Excerpt from Carcinoid Tumor

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Background

Origin and general involvement and presentation

Carcinoid tumors are derived from primitive stem cells in the gut wall but can be seen in other organs (Broaddus, 2003), including the lungs (Moraes, 2003), mediastinum, thymus (Soga, 1999), liver, pancreas, bronchus, and ovaries (Piura, 1995). In children, most tumors occur in the appendix and are benign and asymptomatic.

Although rare, aggressive and metastatic disease (eg, to the brain) does occur; even tumors in the appendix can metastasize (Hlatky, 2004; Volpe, 2000). Depending on size and location, carcinoid tumors can cause various symptoms, including carcinoid syndrome. Carcinoid tumors of the ileum and jejunum, especially those larger than 1 cm, are most prone to produce this syndrome, at least in adults.

Classification

Carcinoid tumors generally are classified based on the location in the primitive gut (ie, foregut, midgut, hindgut) that gives rise to the tumor.

Foregut carcinoid tumors are divided into sporadic primary tumors and tumors secondary to achlorhydria. The term sporadic primary foregut tumor encompasses carcinoids of the bronchus, stomach, proximal duodenum, and pancreas.

Midgut tumors are derived from the second portion of the duodenum, the jejunum, the ileum, and the right colon. These account for 60-80% of all carcinoid tumors (especially those of the appendix and distal ileum) in adults and are also seen in children (Schmittenbecher, 2001). Appendicular carcinoid tumors are most common (Bethel, 1997; Pelizzo, 2001). In children, more than 70% of these tumors occur at the tip of the appendix and are often an incidental finding in appendectomy specimens. In one study, carcinoid tumors were found in 0.169% of 4747 appendectomies (Doede, 2000). Bulky tumors are relatively rare and require somewhat extensive cecectomy or, when tumor infiltration is beyond the cecum, ileocecal resection (Soreide, 2000; D'Aleo, 2001; Pelizzo, 2001).

Hindgut carcinoid tumors include those of the transverse colon, descending colon, and rectum.

Carcinoid tumors can also arise from the Meckel diverticulum, cystic duplications, and the mesentery. Each of these entities has distinctive clinical, histochemical, and secretory features. For example, foregut carcinoids are argentaffin negative and have low serotonin content but secrete 5-hydroxytryptophan (5-HTP), histamine, and several polypeptide hormones. These tumors can metastasize to bone and may be associated with atypical carcinoid syndrome, acromegaly, Cushing disease, other endocrine disorders, telangiectasia, or hypertrophy of the skin in the face and upper neck.

Midgut carcinoids are argentaffin positive and can produce high levels of serotonin 5-hydroxytryptamine (5-HT), kinins, prostaglandins, substance P (SP), and other vasoactive peptides. These tumors have a rare potential to produce corticotropic hormone (previously adrenocorticotropic hormone [ACTH]). Bone metastasis is uncommon.

Hindgut carcinoids are argentaffin negative and rarely secrete 5-HT, 5-HTP, or any other vasoactive peptides. Therefore, they do not produce related symptomatology. Bone metastases are not uncommon in these tumors.

Pathophysiology

Carcinoid tumors are of neuroendocrine origin and are derived from primitive stem cells, which can give rise to multiple cell lineages. In the intestinal tract, these tumors develop deep in the mucosa, growing slowly and extending into the underlying submucosa and mucosal surface. This results in the formation of small firm nodules, which bulge into the intestinal lumen. These tumors have a yellow, tan, or gray-brown appearance that can be observed through the intact mucosa. The yellow color is a result of cholesterol and lipid accumulation within the tumor. Tumors can have a polypoid appearance and occasionally become ulcerated. With expansion and infiltration through the submucosa into the muscularis propria and serosa, carcinoid tumors can involve the mesentery. Metastases to the mesenteric lymph node and liver, ovaries, peritoneum, and spleen can occur.

Upon histologic examination, carcinoid tumors have 5 distinctive patterns: (1) solid, nodular, and insular cords; (2) trabecular or ribbons with anastomosing features; (3) tubules and glands or rosettelike patterns; (4) poorly differentiated or atypical patterns; and (5) mixed patterns. A combination of these patterns is often observed. Tubules can contain mucinous secretions, and individual tumor cells can contain mucin-positive material, which includes the various acidic and neutral intestinal mucin. Tumors rarely have eosinophilic stroma. Capillaries are often prominent. Cells are uniformly round or polygonal with a central nucleus and punctate chromatin, as well as small nucleoli and infrequent mitosis. The cytoplasm can be slightly acidophilic, basophilic, or amphophilic. Eosinophilic granules may be present.

In midgut carcinoids, cells are arranged in closely packed, round, regular, monomorphous masses. In the appendix, carcinoids appear as discrete yellow nodules in the lumen. Lesions associated with diffuse wall thickening are relatively uncommon. Carcinoid tumors commonly affect the tip of the appendix. Most carcinoid tumors invade the wall of the appendix, and lymphatic involvement is nearly universal. About 75% of patients have evidence of peritoneal involvement. However, only a few patients have regional or distant dissemination. The size of the tumor can be correlated with outcome of the disease; tumors smaller than 1.5 cm in diameter (after formalin fixation) rarely result in distant metastases or recurrences.

Carcinoid tumors can be associated with concentric and elastic vascular sclerosis that results in obliteration of vascular lumina and ischemia. A common finding is elastosis and fibrosis that surround nests of the tumor cells and that result in matting of the involved tissues and lymph nodes. Fibroblastic proliferation may result from the stimulation of fibroblast cells by growth factor. This stimulation may be a result of a local release of tumor growth factor (TGF)-beta, beta–fibroblast growth factor (beta-FGF), and platelet-derived growth factor.

Other products of carcinoid tumors include the following:

• Acid phosphatase



• Alpha-1-antitrypsin



• Amylin



• Atrial natriuretic polypeptide



• Calbindin-D28k



• Catecholamines



• Dopamine



• Fibroblast growth factor



• Gastrin



• Gastrin-releasing peptide (bombesin)



• Glucagon, glicentin



• 5-Hydroxyindoleacetic acid (5-HIAA)



• 5-Hydroxytryptamine (5-HT)



• Histamine



• Insulin



• Kallikrein



• Kinins



• Motilin



• Neuropeptide



• Neurotensin



• Pancreastatin



• Pancreatic polypeptide



• Platelet-dermal growth factor



• Prostaglandins



• Pyroglutamyl-glutamyl-prolinamide



• Secretin



• Serotonin



• Somatostatin (ie, SRIF)



• Tachykinins



• Neuropeptide K



• Neuropeptide A



• Substance P (SP)



• Transforming growth factor-beta



• Vasoactive intestinal polypeptide (VIP)

Classic carcinoid tumor cells are argentaffinic and argyrophilic. At present, immunostain and hormonal markers are used for diagnosis.

Carcinoids may have somatostatin receptors. Five identified somatostatin receptors are members of the G-protein receptor family. Five distinct genes on chromosomes 11, 14, 16, 17, and 20 encode somatostatin receptors. Somatostatin receptors are used to advantage for diagnosing and treating this disease.

Frequency

United States

Carcinoids are the most common neuroendocrine tumors, with an estimated 1.5 clinical cases per 100,000 population. The incidence in autopsy cases is higher than this at 650 cases per 100,000 population. The exact incidence in children is not known. Most tumors occur in adults and are rarities in children.

International

In 1980-1989, the overall age-standardized incidence rate for male and female populations in England were estimated to be 0.71 (0.68-0.75 and 0.87 (0.83-0.91), respectively. In Scotland, the respective rates were 1.17 (0.91-1.44) per 100,000 population and 1.36 (1.09-1.63) per 100,000 population (Newton 1994).

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