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First Published Online December 17, 2008
The Oncologist, Vol. 13, No. 12, 1255-1269, December 2008; doi:10.1634/theoncologist.2008-0207
© 2008 AlphaMed Press

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Endocrinology

Carcinoid Tumors

Scott N. Pinchot, Kyle Holen, Rebecca S. Sippel, Herbert Chen

Section of Endocrine Surgery, Department of Surgery, and Section of Hematology and Oncology, Department of Medicine, University of Wisconsin, Madison, Wisconsin, USA

Key Words. Carcinoid cancer • Neuroendocrine • Somatostatin • Chromogranin A • serotonin

Correspondence: Herbert Chen, M.D., F.A.C.S., University of Wisconsin Hospital and Clinics, H4/750 Clinical Science Center, 600 Highland Avenue, Madison, Wisconsin 53792, USA. Telephone: 608-263-1387; Fax: 608-263-7652; e-mail: chen{at}surgery.wisc.edu

Received September 18, 2008; accepted for publication November 17, 2008; first published online in THE ONCOLOGIST Express on December 17, 2008.

Disclosure: Employment/leadership position: None; Intellectual property rights/inventor/patent holder: None; Consultant/advisory role: Herbert Chen, Novartis, Covidien; Honoraria: None; Research funding/contracted research: None; Ownership interest: None; Expert testimony: None; Other: None.

The content of this article has been reviewed by independent peer reviewers to ensure that it is balanced, objective, and free from commercial bias. No financial relationships relevant to the content of this article have been disclosed by the authors, planners, independent peer reviewers, or staff managers.


   ABSTRACT
Top
 Abstract
Introduction
 Organ-Related Features of...
 Diagnosis
 Surgical Treatment
 Malignant Carcinoid Syndrome and...
 Management of Metastatic Disease
 Summary
 Author Contributions
 References
 
Carcinoid tumors are rare, slow-growing neuroendocrine tumors arising from the enterochromaffin cells disseminated throughout the gastrointestinal and bronchopulmonary systems. Though they have been traditionally classified based on embryologic site of origin, morphologic pattern, and silver affinity, newer classification systems have been developed to emphasize the considerable clinical and histopathologic variability of carcinoid tumors found within each embryologic site of origin. These neoplasms pose a diagnostic challenge because they are often innocuous at the time of presentation, emphasizing the need for a multidisciplinary diagnostic approach using biochemical analysis, standard cross-sectional imaging, and newer advances in nuclear medicine. Similarly, treatment of both primary and disseminated carcinoid disease reflects the need for a multidisciplinary approach, with surgery remaining the only curative modality. The prognosis for patients with these tumors is generally favorable; however, it can be quite variable and is related to the location of the primary tumor, extent of metastatic disease at initial presentation, and time of diagnosis.


   INTRODUCTION
Top
 Abstract
 Introduction
Organ-Related Features of...
 Diagnosis
 Surgical Treatment
 Malignant Carcinoid Syndrome and...
 Management of Metastatic Disease
 Summary
 Author Contributions
 References
 
Historical Background
Although Theodor Langhans (1839–1915) was the first to describe the histology of a carcinoid tumor in 1867 [1], it is generally Otto Lubarsch (1860–1933) who is credited with the first report of two patients with ileal carcinoid tumors discovered at autopsy, in 1888 [2, 3]. In 1907, Siegfried Obendorfer (1876–1944), a German pathologist at the University of Munich, coined the term karzinoide, or "carcinoma-like," to describe the unique feature of behaving like a benign tumor despite resembling a carcinoma microscopically [4]. Recognition of the endocrine-related properties of carcinoid tumors did not occur until much later. In 1948, Rapport and colleagues isolated and named serotonin (5-hydroxytryptamine), initially identified as a vasoconstrictor substance in the serum [5]; by 1952, it was determined that the origin of this amine was the Kulchitsky cell [6]. Just 1 year later, Lembeck identified serotonin in an ileal carcinoid and confirmed it as the major hormone responsible for carcinoid syndrome [7].

Tumor Biology
Carcinoids are rare neuroendocrine tumors (NETs) thought to arise from the enterochromaffin (Kulchitsky) cells found throughout the crypts of Lieberkühn of the gut [8]. Specifically, the term enterochromaffin refers to the ability to stain with chromium or chrome salts, a common feature of serotonin-containing cells. Similarly, the granules of carcinoid tumors have a high affinity for silver stains, justifying the use of the nomenclature argentaffinoma, which was used interchangeably with carcinoid tumor years ago [3].

The diagnosis of carcinoid tumor is initially based on histology with confirmation by positive immunohistochemical staining, defined as positive staining for one or more neuroendocrine markers (such as chromogranin A [CgA]or synaptophysin), or electron microscopy in which the cells in most tumors are found to contain membrane-bound secretory granules with dense-core granules in the cytoplasm [9]. Within these granules are a wide variety of biogenic amines and hormones characteristic of NETs (Table 1).


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  		Table 1. Common secretory products of carcinoid tumors

 
The most common biologically active substance secreted from carcinoid tumors is serotonin, a vasoactive peptide whose biosynthesis is accomplished nearly exclusively by the enterochromaffin cells. Synthesized from the amino acid tryptophan, the release of serotonin into the systemic circulation can cause the classic symptoms of carcinoid syndrome, which include diarrhea, episodic flushing, bronchoconstriction, and eventual right-sided valvular heart disease [10].

Incidence
Though relatively rare, carcinoid tumors represent the most common gastrointestinal NETs [11–14]. In a series of 13,715 carcinoid cases reported to the Surveillance, Epidemiology, and End Results (SEER) program of the National Cancer Institute, the age-adjusted incidence rates for white men and women over the last decade were 2.47 and 2.58 per 100,000 population per year, respectively, whereas they were somewhat higher for black men and women (4.48 and 3.98 per 100,000 population per year, respectively) [13]. In a separate report from the SEER database of 20,436 carcinoid cases from 1973–2004, carcinoid tumors comprised 0.66% of all malignancies over this time frame and demonstrated a 3%–10% increase in tumor incidence depending on the subtype [14]. Overall, the increasing incidence of carcinoid disease is thought to be largely a result of the introduction of more sensitive diagnostic tools and an overall increased awareness among physicians [14]; however, the changes in relative incidence may also be a result, in part, of variations in reporting of carcinoid tumors. Benign-appearing carcinoid tumors, for instance, were not recorded in the SEER database until 1986 [11]. The increased incidence may also be related to the aging population, given that this is a tumor more common in older adults.

Until recently, carcinoid tumors were thought to be significantly less common than other gastrointestinal tumors. However, in a recent SEER database review of over 35,600 patients, Yao and colleagues [15] demonstrated the prevalence—that is, the number of people alive on a certain date in a population who have never had a diagnosis of that disease—of carcinoid tumors exceeded that of many gastrointestinal tumors. In fact, when compared with other gastrointestinal neoplasms, the estimated 29-year limited-duration prevalence of NETs was 103,312 in 2004, making these tumors significantly more common than esophageal cancer (28,664), gastric cancer (65,836), pancreatic cancer (32,353), and hepatobiliary cancer (21,427) in the U.S. [15].

The majority of carcinoids are found within the gastrointestinal tract (55%) and bronchopulmonary system (30%) [16]. Population-based statistics have shown that, within the gastrointestinal tract, the small intestine is the most common site of carcinoids (45%), followed by the rectum (20%), appendix (17%), colon (11%), and stomach (7%). Far less common anatomic sites have been reported in the literature, including carcinoids of the breast, larynx, thymus, and gall bladder [17–20]. Traditionally, the appendix had been identified as the most common site of carcinoid tumors within the gastrointestinal tract; however, recent studies suggest that the incidence of primary appendiceal carcinoid disease is declining while the incidence of gastric and rectal carcinoid disease is on the rise. This evolution of carcinoid epidemiology presumably stems from improvements in technology and diagnosis over the last several decades, such as better endoscopic recognition of early, presymptomatic carcinoids in these anatomic locations.

Tumor Classification
Carcinoid tumors have traditionally been classified based on embryologic site of origin, morphologic pattern, and silver affinity. This classification system, originally proposed by Williams and Sandler in 1963 [21], subdivided carcinoids into tumors of the foregut (respiratory tract, thymus, stomach), the midgut (small intestine, appendix, proximal colon), and the hindgut (distal colon, rectum, genitourinary tract). Microscopically, foregut carcinoid tumors characteristically exhibit a trabecular pattern, whereas midgut tumors typically appear as sheets of monotonous polygonal cells [3]. Likewise, the early divisions of carcinoid tumors were based on the staining characteristics when stained with silver. Cells of foregut and rectal tumors accumulate cytoplasmic silver deposits only after being treated with a reducing agent, bestowing the term argyrophil cells. Conversely, the cytoplasm of midgut tumors contains granules that stain black with ammoniacal silver nitrate, which is known as a positive argentaffin reaction [3]. Unfortunately, the clinical behavior of carcinoids within each embryologic division has been shown to vary considerably. For instance, both chronic atrophic gastritis type A (CAG-A)-associated carcinoid tumors and carcinoid tumors associated with multiple endocrine neoplasia type 1 (MEN-1) found within the stomach exhibit an indolent disease course and are rarely associated with carcinoid syndrome, whereas sporadic gastric carcinoid tumors are often aggressive, displaying a high incidence of metastases and atypical carcinoid syndrome features. As such, many authors have chosen to subdivide carcinoid tumors not only on the site of origin but also on variations in the histologic characteristics of these tumors [22]. Based upon this classification, carcinoid tumors may be characterized as typical or atypical. Typical carcinoids are well differentiated, exhibiting a distinct recognized histologic pattern (insular, trabecular, glandular, mixed, or undifferentiated) of carcinoid morphology [23]. Conversely, atypical carcinoids may exhibit increased nuclear atypia, focal necrosis, or high mitotic indices.

More recently, the World Health Organization (WHO), in an effort to clarify the classification of carcinoid tumors and to standardize a system that would enable clinicians to compare patients and predict outcomes accurately, proposed a new classification of gastroenteropancreatic NETs [24]. Based on their malignant potential, the tumors are divided into five main categories: (a) well-differentiated endocrine tumor (proliferation index [PI] <2%), (b) well-differentiated endocrine carcinoma (PI >2% but <15%), (3) poorly differentiated endocrine carcinoma (PI >15%), (4) mixed exocrine–endocrine tumors, and (5) tumor-like lesions.

PIs are typically based on monoclonal antibody (MIB-1) binding to the Ki-67 antigen, an important marker for cellular proliferation and mitotic activity. The Ki-67 protein is detected in nuclear fractions of proliferating cells in the G1, S, G2, and M phases of the cell cycle; however, quiescent cells in G0 do not express the antigen. Interestingly, several recent retrospective studies have identified the Ki-67 labeling index as an important independent predictor of carcinoid tumor biological behavior and patient survival [25, 26]. Several single-institution experiences with carcinoid tumors have demonstrated a correlation between low Ki-67 values and longer survival. Likewise, mean Ki-67 values were found to be significantly less in benign than in malignant tumors, and poorly differentiated tumors were characterized by very high Ki-67 indices that all exceeded 14% [27]. Based on these studies that suggest a role for Ki-67 as a prognostic factor, some authors have concluded that the Ki-67 labeling index may be used to establish indications for chemotherapy and clinically follow postoperative patients. Though no prospective trials exist, Vilar et al. [28] have postulated that tumors with high Ki-67 may respond better to chemotherapy. Certainly, the role of Ki-67 labeling will continue to expand therapeutic and palliative strategies.


   ORGAN-RELATED FEATURES OF CARCINOID TUMORS
Top
 Abstract
 Introduction
 Organ-Related Features of...
Diagnosis
 Surgical Treatment
 Malignant Carcinoid Syndrome and...
 Management of Metastatic Disease
 Summary
 Author Contributions
 References
 
Carcinoid tumors have been reported in a wide range of organs, but most commonly involve the gastrointestinal tract or bronchopulmonary system. The clinical nature—namely, aggressiveness or metastatic potential—and prognosis of carcinoid tumors vary widely depending on the location of the primary tumor (Fig. 1A, 1B).


Figure 1
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  		Figure 1. Cross-sectional imaging of a carcinoid tumor. (A): Computed tomography (CT) scan of the chest showing a solitary left-sided pulmonary carcinoid tumor. Well-differentiated (typical) pulmonary carcinoid tumors represent nearly two thirds of all bronchopulmonary carcinoid neoplasms and are commonly found in the perihilar region. (B): CT scan of the abdomen showing multiple liver metastases in a patient with metastatic carcinoid disease. (C): CT scan showing the typical appearance of a small bowel carcinoid, represented by a mesenteric soft tissue mass with radiating strands.

 
Bronchopulmonary Carcinoid Tumors
Pulmonary carcinoid tumors account for 1%–2% of all lung malignancies in adults and approximately 25%–30% of all carcinoid tumors [13, 29, 30]. In a recent review of data from the SEER registry, Modlin et al. [13] demonstrated annual incidence rates of bronchial carcinoids of 0.52 and 0.89 per 100,000 population in white males and females, respectively (the corresponding values for black males and females were somewhat higher, at 0.39 and 0.57, respectively). Pulmonary carcinoid tumors are thought to arise from Kulchitsky cells disseminated throughout the bronchopulmonary mucosa [31]. Though these tumors share certain morphologic and biochemical characteristics, confusion has plagued reasonable attempts to devise a classification system for these tumors. In 2004, the WHO devised a new classification for bronchopulmonary carcinoids based on a spectrum of clinicopathologic entities ranging from hyperplastic neuroendocrine cell lesions (carcinoid tumorlets, diffuse idiopathic pulmonary neuroendocrine cell hyperplasia [DIPNECH]) to high-grade NETs (small cell carcinoma and large cell neuroendocrine carcinoma) [32].

Pulmonary neuroendocrine cell hyperplasia and tumorlets (typical carcinoid tumors that measure ≤5 mm in greatest dimension and extend beyond the basement membrane [33]) represent perhaps the earliest manifestations of neuroendocrine disease in the bronchopulmonary system [34]. The 2004 WHO classification of lung tumors applies the term DIPNECH to a proliferation of scattered single cells, small nodules (neuroendocrine bodies), or linear proliferations of pulmonary neuroendocrine cells confined to the bronchial and bronchiolar epithelium [32]. The clinical relevance of these lesions is controversial. Initially identified in the clinical context of chronic pulmonary diseases like obliterative bronchiolitis, bronchiectasis, and idiopathic pulmonary fibrosis, carcinoid tumorlets were thought to represent benign hyperplastic lesions of little clinical relevance [34]. However, recent data suggest the potential malignant nature of these lesions, as carcinoid tumorlets have been demonstrated in association with typical carcinoid tumors of the bronchopulmonary system and with lymph node metastases [35–38].

Representing nearly two thirds of pulmonary carcinoids, well-differentiated NETs of the lungs and bronchi (typical carcinoids) are composed of cytologically bland cells that exhibit minor cellular atypia and rare mitoses [11]. Based on the 2004 WHO classification, these tumors must demonstrate fewer than two mitoses per 10 high power fields (10HPF), lack necrosis, and be >5 mm [32]. They usually present as perihilar masses in the fifth decade of life and demonstrate a relatively indolent disease course; however, some patients may present with recurrent pneumonia, cough, hemoptysis, and chest pain [39]. Ectopic secretion of biologically active hormones is not uncommon, as these tumors may secrete corticotrophin and growth hormone with relative frequency; however, carcinoid syndrome occurs in <5% of patients with these tumors [7] because of the relative paucity of serotonin secretion. Metastases from typical pulmonary carcinoids have been reported in approximately 12% of cases, and the overall survival rate is thought to be >90% [11, 22, 39, 40].

Approximately one third of bronchopulmonary carcinoids are atypical tumors, intermediate grade NETs whose pathologic criteria depend on the presence of carcinoid morphology and at least one of the following: (a) necrosis or (b) 2–10 mitoses per 10HPF [32]. Unlike typical pulmonary carcinoids, atypical carcinoids usually occur in the periphery of the lungs of older patients [41, 42]. Their clinical course is aggressive, with a relatively high incidence of mediastinal lymph node metastases (>50%) and an abbreviated 5-year survival rate of only 40%–75% [40–42].

Gastric Carcinoid Tumors
Originating from the histamine-containing enterochromaffin-like (ECL) cells of the embryologic foregut, gastric carcinoid tumors represent approximately 1.8% of all gastric neoplasms [43] and approximately 7% of all carcinoids [16]. Because they are most often discovered incidentally during endoscopy, the incidence of gastric carcinoid tumors has increased in recent years as endoscopic technology continues to improve both technologically and diagnostically. Carcinoids of the stomach are generally divided into three distinct groups based on their clinical and histological characteristics: carcinoid tumors associated with CAG-A, carcinoid tumors associated with Zollinger-Ellison syndrome (ZES) or MEN-1, and carcinoid tumors that occur sporadically.

Type I gastric carcinoids account for 70%–80% of all gastric carcinoids [44]. These tumors are small, benign tumors associated with chronic atrophic gastritis and chronic hypergastrinemia. The relative importance of gastrin in the development of type I gastric carcinoids is lent support by animal studies in which lifelong inhibition of acid secretion in rats induced by potent inhibitors of acid secretion or subtotal fundectomy was found to be associated with the development of carcinoid tumors of ECL cells in the gastric corpus [45–47]. To date, however, no cases of carcinoid tumor have been attributed to the use of proton pump inhibitor therapy in humans, suggesting the importance of other factors in the development of type I gastric carcinoids. These tumors often exhibit an indolent disease course and tend to be nonfunctional and asymptomatic [45]. Likewise, metastases are rare, occurring in <10% of tumors <2 cm in greatest dimension [48].

Accounting for approximately 5% of gastric carcinoids, type II tumors arise in the setting of MEN-1 and ZES. Like type I gastric carcinoids, they are thought to arise from ECL cells under the influence of hypergastrinemia, resulting in low-grade malignant behavior and associated hyperplasia of surrounding ECL cells [11]. Allelic loss of the MEN1 gene locus, a tumor-suppressor gene located on chromosome 11q13, is thought to be involved in the pathogenesis of many of these tumors [49]. Though type II gastric carcinoids are generally indolent and behave similar to type I lesions, these tumors may be large and polypoid, unlike most small type I carcinoids.

Type III gastric carcinoids account for nearly 15%–25% of tumors [47]. They are usually large, solitary, sporadic tumors unassociated with hypergastrinemic states. Sporadic carcinoid tumors may be aggressive, with a high incidence of metastases and a 5-year survival rate <75% [48]. Unlike type I and II lesions, which produce serotonin, these tumors are prone to the development of atypical carcinoid syndrome related to the production of 5-hydroxytryptophan (5-HTP), characterized by flushing, hypotension, excessive lacrimation, edema, and bronchoconstriction [7]. Excessive production of 5-HTP is thought to be related to the absence of the enzyme aromatic acid decarboxylase, which converts 5-HTP to serotonin.

Small Intestinal Carcinoid Tumors
Within the gastrointestinal tract, nearly 45% of carcinoids arise in the small intestine, making this the most common location for carcinoid tumors [7]. Likewise, carcinoid tumors account for the highest percentage of small bowel tumors, representing approximately one third of all small intestinal neoplasms [50]. Presumed to arise from the intraepithelial endocrine cells disseminated throughout the intestine, small bowel carcinoids most commonly occur in the distal ileum within 60 cm of the ileocecal valve [11, 13]; moreover, the incidence of these tumors increases with proximity to the cecum. These tumors commonly present in the sixth or seventh decade of life with symptoms of abdominal pain or small bowel obstruction (SBO). SBO has been recognized as an increasing feature of this tumor because of anecdotal evidence of tumor infiltration into the mesentery, provoking an intense fibrotic reaction that results in kinking of the bowel segments with resultant intestinal ischemia (Fig. 2). Small bowel carcinoids are frequently multiple, exhibiting multicentricity in up to 30% of patients [51], and often display metastases to the lymph nodes (39%) or the liver (31%) [7]. Development of typical carcinoid syndrome is rare, manifesting in approximately 5%–7% of patients; however, younger patients are more likely to develop carcinoid syndrome and display a worse prognosis [7, 52]. The overall 5-year survival rates are estimated at 65% and 35% for locoregional and distant disease, respectively [53].


Figure 2
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  		Figure 2. Carcinoid tumor of the small intestine. These tumors are fairly well circumscribed but not encapsulated, white or pale yellow tan, and very firm because of a marked desmoplastic reaction. Carcinoid tumors of the small intestine are frequently associated with mechanical obstruction of the intestine as a result of extensive mesenteric fibrosis (shown here).

 
Appendiceal Carcinoid Tumors
Thought to arise from the subepithelial endocrine cells in the lamina propria and submucosa, appendiceal carcinoid tumors are the most common neoplasms affecting the appendix [54, 55]. They are most often discovered during the fourth or fifth decade of life as an incidental finding during surgery performed for other reasons. Most patients with appendiceal carcinoids are asymptomatic, likely because of the location of the neoplasm in relation to the appendiceal base; the vast majority (75%) are located in the distal third of the appendix, where the risk for obstruction is low, with the remainder located in the middle third, and <10% at the base [11]. In a series of 150 appendiceal carcinoids, Moertel et al. [56] demonstrated that most appendiceal neoplasms were <1 cm in largest dimension, though larger tumors (>2 cm) appeared to be associated with a poorer prognosis and greater patient discomfort. In fact, >50% of the patients who had large appendiceal carcinoids in one study presented with a clinical picture suggestive of acute appendicitis [57]. The prognosis for tumors <2 cm in size is quite favorable, because few of these neoplasms metastasize. The 5-year survival rate overall is approximately 71% (94% for local disease, 85% for regional metastases, and 34% in the presence of distal disease) [7, 53].

Colonic Carcinoid Tumors
Carcinoid tumors of the colon are extremely rare tumors, representing <11% of all carcinoid tumors and only 1% of colonic neoplasms [53, 58]. Though they are thought to arise from serotonin-producing epithelial endocrine cells disseminated throughout the colon, carcinoid syndrome is rare in these patients, presenting in <5% of cases [59]. Typically, carcinoid tumors of the colon present in the sixth to seventh decade of life during evaluation for anorexia, abdominal pain, and unintentional weight loss [59]. Data from several series demonstrate that carcinoid tumors of the colon are diagnosed late in the course of the disease, and the average size of these tumors was approximately 5 cm at diagnosis [58, 59]. Additionally, at diagnosis, approximately two thirds of patients have local nodal or distant metastases, resulting in an overall 5-year survival rate of 25%–41% [7].

Rectal Carcinoid Tumors
Most rectal carcinoids are asymptomatic and are discovered incidentally during proctoscopy, sigmoidoscopy, or digital rectal examination. Patients who do have symptoms typically present with rectal pain, bleeding, or constipation. Though these neoplasms represent only 1.3% of all rectal tumors [53], the true incidence of rectal carcinoids appears to be on the rise because of recent advances in endoscopic technology. Like carcinoids of the small bowel and colon, these tumors are thought to arise from the epithelial endocrine cells; however, unlike these neoplasms, rectal carcinoids contain glucagon and glicentin-related peptides, rather than serotonin [11]. Development of typical carcinoid syndrome is rare. Interestingly, the size of rectal carcinoids correlates closely with the aggressiveness of the tumor and metastatic potential. Recent series have shown that tumors <1 cm rarely metastasize, while lymph node and liver metastases are seen in up to 70% of cases in which the primary tumor is >2 cm [13]. Overall 5-year survival rates from the SEER database for localized, regional, or distant disease spread beyond the rectum and rectosigmoid junction over a 10-year period were 90%, 49%, and 26%, respectively [13].


   DIAGNOSIS
Top
 Abstract
 Introduction
 Organ-Related Features of...
 Diagnosis
Surgical Treatment
 Malignant Carcinoid Syndrome and...
 Management of Metastatic Disease
 Summary
 Author Contributions
 References
 
Carcinoid tumors are rare, slow-growing neoplasms that pose a diagnostic challenge because they are often innocuous at the time of presentation. However, though the initial symptoms of carcinoid may be nonspecific, there are useful diagnostic techniques that may facilitate tumor identification and localization.

Urinalysis
Traditionally, the biochemical diagnosis of carcinoid tumors has been based on the measurement of serotonin metabolites in a 24-hour urine collection. Elevation of the pharmacologically inactive metabolite of serotonin, 5-hydroxyindoleacetic acid (5-HIAA), in a 24-hour sample has been found to be highly specific (100%) for the diagnosis of carcinoid disease but lacks sensitivity (73%) [7, 60]. The low sensitivity is not surprising, given that a negative urine 5-HIAA is expected for any patient who has a carcinoid tumor that does not secrete serotonin. Likewise, 5-HIAA levels may not be elevated in atypical carcinoid disease and may be falsely elevated in other conditions such as celiac sprue, Whipple's disease, and SBO [61]. Importantly, urine 5-HIAA must be performed on a 24-hour urine specimen because of fluctuations in serotonin over the course of a day. Also, there are medications and foods (i.e., avocados, bananas, walnuts, etc.) that can affect the results of the urine 5-HIAA level and should be avoided during the collection. Like 5-HIAA, platelet and urinary serotonin levels are highly specific for carcinoid and may be useful in patients with tumors that produce low levels of serotonin [62]. In fact, recent data suggest that the combination of urinary 5-HIAA levels with platelet and urinary serotonin levels results in accurate carcinoid identification in at least 84% of patients [7].

Serum Analysis
Serum analysis of CgA, the major member of the granin family of acidic secretory glycoproteins that are expressed in neuroendocrine cells and are cosecreted with bioactive hormones, is perhaps the most specific serum biomarker for carcinoid disease. In a recent series of 238 patients with carcinoid tumors, CgA levels were found to be much higher in patients with neuroendocrine disease when compared with healthy control patients (p < .001) [63]. Likewise, when comparing all patients without reported neoplasia and patients with NETs, the specificity of CgA serum analysis for diagnosis was 84%–95% whereas the sensitivity was in the range of 75%–85%. Unlike a urine 5-HIAA test, serum CgA testing does not rely on serotonin secretion by the tumor, and therefore it can be a better test for atypical carcinoids and nonsecreting tumors. False-positive results may be seen with hepatic or renal failure, inflammatory bowel disease, atrophic gastritis, or chronic proton pump inhibitor use [64]. Likewise, a 40% false-positive rate has been demonstrated in patients with multiple myeloma [65].

Diagnostic Imaging
Once the biochemical diagnosis of carcinoid disease is confirmed, a multimodal approach using combinations of imaging studies facilitates tumor localization. Traditionally, abdominal computed tomography (CT) has been the most commonly used means of cross-sectional imaging to identify and localize carcinoid tumors and their metastases [7]. Unfortunately, the sensitivity of abdominal CT is poor (44%–55%), though recent data suggest that the sensitivity of CT may be improving with modern fast, thin-sectional scanners capable of producing multiplanar reconstructions [66]. CT scanning is thought to be especially helpful in identifying locally advanced disease with typical mesenteric involvement, seen as an ill-defined mass near the root of the mesentery with characteristic radiating dense soft tissue strands caused by thickened neurovascular bundles [66]. Likewise, abdominal CT is thought to be helpful in identifying liver metastases [67].

Primary tumors of the small intestine and colon may sometimes be detected by barium studies, which may be undertaken because of symptoms such as abdominal pain or diarrhea. Characteristically, the tumors appear as submucosal filling defects or polypoidal or ulcerated masses [67]. Within the ileum, luminal narrowing, fold thickening, and spiculation may be seen because of locoregional fibrosis and ischemia. Unfortunately, the findings of barium studies are frequently nonspecific and tumors may be missed.

Nuclear Medicine
The use of radiolabeled receptor-binding peptides and scintigraphy offers considerable diagnostic and therapeutic information in patients with carcinoid tumors. Localization of the primary tumor site with 111In-labeled octreotide (somatostatin receptor scintigraphy, or OctreoscanTM; Covidien AG, Mansfield, MA) is superior to that of cross-sectional imaging with CT or magnetic resonance imaging. The benefits of Octreoscan include: (a) diagnosis and localization of primary or recurrent carcinoids, (b) prediction of tumor response to octreotide analogue therapy, and (c) staging of carcinoid disease and differentiation from similar-appearing benign disease [66]. The diagnostic sensitivity of Octreoscan in patients with asymptomatic gastrointestinal NETs has been estimated to be in the range of 80%–90% [68]; fortunately, in those with symptoms of carcinoid syndrome, sensitivities are >90% [69]. Limitations to octreotide scintigraphy do exist, as Octreoscan is rarely positive in the evaluation of colorectal carcinoids; however, for those primary tumors that are positive, Octreoscan may be predictive of response to somatostatin receptor analogues and may provide a useful tool for follow-up. Importantly, it must be understood that active octreotide therapy for carcinoid syndrome will make Octreoscan much less useful because there will be receptor saturation.

Metaiodobenzylguanidine (MIBG) scintigraphy, an alternative to Octreoscan, may also be used to localize carcinoid disease. Localization with MIBG, a norepinephrine analogue, is believed to be through the reuptake mechanisms regulating norepinephrine entry into the catecholamine storage vesicles of carcinoid tumors [67]. MIBG scans have been found to be positive in 60%–70% of all patients with carcinoid tumors [7], though the reported sensitivity of this test in cases of extra-adrenal carcinoid disease is significantly lower than that of Octreoscan. Interestingly, however, Taal et al. [70] demonstrated an overall sensitivity of 95% for localizing carcinoid disease when MIBG and Octreoscan were used together in 20 patients.

The role of 18F-labeled fluorodeoxyglucose positron emission tomography (FDG-PET) is unclear in the staging of well-differentiated NETs; in fact, significant uptake with FDG-PET has not been demonstrated because of the relatively indolent disease course and low metabolic rate of carcinoid tumors. Recent advances in PET tracer development have been promising. Both 18F-dihydroxy-phenyl-alanine and 11C–5-HTP, though not clinically available, have shown superior detection and localization of carcinoid tumors when used in combination with high-resolution PET [71].


   SURGICAL TREATMENT
Top
 Abstract
 Introduction
 Organ-Related Features of...
 Diagnosis
 Surgical Treatment
Malignant Carcinoid Syndrome and...
 Management of Metastatic Disease
 Summary
 Author Contributions
 References
 
Effective treatment of carcinoid tumors requires a multidisciplinary approach in which combined modalities are used, including surgical resection of the primary tumor and debulking, hepatic chemoembolization, and medical therapy. Though specific treatment decisions are complex and related to the location of the primary carcinoid disease and the presence of distal metastases, the preferred initial treatment for carcinoid tumors remains surgical resection. Traditionally, the extent of surgical resection was dependent on the size of the primary tumor and its location, while a location-specific prognosis was commonly based on the extent of carcinoid disease, tumor histology, depth of tumor invasion, and gender [7, 72–74]. In a more recent SEER database review of >35,618 patients with neuroendocrine disease, multivariate analysis revealed that, in patients with well-differentiated to moderately differentiated NETs, disease stage, primary tumor site, histologic grade, sex, race, age, and year of diagnosis were predictors of outcome (p < .001) [15].

Bronchopulmonary Carcinoid Tumors
Surgical resection is the preferred treatment of bronchopulmonary carcinoid tumors in those patients with adequate functional pulmonary reserve. In patients with relatively small (<2 cm), localized tumors of the peripheral lung parenchyma, conservative resection via a wedge or segmental resection has been shown to result in low recurrence rates and excellent long-term survival [11, 39, 40, 75]. Tumors with extensive central bronchopulmonary involvement, those with large peripheral parenchymal involvement (>2 cm), and atypical carcinoids may require more extensive surgical resection with a lobectomy or pneumonectomy [11]. Given the significance of nodal involvement in long-term prognostic models of pulmonary carcinoid disease, recent data have demonstrated an advantage to systematic radical mediastinal lymphadenectomy in all patients at the time of initial treatment [76].

Gastric Carcinoid Tumors
Recent evidence suggests that type I gastric carcinoids have been overtreated. In a recent multi-institutional study of 65 patients with gastric carcinoid tumors, Borch and colleagues demonstrated that a majority of type I carcinoids were asymptomatic and were often detected incidentally at the time of upper endoscopy for other nonrelated symptoms [44]. As such, tumors <1–2 cm in greatest dimension may be clinically observed or removed endoscopically [11, 47]. Antrectomy, by eliminating the trophic effect of gastrin, can be useful for large, multiple, or recurrent type I carcinoids [43]. The treatment of type II gastric carcinoids is more complex, largely because of the presence of multicentric disease and the relative frequency of distant metastases. Currently, the treatment of type II carcinoids associated with ZES is similar to that of type I tumors; however, when tumors become >2 cm, gastrectomy should be considered [7, 47]. Treatment recommendations for type III tumors are universal, given the much poorer prognosis and aggressive nature of these tumors. As such, radical gastrectomy, regardless of tumor size, is the mainstay of current therapy for these lesions [47, 48].

Small Intestinal Carcinoid Tumors
Small bowel carcinoids frequently present with nodal and mesenteric metastases, the latter of which may induce an intense local desmoplastic reaction capable of producing SBO secondary to fibrosis and ischemia. The surgical management of patients with small bowel carcinoids depends largely on the tumor size, location, and metastatic spread [77]. For tumors <1 cm in greatest dimension without evidence of regional lymph node metastases, segmental resection alone with close postoperative surveillance is adequate. A more aggressive surgical approach is necessary for patients with tumors >1 cm, those with locoregional lymph node metastases, and those with mesenteric spread. In these patients, the preferred treatment is a small bowel resection with the associated mesentery and mesenteric lymph nodes [78], the latter of which has been shown to be associated with longer disease-free survival [79]. Importantly, in the presence of aggressive disease, the primary small bowel tumor is often small when compared with the associated regional lymphadenopathy or distant metastases; however, even in the presence of distant disease spread, there is evidence to suggest that outcomes are better if the primary tumor is resected.

Appendiceal Carcinoid Tumors
Tumor size has been shown to be the best predictor of prognosis in patients with appendiceal carcinoid tumors [11]; as such, the surgical management of appendiceal carcinoids depends largely on the size and location of the primary tumor. According to current guidelines, simple appendectomy is adequate for the treatment of small carcinoid tumors (<l cm). Indications for more extensive surgery than simple appendectomy have been shown to include tumor size >2 cm, lymphatic invasion, lymph node involvement, spread to the mesoappendix, tumor-positive resection margins, and cellular pleomorphism with a high mitotic index [80]. Given that approximately one third of patients with tumors >2 cm in diameter present with or develop nodal and distant metastases, most experts advocate a right hemicolectomy as the appropriate treatment option [56, 80, 81]. The management of tumors between 1 cm and 2 cm continues to be debated; however, a more aggressive treatment algorithm that includes right hemicolectomy is often employed, especially in younger patients [81]. Additional prognostic factors (gender and depth of penetration) may be used in choosing between appendectomy and hemicolectomy in these patients [82].

Colorectal Carcinoid Tumors
Shebani and colleagues demonstrated that nearly 55% of patients with carcinoid tumors involving the colon present with liver or nodal metastases [82]. Given this propensity for metastatic spread, most experts suggest a formal hemicolectomy with mesenteric resection as the preferred treatment for all carcinoid tumors of the colon. Like appendiceal carcinoids, the size of rectal carcinoid tumors is closely correlated with metastatic risk and long-term survival rates. Rectal carcinoids <2 cm rarely metastasize, directing the conclusion that for these smaller lesions local excision is sufficient; for lesions >2 cm, a low anterior resection or abdominal perineal resection should be performed provided distant metastases are absent [83].


   MALIGNANT CARCINOID SYNDROME AND CARCINOID HEART DISEASE
Top
 Abstract
 Introduction
 Organ-Related Features of...
 Diagnosis
 Surgical Treatment
 Malignant Carcinoid Syndrome and...
Management of Metastatic Disease
 Summary
 Author Contributions
 References
 
The term carcinoid syndrome refers to a constellation of symptoms mediated by various humoral factors, namely, serotonin and the tachykinins, elaborated by carcinoid tumors [84, 85]. In the presence of localized disease, carcinoid neoplasms produce serotonin, which is taken up and stored in platelets while the excess is inactivated from the liver and lung and transformed into 5-HIAA. In the presence of liver metastases, however, patients may develop malignant carcinoid syndrome, which results when vasoactive substances produced by the carcinoid tumor escape hepatic degradation and gain access to the systemic circulation. It is also because of the high level of serotonin degradation by the liver that it is relatively uncommon for disease localized to the gut to display symptoms of serotonin secretion. Clinical findings of carcinoid syndrome include skin flushing, excessive diarrhea, right-sided heart disease, and bronchoconstriction [7].

Nearly 40% of patients exhibiting carcinoid syndrome develop carcinoid heart disease (CHD) with fibrotic endocardial plaques and associated heart valve dysfunction that classically involves the tricuspid valve [86]. Advanced changes in tricuspid valvular disease have been shown to be associated with poor long-term survival [87], and carcinoid valvular disease, rather than tumor dissemination, is the cause of death in approximately one third of these patients [88]. Though the mechanism behind CHD is not fully understood, serotonin is presumed to be the catalyst for the cardiac fibrotic process based on murine in vivo models of CHD [89]. Nearly 95% of patients present with right-sided heart valve disease, characterized by tricuspid insufficiency and pulmonary stenosis (the so called TIPS process) and the subsequent development of pulmonary hypertension [86]. Left-sided cardiac disease may be seen in up to 10% of patients, as is commonly associated with angina and coronary vasospasm.


   MANAGEMENT OF METASTATIC DISEASE
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 Abstract
 Introduction
 Organ-Related Features of...
 Diagnosis
 Surgical Treatment
 Malignant Carcinoid Syndrome and...
 Management of Metastatic Disease
Summary
 Author Contributions
 References
 
Surgery is the only way to achieve a complete cure and remains the mainstay of treatment for all patients with primary carcinoid tumors. However, because of the relatively indolent disease course of carcinoid tumors, many patients present with synchronous or metachronous metastatic lesions. In fact, up to 75% of patients with carcinoid tumors develop hepatic metastases regardless of the location of the primary tumor [90]. Meeting the goals of carcinoid tumor management—namely, symptom control, biochemical control, objective tumor control, and quality-of-life improvement—in patients with widespread disease and/or hepatic metastases relies on a multidisciplinary treatment approach [91].

Surgical Debulking
Cytoreductive surgery, a mainstay in the management of widely metastatic disease, aims to control symptoms and improve survival by removing or destroying disseminated tumor metastases [77, 91]. Although aggressive surgical debulking may not be curative, recent data suggest a significant palliative effect of cytoreduction. In a meta-analysis of cytoreductive partial hepatectomy in patients with advanced, metastatic carcinoid disease, surgical debulking yielded a 5-year survival rate >70% and complete resolution of carcinoid symptoms in 86% of patients [92]. Likewise, in another recent study, cytoreductive therapy relieved 83% of patients of mesenteric ischemia resulting from carcinoid encasement of the mesentery [93].

Somatostatin Analogues
Somatostatin is a naturally occurring regulatory peptide that acts primarily as a negative regulator of a variety of different cell types, blocking processes such as hormone secretion, cell growth, and smooth muscle contraction. The intracellular functions of somatostatin are initiated by the binding of the peptide to one or more of five different cell-surface receptor proteins—somatostatin subtype receptor (SSTR)-1 to SSTR-5—thereby activating one or more intracellular G-proteins and initiating biochemical signaling pathways. To date, two analogues of somatostatin—octreotide, an octapeptide analogue of somatostatin with a relatively short half-life, and lanreotide, a long-acting somatostatin analogue—are commercially available for the treatment of carcinoid tumors [7]. While both analogues bind primarily to SSTR-2, SSTR-3, and SSTR-5 [94], the clinical efficacy of each seems related only to binding of SSTR-2 [95].

Though long-acting somatostatin analogues have been shown to be highly effective in reducing NET markers and controlling the symptoms of carcinoid syndrome [7, 96, 97], tumor regression by radiographic criteria is relatively rare (4%) [98]. However, in a study by Aparacio and colleagues [99], somatostatin analogue therapy stabilized tumor growth in nearly 60% of patients over a period of 11 months.

Although treatment of patients with carcinoid tumors with daily s.c. injections of standard doses of somatostatin analogues may result in significant symptomatic or subjective responses, the median duration of response to standard somatostatin analogue treatment is 12 months [100]. The mechanism for this loss of therapeutic effect with repeated dosing of somatostatin analogue in carcinoid patients—also known as tachyphylaxis—is unknown, though many believe the phenomenon represents SSTR downregulation or desensitization as a result of prolonged high-dose somatostatin therapy. Recent data by Corleto et al. [101] suggest that single, low-dose administration of octreotide may avoid SSTR desensitization.

Systemic Chemotherapeutic Options
Besides somatostatin analogues, common chemotherapeutic options for metastatic carcinoid syndrome include interferon-{alpha} and cytotoxic agents. The former has been shown to inhibit protein and hormone synthesis in tumor cells, inhibit angiogenesis, and stimulate the immune system [91]. Additionally, interferon-{alpha} has been shown to upregulate the expression of somatostatin receptors and may therefore act synergistically with somatostatin analogues in the treatment of classic carcinoid syndrome [91]. Cytotoxic agents are typically employed as first-line treatments for malignant gastrointestinal NETs with elevated proliferation indices (Ki-67 antibody >5%–10%). Traditionally, single-agent cytotoxic treatments have produced limited benefit in patients with NETs, with response rates of <30% [91]. Therefore, combination therapies—the most common combination of streptozocin, 5-fluorouracil, and doxorubicin elicits a response rate >50% in malignant pancreatic tumors—are commonly used in the treatment algorithms of highly proliferating carcinoid tumors. A list of closed clinical trials, many of which employ a combination therapy approach, is provided in Table 2. Unfortunately, data from many of these studies are currently pending.


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  		Table 2. Closed or completed clinical trials for metastatic carcinoid disease

 
Management of Hepatic Metastases
Many studies have shown that liver resection can play an important role in patients with hepatic metastases from the primary carcinoid tumor, and surgical resection may result in symptom relief and prolonged survival [90]. Though no prospective data exist, retrospective data from Que et al. [102] have demonstrated longer survival in patients with metastatic gastrointestinal carcinoid tumors when >90% of the hepatic metastases were resected. Landry and colleagues [90] confirmed this trend toward longer survival for patients who underwent surgical resection of hepatic metastases, citing a 5-year survival rate of nearly 75% in these patients.

In patients with hepatic carcinoid metastases who are not candidates for complete surgical resection, several potential therapies—including radiofrequency ablation (RFA) and hepatic chemoembolization—may be offered. RFA provides a novel approach for those with limited hepatic involvement by using selective thermal coagulation of the tumor to destroy isolated metastases. In a retrospective study of 73 patients with metastatic foregut or midgut carcinoid tumors or endocrine pancreatic tumors (EPTs), Eriksson and colleagues [103] demonstrated apparently total clearance of liver metastases in 17%, 41%, and 46% of foregut carcinoids, midgut carcinoids, and EPTs, respectively. Likewise, symptom improvement was noted in 71% of patients with carcinoid syndrome, and 75% also experienced a reduction in their 5-HIAA and CgA levels by at least 50%. Similarly, though data in hepatic carcinoid metastases are limited to a few case reports and small series, several studies [104, 105] have demonstrated the effectiveness of RFA in the treatment of unresectable hepatocellular carcinomas and hepatic metastases of colon carcinoma.

Hepatic chemoembolization (HCE) may be used in those with unresectable but liver dominant carcinoid disease. In a report of 20 patients with liver metastases from islet cell tumors of the pancreas or carcinoid tumors, Yao and colleagues [106] demonstrated a significant radiographic response, stabilization of hepatic tumor burden, or improvement in clinical symptoms in 90% of their cohort. The details of their technique for chemoembolization included cisplatin (10 mg/ml), doxorubicin (3 mg/ml), and mitomycin-C (10 mg/ml) combination therapy with either viscous collagen agent or ethiodol and polyvinyl alcohol particles in suspension. Factors related to sustained responses for HCE included previous surgical debulking, more than four HCE procedures, and liver metastases ≤5 cm [106].

Radiolabeled Somatostatin Analogues
In recent years, several research groups in nuclear medicine and radiopharmacy have sought to develop radiolabeled receptor-binding somatostatin analogues that could act as vehicles to guide radioactivity to SSTR-expressing tissues, such as carcinoid metastases. The first promising dodecanetetraacetic acid-chelated somatostatin analogue—90Y-1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid (DOTA)0,Tyr3, octreotide (90Y-DOTATOC)—employed the use of a radiolabeled somatostatin analogue couple with 90Y, a pure β-emitter [107]. In a phase II study to evaluate the tumor response of NETs to high-dose targeted irradiation with 90Y-DOTATOC, Waldherr and colleagues [108] demonstrated an objective response rate of 38% in approximately 13 patients with EPTs; likewise, a significant reduction in clinical symptoms was noted in these patients. More recently, treatment with 177Lu-DOTA0,Tyr3octreotate (177Lu-DOTATATE), a compound with greater SSTR-2 affinity, was shown to effect complete or partial tumor responses in nearly 30% of patients with neuroendocrine disease [107]. Importantly, 90Y-DOTATOC seems to be more effective in larger tumors whereas 177Lu-DOTATATE effects better tumor responses in smaller lesions; as such, combination therapies using both 90Y-DOTATOC and 177Lu-DOTATATE are currently being explored.

Future Targeted Therapies
It is well known that the growth, differentiation, phenotype, and hormonal expression of carcinoid tumors depend upon a network of cellular signaling cascades. At this time, several pathways and individual molecules have been implicated in the tumorigenesis of carcinoids and are currently under evaluation. Novel agents targeting vascular endothelial growth factor (VEGF) and mammalian target of rapamycin have been demonstrated to have promising activity in patients with advanced NETs. Inhibition of angiogenesis by targeting VEGF is especially promising given the highly vascular nature of NETs. In our own laboratory, recent data suggest the importance of alternative pathways, which include alterations in Raf-1/mitogen-activated protein kinase–extracellular signal–related kinase (ERK) kinase (MEK)/ERK activation [109–111], Notch1 activation [112, 113], and glycogen synthase kinase-3β inhibition [114].


   SUMMARY
Top
 Abstract
 Introduction
 Organ-Related Features of...
 Diagnosis
 Surgical Treatment
 Malignant Carcinoid Syndrome and...
 Management of Metastatic Disease
 Summary
Author Contributions
 References
 
Derived from the cells of the disseminated neuroendocrine system, carcinoid tumors are rare, slow-growing NETs that display a relatively indolent disease course. As such, they are frequently diagnosed late, following the development of widely disseminated metastases. Once metastatic, tumor secretion of various bioactive hormones and peptides causes the debilitating symptoms of malignant carcinoid syndrome. Currently, the only curative therapy remains surgical intervention; however, recent advances that have targeted pathways that regulate carcinoid tumor growth and secretion are promising. Regardless, the prognosis and treatment of carcinoid disease is dependent on a multitude of factors, including tumor size, location, patient age, and histology, emphasizing the need to tailor each therapy to the individual patient.


   AUTHOR CONTRIBUTIONS
Top
 Abstract
 Introduction
 Organ-Related Features of...
 Diagnosis
 Surgical Treatment
 Malignant Carcinoid Syndrome and...
 Management of Metastatic Disease
 Summary
 Author Contributions
References
 
Conception/design: Scott N. Pinchot, Rebecca Sippel, Kyle Holen, Herbert Chen

Provision of study materials: Rebecca Sippel, Kyle Holen

Collection/assembly of data: Scott N. Pinchot, Rebecca Sippel, Kyle Holen, Herbert Chen

Data analysis: Scott N. Pinchot, Herbert Chen

Manuscript writing: Scott N. Pinchot, Herbert Chen

Final approval of manuscript: Rebecca Sippel, Kyle Holen, Herbert Chen


   REFERENCES
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 Abstract
 Introduction
 Organ-Related Features of...
 Diagnosis
 Surgical Treatment
 Malignant Carcinoid Syndrome and...
 Management of Metastatic Disease
 Summary
 Author Contributions
 References
 

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