Chapter 30. Tumors of the Small Intestine

Tumors of the small intestine, both benign and malignant, are rare. With the potential to arise from virtually every cell type within the small intestine—the epithelium, neural tissues, lymphatic and mesenchymal cells—the small bowel may also be the site of metastases from other primary tumors. The variety and uncommon nature of these tumors makes generalizations regarding their management difficult. In this chapter we review the epidemiology and clinical diagnostic and management strategies for benign and malignant neoplasms of the small bowel.

While the small bowel accounts for 75% of the length and 90% of the mucosal surface area of the gastrointestinal tract, fewer than 3% of gastrointestinal malignancies arise in this organ. Most of these tumors are clinically silent. Autopsy series have identified incidental small bowel tumors in 0.2–0.3% of hospital deaths—a rate 15 times the operative incidence of small bowel resections for tumors.1

Given the rare nature of these tumors, most published reports are collections of relatively small series of tumors accrued over a period of many years. Hence, interestingly, these reports differ regarding the type of small bowel tumors, the distribution of tumors, and until the advent of molecular diagnostic criteria for GIST (gastrointestinal stromal tumors), in the classification of tumors of stromal origin. Nonetheless, in most series adenocarcinoma, GIST, carcinoid tumor, and lymphoma comprise the most common malignant tumors and are approximately equally represented.2,3 Small bowel tumors are more prevalent in older than in younger patients, and a recent analysis identified that over 65% of patients with small bowel adenocarcinoma were age 60 or older.3 The proportion of small bowel tumors that are benign varies from 14 to 52% in different series, a disparity explained by the failure to detect the typically asymptomatic benign lesions.

There are no satisfactory explanations for the observed variation in prevalence of small bowel tumors around the world. Carcinoids are uncommon tumors in Asian series, while GIST comprise a higher proportion of reported series in the East.4,5 Men are more likely to develop small bowel neoplasms than women, with a male preponderance reported for both benign and malignant tumors.

Given the length of the small bowel and its large mucosal surface, it is intriguing that it is such an uncommon site for malignancy. Unlike the adenoma-carcinoma sequence seen in the colon, a clear molecular progression sequence has not been defined in the small bowel outside the known polyposis syndromes. Only periampullary adenomas are known to be premalignant lesions with the potential to progress to adenocarcinomas. Adenomatous polyps arising elsewhere in the small bowel presumably have similar potential for malignant transformation, although the molecular traits of this transformation remain unknown. Such progression has not been definitively documented at other sites in the small bowel.

Based on theories of luminal injury defined in the colonic mucosa, several hypotheses are proposed regarding the pathogenesis of epithelial-derived small bowel tumors. Unlike the colon with its high bacterial luminal content, the lumen of the healthy small bowel is largely free of bacteria; bacterial metabolites implicated in the genetic alterations of colon carcinogenesis are absent. Transit through the small bowel is rapid—30 minutes to 2 hours—so exposure to potential toxins and metabolites is much more limited. The alkaline, mucus-rich succus entericus of the small bowel may have protective capacity and less noxious potential than the more solid contents of the colon. Enterocytes of the brush border epithelium express the enzyme benzopyrene hydroxylase, possibly protecting against mucosal damage by detoxifying the carcinogen benzopyrene. And last, high levels of luminal IgA and greater distribution of lymphoid tissue in the small intestinal epithelium and submucosa may provide an additional protective mechanism via an immune surveillance mechanism.

Bile acids and their metabolites have been implicated in the pathogenesis of small bowel adenocarcinoma. Postcholecystectomy patients may be at greater risk for the development of small bowel malignancy. In one study of patients with small intestinal malignancy, 12% had a history of cholecystectomy, and of those with duodenal adenocarcinoma, 25% had prior cholecystectomy. However, a causative relationship between cholecystectomy and small intestinal adenocarcinoma remains unproven.

High-Risk Population

Several heritable and inflammatory gastrointestinal conditions are associated with an increased risk for development of small bowel tumors.

Familial Adenomatous Polyposis

Patients with familial adenomatous polyposis (FAP) carry a lifetime risk approaching 100% for the development of adenomatous polyps of the duodenum, and these lesions may progress to adenocarcinoma. FAP patients have a 331-fold increased risk for development of adenocarcinoma of the duodenum over the normal population,3 and this is the leading cause of cancer death in patients with FAP previously treated by colectomy. These patients require regular screening esophagogastroduodenoscopy (EGD) and endoscopic or surgical excision of enlarging adenomas.

Crohn's Disease

Patients with active jejunoileitis of Crohn's disease have a 100-fold increased incidence of adenocarcinoma. Active disease in the terminal ileum is the most frequent site of malignancy.6 Abdominal complaints and symptoms consistent with their primary condition may delay evaluation and diagnosis, leading to detection of tumors at advanced stages. The prognosis for patients with adenocarcinoma arising in Crohn's disease is poor.7 For patients undergoing bowel-preserving procedures such as stricturoplasty, a biopsy of the site of past or active disease is advocated to look for dysplasia or in situ carcinoma. Such findings, while rare, would warrant resection rather than bowel-preserving approaches.

Celiac Disease

Celiac disease is associated with increased risk of lymphoma and is seen in up to 14% of patients.8 A gluten-free diet has been postulated to decrease this risk, although this has not been substantiated by a recent study.9

Miscellaneous Conditions Associated with Small Bowel Neoplasms

Patients with Peutz-Jeghers syndrome develop benign hamartomas throughout the intestinal tract. Surveillance is indicated, as these lesions are at risk of malignant transformation into adenocarcinoma.10 Patients with von Recklinghausen's disease may develop neurofibromas in the gastrointestinal tract that can undergo malignant transformation. Patients on chronic immune suppression therapy are at particular risk for small bowel malignancies, especially lymphomas and sarcomas. Transplant recipients on immunosuppression have a 45- to 100-fold increase in non-Hodgkin's lymphoma (NHL), a condition termed posttransplant lymphoproliferative disorder (PTLD).11 PTLD accounts for 30% of all malignancies in cyclosporine-treated patients but accounts for only 12% of malignancies in patients without cyclosporine in their regimen. PTLD tends to develop rapidly, often within 12 months of transplant. Greater degrees of immunosuppression carry greater risk for development of PTLD. Human immunodeficiency virus (HIV) infection is also associated with the development of lymphoma in up to 30% of patients. Most are extranodal and the gastrointestinal tract is the involved site in 10–25% of cases. More than 90% of patients present with stage IV disease and median survival is only 6 months.

Patients with small bowel tumors present with nonspecific gastrointestinal and constitutional complaints. In hindsight, the gradual development of symptoms is usually evident. The most common symptoms include vague abdominal discomfort and cramps, gradual weight loss, anemia, nausea, and vomiting. These nonspecific complaints, coupled with the fact that most patients are older and often on medications that may also elicit these complaints, result in a high rate of misdiagnosis and delay in diagnosis. In most series, the average duration of symptoms prior to diagnosis ranges from weeks to many months. Initial evaluation to exclude more common conditions, including evaluation of the gastroduodenum, colon, and biliary tract are completed, but, when negative, further evaluation of the small bowel is delayed or deferred.

Benign lesions rarely cause abdominal pain or obstruction; rather, their presence is often heralded by acute gastrointestinal hemorrhage. Benign neoplasms may grow to a large size prior to detection and may simply be discovered incidentally on a radiological examination or at laparotomy.

The diagnosis of small bowel tumors is hampered by a number of factors. In addition to the fact that these are rare tumors that produce nonspecific gastrointestinal complaints, the ability to fully image and observe the small intestine is limited. Despite the introduction of capsule endoscopy, which allows for luminal visualization of the entire small bowel mucosal surface, accurate preoperative diagnosis is in fact uncommon prior to surgery.12,13

History and physical examination are nonspecific. Abdominal mass, heme-positive stool, or signs of intestinal obstruction are usually absent. Laboratory data may demonstrate iron deficiency anemia in a minority of patients.

Plain abdominal films are an appropriate initial diagnostic test, although they are rarely helpful unless the patient presents with obstructive symptoms.

After ruling out more common conditions that could elicit similar gastrointestinal and abdominal complaints with endoscopic evaluation of the gastroduodenum and colon, computed tomography (CT) of the abdomen is the appropriate initial imaging test. CT may reveal bulky tumors (Fig. 30-1) or more subtle findings suggestive of small bowel tumors, such as thickening of the small bowel wall. Thickening of the bowel wall to greater than 1.5 cm or the detection of discrete mesenteric lymph nodes or masses greater than 1.5 cm in diameter is highly suggestive of malignancy. If obstructing lesions are present, CT scan may reveal a transition zone demarcating dilated proximal bowel from decompressed distal bowel.

Tumors of the distal small bowel may cause jejunoileal or ileocolic intussusception. During intussusception, the small bowel tumor serves as the lead point to pull the small bowel into the distal small bowel or colonic lumen; the mass lesion precludes spontaneous reduction. CT findings of ileocolic or jejunoileal intussusception include the presence of concentric rings with a donut appearance involving the bowel. This sign is nearly pathognomonic for small bowel tumor. In adults, radiographic attempts to reduce an intussusception should not be made. Rather, prompt surgical exploration and resection of the nonreduced intussuscepted bowel segment with mesenteric resection should be completed without intraoperative attempts at complete reduction; rather, the intestine should be reduced gently to the palpated lead point, followed by intestinal resection and primary anastomosis. Attempts at complete reduction often lead to inadvertent enterotomy or exposure of a perforation within the intussusception.

Luminal contrast radiographic studies may be used if abdominal CT imaging fails to reveal evidence of a small bowel tumor, usually an upper gastrointestinal contrast series with small bowel follow-through. A small bowel follow-through study will show an abnormality in 53–83% of cases, although direct evidence of a tumor is detected in only 30–44%.

While enteroclysis (a dynamic contrast technique using a slurry of barium and methylcellulose infused into the small bowel via a nasoduodenal tube to uniformly distend the small bowel lumen) was formerly utilized to study the mucosal surface of the small bowel lumen, this procedure has been largely replaced by video capsule endoscopy (VCE). Similarly, small bowel enteroscopy is far less commonly utilized with the advent of VCE.

For proximal jejunal lesions that cannot be visualized by routine EGD, “push” enteroscopy utilizes a pediatric colonoscope for direct examination of the lumen of the proximal 2–3 ft of small bowel.14 Formerly utilized, Sonde “pull” small bowel enteroscopy, which relied on peristalsis to passively pull an enteroscope with a wide-angle lens into the distal ileum or colon, is now a procedure of only historical interest.

Intraoperative enteroscopy allows a much more complete evaluation of the small bowel. It is of value in detection of occult bleeding from the small bowel but is rarely utilized for the diagnosis of small bowel tumors, for most can usually be readily identified by careful palpation or visualization of the bowel once operation is pursued.

VCE is now widely employed in the diagnosis of small bowel tumors in patients with otherwise negative diagnostic studies. The device is an ingestible 11- × 26-mm capsule, swallowed by the patient, that contains a miniature video camera, light source, battery, and transmitter that sends images (up to 50,000 overall) to a recording device worn by the patient.15 Currently the device does not have the capacity for biopsies or for precise localization of lesions, although such capability is in development. The device can be very useful in identifying lesions within the lumen of the small bowel (Fig. 30-2). The major complication of VCE is capsule retention, which is reported in 5% of cases, although the rate of requirement for surgical retrieval is less than 1%.16

While a number of small intestinal tumors are metabolically active and express hormones, somatostatin scintigraphy (octreotide scanning) is of limited use in detection of primary small bowel carcinoids or other neuroendocrine tumors. Positron emission tomography (PET) scanning also has limited utility in providing a discriminate diagnosis, as there is significant overlap between benign and malignant conditions. While diagnostic methods continue to improve, many patients with small bowel neoplasms still have initial presentation as a surgical emergency, and more than half of patients with malignant disease have metastatic spread at the time of operation.

Although accounting for 30–50% of primary neoplasms of the small bowel, benign tumors are poorly characterized. Half the patients with benign tumors are symptom free, and most will be diagnosed at the time of presentation with a surgical emergency such as obstruction, gastrointestinal hemorrhage, or perforation. Gastrointestinal bleeding is the most common presenting complication, presumably a consequence of spontaneous necrosis when the benign lesion outgrows the available blood supply.5

Once these lesions are diagnosed, surgical segmental intestinal resection is appropriate. While local excision via endoscopic mucosal resection or operative enterotomy with submucosal excision is feasible, it is generally not possible to grossly differentiate between benign and malignant lesions. Hence, transmural resection is preferred for indeterminate lesions. Open and laparoscopic approaches have been described.

Brunner Gland Adenomas

Brunner gland adenomas are rare tumors of the proximal duodenum.17 Originating in the Brunner glands of the duodenal submucosa that secrete alkaline bicarbonate-rich fluid and mucus, the pathogenesis of glandular hyperplasia and subsequent adenoma formation from this cell population remains unknown. Although Brunner gland adenomas have not been described to transform into carcinomas, endoscopic mucosal resection is advised to prevent complications, including acute and chronic bleeding.

Adenomas

As in the colon, small bowel adenomas are histologically classified as tubular, tubulovillous, or villous. Most common in the periampullary region, they can develop throughout the small bowel mucosa. Increased size correlates with malignant potential, and excision is advised when diagnosis is established, often as an incidental finding. Adenomas larger than 2 cm in diameter should be considered worrisome for malignancy. Large, periampullary duodenal adenomas may present with obstructive jaundice. In these cases ultrasound will reveal evidence of biliary obstruction, prompting upper endoscopy with endoscopic retrograde biliary and pancreatic duct evaluation (endoscopic retrograde cholangiopancreatography), which will reveal the presence of the ampullary lesion. Without these physical signs to direct the workup, duodenal adenomas are detected during evaluation of gastrointestinal blood loss or other abdominal complaints, with either contrast upper gastrointestinal series or EGD, which are equally sensitive in most series. Adenomas usually appear as intraluminal filling defects and may be pedunculated (Fig. 30-3). CT scan may differentiate adenoma from carcinoma, as carcinomas are often associated with bowel wall thickening. Endoscopic ultrasound is becoming essential in the evaluation of duodenal adenomas to evaluate depth and to determine if mucosal excision or surgical resection is more appropriate. Transduodenal local excision for small lesions is appropriate, while lesions larger than 3 cm in size have a high rate of associated malignancy and are most appropriately treated with either pancreas-sparing duodenectomy, or pancreaticoduodenectomy for larger lesions or periampullary tumors in suitable operative candidates.18 Surgical series of resected ampullary adenoma report in situ or frank adenocarcinoma in 34–40% of patients. Local recurrence is common for periampullary adenomas treated with excision only: 40% at 10 years, 25% of which were malignant, in a recent retrospective series from the Mayo clinic. For those treated with excision only, annual surveillance with endoscopy is appropriate.19

Lipomas

Lipomas of the gastrointestinal tract are typically identified as incidental findings on abdominal imaging. They rarely cause symptoms; although as polypoid, compressible intraluminal lesions, they may serve as lead points for intussusception. Lipomas are circumscribed lesions arising in the bowel wall appearing as fat density on CT imaging. Small tumors under 2 cm require no intervention, while larger lesions or growing lesions should be resected to rule out malignant liposarcoma.

Hamartomas

The hamartoma is the characteristic lesion of Peutz-Jeghers syndrome, an autosomal dominant condition characterized by multiple gastrointestinal hamartomas and mucocutaneous pigmentation. The tumors are widely distributed throughout the bowel in affected individuals and in rare cases are associated with intussusception, bleeding, or obstruction. While malignant transformation has been described, this is a rare event. Given the broad distribution of the tumors, prophylactic excision is not feasible and surgical intervention is appropriate only to treat complications caused by the tumors.10

Hemangiomas

Hemangiomas are rare congenital lesions of the small bowel. They appear to grow slowly and may become symptomatic in midlife, when acute or chronic bleeding may develop. Arising from the submucosal vascular plexuses, hemangiomas are usually solitary and not at risk for malignant transformation. Hemangiomas associated with bleeding should be locally excised or resected with a limited small bowel resection. Endoscopic sclerotherapy or angiographic embolization has also been reported as a treatment option depending on the size and position of the tumor.

The small bowel can give rise to a number of different primary tumors and is also a site for metastasis from tumors of other origins. Primary malignancies include adenocarcinoma, GIST, carcinoid, lymphoma, and leiomyosarcoma, with rare reports of other lesions, including liposarcoma, myxoliposarcoma, and lymphangiosarcoma. Metastatic tumors may come from any other cancer, but the most common metastatic lesions are from melanoma and lymphomas.

Malignant tumors are much more likely to elicit symptoms than benign tumors, including abdominal pain, weight loss, anorexia, and acute or chronic blood loss. As a group, patients with malignant small bowel tumors present at advanced stages and have a poor prognosis.

Up to 30% of patients with small bowel malignancy develop a second primary tumor in another organ. For patients with GI carcinoid tumors, the incidence of second primaries is 50%. The second primary cancer may arise in any organ, but the most frequent second primary sites are the colorectum and breast.20,21

Adenocarcinoma

Epidemiology

Adenocarcinoma accounts for about 35% of small bowel tumors, making it the most common primary malignancy.7 The frequency of small bowel tumors decreases along the length of the small bowel, with 80% located in the duodenum and proximal jejunum. Men are slightly more likely to develop adenocarcinoma than women. Risk factors for development of adenocarcinoma include polyposis syndromes, Crohn's disease, and celiac disease.

Clinical Presentation

Clinical presentation is dictated by the size and position of the tumor. Large tumors form the classic circumferential annular “apple core” constriction leading to obstruction with symptoms of anorexia, vomiting, and crampy pain (Fig. 30-4). Periampullary lesions may cause biliary obstruction with secondary jaundice. In absent advanced or strategically placed lesions with obstruction, the only complaint may be vague, persistent abdominal pain.

Diagnosis

For patients with advanced lesions, plain abdominal films may show gastric distention or proximal small bowel obstruction. For the jaundiced patient, ultrasound or abdominal CT or magnetic resonance cholangiopancreatography may demonstrate the duodenal mass and site of biliary obstruction. Upper gastrointestinal contrast studies or EGD have equal diagnostic rates of 85–90%, while EGD allows diagnostic tissue biopsy. CT reveals approximately 50% of small bowel adenocarcinomas, and the appearance is that of a heterogeneous infiltrating mass. Despite diagnostic strategies, preoperative diagnosis of cancers beyond the duodenum is achieved in only 20–50% of cases.

Management

Surgical resection offers the only potential cure. Many patients have intra-abdominal metastases at initial surgery, with R0 resection (ie, no gross or microscopic disease left) achieved in only 50–65% of cases. Pancreaticoduodenectomy is appropriate for proximal duodenal tumors. In the third and fourth portions of the duodenum and in the mesenteric small bowel, a segmental resection with lymphadenectomy should be performed. Palliative procedures to relieve obstruction or control hemorrhage should be completed at the time of exploration for patients with metastatic disease. Endoscopic expandable stents (Wall type) may be the best strategy to palliate proximal gastrointestinal obstruction from recurrent or metastatic disease. Gastrojejunal bypass or gastrostomy tubes may be of palliative value for decompression or nutritional support in patients with carcinomatosis or unresectable disease.

Staging and Prognosis

The American Joint Committee on Cancer staging system applies to small bowel adenocarcinoma.22 The tumor (T) classification describes depth of invasion with T1 and T2 within the bowel wall and T3 and T4 lesions penetrating the bowel wall. The node (N) classification is defined by the presence or absence of lymph node metastases, and distant metastases are classified by M. Most patients present with stage III (lymph node involvement) or IV disease (distant metastases), which carry a poor prognosis.

The most significant prognostic factor is lymph node metastases, with poor survival linked to node-positive disease. Likely because of limited reported experience, the primary tumor features, including the degree of differentiation, do not appear to impact survival. A recent retrospective analysis showed that positive margins, extramural venous spread, positive lymph nodes, and a history of Crohn's disease are associated with poor prognosis.6

Adjuvant therapies including chemotherapy and/or radiation therapy have not demonstrated efficacy, although clinical trials are ongoing.20

Non-Hodgkin's Lymphoma

The gastrointestinal tract is the most common extranodal site for development of non-Hodgkin's lymphoma (NHL), comprising approximately 20% of all cases of NHL. Most GI lymphomas arise in the stomach (60%), followed by the small bowel (30%), and then in the colon. Most small bowel lymphomas are distributed in the jejunum and ileum reflecting the distribution of lymphoid tissue in the bowel. Diagnostic criteria for primary GI NHL include the absence of superficial adenopathy on physical examination, absence of mediastinal adenopathy by chest imaging, normal peripheral blood cell counts, and absence of splenic or hepatic involvement. At surgery, disease must be restricted to the primary tumor with mesenteric lymph node involvement.23

The majority of cases of primary intestinal NHL are B-cell type with T-cell lymphoma comprising only 10–25%. Low-grade lymphomas derived from mucosal-associated lymphoid tissue (MALT) typically arise in the stomach in association with Helicobacter pylori infection. These tumors may regress with treatment of this infection.24 T-cell lymphomas tend to have a worse prognosis than B-cell tumors.

Clinical Presentation

The majority of patients present with nonspecific abdominal complaints. Malabsorption, obstruction, or palpable mass may be present. Although rare, small intestinal lymphomas may present with perforation.

Diagnosis

Lymphomas may grow to large size before clinical symptoms present. Most small bowel lymphomas will be demonstrable on CT scan as a mass, bowel wall thickening, displacement of adjacent organs, or luminal obstruction (Fig. 30-5). Multiple lesions are present in 10–25% of patients. Tissue diagnosis requires biopsy of the submucosal lesion by endoscopy or CT-guided biopsy.

Staging and Prognosis

Staging is based on site involvement as outlined in Table 30-1. Like tumors elsewhere in the small intestine, most patients present with stage III or IV disease. Fewer than 30% of patients have surgically resectable tumors and prognosis, although improving with new chemotherapy regimens, is poor.22

Treatment

With no randomized series and small numbers of cases at single institutions, the optimal treatment of GI NHL remains controversial. Most agree that surgical resection of isolated small bowel lymphoma for local control and prevention of perforation and bleeding are the cornerstones of treatment. For more extensive gastrointestinal lymphoma, there is no evidence-based consensus on optimal management, although a variety of chemotherapeutic regimens have been utilized.23,24

Carcinoid Tumors

Carcinoid tumors arise from the enterochromaffin cells at the base of the crypts of Lieberkühn. Enterochromaffin cells are capable of amine precursor uptake and decarboxylation (APUD) and tumors derived from these can secrete vasoactive peptides responsible for the carcinoid syndrome. Eighty percent of carcinoids arise in the gastrointestinal tract, 10% in the bronchus or lung, and others in rare sites, including the ovaries, testicles, pancreas, and kidneys. The appendix is the most common site in the GI tract for primary carcinoid tumors, followed by the small bowel. Thirty percent of GI carcinoids arise in the jejunum or ileum and have the most aggressive clinical features.

Carcinoids represent 5–35% of small bowel neoplasms; the mean age of presentation is 60 years with a slight male preponderance. Autopsy rates reveal an incidence of occult tumors approximately 2000 times that of the annual clinical incidence rate, indicating that the overwhelming majority never develop clinical findings.24,25

Clinical Presentation and Diagnosis

Most carcinoids grow slowly and have insidious clinical manifestations; in hindsight, symptoms may be present for 2–20 years prior to diagnosis. Carcinoid syndrome secondary to metastatic disease is the presenting sign in 40% of patients. Rarely, intestinal necrosis secondary to desmoplastic occlusion of the mesenteric vessels may develop, leading to initial presentation as a surgical emergency.

The most common presenting symptom for patients with small bowel carcinoid is abdominal pain. The polypoid lesions serve as a lead point for intussusception characterized by intermittent symptoms and signs of obstruction. Abdominal films often demonstrate a distal small bowel obstruction, and the CT findings of intussusception are distinctive, demonstrating a multilayer ringed structure in the ileocolic region (Fig. 30-6).

Appendiceal carcinoids are typically solitary lesions. However, for carcinoids arising in other areas of the gut, multiple tumors are observed in 30–40% of patients.26 In addition, 30–50% of small bowel carcinoids are associated with second primary malignancies, most frequently of the breast and colon. Gastrointestinal carcinoids have the capacity to elicit a marked desmoplastic reaction in the mesentery of the small bowel. The fibrotic reaction can cause sclerosis of mesenteric vessels, leading to kinking of the bowel or intestinal ischemia and necrosis. The fibrosis affects not only peritumoral tissues, but distant tissues in the heart and lungs and is attributed to the humoral products of the tumors, although the specific factors are unknown.27,28

Staging and Prognosis

Appendiceal carcinoids, even at a small size, may cause appendicitis due to luminal compression; hence, early diagnosis of appendiceal carcinoid is common. In contrast, small bowel carcinoids exhibit a more aggressive phenotype and are frequently associated with lymph node spread and hepatic metastasis at initial presentation. Tumor size is proportional to the risk for metastatic spread. For jejunoileal carcinoids smaller than 1 cm, there is a 20–30% incidence of nodal and hepatic spread. Tumors 1–2 cm in size have nodal spread in 60–80% and hepatic disease in 20%. The rate of nodal and hepatic metastasis for tumors larger than 2 cm is greater than 80% and 40–50%, respectively.25 Only very small jejunoileal carcinoid tumors, those less than 1 cm, can be treated with local excision. All others should be treated with segmental bowel and mesenteric resection.29

Carcinoid Syndrome

Carcinoid syndrome refers to vasomotor, gastrointestinal, and cardiac manifestations induced by systemic circulation of peptides produced by carcinoid tumors. The APUD cells of carcinoid tumors can produce vasoactive products, including serotonin, histamine, kallikrein, bradykinin, and prostaglandins, although the specific mediator or mediators of the syndrome remain unknown. Carcinoid syndrome is confirmed by finding elevated 24-hour 5-hydroxyindoleacetic acid (5-HIAA) urinary excretion, the primary stable metabolite of serotonin.

Attacks are characterized by intense flushing and tachycardia. Watery diarrhea, at times explosive and associated with cramping, may occur in some patients. Attacks may be spontaneous or precipitated by stress, alcohol, a large meal, or sexual intercourse. Flushing, a 5- to 10-minute sensation of heat associated with facial and truncal erythema, is the most common finding and affects approximately 80% of patients. Diarrhea occurs in most patients and is likely related to serotonin release, as serotonin antagonists can effectively treat this symptom. Abdominal cramps and malabsorption may occur. Cardiac manifestations are present in 60–70% of patients with advanced disease, due to tricuspid and pulmonary valve endocardial fibrosis, possibly secondary to high levels of 5-HIAA. As the disease progresses, the fibrotic plaque stiffens, leading eventually to right heart failure.

Carcinoid syndrome is due to metastatic disease in either the liver or retroperitoneum. Monoamine oxidase in the liver metabolizes serotonin to metabolites without vasomotor activity, one of the major effector hormones. Carcinoid syndrome occurs when metabolically active tumor is present in a site without portal drainage, such as a bronchial carcinoid or retroperitoneal tumor, or when hepatic metastatic tumor burden exceeds the capacity of hepatic monoamine oxidase to metabolize serotonin. Patients with gastrointestinal carcinoids that drain into the portal circulation must have metastatic disease prior to the development of the syndrome.

Management of patients with carcinoid syndrome due to metastatic hepatic tumor burden is optimized by utilization of surgical, imaging-guided interventional procedures and medical therapies. Given the relatively slow growth of carcinoid tumors, including metastatic disease, surgical debulking of extensive hepatic disease or formal hepatic resection for resectable metastases can improve symptoms and prolong life. Five- and 10-year survival for patients with residual abdominal tumor and hepatic metastases approaches 60%. While in general the initial surgery for resection of carcinoid tumor burden, including hepatic metastases, should attempt to debulk as much tumor as possible, the procedure must be planned to avoid catastrophic injuries such as those to the superior mesenteric vessels that could lead to short gut syndrome.30 Hepatic artery embolization or radiofrequency ablation may be more appropriate for widespread hepatic metastases and can give marked symptomatic relief and durable tumor control.31

Medical therapy is based on somatostatin analogues (octreotide), including short- and long-acting peptides for relief of carcinoid syndrome symptoms. Carcinoid tumors express somatostatin receptors, and the somatostatin analogues inhibit vasoactive peptide release from carcinoid tumors. Palliation of symptoms is effective in 90% of patients with octreotide. Some studies have demonstrated a tumorstatic or tumor reduction effect after the administration of somatostatin, although these latter findings have not been consistently reproduced. Efficacy of treatment can be documented by following excretion of the tumor marker 5-HIAA.

Chemotherapeutic agents for the treatment of metastatic carcinoid tumor include doxorubicin, 5-fluorouracil, dacarbazine, and interferon-α, with response rates of approximately 20%. Combination protocols most often utilize streptozotocin and 5-fluorouracil.

Preliminary reports on the use of targeted radiotherapeutics have been presented. Somatostatin analogues bind to somatostatin receptors on carcinoid tumors with high affinity. After binding is done, the ligand-receptor complex is internalized. This internalization has led to the development of “smart bombs”—radiolabeled somatostatin analogues that theoretically deliver radiation specifically to carcinoid cells. 111Indium-labeled pentetreotide demonstrated an enhanced tumor regression response compared to unlabeled analogue in one study.32

Gastrointestinal Stromal Tumors

Although gastrointestinal stromal tumors (GIST) are the most common nonepithelial tumors of the small bowel, they are in fact rare tumors of the GI tract, representing only 0.2% of all GI tumors. Approximately 25% of GIST arise in the small bowel, with 50% gastric, 15% rectal, and 10% colonic in origin.33 Men and women are equally at risk and peak incidence occurs in patients aged between 50 and 70 years. GIST tumors arise from the interstitial cell of Cajal, the pacemaker cell of the GI tract intercalated between the intramural neurons and the smooth muscle cells. The molecular diagnostic feature of GIST is the presence of activating c-kit mutations, a transmembrane receptor tyrosine kinase involved in the regulation of cellular proliferation, apoptosis, and differentiation. Over 95% of GIST express kit (CD117) mutations, a molecular marker that distinguishes them from histologically similar mesenchymal tumors of the small bowel, including leiomyomas, leiomyosarcoma, schwannomas, and others.34 Retrospective molecular analysis of mesenchymal tumors has led to reclassification of up to 70% small bowel tumors as GIST that had previously been classified as a variety of mesenchymal tumors.35

GISTs are characterized by indolent clinical symptoms, including vague abdominal pain, weight loss, and occult gastrointestinal bleeding. Of all small bowel tumors, GISTs often grow to a large size prior to surgical presentation. They tend to grow insidiously as extraluminal masses from their submucosal origin in a noninvasive manner, characteristically pushing adjacent organs away from the expanding mass. Gastrointestinal hemorrhage may develop in patients with necrotic GIST in communication with the bowel lumen.

Given the propensity of GIST to grow to a large size prior to diagnosis, CT scan is most likely to be the initial positive test. A characteristic finding is the presence of a large space-occupying mass, often with evidence of central necrosis and compression of adjacent organs and calcifications (Fig. 30-7).

Regardless of size, all GIST tumors should be considered to be malignant.33 Malignant potential is determined by two major criteria: tumor size and mitotic rate. Biologically aggressive tumors are large tumors with a high mitotic index, while tumors with benign features are small and exhibit a low mitotic index. Tumors are thus classified into very low- to high-risk for malignant potential, a classification that has prognostic significance.

Treatment

Surgery is the primary therapeutic option with the goal being complete resection. At operation, wide local excision of the primary tumor to achieve gross negative margins with incontinuity resection of adherent organs is appropriate to attain curative resection. Lymph node metastasis is rare, negating the need for wide mesenteric resection. Wedge resection of gastric lesions of amenable shape and position in the gastric wall provides equivalent outcomes to partial gastrectomy without the negative side effects of partial gastrectomy.

Molecular Therapeutics and Gists.

Given the central role of activating mutations in the tyrosine kinases kit and more recently platelet-derived growth factor receptor alpha (PDGFRA) in the pathogenesis of GIST,34 this tumor has served as a prototype for molecular therapeutic drug development. Activation of kit leads to phosphorylation of a receptor substrate protein, initiating an intracellular phosphorylation cascade leading to nuclear activation of transcription events, resulting in cell proliferation and survival. The discovery of a drug that inactivates kit with a safe therapeutic margin has revolutionized the treatment of metastatic GIST. Imatinib mesylate is a small molecule that occupies the adenosine triphosphate (ATP)–binding pocket of the kit kinase domain, blocking phosphorylation of the receptor and intracellular signaling. This binding arrests cellular proliferation and survival signaling.

Clinical use of imatinib is now routine in the management of GIST. This oral agent is well tolerated and highly effective for patients with metastatic GIST. While complete regression of tumor is rare, partial regression of disease and arrest of progression of disease can be achieved for durable intervals with continuous treatment in up to 80% of patients. Efficacy of treatment can be predicted and followed using fluorodeoxyglucose-positron emission tomography scanning; these highly biologically active tumors will become metabolically silent with imatinib therapy in those patients with responsive tumors. Emergence of resistant clones within tumors has been recognized with prolonged use of imatinib. Newer receptor tyrosine kinase inhibitors, including sunitinib malate, have demonstrated efficacy for patients with tumor recurrence and resistance to imatinib with increased progression-free survival and overall survival.36,37

Neoadjuvant use of imatinib has been shown to result in a 70% response rate; although based on current available evidence, it is still unclear if preoperative therapy for GIST results in a clinically significant effect, leading to increased resectibility or enhanced long-term survival.38 The efficacy of imatinib in the adjuvant setting has been evaluated in the ACOSOG Z9001 (American College of Surgeons Clinical Oncology Group Z9001) trial, finding improved disease-free survival for patients with tumors greater than 3 cm who received imatinib. For these patients, imatinib is indicated for life. Although overall survival advantage was not achieved in this trial, adjuvant trials in North America and Europe continue.

Metastatic Lesions to the Small Bowel

While metastases to the small bowel are rare as a group, they are in fact more common than primary small bowel neoplasms.

Metastatic spread can occur by direct invasion, hematogenous spread, or intraperitoneal seeding. Colon and pancreatic cancers are the most common primary sites for direct invasion. Hematogenous metastases spread most frequently from lung and breast carcinoma or melanoma. Peritoneal seeding may arise from any intra-abdominal malignancy including gastric, hepatic, ovarian, appendiceal, and colonic primary tumors.39

CT scan may identify metastatic lesions or reveal sites of partial or complete luminal obstruction. Metastases can be identified as bowel wall thickening or mesenteric masses. For small lesions, CT scan may be negative, while small bowel follow-through study may reveal an irregular luminal filling defect. Carcinomatosis is frequently not specifically identifiable on imaging studies, although PET-CT is useful for identification of small bowel metastases in some tumor types.

Optimal palliative management is based on clinical criteria. Segmental intestinal resection or bypass to relieve hemorrhage, obstruction, or pain is indicated except in the most terminal stages of disease. While cases of prolonged survival after intestinal resection of solitary metastases have been reported, progression of metastatic disease is more common.

Management of patients with carcinomatosis, regardless of tumor origin, remains challenging. Endoscopic luminal stents for obstructing duodenal lesions may offer short-term palliation, while intestinal bypasses and decompressive gastrostomy tubes are indicated for patients with advanced or more distal disease to enhance palliative care.