Metastatic Neuroendocrine Tumors
Definition
Lymph node metastases of neuroendocrine tumors.
Pathogenesis
Neuroendocrine tumors encompass a broad spectrum of neoplasms ranging from well-differentiated neoplasms, also known as carcinoid tumors (from the german karzinoide or carcinoma-like), to more poorly differentiated neuroendocrine tumors (atypical carcinoid and large-cell neuroendocrine carcinoma), to small-cell carcinoma. Well-differentiated neuroendocrine tumors are most common in the gastrointestinal (GI) tract, and both large-cell neuroendocrine carcinoma and small-cell carcinoma are most common in the lung. However, neuroendocrine tumors rarely can arise from virtually anywhere in the body including the pituitary gland, middle ear, thymus, thyroid gland, pancreas, kidney, adrenal glands, prostate gland, ovary, and testis to name some anatomic sites recently reported in the literature.
Neuroendocrine tumors arise from cells of the diffuse neuroendocrine system. In the GI tract, neuroendocrine cells are present in the basal mucosa and are widely distributed from the esophagus to the anus (1,2). Thus, the GI tract may be the largest endocrine organ in the body (1). Although initially thought to be of one cell type, it is now clear that a large number of neuroendocrine cell types exist, with at least 20 types in the GI tract alone (1). The classic studies of A.G.E. Pearse showed that GI neuroendocrine cells have in common the capacity for amine precursor uptake and decarboxylation (APUD). Thus, these cells were named APUD cells, and neoplasms derived from these cells were referred to as APUDomas (3). Neuroendocrine cells also have been referred to as Kulchitsky cells, enterochromaffin-like cells, or named after their cell products (e.g., G or gastrin cells) (1,2,4). Although APUD cells were once thought to have arisen from neural crest cells that had migrated to various locations, the cells of the diffuse neuroendocrine system are now thought to be of endodermal derivation. Further, these cells are thought to be primitive, with the capacity to differentiate into multiple cell types, including endocrine cells. The presence of both endocrine and nonendocrine cells in some neuroendocrine tumors supports the idea that neuroendocrine tumors are derived from primitive cells capable of differentiation in multiple directions (1,2,5).
With our increased understanding of the various cell types in the diffuse neuroendocrine system, it is now recognized that well-differentiated neuroendocrine tumors (henceforth referred to as carcinoid tumors as this term, although imprecise, is well-entrenched in the literature) represent a group of closely related neoplasms rather than a single pathologic entity. In the past, carcinoid tumors were subdivided according to their embryologic derivation into three groups: foregut, midgut, and hindgut. However, it is now clear that this approach is not scientifically precise nor is it particularly helpful diagnostically.
All carcinoid tumors are capable of invasion and metastasis, but in general their clinical course is relatively benign, and the frequency of metastases varies with their anatomic site of origin and size (1,6). Small-cell carcinoma is highly malignant, with potential for early, widespread dissemination. In the middle of this spectrum is atypical carcinoid tumor (defined later) and large-cell neuroendocrine carcinoma. Atypical carcinoid tumor has a more aggressive clinical course and higher frequency of lymph node metastases than typical carcinoid tumors, but histologically retains neuroendocrine features and is less aggressive than small-cell carcinomas. Large-cell neuroendocrine carcinomas retain some neuroendocrine architectural features but are clinically more aggressive than atypical carcinoid (7).
Carcinoid tumors of the GI tract and lung and small-cell carcinoma of the lung are the primary focus of this chapter, as these represent the majority of carcinoid tumors and small-cell carcinomas.
Clinical Syndrome
Carcinoid (Well-differentiated Neuroendocrine) Tumors of the Gastrointestinal Tract
The incidence of carcinoid tumors of the GI tract as a group is 2.0 per 100,000 for men and 2.4 per 100,000 for women (2). The frequency and clinical behavior of carcinoid tumors arising in the GI tract vary greatly with location, size, and level of invasion (through versus confined within the muscularis propria). In a large analysis of 13,715 carcinoid tumors, 67.5% of all carcinoid tumors arose in the GI tract (with 25.3% in the lung and 7.2% at other sites) (6). The most frequent sites in the GI tract were the small intestine (41.8%), rectum (27.4%), and stomach (8.7%). Carcinoid tumors less often arise in the appendix, and they are rare in the esophagus and colon. Five-year survival rates are highest for patients with carcinoid tumors arising in the rectum and appendix, and poorest for patients with small-intestinal tumors (1,6). Carcinoid tumors can produce a variety of substances including serotonin, histamine, prostaglandins, kallikrein, bradykinins, substance P, gastrin, corticotrophin, and neuron-specific enolase. Metastases, in general, produce the same endocrine substances as the primary neoplasms. However, in some metastases, the neoplasm loses its ability to produce hormones, and in others the metastases have been shown to secrete entirely different substances (8).
Carcinoid tumors of the small intestine, here referring mostly to tumors in the distal jejunum and ileum, represent approximately 25% to 30% of all GI tract neuroendocrine tumors (1,2). These tumors occur most often in patients in the sixth decade, and men and women are affected equally. Commonly, these neoplasms are diagnosed relatively late, as a result of their location, and can be large (>2 cm), with invasion
through the muscularis propria (1,2). Carcinoid tumors can be multiple in approximately 30% of patients (1,9). Lymph node metastases are frequent, and liver metastases occur in up to 25% of patients. These neoplasms commonly secrete serotonin, which the liver normally metabolizes. In patients with liver metastases, however, serotonin metabolism is compromised and patients can develop carcinoid syndrome. The latter is characterized by flushing or cyanosis of the face and anterior chest, watery and explosive diarrhea, tachycardia or intermittent hypertension, bronchospasm, and telangiectasia, and can result in heart failure due to endocardial fibrosis, most severe in the right side of the heart and usually causing valvular stenosis or regurgitation (10). Approximately 10% of patients with carcinoid tumors (of all types) develop carcinoid syndrome, but this number is higher for patients with small-intestinal tumors.
through the muscularis propria (1,2). Carcinoid tumors can be multiple in approximately 30% of patients (1,9). Lymph node metastases are frequent, and liver metastases occur in up to 25% of patients. These neoplasms commonly secrete serotonin, which the liver normally metabolizes. In patients with liver metastases, however, serotonin metabolism is compromised and patients can develop carcinoid syndrome. The latter is characterized by flushing or cyanosis of the face and anterior chest, watery and explosive diarrhea, tachycardia or intermittent hypertension, bronchospasm, and telangiectasia, and can result in heart failure due to endocardial fibrosis, most severe in the right side of the heart and usually causing valvular stenosis or regurgitation (10). Approximately 10% of patients with carcinoid tumors (of all types) develop carcinoid syndrome, but this number is higher for patients with small-intestinal tumors.
Carcinoid tumors of the rectum are uncommon and also occur most often in the sixth decade. These tumors are usually small and localized (2,6,11,12). Regional lymph node metastases occur in less than 5% of patients (6), and carcinoid syndrome is rare. Carcinoid tumors of the appendix occur in a younger patients, ages 30 to 50 years, and women are more often affected (1,2,6). Most of these tumors are detected incidentally, usually in appendices removed for appendicitis. In one study, the frequency of a carcinoid tumor was 1 in 300 appendectomy specimens (13). Lymph node metastases can occur in up to one-third of patients, usually when the carcinoid tumor is larger than 2.0 to 2.5 cm. In the duodenum, carcinoid tumors represent less than 5% of all GI tract neuroendocrine neoplasms. Duodenal carcinoids occur most often in the sixth decade, with a slight male predominance. These neoplasms are a heterogeneous group and can be functional or nonfunctional. Functional tumors include gastrin- and somatostatin-secreting neoplasms (gastrinoma and somatostatinoma, respectively). The former can be either familial or sporadic, with the former often multiple and associated with Zollinger-Ellison syndrome (1,2,14). Nonfunctional tumors, designated, G- and D-cell tumors also occur. G-cell tumors and gastrinomas commonly metastasize to lymph nodes, in 50% to 60% of cases, and 10% of cases can metastasize to the liver (1). D-cell and somatostatinomas are usually solitary but also can metastasize (1,2).
In the stomach, three types of carcinoids (well-differentiated neuroendocrine tumors) have been described (1,2,15). These tumors account for up to 40% of GI carcinoids (1). The most common group is associated with chronic atrophic gastritis type A and pernicious anemia. These tumors occur in patients approximately 40 to 70 years of age, are more common in women, and are usually small and multicentric. A second group is composed of tumors derived from gastrin-secreting cells. These tumors are also usually small and multicentric and are often associated with Zollinger-Ellison syndrome. The third group of tumors is sporadic. These tumors are solitary and larger and tend to have the highest frequency of lymph node and liver metastases (1,2).
Carcinoid and Atypical Carcinoid Tumors of the Lung
Typical carcinoid tumors of the lung represent approximately 25% of all carcinoid tumors, and fewer than 5% of all lung neoplasms. Patients have a very good prognosis, and metastases to regional lymph nodes occur in 5% to 10% of patients, usually many years after the initial diagnosis (7,16). Carcinoid syndrome is rare in this group of patients. Atypical carcinoid tumors, by contrast, are less common and lymph node metastases are much more frequent (7).
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