Neuroendocrine Tumors of the Luminal Gastrointestinal Tract
NETs of the luminal gastrointestinal tract (carcinoid tumors) are derived from chromaffin or Kulchitsky cells, which can be found in the gastrointestinal, urogenital, and bronchial epithelia. Approximately 70% arise in the gastrointestinal tract, with an annual incidence of about two to three cases per 100,000 persons.[2,34] They most commonly arise in the small bowel (29%), appendix (19%), and rectum (12.6%). There are a number of similarities between carcinoid tumors and other neuroendocrine tumors; carcinoids thus require specific histologic and cytochemical staining in order to be identified under light microscopy. Some experts have advocated moving away from use of the term “carcinoid”; however, it remains in widespread use.[1,36]
The signs and symptoms of carcinoid tumors can be highly variable. The classic carcinoid syndrome consists of facial flushing, diarrhea, diaphoresis, weight loss, endocardial thickening of the right-sided heart valves, and bronchoconstriction. The occurrence and severity of symptoms is directly related to whether the bulk of tumor drains into the systemic circulation (liver or retroperitoneal nodal metastasis) and bypasses the liver. Most patients with the carcinoid syndrome will have an ileal primary tumor with nodal and liver metastases. The most common diagnostic test for symptomatic carcinoid tumors is measurement of the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) in a 24-hour urine sample. The best agent for medical management of symptomatic carcinoid disease is the somatostatin(Drug information on somatostatin) analogue octreotide(Drug information on octreotide). Most patients respond to octreotide treatment and have significant improvement in their symptoms. Octreotide should also be used preoperatively and intraoperatively to minimize the risk of a carcinoid crisis (unresponsive hypotensive episodes), which can be precipitated in patients with carcinoid syndrome by stressful situations, such as induction of anesthesia. Long-acting octreotide (Sandostatin LAR) may also be useful to inhibit tumor growth and decrease tumor progression postoperatively.
Imaging of carcinoids is typically done using CT or MRI. Carcinoids generally express somatostatin receptors, making SRS a fairly sensitive adjunct for evaluating the primary tumor and metastatic disease. Gastric, duodenal, and rectal carcinoids are usually evaluated using endoscopy. However, localization of small-bowel carcinoids can be difficult. Abdominal CT imaging does not always locate the primary tumor but may detect liver metastases, regional lymph nodes, or bowel wall thickening and cicatrization consistent with mesenteric nodal metastases from carcinoid tumors (Figure 7).
Approximately one-third of all small- bowel tumors are carcinoids, and they most commonly arise in the distal ileum.[37,13] Patients may present with carcinoid syndrome, have nonspecific symptoms such as abdominal pain or bowel obstruction, or be asymptomatic. Encasement of the mesenteric vasculature resulting from fibrotic changes at the root of the mesentery (see Figure 7) can occasionally lead to venous obstruction and catastrophic bowel infarction. Only 15% of tumors < 1 cm are associated with metastatic disease, but the risk increases to 61% with tumors of 1 to 2 cm. Overall 5-year survival for all small bowel carcinoids is approximately 65%. This decreases to 30% for those with hepatic metastasis. Given the aggressive nature of these tumors (especially those > 1 cm), wide en bloc segmental resection of the intestine and mesenteric lymph nodes is indicated. A prophylactic cholecystectomy should be performed, since these patients develop symptomatic cholelithiasis from long-term octreotide therapy. The intestine and abdomen should also be carefully examined, since approximately one-third of small-bowel carcinoids are multicentric and 10% to 20% are associated with a second primary tumor.
Appendiceal carcinoids are usually found incidentally once every 200 to 300 appendectomies. Patients are typically young adults, and the tumors are usually < 1 cm in size. Appendectomy is sufficient treatment for all patients with tumors < 2 cm in size that are not present at the base of the appendix (resection margin). In one series with a median follow-up of 26 years, no patients with tumors < 2 cm developed nodal or distant metastatic disease. In contrast, metastases were found in 21% of patients with tumors 2 to 3 cm in size and in 44% of patients with tumors > 3 cm. Thus, a right hemicolectomy is appropriate for patients with tumors > 2 cm, positive resection margins, or mesoappendiceal invasion. In addition, patients whose tumors show both neuroendocrine and glandular differentiation (often classified as goblet cell carcinoids, adenocarcinoids, or mixed adenocarcinoma carcinoids) should also undergo a right hemicolectomy because the tumors behave similarly to adenocarcinomas. Appendiceal carcinoids do not cause the carcinoid syndrome.
Carcinoid tumors of the rectum are found once every 2,500 sigmoidoscopies. Virtually all are found in the mid-rectum between 4 and 13 cm from the dentate line. Unlike ileal carcinoids, they do not show histological evidence of serotonin production and thus do not cause carcinoid syndrome, even in the presence of metastatic disease. Patients with tumors < 1 cm in size can safely undergo wide local transanal or endoscopic excision. No additional preoperative staging or disease-specific follow-up appears to be necessary.[37,45] Patients with tumors between 1 and 2 cm can generally undergo wide local excision as well, provided there is no invasion into the muscularis propria, no lymphovascular invasion, nor a high mitotic rate (> 2/50 HPF). If any of these factors is present or if the tumor is > 2 cm, a more radical procedure (abdominoperineal or low anterior resection) is strongly, but not routinely, recommended. It is important to recognize that for rectal carcinoids that are > 2 cm in size, the risk of distant metastasis is so high that the marginal benefit of local control obtained from radical surgery may become less important than sphincter preservation.
Special mention should be made of duodenal carcinoid tumors. Patients with small nonampullary duodenal carcinoids < 1 cm in size have been successfully treated using endoscopic excision alone, while tumors between 1 and 2 cm can be treated with transduodenal excision. Patients with tumors > 2 cm will generally require a more extensive procedure. However, the appropriate surgical approach is controversial. A recent surgical series of 24 patients with duodenal carcinoid tumors (gastrinomas and ampullary carcinoids were excluded) reported that, although the majority (89%) of tumors measured less than 2 cm, and most (85%) were limited to the mucosa or submucosa, lymph node metastases were identified in the surgical specimen in 7 of 13 patients (54%) in whom lymph nodes were examined, including 2 patients with tumors smaller than 1 cm and limited to the submucosa. Therefore, the authors concluded that the presence of regional lymph node metastasis cannot be predicted reliably on the basis of tumor size or depth of invasion. In addition, it is now established that carcinoid tumors arising from the ampulla of Vater exhibit considerably more aggressive behavior, with a strong tendency to develop nodal metastasis even at a small size (< 2 cm); pancreaticoduodenectomy is thus recommended irrespective of tumor size.[48-51]
Carcinoid tumors of the colon are typically diagnosed late in the seventh decade of life and are usually accompanied by abdominal pain, anorexia, and weight loss. The tumors are most often found in the cecum. Unfortunately, most carcinoids are large (> 2 cm) at the time of presentation and metastatic in approximately 60% of cases. Overall 5-year survival— 42%—is the lowest of all the carcinoids arising in the gastrointestinal tract. Surgical resection, usually by hemicolectomy, is the treatment of choice.
Gastric carcinoids arise from enterochromaffin-like (ECL) cells that are located in the gastric mucosa. These tumors can be classified into three types (Table). Type I and II carcinoids are believed to develop in the setting of chronic hypergastrinemia (from pernicious anemia and ZES, respectively), which stimulates ECL-cell hyperplasia and leads to gastric carcinoid development. Most of these carcinoids are small (< 1 cm) and 57% to 78% are multicentric, but only about 5% to 10% are metastatic.[53-55] Therefore, the prognosis for type I carcinoids is generally excellent, and these tumors are usually treated with endoscopic resection and surveillance, unless the tumor is too large to be removed endoscopically or is associated with concomitant adenocarcinoma.[53,55] Antrectomy has been proposed as a treatment option for type I gastric carcinoids, since removal of the gastrin-producing G-cells (which stimulate the proliferation of ECL cells) is expected to interrupt the pathogenetic cycle of the disease.[55,56] However, normalization of gastrin levels after antrectomy does not prevent tumor progression in 14% of patients, possibly because of autonomous gastrin-independent ECL hyperplasia or other stimulating factors.[55-57] The treatment of type II carcinoids is the same as that for type I, except that patients with MEN1 should also undergo resection of their gastrinoma(s). However, approximately 5% of these patients with MEN1 develop significant clinical symptoms, such as bleeding, carcinoid syndrome, weight loss, and obstruction caused by aggressive tumor growth; symptoms are likely related to the duration and magnitude of hypergastrinemia. These carcinoids are often diffusely spread throughout the stomach and exhibit a metastatic phenotype, requiring radical surgery. In comparison, type III carcinoids arise sporadically and are diagnosed in 15% to 20% of patients with gastric carcinoids. Patients with type III carcinoids usually have normal levels of gastrin, but their tumors are larger, solitary, invasive beyond the mucosa, and carry a > 50% metastatic potential, requiring formal resection.[54,55] Types II and III gastric carcinoids may cause the carcinoid syndrome without liver metastases, since the serotonin enters the systemic circulation through the coronary vein. In these patients perioperative octreotide is mandatory.
Neuroendocrine Liver Metastases
There is no level 1 evidence to guide the optimal management of patients with NET liver metastases. For patients who have potentially resectable disease, surgical resection is associated with 5-year survival rates of 60% to 70% in retrospective series, and can occasionally lead to cure.[59,60] Cytoreductive surgery may help reduce hormonal secretion and prolong survival. Our current approach is to attempt surgical resection in patients in whom it has been determined, on the basis of preoperative imaging studies, that at least 90% of the liver tumors can be safely removed. Residual disease may be effectively controlled postoperatively with long-acting somatostatin analogues. For patients with clearly unresectable disease, transarterial chemo-, radio-, or bland embolization appears to be effective in controlling hormonal symptoms and delaying the development of liver failure.
Summary and Future Directions
Neuroendocrine tumors of the gastrointestinal tract are a heterogeneous group of neoplasms that nonetheless share common biologic characteristics. Their management continues to evolve, but surgery remains the only curative treatment and is recommended for most patients in whom cross-sectional imaging suggests that complete resection is possible. Preoperative control of hormonal symptoms is mandatory. The extent of resection is specific to tumor type. In general, insulinomas can be enucleated, while gastrinomas should be treated with enucleation of pancreatic head tumors, duodenotomy and local resection of duodenal tumors, and removal of the peripancreatic/periduodenal lymph nodes. Patients with MEN1 often have multifocal disease, and while biochemical and radiographic cure rates after surgery are much lower, overall survival is good. The goal in treating patients with MEN1 should be removal of dominant tumors. Most other functional and nonfunctional tumors are usually large at presentation and require formal surgical resection. For carcinoid tumors, the somatostatin analogue octreotide is an important adjunct in managing the carcinoid syndrome and preventing perioperative carcinoid crisis. The traditional "2-cm rule" that guides a more extensive use of resection for appendiceal carcinoids is not applicable to duodenal, small bowel, and rectal tumors, which can be metastatic at smaller sizes. Endoscopic resection is playing an increasing role in the management of type I and type II gastric carcinoids, as well as in small and superficial duodenal and rectal carcinoids. Although NETs generally have a better prognosis than adenocarcinomas at the same site, they are incurable once they advance to unresectable distant metastatic disease. Long-acting octreotide may be useful for inhibiting tumor growth and decreasing tumor progression. New therapeutic approaches for NETs, such as peptide receptor radiotherapy and systemic agents targeting vascular endothelial growth factor (VEGF) and mammalian target of rapamycin (mTOR) are under development.
Financial Disclosure: The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.