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 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 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.
“Apple core” constricting adenocarcinoma of the proximal jejunum causing proximal partial bowel obstruction.
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.
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.
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
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.
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.
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.
Thickening of the bowel wall on abdominal CT scan characteristic of lymphoma.
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
Table 30-1: Staging for Lymphoma |Favorite Table|Download (.pdf)
Table 30-1: Staging for Lymphoma
Involvement of a single lymph node region; or localized involvement of a single extralymphatic organ or site in the absence of any lymph node involvement
Involvement of two or more lymph node regions on the same side of the diaphragm; or localized involvement of a single extralymphatic organ or site in association with regional lymph node involvement, with or without involvement of other lymph node regions on the same side of the diaphragm
Involvement of lymph node regions on both sides of the diaphragm, which also may be accompanied by extralymphatic extension in association with adjacent lymph node involvement, or by involvement of the spleen, or both
Diffuse or disseminated involvement of one or more extralymphatic organs, with or without associated lymph node involvement; or isolated extralymphatic organ involvement in the absence of adjacent regional lymph node involvement, but in conjunction with disease in distant site(s); any involvement of the liver or bone marrow, or nodular involvement of the lungs
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 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).
Concentric rings in the soft tissue mass in the right lower quadrant reveal an ileocolic intussusception. An ileal carcinoid tumor was the lead point.
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
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 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).
Large gastrointestinal stromal tumor (GIST) arising from the stomach in the left upper quadrant. The diaphragm and the spleen were invaded by the tumor.
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.
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.