The term “karzinoide” was first used in 1907 by pathologist Siegfried Oberndorfer to describe small intestinal tumors that resembled carcinomas on histology, but behaved less aggressively clinically.¹ In the current literature, carcinoids refer to well-differentiated, low-to-intermediate-grade neuroendocrine tumors (NETs) of the bronchopulmonary and gastrointestinal (GI) tracts.² By definition, NETs are epithelial neoplasms with both neural and endocrine differentiation, which arise from many different cell types of the neuroendocrine system.² Carcinoids represent a diverse subset of NETs, which exhibit slow growth but variable clinical presentation, growth pattern, and prognosis, depending on anatomic site and cell of origin.^2–4 This chapter describes the clinical behavior of GI carcinoids, as well as their diagnosis and management by anatomic site. It concludes with a brief description of metastatic carcinoid and carcinoid syndrome, a rare but potentially life-threatening presentation.

GI carcinoids account for 0.5% of all newly diagnosed cancers and 71% of all NETs.⁵ Several large population studies have been conducted to document the incidence of GI carcinoids, their distribution across anatomic sites, and trends in incidence and outcomes over time, based on data from the national U.S. Surveillance, Epidemiology, and End Results (SEER) registry.^5–7 In one series of 11,427 patients with NETs reported to SEER between 1973 and 1997, the average age at diagnosis was 61 years, and cases were distributed evenly across gender.⁶ The majority of NETs arose in the GI tract (55%), followed by the bronchopulmonary tract (30%), pancreas (2%), and other rare sites including, in decreasing order, gynecologic, biliary, head and neck, and genitourinary systems.⁶ Among GI carcinoids, the small intestine was the most common site (45%, predominantly ileum), followed by rectum (20%), appendix (17%), colon (11%), then stomach (7%) (Fig. 40-1).⁶ Notably, pancreatic NETs were considered separately from GI carcinoids in this study. A more recent SEER-based series of 25,531 patients with histologically confirmed GI carcinoid tumors demonstrated similar findings, with 38% of cases arising in the small intestine, 34% in the rectum, 16% in the colon, and 11% in the stomach.⁵ Appendiceal tumors were not considered separately in this latter analysis.

The incidence of NETs has increased over the past 4 decades, with one study showing an increase of approximately 0.85 to 3.84 per 100,000 between 1973 and 1997.⁶ A more recent series estimates the annual incidence of GI carcinoid tumors to be 5 per 100,000,⁷ with the largest increases noted in localized tumors and those of the small intestine, rectum, and stomach.⁵ More widespread use of axial imaging and endoscopy may partially explain this increase in diagnosis and incidence.

GI carcinoids generally present in one of three ways: (1) incidentally on endoscopy or axial imaging, as with many gastric and rectal tumors, or within a surgical specimen, as with an appendiceal carcinoid following appendectomy for appendicitis; (2) with locoregional symptoms, such as abdominal pain, bowel obstruction, bleeding, or bowel ischemia, due to local tumor growth or regional nodal invasion with surrounding mesenteric fibrotic reaction; or (3) with carcinoid syndrome, ie, chronic flushing, diarrhea, and, if advanced, heart failure, most often in the setting of midgut carcinoid metastatic to the liver.^8–10 The locoregional symptoms vary by primary tumor location. Intestinal obstruction and bleeding are most common with small intestinal carcinoids, rectal bleeding and pain tend to occur with rectal carcinoids, weight loss and abdominal pain are more frequently seen with colonic carcinoids, vomiting occurs with gastric carcinoids, and jaundice and upper GI bleeding are most often associated with duodenal and periampullary carcinoids.⁴

About half of all cases present with localized disease, while another quarter each present with regional or distant metastases.^5,6 Notably, patients with carcinoid tumors also have a higher incidence of additional primary cancers compared with the general population. Approximately 25% of patients harbor second malignancies of the small intestine, stomach, or extra-intestinal sites such as the thyroid and kidney.⁵

Nonspecific symptoms often necessitate further laboratory and radiologic evaluation to localize the tumor and confirm the diagnosis of carcinoid. Two commonly used biochemical tests are serum chromogranin A (CgA) level and 24-hour urinary excretion of 5-hydroxyindoleacetic acid (5-HIAA).

CgA is a glycoprotein involved in intracellular vesicular transport. It is synthesized and secreted along with other peptide hormones by many types of non-neoplastic and neoplastic neuroendocrine cells.^3,8 The serum CgA level is elevated in about 90% of GI carcinoids, both functional and nonfunctional, and correlates with tumor burden.^3,11 It can be falsely elevated in many settings, however, including proton pump inhibitor therapy, pancreatic and small cell lung cancer, chronic renal insufficiency, and atrophic gastritis.^3,8 Therefore, it is a sensitive but nonspecific marker of GI carcinoid. As a consequence, it is less useful for screening or initial diagnosis and more suited for assessing treatment response or disease progression. Of note, CgA staining on immunohistochemical analysis is an important marker used in the histologic diagnosis of NETs.¹¹

Urinary 5-HIAA is a less sensitive but more specific test for carcinoid. A degradation product of serotonin (5-hydroxytryptamine [5-HT]), 5-HIAA is one of the most commonly secreted hormones from GI carcinoid tumors.¹¹ At the molecular level, tryptophan is taken up by neuroendocrine cells, hydroxylated to 5-HT, decarboxylated to serotonin, then stored in granules and ultimately secreted into the bloodstream, after which it is metabolized to 5-HIAA and excreted in the urine.⁸ As a diagnostic test, 24-hour urinary excretion of 5-HIAA is most accurate for detecting midgut carcinoids metastatic to the liver and/or associated with carcinoid syndrome, with an estimated 70% sensitivity and 90% specificity.¹¹ Sensitivity is lower in the absence of carcinoid syndrome, in the setting of low-volume tumor burden, or for foregut and hindgut carcinoids, which rarely produce serotonin.^3,11 Specificity is limited by false positive elevations of urinary 5-HIAA, eg, in the setting of a tryptophan-rich diet.^8,9 Overall, the laboratory evaluation plays a limited role in the initial diagnosis of GI carcinoid, warranting further investigation.

Endoscopy and axial imaging are essential to tumor localization and staging. Endoscopy permits tissue sampling and gross visualization of primary carcinoids arising in the stomach, duodenum, terminal ileum, colon, and rectum. Multidetector computed tomography (CT) of the abdomen and pelvis, with arterial and venous phase intravenous (IV) contrast enhancement, can sometimes detect primary GI carcinoid tumors, which appear as solid hyperattenuating intraluminal masses on multidetector CT.¹⁰

CT is much more useful in delineating regional and distant metastases. For midgut carcinoids metastatic to regional lymph nodes, CT clearly depicts the characteristic mesenteric desmoplastic reaction, which manifests as an irregular, spiculated soft tissue mass infiltrating the mesenteric fat, often with associated calcifications, tethering, or kinking of adjacent bowel loops, and in some cases encasement of branches of the superior mesenteric vessels.¹⁰ CT is also able to detect hypervascular liver metastases with approximately 80% sensitivity and 90% specificity.⁹

Magnetic resonance imaging (MRI) is useful for equivocal liver lesions. Carcinoid metastases generally demonstrate a T2-intense signal and rapid arterial enhancement with washout of contrast on later venous phase images.¹⁰ In the setting of metastatic disease or carcinoid syndrome with an occult primary, additional nuclear imaging with somatostatin receptor scintigraphy (eg, Octreoscan) may add useful information. Somatostatin receptor scintigraphy utilizes tumor cell−specific somatostatin receptor expression and a radiolabeled somatostatin analog (eg, 111-indium pentetreotide) to localize tumor, with variable sensitivity, which is reported to be about 2% to 23% and 80% to 90% for primary and metastatic carcinoids, respectively.^4,12

Tissue diagnosis is ultimately confirmed following biopsy or surgical resection. The characteristic histologic findings include the organization of neoplastic cells into nesting, trabecular, or gyriform patterns, the presence of intracellular secretory granules, and positive immunostaining for neuroendocrine markers, such as CgA, synaptophysin, and neuron-specific enolase.^2,4,13 Additionally, NETs are classified according to two cellular features: (1) degree of cellular differentiation, ie, similarity to their non-neoplastic neuroendocrine cell counterparts and (2) grade, ie, proliferative rate, as measured by the number of mitotic figures per 10 high-power microscopic fields, or immunostaining with the cellular proliferation marker Ki-67.² As previously mentioned, carcinoids are defined as well-differentiated, low-to-intermediate-grade NETs, which harbor lower malignant potential compared with poorly differentiated, high-grade neuroendocrine carcinoma (NEC).²

Several staging systems have been proposed by the American Joint Committee on Cancer (AJCC), World Health Organization (WHO), and European Neuroendocrine Tumor Society (ENETS). Although these systems vary slightly in tumor classification, they generally conform to the tumor-node-metastasis (TNM) paradigm that distinguishes localized disease from regional nodal or distant metastasis.² Details and implications for management and prognosis are discussed by anatomic site below. Treatment guidelines are also summarized in Table 40-1. Ultimately, for any carcinoid tumor, the goal is to determine the site and extent of disease, to resect all tumor (R0 resection) if possible, and to palliate symptoms related to locoregional tumor growth and carcinoid syndrome.

Gastric Carcinoid

Gastric carcinoids, of which there are three different types, generally arise from a subset of neuroendocrine cells called enterochromaffin-like (ECL) cells, which arise in the gastric fundus and body. Under normal conditions, these cells secrete histamine and stimulate neighboring parietal cells to produce acid in response to gastrin.¹⁴ Consequently, gastric carcinoids usually are not associated with serotonin secretion or carcinoid syndrome.^14,15 From a pathophysiologic standpoint, chronic gastrin stimulation leads to ECL cell hyperplasia and subsequent neoplasia.¹⁵ Importantly, the clinical behavior and management vary significantly among the three types of gastric carcinoids, as detailed below.

Type 1 gastric carcinoids are the most common form, comprising 70% to 80% of cases.^13,16 These tumors arise from ECL cells in the setting of chronic atrophic gastritis, achlorhydria, and secondary gastric endocrine (G-cell) hyperplasia with hypergastrinemia.¹⁶ They often occur in middle-aged women and generally present as multiple nonfunctional, small subcentimeter multicentric polyps in the gastric fundus and body.^15,16 Workup, as for all gastric carcinoids, includes upper endoscopy, gastric pH, and serum gastrin measurements.¹⁶ Laboratory evaluation also may reveal low hematocrit, iron, and vitamin B₁₂ levels in the setting of associated pernicious anemia.¹⁶ Most type 1 gastric carcinoids are confined to the submucosa and metastasize in fewer than 10% of cases.^13,15,16 Given the indolent behavior of this subclass, endoscopic resection via snare polypectomy or endoscopic mucosal resection (EMR) is recommended for all type 1 gastric carcinoids smaller than 1 to 2 cm. Surgical resection is reserved for the rare lesion that is greater than 2 cm, or lesions associated with other high-risk features, such as invasion into the muscularis propria as determined by endoscopic ultrasound, poorly differentiated histology, positive endoscopic resection margin, or nodal or distant metastases.¹⁶ Notably, type 1 tumors tend to recur at a median duration of 24 months following resection, with a 3% risk of progression to NEC.¹⁶ The most recent ENETS guidelines published in 2016 recommend serial endoscopic surveillance every 24 months for newly presenting tumors, and every 12 months for recurrent disease.¹⁶ Interestingly, for multiple progressive type 1 tumors, antrectomy to reduce gastrin production represents an alternative but somewhat controversial management option.^13,15