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From the Archives of the AFIP

Gastrointestinal Carcinoids: Imaging Features with Clinicopathologic Comparison¹

¹ From the Departments of Radiologic Pathology (A.D.L.) and Hepatic and Gastrointestinal Pathology (L.H.S.), Armed Forces Institute of Pathology, Alaska and Fern Sts NW, Washington, DC 20306-6000; and Department of Radiology and Nuclear Medicine, Uniformed Services University of the Health Sciences, Bethesda, Md (A.D.L.). Received September 15, 2006; revision requested October 13 and received October 20; accepted October 23. All authors have no financial relationships to disclose. Address correspondence to A.D.L. (e-mail: levya{at}afip.osd.mil).

	Abstract

Top Abstract LEARNING OBJECTIVES FOR TEST... Introduction Epidemiology General Pathologic Features Site-Specific Features Scintigraphy in the Management... Conclusions References

 
Gastrointestinal carcinoids are well-differentiated endocrine neoplasms that belong to a diverse group of tumors that arise from cells of the diffuse endocrine system. A wide variety of specialized endocrine cells that populate the gastrointestinal mucosa and submucosa give rise to carcinoids. Consequently, carcinoids may occur throughout the gastrointestinal tract and produce a variety of hormones and protein products that are associated with specific clinical symptoms. Biologic behavior of carcinoids varies by site and cell type, but all gastrointestinal carcinoids are considered to have malignant potential. They may produce specific syndromes such as Zollinger-Ellison syndrome, or they may occur in association with inherited syndromes such as multiple endocrine neoplasia type 1 or neurofibromatosis type 1. Metastatic carcinoids may produce carcinoid syndrome. The small intestine is the most common location for gastrointestinal carcinoids. Most small intestinal carcinoids arise from enterochromaffin cells of the distal ileum that produce serotonin. Small intestinal carcinoids often have an aggressive biologic behavior and, as such, patients frequently have metastases to regional lymph nodes and the liver at initial presentation. Pathologic and radiologic manifestations of serotonin-producing small intestinal carcinoids are related to local and regional effects of serotonin and its metabolites. In contrast, carcinoids of the appendix and rectum are commonly discovered incidentally as small lesions that are unassociated with clinical evidence of hormone production and have a more indolent clinical course. Carcinoids of the stomach, duodenum, and colon are uncommon but have distinctive clinical, pathologic, and radiologic appearances. Knowledge of the diverse clinical, pathologic, and radiologic spectrum of gastrointestinal carcinoids is important in the imaging and management of patients with suspected carcinoids or focal gastrointestinal masses.

	LEARNING OBJECTIVES FOR TEST 6

Top Abstract LEARNING OBJECTIVES FOR TEST... Introduction Epidemiology General Pathologic Features Site-Specific Features Scintigraphy in the Management... Conclusions References

 
After reading this article and taking the test, the reader will be able to:

• Identify the radiologic and pathologic features of gastrointestinal carcinoids.
  
• Describe the various types of carcinoids that occur throughout the gastrointestinal tract.
  
• Discuss the differential diagnosis of carcinoids throughout the gastrointestinal tract.
  

	Introduction

Top Abstract LEARNING OBJECTIVES FOR TEST... Introduction Epidemiology General Pathologic Features Site-Specific Features Scintigraphy in the Management... Conclusions References

 
Carcinoid tumors represent a group of well-differentiated tumors originating from the diffuse endocrine system outside the pancreas and thyroid. Carcinoids most frequently occur in the gastrointestinal tract (66.9%), followed by the tracheo-bronchial system (24.5%) (1). In rare cases, they may arise in the liver, gallbladder, ovary, testis, and thymus. In the gastrointestinal tract, they originate from endocrine cells that populate the mucosa and submucosa. Gastrointestinal endocrine cells perform a variety of biologic and hormonal functions. Consequently, there is wide diversity to the clinical manifestation, prevalence at specific anatomic sites, biologic behavior, hormone production, morphology, and immunophenotype of gastrointestinal carcinoid tumors.

Gastrointestinal tumors with endocrine cell differentiation represent a group of related neoplasms rather than a single pathologic entity. These tumors range from small, benign, carcinoid tumors of the stomach and appendix to the classic serotonin-producing small intestinal carcinoid to highly malignant, undifferentiated small cell carcinomas and malignant neoplasms that contain both endocrine and glandular lines of differentiation. Many of these tumors deviate from the classic histologic features of carcinoids and, with immunohistochemical staining and ultrastructural techniques, can be recognized as having endocrine differentiation. As a result, a variety of carcinoids (benign, malignant, typical, atypical, and pleomorphic) have been described in the literature, which leads to considerable diagnostic confusion. At the Armed Forces Institute of Pathology (AFIP), we believe a tumor should be diagnosed as a carcinoid only when it displays the classic histologic features of a well-differentiated endocrine tumor.

Originally described by Langhans in 1867 (2) and Lubarsch in 1888 (3), these tumors were referred to as karzinoide ("carcinoma-like") by Oberndorfer in 1907 (4), because the tumors were less aggressive than most gastrointestinal carcinomas. Gosset and Masson (5) showed that these tumors contained silver-salt–reducing (argentaffinic) granules, and they originated the concept that carcinoid tumors are composed of argentaffin cells derived from the Kulchitsky cells of the small intestine. Since these original descriptions, there have been many classification systems proposed for gastrointestinal carcinoids. Williams and Sandler (6) proposed a classification based on the differences in clinical and pathologic features of carcinoids related to their anatomic location and the embryologic origin of the gastrointestinal tract: foregut (bronchopulmonary, stomach, pancreas, proximal duodenum), midgut (mid-duodenum, jejunum, ileum, appendix, ascending colon, and mid-transverse colon), and hindgut (mid-transverse colon and rectum). Although this classification system oversimplifies carcinoid tumors, particularly in terms of their behavior, it is useful because each of these anatomic regions gives rise to carcinoid tumors with unique clinical, pathologic, and radiologic features.

This article reviews the current literature and our experience with gastrointestinal carcinoids accessioned into the Radiologic Pathology Archives at the AFIP. The clinical, pathologic, and radiologic spectrum of gastrointestinal carcinoids is presented, with emphasis on clinicopathologic correlation of the imaging features.

	Epidemiology

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Carcinoid tumors are relatively uncommon neoplasms, occurring in 1.9 per 100,000 persons annually worldwide (7). The most recent and comprehensive epidemiologic data on gastrointestinal carcinoids in Western populations are derived from the analysis by Modlin et al (1) of 13,715 carcinoid tumors registered in databases at the National Cancer Institute from 1973 to 1999. Modlin and colleagues reported that the incidence of carcinoids has increased over the past 30 years and that 41.8% of gastrointestinal carcinoids occurred in the small intestine, followed in decreasing order of frequency by the rectum (27.4%), appendix (24.1%), and stomach (8.7%) (1). For many years, it has been accepted that the appendix is the most common location for gastrointestinal carcinoids, a conclusion based on the 1975 analysis of 2837 National Cancer Institute cases by Godwin (8). Several authors noted that the apparent decline in the incidence of appendiceal carcinoids reported by Modlin et al should be viewed cautiously, as recent statistical data may not reflect the true incidence of appendiceal carcinoids because of the decreasing rate of appendectomies related to the increasing accuracy of diagnosing inflammatory appendicitis preoperatively (1,9,10). In addition, Modlin et al noted that one of the tumor registry databases in their study contained both benign and malignant appendiceal carcinoids and that the other databases did not, which may have altered the statistical data.

The average age of patients at diagnosis for all carcinoids is 61.4 years (1). Although demographics vary by the anatomic location of the carcinoids, there is evidence that the incidence is highest in black men for all anatomic sites except the appendix and bronchopulmonary region (1,7). There is a significant association of gastrointestinal carcinoids with other tumors, and this association is highest with small intestinal carcinoids. Synchronous or metachronous malignancies occur in 29% of patients with small intestinal carcinoids (1). Gastrointestinal adenocarcinomas are the most commonly associated malignancy (11).

Carcinoid syndrome occurs in less than 10% of patients with carcinoid tumors (12). Clinically, the syndrome develops when vasoactive substances produced by the carcinoid enter systemic circulation without undergoing metabolic degradation. The syndrome most commonly occurs in patients with ileal carcinoids and hepatic or retroperitoneal metastases. The classic carcinoid syndrome consists of cutaneous flushing, sweating, bronchospasm, colicky abdominal pain, diarrhea, and right-sided cardiac valvular fibrosis. Alcohol intake, emotional stress, or exercise may precipitate or exacerbate the symptoms.

	General Pathologic Features

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A diverse variety of endocrine cells normally populate the gastrointestinal mucosa and submucosa. The type, location, and secretory products of gastrointestinal endocrine cells are well defined and are summarized in the Table (13,14). Although individual carcinoid tumors have specific histologic and immunohistochemical features based on their anatomic location and endocrine cell type, all carcinoids share common pathologic features that characterize them as well-differentiated endocrine tumors.

View larger version (220K): [in this window] [in a new window] [Download PPT slide]   Figure 1a.  Histologic features of gastrointestinal carcinoids. (a) Photomicrograph (original magnification, x10; hematoxylin-eosin [H-E] stain) of an ileal EC-cell carcinoid shows an insular growth pattern with nests of uniform tumor cells separated by a delicate stroma. (b) Photomicrograph (original magnification, x20; H-E stain) of an ileal EC-cell carcinoid shows tumors cells with uniform nuclei and bright red, cytoplasmic secretory granules (arrow).

View larger version (214K): [in this window] [in a new window] [Download PPT slide]   Figure 1b.  Histologic features of gastrointestinal carcinoids. (a) Photomicrograph (original magnification, x10; hematoxylin-eosin [H-E] stain) of an ileal EC-cell carcinoid shows an insular growth pattern with nests of uniform tumor cells separated by a delicate stroma. (b) Photomicrograph (original magnification, x20; H-E stain) of an ileal EC-cell carcinoid shows tumors cells with uniform nuclei and bright red, cytoplasmic secretory granules (arrow).

	Site-Specific Features

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Gastric Carcinoids
Gastric carcinoids are relatively uncommon compared with primary epithelial, lymphoid, and mesenchymal neoplasms of the stomach. As reported by Modlin et al (1), the incidence of gastric carcinoids in the United States has risen over the past 50 years. The most recent Surveillance, Epidemiology, and End Results (SEER) data show that gastric carcinoids account for 8.7% of all gastrointestinal carcinoids and 1.8% of gastric malignancies (1).

The majority of gastric carcinoids are ECL-cell carcinoids that arise from oxyntic mucosa in the gastric body and fundus (15). Three distinct subtypes of ECL-cell carcinoids are recognized: type I, which is associated with autoimmune chronic atrophic gastritis; type II, which is associated with Zollinger-Ellison syndrome (ZES) in patients with multiple endocrine neoplasia type 1 (MEN-1); and type III, which are sporadic carcinoids not associated with atrophic gastritis or hypergastrinemia. Very rarely, non–ECL-cell carcinoids may occur within the stomach (eg, G-cell carcinoids, adrenocorticotrophic hormone–producing carcinoids, or EC-cell serotonin-producing carcinoids).

Clinical Features.— Type I ECL-cell carcinoids are the most common type in the stomach, representing 74% of gastric endocrine tumors. They occur most frequently in women (female-to-male ratio, 2.5:1) at a mean age of 63 years (16). Patients with type I ECL-cell carcinoids usually do not have clinical symptoms directly related to the tumors. The lesions are usually encountered during endoscopy performed for dyspepsia, anemia that may be due to chronic atrophic gastritis, or other reasons. Achlorhydria and, less commonly, pernicious anemia may be present. Hypergastrinemia or evidence of antral G-cell hyperplasia is usually observed (15).

Type II gastric ECL-cell carcinoids account for 6% of gastric endocrine neoplasms, occur in patients at a mean age of 50 years, and have no gender predilection (16). Hypergastrinemia from a gastrin-producing endocrine neoplasm of the pancreas or the small intestine produces ZES in patients with MEN-1. Elevated serum levels of gastrin stimulate ECL-cell hyperplasia. In the setting of MEN-1, multiple carcinoids develop in ECL-cell hyperplasia. Because gastric carcinoids are rarely seen in patients with ZES alone, it is surmised that the genetic abnormalities related to altered tumor suppression in MEN-1 contribute to the development of carcinoids from ECL-cell hyperplasia. Clinically, elevated gastrin levels produce signs and symptoms of a hypertrophic, hypersecretory gastritis: abdominal pain or bleeding from multiple or recurrent peptic ulcers, diarrhea, and elevated serum levels of gastrin.

Type III gastric ECL-cell carcinoids represent 13% of gastric endocrine tumors and occur most commonly in men (male-to-female ratio, 2.8:1) at a mean age of 55 years (16). There is no associated hypergastrinemia or chronic atrophic gastritis. These patients typically present with signs and symptoms related to a solitary, aggressive mass and have no endocrine manifestations. Therefore, the clinical manifestations in these patients are similar to those in patients with other gastric neoplasms: bleeding, abdominal pain, anorexia, and weight loss.

Pathologic Features.— Type I ECL-cell carcinoids are characteristically small (<1 cm), multiple mucosal nodules in the gastric fundus and body; they often occur in patients with chronic atrophic gastritis and endocrine cell hyperplasia (Fig 2). At histologic analysis, both type I and II ECL-cell tumors are composed of round or polygonal cells with uniform, centrally located nuclei, finely stippled chromatin, and small nucleoli. The cells are arranged in a trabecular or rosette pattern with occasional infiltrating ribbons or cords that are usually limited to the mucosa and submucosa (17). These tumors usually stain positive with argyrophilic staining techniques. With immunohistochemical staining, these tumors usually stain positive for chromogranin A and synaptophysin. In most cases, type I and II gastric carcinoids have absent or rare mitoses, a characteristic that reflects their tendency to have benign biologic behavior. However, limited metastatic spread to lymph nodes has been reported in 5% of type I carcinoids (16,18,19). Similar to type I carcinoids, type II carcinoids are usually multiple, but they are more variable in size. Their propensity for metastasis is also greater than type I carcinoids. Metastasis occurs in 10%–30% of patients with type II ECL-cell carcinoids (16,19).

View larger version (160K): [in this window] [in a new window] [Download PPT slide]   Figure 2a.  Type I gastric carcinoid. (a) Spot view of the stomach from an air contrast upper gastrointestinal series in a 43-year-old woman with innumerable small mucosal and submucosal polypoid masses. Several masses contain ulcer craters (arrow). (b) Computed tomographic (CT) scan obtained with oral contrast material shows a soft-tissue nodule (arrow) along the lesser curvature of the stomach in a 50-year-old man who was asymptomatic and found to have chronic atrophic gastritis and multiple type I gastric carcinoids at screening endoscopy. (c) Photomicrograph (original magnification, x30; H-E stain) of a specimen from another patient shows a carcinoid arising in the setting of chronic atrophic gastritis. Intestinal metaplasia of gastric glands (arrowhead) is adjacent to small endocrine nests of a carcinoid (arrow).

View larger version (173K): [in this window] [in a new window] [Download PPT slide]   Figure 2b.  Type I gastric carcinoid. (a) Spot view of the stomach from an air contrast upper gastrointestinal series in a 43-year-old woman with innumerable small mucosal and submucosal polypoid masses. Several masses contain ulcer craters (arrow). (b) Computed tomographic (CT) scan obtained with oral contrast material shows a soft-tissue nodule (arrow) along the lesser curvature of the stomach in a 50-year-old man who was asymptomatic and found to have chronic atrophic gastritis and multiple type I gastric carcinoids at screening endoscopy. (c) Photomicrograph (original magnification, x30; H-E stain) of a specimen from another patient shows a carcinoid arising in the setting of chronic atrophic gastritis. Intestinal metaplasia of gastric glands (arrowhead) is adjacent to small endocrine nests of a carcinoid (arrow).

View larger version (158K): [in this window] [in a new window] [Download PPT slide]   Figure 2c.  Type I gastric carcinoid. (a) Spot view of the stomach from an air contrast upper gastrointestinal series in a 43-year-old woman with innumerable small mucosal and submucosal polypoid masses. Several masses contain ulcer craters (arrow). (b) Computed tomographic (CT) scan obtained with oral contrast material shows a soft-tissue nodule (arrow) along the lesser curvature of the stomach in a 50-year-old man who was asymptomatic and found to have chronic atrophic gastritis and multiple type I gastric carcinoids at screening endoscopy. (c) Photomicrograph (original magnification, x30; H-E stain) of a specimen from another patient shows a carcinoid arising in the setting of chronic atrophic gastritis. Intestinal metaplasia of gastric glands (arrowhead) is adjacent to small endocrine nests of a carcinoid (arrow).

Imaging Features.— Type I and II ECL-cell carcinoids are multifocal, smoothly marginated, 1–2-cm mural masses located in the gastric body and fundus that are best seen at double-contrast upper gastrointestinal radiography or endoscopy. In our experience, type I and II carcinoids may be shown as enhancing mucosal or submucosal masses at finely collimated, intravenous contrast material–enhanced CT. However, in the series reported by Binstock et al (20), small (<1 cm) tumors were not seen on CT scans. Regardless of cell type and biologic potential, larger carcinoids may have mucosal ulcerations on the surface of the mass. Ulcer craters are readily identified at double-contrast upper gastrointestinal radiography or CT as focal, irregular collections of barium, contrast material, or air on the surface of the mass (Fig 2a).

In the setting of ZES and MEN-1, double-contrast upper gastrointestinal radiography may show diffusely thickened gastric folds and a multi-nodular gastric mucosal contour. Multiple erosions and ulcers may be present. Hypersecretion of gastric fluids may cause flocculation of barium and poor gastric mucosal coating. On CT scans, marked gastric mural thickening and innumerable nodular mucosal and mural masses may be present (21) (Fig 3). In our experience, the nodular, thickened gastric wall in patients with ZES and MEN-1 shows enhancement during the arterial phase of contrast-enhanced multidetector CT (Fig 4). In patients with hypergastrinemia and suspected gastric carcinoids, careful attention should be paid to CT technique because distention of the stomach with neutral contrast media and scanning during the arterial and portal venous phases of contrast material enhancement may maximize detection of the primary lesions within the stomach as well as liver metastases (22).

View larger version (147K): [in this window] [in a new window] [Download PPT slide]   Figure 3a.  Type II gastric carcinoid in a 49-year-old man with ZES and MEN-1. (a) Equilibrium phase CT scan shows diffusely thickened and nodular gastric mucosa from the hypertrophic hypersecretory gastropathy of ZES and a focal 3-cm polypoid carcinoid (arrow). The hypoattenuating mass in the left lobe of the liver (arrowhead) was proved to be a hemangioma. (b) Photograph of the resected stomach shows the carcinoid as a polypoid mass (arrow) in a background of erythematous, hypertrophic mucosa. Scale is in centimeters.

View larger version (121K): [in this window] [in a new window] [Download PPT slide]   Figure 3b.  Type II gastric carcinoid in a 49-year-old man with ZES and MEN-1. (a) Equilibrium phase CT scan shows diffusely thickened and nodular gastric mucosa from the hypertrophic hypersecretory gastropathy of ZES and a focal 3-cm polypoid carcinoid (arrow). The hypoattenuating mass in the left lobe of the liver (arrowhead) was proved to be a hemangioma. (b) Photograph of the resected stomach shows the carcinoid as a polypoid mass (arrow) in a background of erythematous, hypertrophic mucosa. Scale is in centimeters.

View larger version (132K): [in this window] [in a new window] [Download PPT slide]   Figure 4a.  Type II gastric carcinoid in a 66-year-old woman with persistent hypergastrinemia after parietal cell vagotomy and Whipple resection for ZES in MEN-1 and with persistently elevated serum gastrin levels. (a) Nonenhanced CT scan shows a markedly thickened gastric wall. (b) Arterial phase CT scan shows innumerable enhancing nodules lining the thickened rugal folds. (c) Late portal venous phase CT scan shows that the folds are homogeneous in attenuation. (d) Photograph of the resected gastrectomy specimen reveals innumerable small nodules of carcinoids throughout the gastric mucosa.

View larger version (142K): [in this window] [in a new window] [Download PPT slide]   Figure 4b.  Type II gastric carcinoid in a 66-year-old woman with persistent hypergastrinemia after parietal cell vagotomy and Whipple resection for ZES in MEN-1 and with persistently elevated serum gastrin levels. (a) Nonenhanced CT scan shows a markedly thickened gastric wall. (b) Arterial phase CT scan shows innumerable enhancing nodules lining the thickened rugal folds. (c) Late portal venous phase CT scan shows that the folds are homogeneous in attenuation. (d) Photograph of the resected gastrectomy specimen reveals innumerable small nodules of carcinoids throughout the gastric mucosa.

View larger version (128K): [in this window] [in a new window] [Download PPT slide]   Figure 4c.  Type II gastric carcinoid in a 66-year-old woman with persistent hypergastrinemia after parietal cell vagotomy and Whipple resection for ZES in MEN-1 and with persistently elevated serum gastrin levels. (a) Nonenhanced CT scan shows a markedly thickened gastric wall. (b) Arterial phase CT scan shows innumerable enhancing nodules lining the thickened rugal folds. (c) Late portal venous phase CT scan shows that the folds are homogeneous in attenuation. (d) Photograph of the resected gastrectomy specimen reveals innumerable small nodules of carcinoids throughout the gastric mucosa.

View larger version (139K): [in this window] [in a new window] [Download PPT slide]   Figure 4d.  Type II gastric carcinoid in a 66-year-old woman with persistent hypergastrinemia after parietal cell vagotomy and Whipple resection for ZES in MEN-1 and with persistently elevated serum gastrin levels. (a) Nonenhanced CT scan shows a markedly thickened gastric wall. (b) Arterial phase CT scan shows innumerable enhancing nodules lining the thickened rugal folds. (c) Late portal venous phase CT scan shows that the folds are homogeneous in attenuation. (d) Photograph of the resected gastrectomy specimen reveals innumerable small nodules of carcinoids throughout the gastric mucosa.

View larger version (107K): [in this window] [in a new window] [Download PPT slide]   Figure 5a.  Type III gastric carcinoid in a 36-year-old man who complained of hematemesis. (a) Prone view of the stomach from an air contrast upper gastrointestinal series shows a smoothly marginated, mural mass with central ulceration (arrow) along the superior edge of the lesser curvature of the stomach. (b) Endoscopic photograph shows the smoothly marginated mural mass with central ulceration and umbilication. The mass was proved to be a 3-cm carcinoid.

View larger version (150K): [in this window] [in a new window] [Download PPT slide]   Figure 5b.  Type III gastric carcinoid in a 36-year-old man who complained of hematemesis. (a) Prone view of the stomach from an air contrast upper gastrointestinal series shows a smoothly marginated, mural mass with central ulceration (arrow) along the superior edge of the lesser curvature of the stomach. (b) Endoscopic photograph shows the smoothly marginated mural mass with central ulceration and umbilication. The mass was proved to be a 3-cm carcinoid.

Duodenal Carcinoids
Duodenal carcinoids are rare, representing 2%–3% of all gastrointestinal neuroendocrine tumors (1,13). The majority (62% of cases) are G-cell tumors. One-third of these are functioning tumors that produce the clinical manifestations of ZES (23). Duodenal G-cell carcinoids may occur in patients without MEN-1. In those patients with MEN-1, 90% develop G-cell carcinoids. Somatostatin-producing (D-cell) tumors represent 21% of duodenal carcinoids and occur exclusively in and around the ampulla of Vater (13). There is a strong association between D-cell carcinoids and neurofibromatosis type 1 (NF-1). The classic EC-cell serotonin-producing carcinoid that is most common in the midgut is very rare in the duodenum. Likewise, carcinoids that produce calcitonin, cholecystokinin, vasoactive intestinal polypeptide, bombesin, pancreatic polypeptide, or multiple hormones rarely occur in the duodenum.

Clinical Features.— Patients with duodenal carcinoids have a wide age range at presentation (19–90 years; mean age, 53 years) (24,25). Although some studies have noted a male gender predilection, others show no gender predilection (24,25). Duodenal carcinoids may be discovered incidentally or may produce symptoms from hormonal or peptide production. Those tumors that occur in the periampullary region may obstruct the ampulla of Vater and produce jaundice.

Gastrin production from G-cell carcinoids (also called gastrinomas if serum gastrin levels are elevated) may result in ZES. The clinical manifestations of serum gastrin elevation include nausea, vomiting, abdominal pain, bleeding from multiple and recurrent peptic ulcers, gastroesophageal re-flux from excess acid production, and diarrhea from hypergastrinemia. Abdominal pain is the most common symptom, and the combination of abdominal pain and diarrhea is present in 50% of patients. Eighty-five percent of sporadic gastrinomas occur in the "gastrinoma triangle," which is anatomically defined as the region bounded by the confluence of the cystic and common bile ducts superiorly, the second and third portions of the duodenum inferiorly, and the neck and body of the pancreas medially (Fig 6) (26). It has been postulated that gastrinomas arising in the gastrinoma triangle originate from stem cells of the ventral pancreatic bud that become dispersed and incorporated into the lymph tissue and duodenal wall during normal embryonic rotation of the ventral pancreas, which occurs at the anatomic location defined as the gastrinoma triangle (27). In contrast to sporadic gastrinomas, which are usually solitary lesions, gastrinomas that occur in patients with ZES and MEN-1 are usually multiple, less than 5 mm in size, and located in the proximal duodenum.

View larger version (77K): [in this window] [in a new window] [Download PPT slide]   Figure 6.  Drawing illustrates the anatomic region known as the gastrinoma triangle.

Pathologic Features.— Duodenal G-cell carcinoids are small polypoid nodules within the sub-mucosa or infiltrative intramural masses. At histo-logic analysis, duodenal G-cell carcinoids are composed of uniform cells with scanty, eosinophilic cytoplasm and round nuclei with stippled chromatin. The cells form acini that are arranged in gyriform trabeculae or pseudorosettes that are separated by delicate and vascular stroma, which may contain amyloid (13,30). Necrosis is not present. G-cell carcinoids show predominant immunoreactivity for gastrin, but immunoreactivity for other peptides such as cholecystokinin, pancreatic polypeptide, neurotensin, somatostatin, and insulin may occasionally be present in small quantities (23).

Duodenal D-cell carcinoids are usually small, homogeneous, 1–2-cm intramural or polypoid periampullary nodules (Fig 7) (28,31). The overlying duodenal mucosa may have focal ulceration. At histologic analysis, the glandular structures of duodenal D-cell carcinoids are arranged in a trabecular pattern and often intermingle with the ducts and muscular elements of the ampulla of Vater (13). The neoplastic glands are composed of uniform cells with finely granular, eosinophilic cytoplasm and basally located nuclei that contain small nucleoli and little mitotic activity (29). The most characteristic and striking microscopic feature of D-cell carcinoids is the presence of densely calcified, concentrically laminated psammoma bodies (Fig 7c) (28,31,32). With immunohistochemical staining, these tumors are positive for neuron-specific enolase, chromogranin A, synaptophysin, and somatostatin (13), hence the term psammomatous somatostatinoma. Clinically, this immunophenotype, as well as the presence of psammoma bodies, is an important distinguishing feature for the pathologist interpreting endoscopic mucosal biopsy specimens of a periampullary mass because duodenal carcinoids may simulate adenocarcinoma.

View larger version (137K): [in this window] [in a new window] [Download PPT slide]   Figure 7a.  Periampullary D-cell carcinoid in a 31-year-old woman who complained of jaundice. (a) Arterial phase CT scan shows a homogeneously enhancing, 1.5-cm periampullary mass (arrow). (b) Photograph of the cut surface of the resected specimen demonstrates the periampullary carcinoid (arrow) and peripancreatic lymph node metastases (arrowheads). P = pancreatic head. (c) Photomicrograph (original magnification, x40; H-E stain) shows basophilic psammoma bodies (arrow) characteristic of a D-cell carcinoid.

View larger version (161K): [in this window] [in a new window] [Download PPT slide]   Figure 7b.  Periampullary D-cell carcinoid in a 31-year-old woman who complained of jaundice. (a) Arterial phase CT scan shows a homogeneously enhancing, 1.5-cm periampullary mass (arrow). (b) Photograph of the cut surface of the resected specimen demonstrates the periampullary carcinoid (arrow) and peripancreatic lymph node metastases (arrowheads). P = pancreatic head. (c) Photomicrograph (original magnification, x40; H-E stain) shows basophilic psammoma bodies (arrow) characteristic of a D-cell carcinoid.

View larger version (201K): [in this window] [in a new window] [Download PPT slide]   Figure 7c.  Periampullary D-cell carcinoid in a 31-year-old woman who complained of jaundice. (a) Arterial phase CT scan shows a homogeneously enhancing, 1.5-cm periampullary mass (arrow). (b) Photograph of the cut surface of the resected specimen demonstrates the periampullary carcinoid (arrow) and peripancreatic lymph node metastases (arrowheads). P = pancreatic head. (c) Photomicrograph (original magnification, x40; H-E stain) shows basophilic psammoma bodies (arrow) characteristic of a D-cell carcinoid.

View larger version (165K): [in this window] [in a new window] [Download PPT slide]   Figure 8a.  Duodenal G-cell carcinoids. (a) Spot radiograph from an upper gastrointestinal series shows a well-defined round polyp (arrow) in the duodenal bulb in a 55-year-old woman who complained of dyspepsia and epigastric pain. (b, c) Intravenous contrast-enhanced CT scan (b) of a 47-year-old woman with ZES demonstrates multiple small enhancing polyps (arrowheads) in the proximal duodenum, findings confirmed in the endoscopic photograph (c), which shows well-defined mucosal polyps (arrows).

View larger version (134K): [in this window] [in a new window] [Download PPT slide]   Figure 8b.  Duodenal G-cell carcinoids. (a) Spot radiograph from an upper gastrointestinal series shows a well-defined round polyp (arrow) in the duodenal bulb in a 55-year-old woman who complained of dyspepsia and epigastric pain. (b, c) Intravenous contrast-enhanced CT scan (b) of a 47-year-old woman with ZES demonstrates multiple small enhancing polyps (arrowheads) in the proximal duodenum, findings confirmed in the endoscopic photograph (c), which shows well-defined mucosal polyps (arrows).

View larger version (115K): [in this window] [in a new window] [Download PPT slide]   Figure 8c.  Duodenal G-cell carcinoids. (a) Spot radiograph from an upper gastrointestinal series shows a well-defined round polyp (arrow) in the duodenal bulb in a 55-year-old woman who complained of dyspepsia and epigastric pain. (b, c) Intravenous contrast-enhanced CT scan (b) of a 47-year-old woman with ZES demonstrates multiple small enhancing polyps (arrowheads) in the proximal duodenum, findings confirmed in the endoscopic photograph (c), which shows well-defined mucosal polyps (arrows).

Clinical Features.— Carcinoids of the jejunum and ileum occur equally in men and women at a mean age of 65.4 years (1). Patients with these lesions are often asymptomatic. When symptoms occur, they may be secondary to local effects of the primary tumor or metastatic disease to the mesenteric lymph nodes or liver. The primary tumor may cause small intestinal obstruction, ischemia, or bleeding. Some patients may complain of a long history of intermittent, crampy abdominal pain, weight loss, fatigue, abdominal distention, diarrhea, or nausea and vomiting (12,35).

Pathologic Features.— In the small intestine, the primary lesions are usually small, rarely exceeding 3.5 cm (13). In contrast, the metastatic deposits of carcinoid in the lymph nodes, mesentery, and liver vary in size and may attain such large sizes that they overshadow the primary tumor. Serotonin-containing EC-cell carcinoids are more commonly located in the ileum than in the jejunum. Multiple tumors are present in 30% of cases (11,36). EC-cell carcinoids may manifest as small, firm nodules in the intestinal wall (Fig 9). They may protrude as a polypoid nodule or mass into the lumen and serve as the lead point for intussusception. More classically, these tumors in-filtrate through the intestinal wall to involve the subserosa and adjacent mesentery (Fig 10). Extensive involvement of the subserosa and adjacent mesentery stimulates a considerable desmoplastic reaction that results in kinking, retraction, and angulation of the bowel (Fig 10b). At histologic analysis, distinct nests of tumors cells may be seen between the fibers of the muscularis propria. These infiltrative cords of cells insinuate themselves through the muscularis propria and form focal tumor masses in the subserosa of the intestine that extend into the adjacent mesentery (Fig 10c). The consequence of this pattern of infiltrative growth and the local release of serotonin and other substances produced by the tumor cells is the formation of dense fibrosis or desmoplasia, which is seen most prominently in the submucosa (Fig 10c) and adjacent mesentery (13). Mesenteric arteries and veins located both near and far from the tumor may be thickened and have multi-focal luminal stenoses or occlusions from substances released from the tumor. This finding has been termed elastic vascular sclerosis and may result in intestinal ischemia (37).

View larger version (121K): [in this window] [in a new window] [Download PPT slide]   Figure 9a.  Histologic features of EC-cell ileal carcinoids. (a) Photomicrograph (original magnification, x2; H-E stain) shows the rounded, nodular configuration of an ileal carcinoid. (b) Photomicrograph (original magnification, x10; H-E stain) shows an infiltrative pattern of growth. Nests of tumor cells (arrows) are present in the submucosa with surrounding eosinophilic fibrosis.

View larger version (151K): [in this window] [in a new window] [Download PPT slide]   Figure 9b.  Histologic features of EC-cell ileal carcinoids. (a) Photomicrograph (original magnification, x2; H-E stain) shows the rounded, nodular configuration of an ileal carcinoid. (b) Photomicrograph (original magnification, x10; H-E stain) shows an infiltrative pattern of growth. Nests of tumor cells (arrows) are present in the submucosa with surrounding eosinophilic fibrosis.

View larger version (139K): [in this window] [in a new window] [Download PPT slide]   Figure 10a.  Mural desmoplasia in ileal carcinoids. (a) Photograph of the cut surface of an opened, resected ileum shows a carcinoid (*), which produces retraction and focal desmoplastic thickening of the adjacent muscularis propria (arrow). (b) Photograph of cut sections of distal ileum from a different patient demonstrates more extensive kinking and angulation of the ileal wall. The desmoplastic kinking forms a hairpin turn (arrow) in the ileal wall. (c) Photomicrograph (original magnification, x2; H-E stain) from another patient shows infiltrative nests of tumor (arrows) extending from the primary tumor (T) through the muscularis propria to the mesenteric surface of the bowel. On the mesenteric side, a secondary mass (M) has formed.

View larger version (172K): [in this window] [in a new window] [Download PPT slide]   Figure 10b.  Mural desmoplasia in ileal carcinoids. (a) Photograph of the cut surface of an opened, resected ileum shows a carcinoid (*), which produces retraction and focal desmoplastic thickening of the adjacent muscularis propria (arrow). (b) Photograph of cut sections of distal ileum from a different patient demonstrates more extensive kinking and angulation of the ileal wall. The desmoplastic kinking forms a hairpin turn (arrow) in the ileal wall. (c) Photomicrograph (original magnification, x2; H-E stain) from another patient shows infiltrative nests of tumor (arrows) extending from the primary tumor (T) through the muscularis propria to the mesenteric surface of the bowel. On the mesenteric side, a secondary mass (M) has formed.

View larger version (128K): [in this window] [in a new window] [Download PPT slide]   Figure 10c.  Mural desmoplasia in ileal carcinoids. (a) Photograph of the cut surface of an opened, resected ileum shows a carcinoid (*), which produces retraction and focal desmoplastic thickening of the adjacent muscularis propria (arrow). (b) Photograph of cut sections of distal ileum from a different patient demonstrates more extensive kinking and angulation of the ileal wall. The desmoplastic kinking forms a hairpin turn (arrow) in the ileal wall. (c) Photomicrograph (original magnification, x2; H-E stain) from another patient shows infiltrative nests of tumor (arrows) extending from the primary tumor (T) through the muscularis propria to the mesenteric surface of the bowel. On the mesenteric side, a secondary mass (M) has formed.

Imaging Features.— The imaging appearance of jejunal and ileal carcinoids varies by tumor size, extent of mesenteric involvement, and presence or absence of lymph node or liver metastases. Small, polypoid and nodular carcinoids located in the mucosa and submucosa of the intestinal wall are best evaluated with enteroclysis or small bowel series. In many cases, small nodular carcinoids may be very difficult to detect with a conventional small bowel series. When identified, they are characteristically solitary or multifocal, smooth, rounded nodules or mucosal elevations in the distal ileum (Fig 11) (38). The mucosa overlying the nodule of carcinoid may ulcerate, producing a barium-filled crater on the surface of the lesion. Small solitary or multifocal carcinoids are typically not identified on CT scans, but larger, polypoid lesions may be identified and occasionally produce intussusception (Fig 12). Similarly, small primary tumors may be difficult to visualize with magnetic resonance (MR) imaging. They are best visualized on gadolinium-enhanced T1-weighted MR images obtained with fat suppression, where they manifest as nodules or focal areas of mural thickening with moderately intense gadolinium enhancement (Fig 13) (39).

View larger version (96K): [in this window] [in a new window] [Download PPT slide]   Figure 11a.  EC-cell carcinoid of the distal ileum in a 45-year-old woman who complained of crampy abdominal pain. (a) Spot radiograph from a barium small bowel series shows a smoothly marginated, intraluminal polypoid mass (arrows) in the distal ileum. (b) Photograph of the ileocolic resection specimen shows the bisected, polypoid carcinoid in the distal ileum (arrow) and a large metastasis in a mesenteric node (N).

View larger version (114K): [in this window] [in a new window] [Download PPT slide]   Figure 11b.  EC-cell carcinoid of the distal ileum in a 45-year-old woman who complained of crampy abdominal pain. (a) Spot radiograph from a barium small bowel series shows a smoothly marginated, intraluminal polypoid mass (arrows) in the distal ileum. (b) Photograph of the ileocolic resection specimen shows the bisected, polypoid carcinoid in the distal ileum (arrow) and a large metastasis in a mesenteric node (N).

View larger version (132K): [in this window] [in a new window] [Download PPT slide]   Figure 12a.  Multifocal ileal carcinoids with intussusception in a 43-year-old woman who complained of abdominal pain and nausea. (a, b) Intravenous contrast-enhanced CT images show multiple intraluminal polypoid masses (arrows in a) in the ileum and intussusception (curved arrow in b). (c) Photograph of the resected ileum shows multiple nodules of carcinoid.

View larger version (133K): [in this window] [in a new window] [Download PPT slide]   Figure 12b.  Multifocal ileal carcinoids with intussusception in a 43-year-old woman who complained of abdominal pain and nausea. (a, b) Intravenous contrast-enhanced CT images show multiple intraluminal polypoid masses (arrows in a) in the ileum and intussusception (curved arrow in b). (c) Photograph of the resected ileum shows multiple nodules of carcinoid.

View larger version (126K): [in this window] [in a new window] [Download PPT slide]   Figure 12c.  Multifocal ileal carcinoids with intussusception in a 43-year-old woman who complained of abdominal pain and nausea. (a, b) Intravenous contrast-enhanced CT images show multiple intraluminal polypoid masses (arrows in a) in the ileum and intussusception (curved arrow in b). (c) Photograph of the resected ileum shows multiple nodules of carcinoid.

View larger version (170K): [in this window] [in a new window] [Download PPT slide]   Figure 13a.  EC-cell small bowel carcinoid in a 59-year-old woman who complained of a 4-year history of flushing and diarrhea. (a) Spot radiograph from a small bowel barium series shows distorted and matted segments of the distal ileum with irregular thickening (arrows). (b) Intravenous contrast-enhanced CT scan shows matted small bowel segments in the right lower quadrant that have concentric mural thickening (arrowheads) and an adjacent spiculated mesenteric mass (arrow). (c) Gadolinium-enhanced fat-saturated T1-weighted MR image shows diffuse enhancement of the involved bowel segments (arrows). The mesenteric mass is not as well seen compared with the CT scan in b. (d) Intraoperative photograph of the retracted small bowel mesentery shows metastatic deposits (arrows) studding the mesentery. Liver metastases were also found.

View larger version (129K): [in this window] [in a new window] [Download PPT slide]   Figure 13b.  EC-cell small bowel carcinoid in a 59-year-old woman who complained of a 4-year history of flushing and diarrhea. (a) Spot radiograph from a small bowel barium series shows distorted and matted segments of the distal ileum with irregular thickening (arrows). (b) Intravenous contrast-enhanced CT scan shows matted small bowel segments in the right lower quadrant that have concentric mural thickening (arrowheads) and an adjacent spiculated mesenteric mass (arrow). (c) Gadolinium-enhanced fat-saturated T1-weighted MR image shows diffuse enhancement of the involved bowel segments (arrows). The mesenteric mass is not as well seen compared with the CT scan in b. (d) Intraoperative photograph of the retracted small bowel mesentery shows metastatic deposits (arrows) studding the mesentery. Liver metastases were also found.

View larger version (105K): [in this window] [in a new window] [Download PPT slide]   Figure 13c.  EC-cell small bowel carcinoid in a 59-year-old woman who complained of a 4-year history of flushing and diarrhea. (a) Spot radiograph from a small bowel barium series shows distorted and matted segments of the distal ileum with irregular thickening (arrows). (b) Intravenous contrast-enhanced CT scan shows matted small bowel segments in the right lower quadrant that have concentric mural thickening (arrowheads) and an adjacent spiculated mesenteric mass (arrow). (c) Gadolinium-enhanced fat-saturated T1-weighted MR image shows diffuse enhancement of the involved bowel segments (arrows). The mesenteric mass is not as well seen compared with the CT scan in b. (d) Intraoperative photograph of the retracted small bowel mesentery shows metastatic deposits (arrows) studding the mesentery. Liver metastases were also found.

View larger version (120K): [in this window] [in a new window] [Download PPT slide]   Figure 13d.  EC-cell small bowel carcinoid in a 59-year-old woman who complained of a 4-year history of flushing and diarrhea. (a) Spot radiograph from a small bowel barium series shows distorted and matted segments of the distal ileum with irregular thickening (arrows). (b) Intravenous contrast-enhanced CT scan shows matted small bowel segments in the right lower quadrant that have concentric mural thickening (arrowheads) and an adjacent spiculated mesenteric mass (arrow). (c) Gadolinium-enhanced fat-saturated T1-weighted MR image shows diffuse enhancement of the involved bowel segments (arrows). The mesenteric mass is not as well seen compared with the CT scan in b. (d) Intraoperative photograph of the retracted small bowel mesentery shows metastatic deposits (arrows) studding the mesentery. Liver metastases were also found.

Small intestinal carcinoids may produce a kink or curvature of the intestinal wall that has been called a hairpin turn. The kinking is the result of tumor infiltration and fibrosis. Fluoroscopic barium evaluation of the small bowel reveals a fixed, rigid, curved segment of small intestine, whereas CT shows a thickened, distorted segment of small intestine (Fig 14). In most cases, the curvature and kinking of the intestine is readily identified in the axial plane, but coronal CT reformations may be necessary to appreciate the classic appearance of the hairpin turn. Occasionally, mural thickening may be related to ischemia. In addition to producing elastic vascular sclerosis, EC-cell carcinoids may invade and occlude vessels, which may result in local, regional, or diffuse intestinal ischemia, depending on the extent of disease. Careful attention should be paid to the pattern and attenuation of mural thickening for signs that suggest ischemia, such as low-attenuation circumferential mural thickening, target sign, and halo sign (40).

View larger version (137K): [in this window] [in a new window] [Download PPT slide]   Figure 14a.  EC-cell carcinoid of the ileum in a 50-year-old man with abdominal pain. (a) View from a barium small bowel series shows a focal, nonobstructing, dilated segment of ileum, which is fixed in a curved configuration (arrows) with irregular fold thickening (arrowheads). (b, c) Contrast-enhanced CT scans show concentric mural thickening and kinking of the affected ileal segment (arrows in b). There is masslike extension into the adjacent mesentery (*) and soft-tissue spiculation and retraction of the mesentery (arrow in c). (d) Photograph of the resected ileum shows mural thickening (arrows) with a hairpin kink.

View larger version (171K): [in this window] [in a new window] [Download PPT slide]   Figure 14b.  EC-cell carcinoid of the ileum in a 50-year-old man with abdominal pain. (a) View from a barium small bowel series shows a focal, nonobstructing, dilated segment of ileum, which is fixed in a curved configuration (arrows) with irregular fold thickening (arrowheads). (b, c) Contrast-enhanced CT scans show concentric mural thickening and kinking of the affected ileal segment (arrows in b). There is masslike extension into the adjacent mesentery (*) and soft-tissue spiculation and retraction of the mesentery (arrow in c). (d) Photograph of the resected ileum shows mural thickening (arrows) with a hairpin kink.

View larger version (164K): [in this window] [in a new window] [Download PPT slide]   Figure 14c.  EC-cell carcinoid of the ileum in a 50-year-old man with abdominal pain. (a) View from a barium small bowel series shows a focal, nonobstructing, dilated segment of ileum, which is fixed in a curved configuration (arrows) with irregular fold thickening (arrowheads). (b, c) Contrast-enhanced CT scans show concentric mural thickening and kinking of the affected ileal segment (arrows in b). There is masslike extension into the adjacent mesentery (*) and soft-tissue spiculation and retraction of the mesentery (arrow in c). (d) Photograph of the resected ileum shows mural thickening (arrows) with a hairpin kink.

View larger version (137K): [in this window] [in a new window] [Download PPT slide]   Figure 14d.  EC-cell carcinoid of the ileum in a 50-year-old man with abdominal pain. (a) View from a barium small bowel series shows a focal, nonobstructing, dilated segment of ileum, which is fixed in a curved configuration (arrows) with irregular fold thickening (arrowheads). (b, c) Contrast-enhanced CT scans show concentric mural thickening and kinking of the affected ileal segment (arrows in b). There is masslike extension into the adjacent mesentery (*) and soft-tissue spiculation and retraction of the mesentery (arrow in c). (d) Photograph of the resected ileum shows mural thickening (arrows) with a hairpin kink.

At the time of diagnosis, 58%–64% of patients with small intestinal carcinoids have disease that has spread beyond the intestine to regional lymph nodes or the liver (1). Carcinoid metastatic in the small bowel mesentery may produce enlarged lymph nodes or masses in the mesentery that have well-defined or spiculated, irregular margins (Fig 15). The local effects of serotonin and other substances released by EC-cell carcinoids in mesenteric lymph nodes may produce mesenteric retraction and soft-tissue stranding within the mesentery that is visible at CT. In general, this soft-tissue stranding is secondary to fibrosis rather than tumor infiltration. The degree of spiculation, which appears as soft-tissue strands radiating from the mesenteric mass on CT scans, correlates with the degree of fibrosis and desmoplasia observed histologically (41). Fibrosis in the mesentery may create a "spoke-wheel" or "sunburst" arrangement of mesenteric vessels. These patterns may be observed when the vessels are evaluated with conventional angiography or multidetector CT. Finally, disease within the mesentery and peritoneum may occasionally be more diffuse than isolated nodal disease. Extensive mesenteric and peritoneal disease may produce miliary peritoneal implants (Fig 13d), large masses, or mesenteric caking (38).

View larger version (170K): [in this window] [in a new window] [Download PPT slide]   Figure 15a.  Ileal carcinoid that was discovered incidentally in a 67-year-old woman who underwent preoperative CT for endometrial carcinoma. (a) Intravenous contrast-enhanced CT scan shows a calcified, spiculated mass (arrow) in the mesentery adjacent to a thickened segment of distal ileum. The mesenteric mass creates retraction of the mesentery and small intestine. (b) Total body indium 111 pentetreotide (OctreoScan; Mallinckrodt, Petten, the Netherlands) scan shows multifocal areas of increased activity in the liver, mesentery, and left inguinal region, findings consistent with metastatic carcinoid.

View larger version (100K): [in this window] [in a new window] [Download PPT slide]   Figure 15b.  Ileal carcinoid that was discovered incidentally in a 67-year-old woman who underwent preoperative CT for endometrial carcinoma. (a) Intravenous contrast-enhanced CT scan shows a calcified, spiculated mass (arrow) in the mesentery adjacent to a thickened segment of distal ileum. The mesenteric mass creates retraction of the mesentery and small intestine. (b) Total body indium 111 pentetreotide (OctreoScan; Mallinckrodt, Petten, the Netherlands) scan shows multifocal areas of increased activity in the liver, mesentery, and left inguinal region, findings consistent with metastatic carcinoid.

View larger version (98K): [in this window] [in a new window] [Download PPT slide]   Figure 16a.  Carcinoid arising in a Meckel diverticulum of an 80-year-old man who complained of weight loss, abdominal pain, and early satiety. (a) Intravenous contrast-enhanced CT scan shows a smoothly marginated, heterogeneously enhancing mesenteric mass (arrow) with focal areas of hypoattenuation from degeneration and necrosis. (b) Photograph of the resected distal ileum and mesentery reveals a large mesenteric lymph node metastasis (M) and a Meckel diverticulum (arrow) that contained the primary carcinoid.

View larger version (90K): [in this window] [in a new window] [Download PPT slide]   Figure 16b.  Carcinoid arising in a Meckel diverticulum of an 80-year-old man who complained of weight loss, abdominal pain, and early satiety. (a) Intravenous contrast-enhanced CT scan shows a smoothly marginated, heterogeneously enhancing mesenteric mass (arrow) with focal areas of hypoattenuation from degeneration and necrosis. (b) Photograph of the resected distal ileum and mesentery reveals a large mesenteric lymph node metastasis (M) and a Meckel diverticulum (arrow) that contained the primary carcinoid.

The imaging differential diagnosis for small intestinal carcinoids includes metastatic disease, primary small intestinal adenocarcinomas, lymphoma, and gastrointestinal stromal tumors. The characteristic curvature of the small intestine and spiculated margins of the mesenteric nodal metastases strongly suggest carcinoid. In cases without the characteristic fibrotic changes, somatostatin-receptor scintigraphy or biopsy will help in establishing the diagnosis. Nonneoplastic diseases such as Crohn disease and localized ischemic enteritis may produce inflammatory changes in the distal ileum and mesentery that simulate carcinoid.

Appendiceal Carcinoids
The majority of appendiceal carcinoids are serotonin-producing EC-cell tumors similar to those that occur in the jejunum and ileum; less frequently, appendiceal carcinoids are L-cell tumors similar to those in the colon (13). Most important, the biologic behavior of both cell types is strikingly different in the appendix compared with in the ileum and nonappendiceal colon. The majority of appendiceal carcinoids have a benign clinical course and as such do not metastasize.

Clinical Features.— Appendiceal carcinoids occur in patients of all ages. Patients with appendiceal carcinoids tend to be much younger compared with patients diagnosed with other appendiceal neoplasms or carcinoids at other sites (1). They are also reportedly more common in female patients. It is unclear whether or not these demographic features reflect the true distribution of appendiceal carcinoids or only the age range of the population that usually undergoes appendectomy for inflammatory appendicitis. In addition, the preponderance of women with appendiceal carcinoids may reflect the greater number of incidental appendectomies performed in women during pelvic operations.

Pathologic Features.— Seventy percent of appendiceal carcinoids are located in the distal tip of the appendix (43). They are usually less than 1 cm in diameter and as such are incidentally discovered during histologic evaluation of an appendectomy specimen (Fig 17). In rare cases, they exceed 2 cm in size and are apparent on palpation of the appendix or preoperative cross-sectional images. At histologic analysis, EC-cell and L-cell carcinoids of the appendix are identical to their counterparts in the ileum and jejunum. However, they usually do not penetrate the appendiceal wall and infiltrate the mesoappendix (13).

View larger version (148K): [in this window] [in a new window] [Download PPT slide]   Figure 17.  Incidental appendiceal carcinoid. Photomicrograph (original magnification, x20; chromo-granin stain) demonstrates a small microscopic carcinoid that stained positive for chromogranin (arrows).

The initial imaging manifestations may reflect inflammatory disease, caused by the tumor obstructing the base or a portion of the appendix. The tumor in these cases may not be readily evident at sonography or CT (45). The carcinoid may manifest as a focal soft-tissue mass within the appendix or as diffuse, circumferential mural thickening on cross-sectional images (Fig 18) (44). In rare cases, appendiceal carcinoids have aggressive biologic behavior and in such instances may have a pattern of metastatic disease to the mesenteric lymph nodes and liver similar to that of jejunoileal carcinoids. The goblet cell carcinoid, a variety that appears more similar to an adenocarcinoma than a carcinoid, has a more aggressive growth potential.

View larger version (121K): [in this window] [in a new window] [Download PPT slide]   Figure 18a.  Appendiceal carcinoid in a 52-year-old man who complained of abdominal pain and fever. CT scans obtained with orally and intravenously administered contrast material (a cephalad to b) demonstrate a diffusely thickened appendix (arrow).

View larger version (118K): [in this window] [in a new window] [Download PPT slide]   Figure 18b.  Appendiceal carcinoid in a 52-year-old man who complained of abdominal pain and fever. CT scans obtained with orally and intravenously administered contrast material (a cephalad to b) demonstrate a diffusely thickened appendix (arrow).

Clinical Features.— Colorectal carcinoids do not exhibit specific gender predilection. Analysis of recent SEER data shows that rectal carcinoids are more common in the black population (1). The mean age of patients at diagnosis for colonic carcinoids is 66 years and for rectal carcinoids, 56.2 years (1,46). Abdominal pain and weight loss are typical symptoms for colonic carcinoids, whereas more than 50% of patients with rectal carcinoids are asymptomatic and the lesions are discovered at routine rectal examination or screening endoscopy (47). When rectal carcinoids cause symptoms, they may produce bleeding, pain, or constipation. Metastatic disease from colonic carcinoids may produce carcinoid syndrome. In contrast, metastatic disease from rectal carcinoids is not associated with carcinoid syndrome (48).

Pathologic Features.— Serotonin-producing EC-cell carcinoids of the cecum mimic cecal adenocarcinomas because they are frequently large, polypoid, or ulcerating masses (13). They are histologically similar to their small intestinal counterparts. L-cell rectal carcinoids are usually solitary, small (<1 cm), submucosal nodules or focal areas of plaque-like thickening (13,47). L-cell carcinoids are usually argyrophilic tumors that have a trabecular growth pattern or, less commonly, acini, glands, or tubular structures (13).

Imaging Features.— The imaging appearances of colorectal carcinoids have not been extensively described in the medical literature. In our experience at the AFIP, carcinoids of the proximal colon are polypoid intraluminal masses that are indistinguishable from polypoid adenomas or adenocarcinomas. Intussusception may occur, and at CT, low-attenuation necrosis and degeneration may be seen within the tumor. Infiltrating tumors that produce annular lesions in the colon have been reported (49) but are uncommon in our experience. Rectal carcinoids are most commonly small mural or polypoid masses (Fig 19). Less frequently, more malignant rectal carcinoids may invade adjacent pelvic structures.

View larger version (172K): [in this window] [in a new window] [Download PPT slide]   Figure 19a.  Rectal carcinoid in a 37-year-old woman who complained of lower abdominal cramps. Anterior-posterior spot radiograph (a) and lateral view (b) of the rectum show a smoothly marginated sessile polyp (arrow) on the right lateral rectal wall.

View larger version (177K): [in this window] [in a new window] [Download PPT slide]   Figure 19b.  Rectal carcinoid in a 37-year-old woman who complained of lower abdominal cramps. Anterior-posterior spot radiograph (a) and lateral view (b) of the rectum show a smoothly marginated sessile polyp (arrow) on the right lateral rectal wall.

Meckel Diverticulum.— Carcinoids arising in Meckel diverticula are usually single, small, asymptomatic, and incidentally discovered (53, 54). When symptoms occur, abdominal pain, bleeding, weight loss, nausea, vomiting, and diarrhea are the most frequent complaints. Carcinoids in Meckel diverticula are more common in men than women, and the mean age of patients at presentation is 57 years (1). The immunohistochemical profile and biologic behavior of carcinoids occurring in Meckel diverticula are similar to those of ileal carcinoids (53). We have seen only a few cases of carcinoid in a Meckel diverticulum. In our experience, the primary tumor in the diverticulum is very small and not evident on cross-sectional images, which show metastatic disease to mesenteric lymph nodes and liver (Fig 16).

Duplication Cysts.— Duplications of the gastrointestinal tract are congenital anomalies that manifest as focal cysts or tubular structures located near the gastrointestinal tract or its embryologic origins. Gastrointestinal duplications have mucosal, submucosal, and muscular elements that histologically resemble the normal gastrointestinal wall. A variety of neoplasms, including carcinoid tumors, have been reported to complicate gastrointestinal duplications. Carcinoid tumors arising in duplications are a rare occurrence, with only a handful of cases reported in the literature (55).

	Scintigraphy in the Management of Carcinoid Tumors

Top Abstract LEARNING OBJECTIVES FOR TEST... Introduction Epidemiology General Pathologic Features Site-Specific Features Scintigraphy in the Management... Conclusions References

 
In the management of patients with gastrointestinal carcinoids, ¹¹¹In pentetreotide scintigraphic studies are used to localize occult primary tumors, stage disease for optimal therapy, and identify receptor status of metastatic lesions for octreotide treatment or chemotherapy (56). Somatostatin-receptor scintigraphy radiolabels somatostatin receptors types 2 and 5, which are present on the majority of gastrointestinal carcinoid tumors. Currently, somatostatin-receptor scintigraphy is the study of choice in the management of patients with carcinoid tumors, and ¹¹¹In pentetreotide is the most commonly used agent (Fig 15b) (57). Sensitivities of 71%–100% (cumulative sensitivity, 86%) have been reported for somatostatin-receptor scintigraphy (58). Somatostatin-receptor scintigraphy is limited in the detection of small (< 1 cm) tumors. The diagnostic accuracy of ¹¹¹In pentetreotide for demonstrating primary and metastatic disease in the abdomen is improved with single photon emission CT (SPECT)–CT fusion imaging (59). Fluorine 18 fluorodeoxyglucose positron emission tomography (PET) has not been shown to depict gastrointestinal carcinoid tumors effectively because of the slow tumor growth and low cellular turnover typical of these tumors (60). PET imaging with ¹⁸F-3,4-dihydroxyphenyalanine (dopa) and ¹¹C-5-hydroxytryptophan has been shown to be more effective (56,61).

	Conclusions

Top Abstract LEARNING OBJECTIVES FOR TEST... Introduction Epidemiology General Pathologic Features Site-Specific Features Scintigraphy in the Management... Conclusions References

 
Gastrointestinal carcinoids comprise a large group of well-differentiated endocrine neoplasms that have a diverse spectrum of clinical, pathologic, and radiologic appearances based on their origin within the gastrointestinal tract. Accurate recognition and diagnosis of gastrointestinal carcinoids is important clinically so that patient management can be applied accordingly.

	Acknowledgments

 
The authors thank Aletta Ann Frazier, MD, Department of Radiologic Pathology, Armed Forces Institute of Pathology, for the medical illustration in the article.

	Footnotes

 

Abbreviations: AFIP = Armed Forces Institute of Pathology, H-E = hematoxylin-eosin, MEN-1 = multiple endocrine neoplasia type 1, NF-1 = neurofibromatosis type 1, SEER = Surveillance, Epidemiology, and End Results, ZES = Zollinger-Ellison syndrome

The opinions and assertions contained herein are the private views of the authors, and are not to be construed as official nor as reflecting the views of the Department of the Army or Defense.

	References

Top Abstract LEARNING OBJECTIVES FOR TEST... Introduction Epidemiology General Pathologic Features Site-Specific Features Scintigraphy in the Management... Conclusions References

 

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