perforation, occurring in 22 to 26 percent compared with 6 to 9 percent, respectively [46-48].
As compared with those with benign tumors, patients with malignant small bowel neoplasms are more often symptomatic, and the majority of symptomatic small bowel tumors are malignant [46,50]. Furthermore, symptoms at presentation tend to differ between benign and malignant tumors. As an example, in a report of 49 patients with a small bowel neoplasm (17 benign and 32 malignant), 47 percent of benign tumors were asymptomatic (versus 6 percent of malignant tumors), and when symptomatic, they more commonly presented with acute gastrointestinal hemorrhage (29 versus 6 percent of malignant tumors). Malignant tumors more commonly presented with abdominal pain (63 versus 24 percent) and weight loss (38 versus 0 percent). Despite these data, clinical presentation alone does not permit the distinction between a benign versus a malignant lesion.
The often vague and nonspecific nature of the symptoms makes early diagnosis of a malignant small bowel tumor difficult. There may be a significant delay from onset of symptoms to diagnosis (in one series, averaging 30 weeks [46]). As a result, by the time a patient becomes symptomatic, their disease is usually advanced, with either involvement of regional lymph nodes or distant metastatic sites.
The differential diagnosis is broad given the nonspecific symptoms. More common causes of small bowel stricturing or obstruction include adhesions, hernia entrapment, inflammatory bowel disease, endometriosis, splenosis, and complications from appendicitis or diverticulitis.
ADENOCARCINOMA — Adenocarcinomas represent from 25 to 40 percent of primary small bowel malignancies [1,2,5,9,10,49,51]. They usually present between the ages of 50 to 70, and there is a slight male predominance. Age of onset tends to be lower in patients with predisposing conditions, such as Crohn disease [25,27,52,53].
As noted above, the risk of small bowel adenocarcinoma is higher in patients who have had colorectal cancer, suggesting a possible common etiology [20]. (See 'Epidemiology' above.)
Also as noted above, inherited syndromes, such as hereditary nonpolyposis colorectal cancer (HNPCC) or familial adenomatous polyposis (FAP), are responsible for fewer than 10 percent of small bowel adenocarcinomas [54,55]. Patients with HNPCC are at increased risk for adenocarcinoma throughout the small bowel, while FAP increases the risk for both adenomas and adenocarcinomas of the duodenum. (See 'Hereditary cancer syndromes' above.)
Location — The incidence of adenocarcinoma is highest in the duodenum (picture 1) and decreases progressively throughout the rest of the small intestine. In two large single-institution series of patients with small bowel adenocarcinoma, 65 and 57 percent of cases arose in the duodenum [56,57].
Explanations for the predilection to the initial part of the small bowel include the metabolism or dilution of ingested carcinogens in transit through the small bowel or interactions of carcinogens with pancreaticobiliary secretions [58]. The possible etiologic role of pancreaticobiliary secretions is supported by a study evaluating 213 cases of duodenal adenocarcinoma identified from the Los Angeles County Tumor Registry, in which the exact subsite within the duodenum was identified. Fifty-seven percent of cases occurred in the second portion of the duodenum, consistent with a primarily periampullary distribution [58].
Crohn disease — An exception to the predominantly proximal location is in patients with Crohn disease. Seventy percent of adenocarcinomas that arise in this setting are in the ileum, the primary site of the inflammatory process. (See "Surveillance and management of dysplasia in patients with inflammatory bowel disease".)
The development of an adenocarcinoma in patients with Crohn disease should be suspected in those with longstanding disease who develop a change in their clinical status, such as an obstruction that fails to resolve with usual medical treatments [59,60]. The risk for adenocarcinoma is directly related to both the extent of small bowel involvement and the duration of Crohn disease. In one report, the cumulative risk of a small bowel adenocarcinoma in patients with small bowel Crohn disease was 0.2 percent at 10 years and 2.2 percent at 25 years [61]. The diagnosis is rarely made preoperatively since the symptoms are similar to those of Crohn disease with an inflammatory or fibrous stricture [52]. (See "Clinical manifestations, diagnosis, and prognosis of Crohn disease in adults".)
Presenting symptoms — The clinical presentation of adenocarcinoma of the small bowel is nonspecific, with the most frequent symptom being abdominal pain. In a series of 491 patients with small bowel adenocarcinoma, presenting symptoms were as follows [57]:
●Abdominal pain – 43 percent
●Nausea and vomiting – 16 percent
●Anemia – 15 percent
●Overt gastrointestinal tract bleeding – 7 percent
●Jaundice – 6 percent
●Weight loss – 3 percent
●Other or no symptoms – 9 percent
An obstructed duodenal adenocarcinoma may present with vomiting due to a gastric outlet obstruction, while in those with more distal lesions, severe cramping abdominal pain may be the presenting symptom. Intestinal obstruction can be caused by progression of an apple core lesion (image 2) or by a large intraluminal polypoid mass.
Largely because of the vague nature of symptoms, the majority of patients have advanced disease (stage III or IV (table 1)) at diagnosis. In a large series of patients with small bowel adenocarcinoma derived from the National Cancer Database (NCDB), the distribution of stage at diagnosis was as follows [62]:
●Stage 0 – 3 percent
●Stage I – 12 percent
●Stage II – 27 percent
●Stage III – 26 percent
●Stage IV – 32 percent
The diagnostic and staging evaluation and treatment of small bowel adenocarcinoma is discussed elsewhere. (See "Diagnosis and staging of small bowel neoplasms".)
NEUROENDOCRINE TUMORS — Neuroendocrine tumors (NETs) of the small bowel have a morphologically unique appearance and are characterized by the production of biologically active amines, which are stored in neurosecretory granules. Secretion of these products by the tumor cells can result in a variety of clinical syndromes caused by the secreted product:
●The vast majority are well-differentiated (grade 1 or 2) gastrointestinal NETs (GINETs), previously termed carcinoid tumors (table 2). Carcinoid syndrome is the term applied to a constellation of symptoms mediated by various humoral factors elaborated by some well-differentiated NETs of the digestive tract and lungs, which synthesize, store, and release a variety of polypeptides, biogenic amines, and prostaglandins (table 3). Some of these tumor products are responsible for carcinoid syndrome, but the relative contributions of each and the specificity of any for particular components of the syndrome are uncertain (table 4). More than 90 percent of patients with carcinoid syndrome have metastatic disease from a small bowel primary NET, typically to the liver. (See "Pathology, classification, and grading of neuroendocrine neoplasms arising in the digestive system", section on '2010 and 2019 World Health Organization classification' and "Clinical features of carcinoid syndrome" and "Diagnosis of carcinoid syndrome and tumor localization".)
●Other functioning NETs of the small bowel that produce specific clinical syndromes are rare when compared with these well-differentiated GINETs. The most common is a gastrinoma of the duodenum, which is defined by the associated clinical syndrome of excess gastrin secretion (Zollinger-Ellison syndrome). Although the majority of gastrinomas, 85 percent, are localized to the pancreas, approximately 15 percent will be found in the upper duodenum. (See "Zollinger-Ellison syndrome (gastrinoma): Clinical manifestations and diagnosis".)
●Other even more rarely reported NETs arising in the small bowel include duodenal somatostatinomas, paragangliomas, and high-grade (poorly differentiated) neuroendocrine carcinomas, which are rarely, if ever, functioning (table 2). (See "Pathology, classification, and grading of neuroendocrine neoplasms arising in the digestive system", section on '2010 and 2019 World Health Organization classification' and "Somatostatinoma: Clinical manifestations, diagnosis, and management" and "High-grade gastroenteropancreatic neuroendocrine neoplasms".)
Well-differentiated gastrointestinal neuroendocrine tumors — Most GINETs arising in the small bowel are typically well-differentiated (grade 1 or 2 (table 5)) NETs, most of which are characterized by an indolent disease course [63]. Notably, duodenal NETs may have a more heterogenous disease course, with a high rate of metastasis both at the time of diagnosis and following resection, even if well differentiated [64].
In modern series, NETs represent approximately 40 percent of primary small intestinal malignancies [2,5,9,10]. They have been reported in patients from 20 to 80 years old, with the highest incidence in the 60s.
Grossly, these tumors appear as firm intramucosal or submucosal nodules, with a yellow cut surface due to their high lipid content. They tend to infiltrate the bowel wall and may extend through the serosa, causing shortening and thickening of the mesentery due to an intense associated desmoplastic reaction (image 3). Microscopically, solid nests of uniform small cells with round or oval nuclei are present with a surrounding intense desmoplastic reaction (picture 2). They demonstrate little or no cellular pleomorphism, hyperchromasia, or increased mitotic activity. (See "Pathology, classification, and grading of neuroendocrine neoplasms arising in the digestive system".)
Small bowel well-differentiated GINETs are most commonly found in the ileum, within 60 cm of the ileocecal valve. The presence of multiple synchronous nodules in 30 percent of patients mandates careful inspection of the entire small intestine to exclude other sites of disease [54].
Because of their indolent growth, most well-differentiated small bowel GINETs are asymptomatic at presentation (ie, there are no symptoms of local obstruction or carcinoid syndrome) and found only incidentally. Symptoms generally relate to mass effects from the primary or metastatic tumors, or they may be caused by tumor production of bioactive amines (carcinoid syndrome):
●The most common syndrome caused by tumor production of bioactive amines is carcinoid syndrome, which usually does not occur until the bioactive amines have gained access to the systemic circulation (typically in the setting of liver metastases). The most common symptoms are watery diarrhea and flushing. (See "Clinical features of carcinoid syndrome".)
●In symptomatic patients who do not have carcinoid syndrome, abdominal pain is the most common initial symptom, occurring in approximately 40 percent [55]. The pain is most often vague and nonspecific. Intermittent obstruction occurs in 25 percent of all small intestinal well-differentiated GINETs. Obstruction may be caused by intraluminal tumor, but often results from mesenteric kinking and distortion brought on by tumor invasion and a secondary desmoplastic response [65]. The latter produces a characteristic radiographic abnormality: a combination of abrupt angulation with a filling defect in the small bowel (image 4).
●Pain may also arise from vascular compromise secondary to large bulky mesenteric nodal metastasis, mesenteric vascular invasion, and/or microvascular metastasis. Possibly contributing to the ischemic process is the vasospastic effect of serotonin produced by the tumor (see below).
Metastatic disease, which is present in 90 percent of symptomatic patients with carcinoid syndrome, correlates not only with the depth of invasion and location, but also the size of the primary lesion. For NETs <1 cm, the risk of distant metastasis is 0 to 2 percent for appendiceal as compared with 15 to 18 percent for small bowel primaries. In contrast, once NETs exceed 2 cm, 47 percent of small bowel primaries will have metastasized to liver; lungs and bone are affected less frequently (table 6).
The current (2017) Tumor, Node, Metastasis (TNM) classification and staging of small bowel NETs (as adopted by the American Joint Committee on Cancer [AJCC], the Union for International Cancer Control [UICC] [66], and the European Neuroendocrine Tumor Society [ENETS] [67]) includes separate staging tables for NETs of the duodenum/ampulla (table 7) [68] and tumors arising in the jejunum and ileum (table 8) [69].
The clinical characteristics of well-differentiated small bowel GINETs are addressed in more detail separately. (See "Clinical characteristics of well-differentiated neuroendocrine (carcinoid) tumors arising in the gastrointestinal and genitourinary tracts", section on 'Jejunoileal small bowel tumors'.)
Carcinoid syndrome — Well-differentiated GINETs are characterized by their ability to secrete serotonin and other bioactive products (table 3); the majority of patients with carcinoid syndrome have metastatic disease, typically involving the liver. This is because symptoms are most common when the secretory products of these tumors gain direct access to the systemic circulation, thus avoiding metabolism in the liver. This scenario occurs most commonly in the presence of hepatic metastases. (See "Clinical features of carcinoid syndrome", section on 'Pathophysiology'.)
However, at least some data support the view that carcinoid syndrome might be more common in locoregional disease than previously thought. This was illustrated in a population-based series of 9512 GINETs arising in individuals aged 65 or over and derived from the linked Surveillance, Epidemiology, and End Results (SEER)-Medicare database [70]. Among patients with small bowel primary NETs, the rates of carcinoid syndrome at diagnosis for patients with localized, regional, and distant disease were 155 of 817 (19 percent), 248 of 670 (37 percent), and 242 of 436 (56 percent), respectively. These data suggest that unappreciated hepatic metastases or carcinoid syndrome in locoregional disease may be more common than previously reported [71-73], especially in small bowel primaries.
The most common symptoms associated with carcinoid syndrome are watery diarrhea and flushing (table 4). The flush is often dramatic and manifests as an intense purplish color on the upper body and arms; it can be precipitated by consuming alcohol, blue cheese, chocolate, or red wine or with exercise. Repeated attacks can lead to the development of telangiectasias and permanent skin discoloration. (See "Clinical features of carcinoid syndrome".)
A life-threatening form of carcinoid syndrome called carcinoid crisis is usually precipitated by a specific event, such as anesthesia, surgery, or chemotherapy. The manifestations include an intense flush, diarrhea, tachycardia, hypertension or hypotension, bronchospasm, and alteration of mental status. Prevention and management are discussed elsewhere. (See "Treatment of the carcinoid syndrome", section on 'Carcinoid crisis: prevention and management'.)
PRIMARY GASTROINTESTINAL TRACT LYMPHOMA — Lymphoma may arise as a primary neoplasm in the intestinal tract or as a component of systemic disease with gastrointestinal (GI) involvement. The diagnosis of a primary GI lymphoma requires the following [74]:
●No peripheral or mediastinal lymphadenopathy
●A normal white blood cell count and differential on the peripheral blood smear
●Tumor involvement must be predominantly in the GI tract
●No evidence of liver or spleen involvement [75,76]
Primary GI tract lymphoma is the most common extranodal form of lymphoma; the stomach and small bowel are the most common sites. As an example, in a study of 371 patients registered in a German multicenter treatment study for GI lymphomas, the following sites were involved [77] (see "Clinical presentation and diagnosis of primary gastrointestinal lymphomas"):
●Stomach – 75 percent
●Small bowel (including duodenum) – 9 percent
●Ileocecal region – 7 percent
●More than one GI site – 6 percent
●Rectum – 2 percent
●Diffuse colonic involvement – 1 percent
In the Middle East, 75 percent of GI lymphomas originate in the small bowel and are associated with immunoproliferative small intestinal disease (IPSID); synonyms include Mediterranean lymphoma and alpha heavy chain disease. By contrast, small intestinal lymphomas are less common in industrialized nations and are not of the IPSID type. (See "Clinical presentation and diagnosis of primary gastrointestinal lymphomas".)
In the United States, small bowel lymphoma occurs predominantly in adults, peaking in the seventh decade, and 60 percent of patients are male [78]. Some of the predisposing conditions include:
●Autoimmune diseases
●Immunodeficiency syndromes (eg, acquired immunodeficiency syndrome [AIDS])
●Long-standing immunosuppressive therapy (eg, post-transplantation)
●Crohn disease
●Radiation therapy
●Nodular lymphoid hyperplasia
The incidence of primary intestinal lymphoma in the United States doubled between 1985 and 1990 [79]. Among the factors implicated in this increase are the increasing number of immunocompromised patients (eg, AIDS, transplantation recipients) and the increasing immigration from resource-limited countries.
Lymphomas arise from the lymphoid aggregates in the submucosa. The distribution of lymphoma in the small intestine parallels the distribution of lymphoid follicles, with the lymphoid-rich ileum representing the most common location. As with sarcoma, lymphomas are characteristically bulky tumors; approximately 70 percent are larger than 5 cm in diameter at presentation.
Most patients present with abdominal pain, anorexia, and weight loss (table 9). Less commonly, infiltration of the mucosa can result in ulceration and bleeding, and extension to the serosa and adjacent tissues may result in a large obstructing mass with or without intussusception and crampy abdominal pain (image 5A-B). The risk of perforation depends on the site of GI tract involvement; perforation is seen in 9 percent of small bowel lymphomas and only 2 percent of gastric lymphomas [77]. (See "Clinical presentation and diagnosis of primary gastrointestinal lymphomas".)
Histologically, these non-Hodgkin lymphomas may be low or high grade, and they may be of B-cell or T-cell origin. The Revised European-American Lymphoma (REAL)/World Health Organization (WHO) classification system, as is used for other non-Hodgkin lymphomas, is predominantly used for classification [80,81], although an alternative classification system for primary GI lymphomas has been proposed [82]. The B-cell lymphomas that most often involve the GI tract consist of the mucosa associated lymphoid tissue (MALT) type, diffuse large B-cell, mantle cell, and Burkitt and Burkitt-like variants. MALT type tumors occur most often in the stomach, while mantle cell lymphoma has a predilection for the colon and small intestine. The less common T-cell lymphomas are most often jejunal. Primary or secondary involvement of the GI tract by Hodgkin lymphoma is extremely rare [83]. (See "Clinical presentation and diagnosis of primary gastrointestinal lymphomas".)
Histologic and clinical factors associated with prognosis include histological subtype of non-Hodgkin lymphoma, histologic grade of differentiation, stage of disease, and International Prognostic Index (IPI). (See "Treatment of extranodal marginal zone lymphoma of mucosa associated lymphoid tissue (MALT lymphoma)".)
SARCOMA — Malignant mesenchymal tumors (sarcomas) represent approximately 10 percent of small bowel neoplasms [1,5,10,49,62,84] and are most common in the jejunum, the ileum, and a Meckel's diverticulum [85]. The most common type of intestinal sarcoma is gastrointestinal stromal tumor (GIST), accounting for 83 to 86 percent of cases [2,86].
Prior to the identification of GISTs by their molecular characteristics, leiomyosarcomas represented the most common small bowel sarcoma. However, the majority of these previously classified leiomyosarcomas in older studies are actually GIST tumors. In a report of 1091 tumors originally classified as "smooth muscle tumors of the small intestine," 906 (83 percent) were GISTs [86]. Among the 176 non-GISTs, there were 53 sarcomas (mostly phenotypically undifferentiated), 32 leiomyosarcomas (3 percent of the total), 13 leiomyomas, 14 sarcomatoid epithelial neoplasms, 13 desmoids, 8 schwannomas, and a variety of other unusual benign and malignant proliferations. (See "Clinical presentation, diagnosis, and prognosis of gastrointestinal stromal tumors".)
Histologically, GISTs can have a similar morphologic appearance to leiomyosarcomas (picture 3) and, thus, must be differentiated based on the expression of c-kit (the CD117 antigen), which represents a component of the KIT tyrosine kinase receptor. Activating mutations in the KIT oncogene are seen in over 80 percent of all GISTs. A subset of GISTs lacking KIT mutations have activating mutations in a related receptor tyrosine kinase, the platelet derived growth factor receptor alpha (PDGFRA). (See "Diagnosis and staging of small bowel neoplasms", section on 'Histology and differential diagnosis'.)
Common presenting symptoms of small bowel sarcomas, including GISTs, include pain, weight loss, bleeding, perforation, or a palpable mass [87]. Because they tend to enlarge extraluminally, obstruction is rare and typically a late-presenting symptom.
METASTATIC LESIONS — Secondary neoplastic involvement of the small intestine is more common than is primary small intestinal neoplasia, given the rarity of small bowel neoplasms. Extraluminal involvement of the small bowel is particularly common in the setting of widespread peritoneal carcinomatosis. Erosion through the bowel wall into the lumen can occur, particularly with tumors that have a predilection to involve the peritoneal cavity, such as ovarian, colon, and gastric cancer.
Hematogenous spread to the bowel is also possible. In studies in which direct extension from peritoneal metastases was excluded, the most common tumors to hematogenously spread to the small bowel were melanoma, lung, breast, cervix, sarcoma, and colon [88-90]. The small bowel is the most common site of gastrointestinal metastases in patients with metastatic melanoma (image 6) [91,92]. (See "Metastatic melanoma: Surgical management", section on 'Gastrointestinal tract'.)
BENIGN TUMORS — The frequency of benign tumors of the small bowel increases from the duodenum to the ileum [93]. Of the various histologic types, adenomas, leiomyomas, and lipomas are the most common.
Adenomas — There are three major types of benign small bowel adenomas: simple villous, tubular, and Brunner's gland adenomas.
Villous adenomas carry a significant potential for malignant transformation. Malignant cells are found in as many as 42 percent of duodenal villous adenomas [94], with an adenoma-carcinoma sequence comparable to that of colorectal cancer [95]. Familial adenomatous polyposis (FAP) is a risk factor; 80 percent of affected patients develop duodenal adenomas, which are often multiple [96]. Adenomas in the duodenum have a predilection for the papilla (ampulla of Vater). (See "Ampullary adenomas: Clinical manifestations and diagnosis" and "Familial adenomatous polyposis: Screening and management of patients and families".)
Coincident colonic adenomas are common in patients who have villous adenomas of the papilla or duodenum, suggesting that colonoscopy is an important component of the diagnostic workup. The usual presentation is with bleeding or obstruction of either the small bowel or biliary tract. On biopsy, the superficial part of the lesion may appear benign, with areas of adenocarcinoma in the deeper parts [94].
Tubular adenomas have a lower malignant potential. They are most common in the duodenum, and are usually asymptomatic, but may present with bleeding or obstruction.
There are no firm guidelines regarding the management of sporadic duodenal adenomas, though many gastroenterologists will remove them endoscopically in the absence of endoscopic features suggesting possible malignancy. Additionally, there are no definitive guidelines regarding the size of endoscopically resectable adenomas; however, most authors recommend that lesions ≥4 cm should not be treated endoscopically [97].
Endoscopic retrograde cholangiopancreatography, endoscopic ultrasound, intraductal ultrasound, and chromoendoscopy can all provide useful information in the evaluation of ampullary adenomas, including the extent of intraductal progression of the adenoma. (See "Ampullary adenomas: Management" and "Ampullary carcinoma: Epidemiology, clinical manifestations, diagnosis and staging", section on 'Endoscopic ultrasonography'.)
Patients with sporadic duodenal adenomas should also be screened for colorectal cancer as they are at increased risk for colorectal neoplasia [98-100].
A Brunner's gland adenoma is a rare small bowel neoplasm. It is caused by hyperplasia of the exocrine glands within the proximal duodenal mucosa. (See "Ampullary adenomas: Clinical manifestations and diagnosis".)
Leiomyomas — Leiomyomas are single, firm, gray or white, well-defined masses that arise in the submucosal layer of the wall of the small intestine (image 7). Microscopically, they consist of well-differentiated smooth muscle cells (picture 4). These tumors usually enlarge extraluminally and, therefore, are not detected until they outgrow their blood supply, causing central necrosis, ulceration, and bleeding into the bowel lumen.
In cases in which the tumor extends intraluminally, obstruction may be the initial symptom (picture 5). (See "Etiologies, clinical manifestations, and diagnosis of mechanical small bowel obstruction in adults".)
Leiomyomas are rare; in the series described above, they accounted for only 13 of the 1091 tumors originally classified as smooth muscle tumors of the small intestine (approximately 1 percent) [86].
Lipomas — Lipomas are the second most common benign tumor arising in the small bowel, and they occur mostly in the ileum and duodenum. They arise from either submucosal adipose tissue or serosal fat and may present with obstruction, small bowel bleeding, or as an incidental finding. These are submucosal lesions with homogeneous fatty tissue on a cut surface. They have a diagnostic low attenuation appearance on computed tomography (CT) scan (image 8A-B) [101].
Other benign lesions — Desmoid tumors, which are commonly seen in patients with FAP, may grow intraluminally, causing obstruction or, extraluminally, presenting as a palpable abdominal mass (image 1). (See "Desmoid tumors: Epidemiology, molecular pathogenesis, clinical presentation, diagnosis, and local therapy".)
Hemangiomas are rare lesions that usually present with bleeding. Hamartomas of the small intestine are seen in patients with the Peutz-Jeghers syndrome. (See "Peutz-Jeghers syndrome: Clinical manifestations, diagnosis, and management".)
SUMMARY
●A variety of tumors, both malignant and benign, may arise within the small intestine. The most common malignant tumors are well-differentiated neuroendocrine tumors (NETs), adenocarcinomas, lymphomas, and sarcomas. Benign lesions that may arise in the small bowel include adenomas, leiomyomas, fibromas, and lipomas. (See 'Types of tumors' above.)
●Malignancies involving the small intestine are rare; they account for only 2 percent of all gastrointestinal tract neoplasms and fewer than 0.4 percent of all cancers in the United States. (See 'Epidemiology' above.)
●The etiology of most small bowel cancers is unknown, although a number of risk factors and predisposing conditions have been described, particularly for small bowel adenocarcinomas. (See 'Hereditary cancer syndromes' above.)
●The most common presenting symptom of a small bowel tumor is abdominal pain, which is typically intermittent and crampy in nature. Other symptoms include weight loss, nausea and vomiting, gastrointestinal bleeding, and intestinal obstruction. As compared with those with benign tumors, patients with malignant small bowel neoplasms are more often symptomatic, and the majority of symptomatic small bowel tumors are malignant. (See 'Clinical presentation' above.)
●The incidence of adenocarcinoma is highest in the duodenum. The most common clinical presentation is abdominal pain; a duodenal adenocarcinoma may present as a gastric outlet obstruction. (See 'Adenocarcinoma' above.)
●Well-differentiated gastrointestinal NETs arising in the small bowel are most commonly found in the ileum, within 60 cm of the ileocecal valve. Because of their indolent growth, most are asymptomatic at presentation and found incidentally. When present, symptoms generally relate to mass effects, including intermittent obstruction. Tumor production of bioactive amines results in carcinoid syndrome (watery diarrhea, flushing, sweating, wheezing, dyspnea, abdominal pain, hypotension) only when the secretory products gain direct access to the systemic circulation, thus avoiding metabolism in the liver; this occurs most commonly in patients with extensive hepatic metastases. (See 'Well-differentiated gastrointestinal neuroendocrine tumors' above.)
●Lymphoma may arise as a primary neoplasm in the intestinal tract or as a component of systemic disease with gastrointestinal involvement. Primary gastrointestinal tract lymphoma is the most common extranodal form of lymphoma; the lymphoid-rich ileum is the most common location. (See 'Primary gastrointestinal tract lymphoma' above.)
●Malignant mesenchymal tumors (sarcomas) represent approximately 10 percent of small bowel neoplasms and are most common in the jejunum and ileum. The most common type of intestinal sarcoma is gastrointestinal stromal tumor. (See 'Sarcoma' above.)
●The frequency of benign tumors of the small bowel increases from the duodenum to the ileum. Villous adenomas carry a significant potential for malignant transformation. Patients with sporadic duodenal adenomas should be screened for colorectal cancer as they are at increased risk. (See 'Adenomas' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges James Cusack Jr, MD, who contributed to an earlier version of this topic review.
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