Carcinoid Tumor 

Updated: Feb 13, 2019
Author: Cameron K Tebbi, MD; Chief Editor: Max J Coppes, MD, PhD, MBA 

Overview

Practice Essentials

Carcinoid tumors are of neuroendocrine origin and derived from primitive stem cells in the gut wall, especially the appendix.[1, 2, 3, 4] They can be seen in other organs,[5] including the lungs,[6] mediastinum, thymus,[7] liver, bile ducts,[8]  pancreas,[9]  bronchus,[10, 11] ovaries,[12] prostate,[13] and kidneys (see the image below). While carcinoid tumors have a tendency to grow slowly, they have a potential for metastasis.

Distribution of carcinoid tumors. Distribution of carcinoid tumors.

Signs and symptoms

Signs and symptoms of carcinoid tumors vary greatly. Carcinoid tumors can be "nonfunctioning" presenting as a tumor mass or "functioning" i.e. producing several biopeptides causing carcinoid syndrome. The sign and symptoms of a "nonfunctioning" tumor depend on the tumor location and size as well as on the presence of metastases. Therefore, findings range from no tumor-related symptoms (most carcinoid tumors) to full symptoms of carcinoid syndrome (primarily in adults). At times, the tumor is found as an incidental finding in a histopathologic examination.[14]  Due to their vague and intermittent symptoms, diagnosis of carcinoid tumors may be delayed, especially in children, in whom the tumor is rare and the diagnosis is unexpected.

Signs and symptoms seen in larger tumors may include the following:

  • Periodic abdominal pain: Most common presentation for a small intestinal carcinoid; often associated with malignant carcinoid syndrome

  • Cutaneous flushing: Early and frequent (94%) symptom; typically affects head and neck; often associated with an unpleasant warm feeling, itching, rash, sweating, palpitation, upper-body erythema and edema, salivation, diaphoresis, lacrimation, and diarrhea

  • Diarrhea and malabsorption (84%): Watery, frothy, or bulky stools, gastrointestinal (GI) bleed or steatorrhea; may or may not be associated with abdominal pain, flushing, and cramps

  • Cardiac manifestations (60%): Valvular heart lesions, fibrosis of the endocardium; may lead to heart failure with tachycardia and hypertension

  • Wheezing or asthmalike syndrome (25%): Due to bronchial constriction; some tremors are relatively indolent and result in chronic symptoms such as cough and dyspnea[15, 16]

  • Pellagra with scale-like skin lesions, diarrhea and mental disturbances

  • Carcinoid crisis can be the most serious symptom of carcinoid tumors and can be life-threatening. It can occur suddenly, after stress, or following chemotherapy and anesthesia.[17]

Classification

Carcinoid tumors generally are classified based on the location in the primitive gut that gives rise to the tumor, as follows:

  • Foregut carcinoid tumors: Divided into sporadic primary tumors (lung, bronchus, stomach, proximal duodenum, pancreas) and tumors secondary to achlorhydria

  • Midgut carcinoid tumors: Derived from the second portion of the duodenum, the jejunum, the ileum, and the right colon

  • Hindgut carcinoid tumors: Includes the transverse colon, descending colon, and rectum

See Clinical Presentation for more detail.

Carcinoid tumors are divided into well-differentiated (i.e., low grade [ENETS G1] and intermediate grade [ENETS G2]) and poorly differentiated (i.e., high grade [ENETS G3]). Classification based on the extent of the tumor are local, regional and distant spread. (See grading and staging)

Diagnosis

The etiology of carcinoid tumors is not known, but genetic abnormalities are suspected. Reported chromosomal abnormalities include changes in chromosomes,[18, 19] such as loss of heterogeneity, and numerical imbalances. The diagnosis is sometimes made because of unrelated findings, such as anemia, endocrine disease, or autoimmune disorders.

Laboratory testing

Laboratory diagnosis of carcinoid tumors depends on the identification of the characteristic biomarkers of the disease.[20, 21, 22] Measurement of biogenic amine levels (eg, serotonin, 5-hydroxyindoleacetic acid [5-HIAA], chromographin-A, catecholamines, histamine) and its metabolites in the platelets, plasma, and urine of patients can be helpful in making the diagnosis.

Imaging studies

Depending on the location of the tumor and metastasis, a combination of the following imaging modalities may be used to evaluate suspected carcinoid tumors:

  • Plain radiography

  • Upper and lower GI radiography with oral contrast agents

  • Computed tomography scanning

  • Magnetic resonance imaging

  • Angiography

  • Ultrasound including endoscopic ultrasound

  • Positron emission tomography scanning

  • Scintigraphy with metaiodobenzylguanidine (MIBG) and octreotide[23, 24]

  • Radionuclide imaging with somatostatin analogs attached to the radioactive tracer

  • Technetium-99m bone scanning

Procedures

Endoscopic procedures, such as the following, may be used for biopsy and diagnosis:

  • Bronchoscopy

  • Esophagogastroscopy

  • Gastroscopy

  • Colonoscopy

See Workup for more detail.

Management

Surgery

If feasible, the treatment of choice for carcinoid tumors is surgical excision. The surgical technique may vary according to the type or location of the tumor. When total resection is not possible, debulking may provide symptomatic relief. In selected cases, cryotherapy can be effective.

Chemotherapy

If metastasis of carcinoid tumor has occurred and in cases where surgical excision is not suitable, consider treatment with currently recommended chemotherapeutic agents, individually or in combination, such as the following:

  • Alkylating agents

  • Doxorubicin

  • 5-Fluorouracil

  • Dacarbazine

  • Actinomycin D

  • Cisplatin

  • Etoposide

  • Streptozotocin

  • Interferon alfa

  • Somatostatin analogs with a radioactive load   

  • Experimental agents such as  177Lu-Dotatate[25]

See Treatment for more detail.

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,[5] including the lungs,[6] mediastinum, thymus,[7] liver, pancreas, bronchus, ovaries,[12] prostate,[13] and kidneys.[26] In children, most tumors occur in the appendix and are benign and asymptomatic. While very rare in children, bronchial carcinoid tumors are the most common primary pulmonary neoplasm in the pediatric age group.[9]

Most carcinoid tumors are slow growing and indolent without symptoms. Nevertheless, aggressive and metastatic disease (eg, to the brain) does occur. Even tumors in the appendix can metastasize.[27, 28] Depending on the size and location, carcinoid tumors can cause various symptoms, including carcinoid syndrome.[17] Carcinoid tumors of the ileum and jejunum, especially those larger than 1 cm, especially in adults, are most prone to produce this syndrome.

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 lung, 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. The image below shows the distribution of carcinoid tumors in adults.

Distribution of carcinoid tumors. Distribution of carcinoid tumors.

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.[29] Appendicular carcinoid tumors are most common.[30, 31]  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.[32] Overall, based on retroactive studies, up to 0.35% of children undergoing appendectomy have appendiceal carcinoid tumors.[14, 33] Bulky tumors are relatively rare and require somewhat extensive cecectomy or, when tumor infiltration is beyond the cecum, ileocecal resection.[34, 35, 31]

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 derived from primitive stem cells, which can give rise to multiple cell lineages.[36] 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. Immunohistochemically, these tumors have a strong positive reaction to keratin and neuroendocrine markers. These include chromogranin and synaptophysin.

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 as 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. Carcinoid tumors of mediastinum can be misclassified as thymoma.

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.

Carcinoid tumors have high potential for metastasis. These cells produce a significant amount of beta-catenin, which enables the tumor cell adhesion, thus promoting metastasis. Induction of Raf1 results in decreased adhesion of carcinoid cells and may be important in the metastatic process.[37]

Frequency

United States

Carcinoids are the most common neuroendocrine tumors, with an estimated 1.5-1.9 clinical cases per 100,000 population. The incidence in autopsy cases is higher at 650 cases per 100,000 population. Evidence in adults suggests that overall incidence of carcinoid tumors has been steadily increasing.[38, 39]  While not entirely clear, it is speculated that this increase is due to more universal utilization of proton pump inhibitors. The exact incidence in children is not known. Most tumors occur in adults and are rare in children.

Historically, prior to availability of improved diagnostic techniques, distant metastasis was reported in 12.9% range. A retrospective cohort study by Kasumova et al reported that out of 10,752 patients, 12.7% were diagnosed with carcinoid tumors, 84.7% with nonfunctional and 2.6% with functional pancreatic neuroendocrine tumors. The incidence of carcinoid tumors rose from 36 (5.7%) diagnosed in 2004 to 497 (27.7%) in 2013. Overall survival was significantly longer for carcinoid compared with functional and nonfunctional tumors, with 5-year survival rates of 63.1%, 58.3%, and 52.6%, respectively. Overall survival for patients having resection improved significantly for carcinoid tumors (89.2%) compared to functional and non-functional tumors (76.6%, and 78.7%, respectively).[40]

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.[41]

 

Prognosis

No systematic data for survival of children with carcinoid tumors is currently available.

 

Presentation

History

Signs and symptoms of carcinoid tumors vary greatly and depend on the location and size of the tumor and on the presence of metastases. Findings range from no tumor-related findings to full symptoms of carcinoid syndrome. Because carcinoid tumors are rare in children, clinicians rely on reports of adult patients to understand the full scope of the manifestations of the disease.

  • Anatomic distribution

    • In general, carcinoid tumors are found in various locations, including the lungs,[42, 43] trachea, bronchus,[44, 11] thymus, liver, rectum, appendix,[1, 3, 4, 45, 46, 47, 48, 49] midgut (with metastasis), prostate, ovaries, kidneys,[26] and testes.[50, 51]

    • Approximately 80% of appendicial tumors are incidentally discovered during surgery for other indications, but some cause or coexist with acute appendicitis. Most appendiceal cases are local and free of metastasis; however, lymph node metastasis has been reported.[50]

    • While rare, repots of bilateral renal involvement are available.[11]

  • Diagnosis and differential diagnosis

    • Because symptoms can be vague and intermittent, diagnosis may be delayed, especially in children, in whom the tumor is rare and the diagnosis is unexpected.

    • Diagnostic difficulties may arise in patients who have flushing without a large tumor or metastases and in those without symptoms.

    • The diagnosis is sometimes made because of unrelated findings, such as anemia, endocrine disease, or autoimmune disease.

    • Tumors in the chest can produce symptoms because of their location or can be discovered using chest radiography.

    • In the absence of positive imaging findings and biochemical markers, in the differential diagnoses disorders such as an adverse reaction to medications, other malignant disorders (eg, chronic myelogenous leukemia), mastocytosis, and other tumors should be considered.

    • The availability of octreotide-receptor scintigraphy allows for the detection of the tumor and metastases. When results are positive, they may also allow for therapy by using octreotide with large doses of therapeutic radioactive agents.

  • Clinical presentations and symptoms

    • The most common clinical presentation for a small intestinal carcinoid is periodic abdominal pain, which can be caused by fibrosis of the mesentery, kinking of the bowel, or intestinal obstruction. A constellation of symptoms called malignant carcinoid syndrome is often associated with this tumor.

    • Production of vasoactive intestinal peptide (VIP) may produce symptoms similar to those of neuroblastoma, which is far more prevalent than carcinoid in children.

    • Ectopic adrenocorticotropic hormone (ACTH) and Cushing syndrome observed with foregut carcinoid tumors must be differentiated from other tumors that produce these symptoms. Likewise, rare acromegaly caused by the carcinoid tumors must be differentiated from pituitary tumors.

    • Carcinoid crisis can occur spontaneously or as a response to stress, such as anesthesia or chemotherapy. Symptoms may include intense flushing, diarrhea, abdominal pain, tachycardia, hypertension or hypotension, altered mental status, and coma. This condition can be life threatening, but treatment with somatostatin analog SMS-201-995 has improved the outcome of patients with carcinoid crisis.

    • An early and frequent (94%) symptom of large carcinoid tumors, especially those of midgut with metastases, is cutaneous flushing, which typically affects the head and neck. Striking color changes range from pallor or erythema to cyanosis. Episodes are often associated with an unpleasant warm feeling, itching, palpitation, upper-body erythema and edema, salivation, diaphoresis, lacrimation, and diarrhea. Exercise, stress, or certain foods (eg, cheese) may trigger an attack, although the flushes can also be spontaneous and unrelated to any stimulation. Initial attacks are short, lasting only a few minutes. With time, the duration increases to hours. Flushes are reported to be longest in association with bronchial carcinoids. Some patients develop a constant red or cyanotic discoloration.

    • Diarrhea and malabsorption occur in as many as 84% of patients. Stools are watery, frothy, bulky, or in the form of steatorrhea. Diarrhea may or may not be associated with abdominal pain, flushing, and cramps. It may be profuse and often colicky.

    • Wheezing or asthmalike syndrome is caused by bronchial constriction and may occur in as many as 25% of patients. Some tremors are relatively indolent and result in chronic symptoms such as cough, shortness of breath, symptoms of asthma or emphysema,[11]  and dyspnea.[16] Bronchopulmonary carcinoid tumor presenting with Cushing syndrome has been reported.[52] Behavior of bronchial carcinoid tumor can range from benign to aggressive with metastasis.[53] A child with a carcinoid tumor who had late relapse in mediastinum and metastasis to cerebellum 16 years after the initial diagnosis with atypical carcinoid tumor has been reported.[53]

    • Other symptoms of carcinoid tumors may include valvular heart lesions. Cardiac manifestations are observed in as many as 60% of patients. Fibrosis of the endocardium, which often involves the right side of the heart, is observed. The fibrous deposit usually involves the ventricular aspect of the tricuspid valve and associated chordae. Fibrosis of the pulmonic valve is relatively uncommon and results in regurgitation or stenosis. Cardiac lesions may lead to heart failure. The mitral valve is infrequently involved.

  • Other

    • Relatively uncommon complaints include joint pain, arthritis, lacrimation, confusion and changes in mental status, ophthalmologic findings associated with flushing or secondary to vascular occlusion, retroperitoneal fibrosis, obstruction of ureter, intra-abdominal fibrosis, Cushing syndrome and male sexual dysfunction.

    • Skin hyperkeratosis and pigmentation and arthritis are also relatively uncommon.

    • Carcinoid tumors have occurred in association with other familial or genetic disorders, such as multiple endocrine neoplasia type 1 (MEN 1)[54] and Peutz-Jeghers syndrome.

    • Multicentric tumor involving more than one organ (eg, larynx and thyroid) has been reported.[55, 56]

    • A second primary tumor in association GI carcinoids can occur. A case of hepatocellular carcinoma post diagnosis of carcinoid tumor has been reported.[57] These secondary tumors tend to be aggressive. In all cases of carcinoid tumor, care should be given to evaluate and follow patients for possible second malignancies.

Causes

The etiology of carcinoid tumors is not known, but genetic abnormalities, especially in pediatric pancreatic neuroendocrine tumors,[9]  are suspected. Reported chromosomal abnormalities include changes in chromosomes, such as loss of heterogeneity, and numerical imbalances.

  • MEN 1 is an autosomal dominant disorder characterized by the occurrence of multiple tumors, particularly in the pancreatic islets, parathyroid and pituitary glands, and neuroendocrine tumors.[58]

    • Germline mutations in the MEN 1 gene can be identified in the general population.

    • Multiple carcinoid tumors occurring in association with MEN 1 have been reported.[59]

    • Although the MEN 1 gene locus is known to be involved in neuroendocrine tumors, the genetic events underlying the neoplastic process are basically unknown.

    • Familial cases other than those associated with MEN 1 are rare, but do occur.[60]

    • In several studies, loss of heterozygosity (LOH) at the MEN 1 locus has been reported.[61, 62, 63, 64, 65, 66]

    • Genetic abnormalities involving chromosome 11 are most common. These can be seen as a part of MEN 1 or independent of MEN 1 abnormalities.[65, 66] In 5 of 9 typical carcinoid tumors of the lung, 3 distinct regions of allelic loss were identified at bands 11q13.1 (D11S1883), 11q14.3-11q21 (D11S906), and 11q25 (D11S910).

    • Some atypical carcinoids have LOH at band 11q13 between markers PYGM and D11S937 and at bands 11q14.3-11q21 (D11S906), 11q23.2-23.3 (D11S939), and 11q25 (D11S910).

    • The region of band 11q13 bearing the MEN 1 gene can also be affected in some atypical carcinoid tumors more than it is in typical carcinoid tumors. Therefore, band 11q13 appears to be important in these tumors. Aggressive atypical carcinoid tumors, defined by high mitosis, vascular invasion and organ metastasis, also appear to have more allelic losses than other tumors.

    • The MEN 1 gene is located on band 11q13 and likely functions as a tumor-suppressor gene. In a study of 46 sporadically occurring tumors, 78% had LOH at this site, with almost the entire allele missing in 5 patients. In the remaining cases, genetic heterozygosity had a discontinuous pattern. Some have postulated that sporadically occurring carcinoid tumors evolve after inactivation of a tumor-suppressor gene on chromosome 11 as well as genetic mutations that affect DNA-mismatch repair.

  • Gastric neuroendocrine tumors are associated with a high incidence of LOH at chromosomal arm 8p and a lowered frequency of LOH at 7q. Chromosomal arm 8p is suspected to be the possible location of the tumor-suppressor gene associated with the genesis of gastric neuroendocrine tumors. In one study, two out of five patients with pancreatic neuroendocrine tumors had Von Hippel-Lindau disease and two others were diagnosed with multiple endocrine neoplasia type1.[67]

  • LOH on the X chromosome is seen in 15% of malignant carcinoid tumors.[63, 64]

  • Numerical imbalances of chromosomes have been observed in carcinoid tumors.

    • In one study of midgut carcinoids, numerical changes were found in 16 of the 18 tumors.

    • The most common aberrations were losses of bands 18q22-qter (67%), 11q22-q23 (33%), and 16q21-qter (22%) with a gain of band 4p14-qter (22%). Rates of alterations were substantially more common in metastases than in primary tumors.

  • Losses of chromosomal arms 18q and 11q were found in the primary tumors and metastases, whereas loss of 16q and gain of 4p were present only in metastases.

  • HER2 expression has been reported in intestinal, but not gastric, tumors.[68]

  • Some studies have implicated homeobox gene Hoxc6 through activation of the oncogenic activator protein-1 signaling pathway and via interaction with JunD in carcinoid tumorigenesis.[69] Mutation in the home domain of Hoxc6, which blocks this interaction, results in inhibition of the carcinoid tumor cell proliferation in vitro.

  • One postulate is that loss of chromosomal arms 18q and 11q may represent an early event and that the loss of 16q and gain of 4p occur as a late event in midgut carcinoids.

 

Workup

Laboratory Studies

Laboratory diagnosis of carcinoid tumors depends on the identification of the characteristic biomarkers of the disease. Measurement of biogenic amines levels (eg, serotonin, 5-HT, catecholamines, histamine) and its metabolites in the platelets, plasma, and urine of patients can be helpful in diagnosis.

  • Urinary 5-HIAA levels are usually increased and aid in the assessment of carcinoid tumors.[70, 71, 72, 73, 74, 75] Measurement of urinary 5-HIAA levels can help in diagnosing carcinoid syndrome but may not help in detecting tumors at an early stage of development when they are potentially curable with resection. Although the detection of urinary 5-HIAA is the single best screening method for carcinoid tumors, the level is not always elevated, and the measurement of other peptides (eg, SP, neuropeptide K, chromogranin) may be necessary for diagnosis and follow-up.

  • Fasting plasma 5-HIAA assay is more stable than whole-blood serotonin assay and is more convenient than 24-hour urine collection.[76] Substances produced by carcinoid tumors are listed in Pathophysiology above.

  • In one study, CDX2 was highly indicative of GI carcinoid tumor, whereas TTF-1 had high specificity for pulmonary tumors.[77] One (17%) of 6 gastric carcinoids stained with CDX2, whereas 8 (53%) of 15 pulmonary carcinoids stained with TTF-1. None of the GI tumors stained with TTF-1.

Imaging Studies

Numerous imaging modalities have been used to detect carcinoid tumors. These modalities include plain radiography, upper-GI and lower-GI radiography with the use of oral contrast agents, CT, MRI, angiography, positron emission tomography (PET), scintigraphy with metaiodobenzylguanidine (MIBG) and octreotide,[23, 24] radionuclide imaging with somatostatin analogs attached to the radioactive tracer, and technetium-99m bone scanning. Depending on the location of the tumor and metastasis, a combination of these may be used.

A study sought to determine the test performance of PET-CT for mediastinal lymph node staging of pulmonary carcinoid tumors. The study found that PET-CT has a poor sensitivity but good specificity to detect the presence of mediastinal lymph node metastases in pulmonary carcinoid tumors. Mediastinal lymph node metastases cannot be ruled out with negative PET-CT uptake, and if the absence of mediastinal lymph node disease is a prerequisite for directing management, tissue sampling should be undertaken.[78, 79]

  • GI series, CT, and MRI may be helpful in some situations.

    • For the diagnosis of chest tumors, CT combined with scintigraphy with octreotide is preferred.

    • In the large bowel, the disease is often detected with colonoscopy and does not provide an imaging challenge. Imaging diagnosis of small-bowel carcinoids is relatively difficult. Small tumors in this location are difficult to detect on upper-GI series and CT scans, and other techniques are required.

    • Mesenteric invasion and liver metastasis are often detected on CT scans. MRI can also be helpful in the diagnosis of hepatic disease but is less sensitive than CT in detection of extrahepatic lesions.

  • With advances in imaging studies, angiography is rarely used and is reserved for equivocal situations.

  • PET scanning can be helpful and is increasingly used for diagnosis and follow-up of the tumors.

  • Scintigraphy with MIBG and octreotide scanning have been used to successfully detect carcinoid tumors.[80] Octreotide scanning appears to be more sensitive than MIBG imaging.

  • Radionuclide imaging with somatostatin analogs attached to radioactive tracer can be used to advantage for diagnosis of carcinoid tumors.

    • Radiotracers currently used include indium-111 diethylenetriamine pentaacetic acid (111 In-DTPA) and yttrium. Most neuroendocrine tumors have receptors for somatostatins. Five somatostatin receptor subtypes, designated SSTR-1 to SSTR-5, are identified. Binding affinity of somatostatin analogs to these subtypes may vary, with highest affinity for SSTR-2, medium affinity for SSTR-2 and SSTR-5, and lowest affinity for SSTR-1 and SSTR-4. Carcinoid tumors often express SSTR-1 to SSTR-3 and, infrequently, SSTR-2. Nevertheless, for tumors that measure less than 1 cm in diameter, the sensitivity of111 In-DTPA octreotide imaging reaches 80-90%.

    • This technique can be used to identify primary and metastatic disease and is approved for radionuclide scanning of carcinoid tumors. An advantage is that, if the result is positive, this technique can be used as a treatment modality.

    • In a study of 40 patients, somatostatin-receptor scintigraphy (SRS) helped in detecting localized tumors in 78% of patients versus 82% with CT scanning. However, SRS helped in identifying primary tumors in 2 patients missed on CT scanning. In 16% of patients, SRS depicted lesions not found with other modalities. No false-positive results were observed.

    • Overall, SRS appears to be the imaging method of choice for localizing and evaluating the extent of carcinoid tumor.

    • Bone metastasis is not uncommon in carcinoid tumors. In a study of 12 patients, 11 of whom had liver metastasis, 8 had bone involvement, as detected on SRS.

    • 6-Fluoro-[18F]L-dihydroxyphenylalanine positron emission/computed tomography for imaging carcinoid tumor has been reported.[81]

    • Technetium-99m bone scanning can aid in the detection of metastases.

Procedures

Endoscopy, including bronchoscopy, esophagogastroscopy, gastroscopy, and colonoscopy, can be used for biopsy and diagnosis. Functional imaging with somatostatin receptor-specific radiotracers with fused functional as well as anatomic imaging have significantly improved the diagnosis and follow up of carcinoid tumors.[82]

Histologic Findings

Please see Pathophysiology above.

 

Treatment

Medical Care

If metastasis of carcinoid tumor has occurred and in cases where surgical excision is not suitable, consider treatment with currently recommended chemotherapy.

  • Chemotherapeutic agents currently used in clinical trials to palliate metastatic carcinoid disease include the following:

    • Alkylating agents

    • Doxorubicin

    • 5-Fluorouracil

    • Dacarbazine

    • Actinomycin D

    • Cisplatin

    • Etoposide

    • Streptozotocin

    • Interferon alfa

    • Somatostatin analogs with a radioactive load

    • Experimental agents such as 177Lu-Dotatate

  • A combination of the agents listed above is typically used.

  • Chemoembolization of hepatic artery for treatment of metastatic carcinoid tumor has been widely used in adults.[83]

  • In one study, 8 adults with carcinoid tumor metastatic to liver were treated with intra-arterial 5-fluorouracil and embolization of hepatic tumors with bovine collagen fiber admixed with iohexol, cisplatin, mitomycin C, and doxorubicin. This treatment resulted in symptomatic relief and tumor regression in 4 patients and stabilized the disease in the rest of the patients.

  • Octreotide, a somatostatin analog, is highly effective in reducing symptoms; however, in the pediatric age group, stunted linear growth is of concern. Survival advantage with the use of this drug has not yet been proven.

    • Octreotide reduces the amount of the growth factor produced and, thus, theoretically impairs growth.

    • Intermittent and continuous infusions of octreotide have been reported. Superior results obtained with the latter modality. Such treatment can result in near-normalization of the plasma insulinlike growth factor I and partial suppression of plasma growth hormone–releasing hormone (GHRH).[84]

    • The availability of a long-acting somatostatin analog that can be given once a month has eliminated the need for injections 2-3 times per day, with equal efficacy.[85]

    • In metastatic carcinoid tumors, long-term use of octreotide is reported. However, receptor alteration induced during the use of this agent requires consecutive drug dosage increase to control the symptoms.[86] At present, no formal, well-designed study has been performed to systematically measure the effects of this modality of therapy. Although experience is limited, adverse effects in children have been similar to those in adults. Adverse effects include gallstones and steatorrhea, which may sometimes require pancreatic enzyme replacement. Local irritation at the injection site is a common complaint. These adverse effects must be weighed against the potential benefits.

    • A randomized, double-blind, placebo-controlled, phase 3 study showed that using everolimus in conjunction with octreotide improved progression-free survival in patients with low-grade and intermediate-grade advanced neuroendocrine tumors.[87, 88]

  • In situ targeted therapy with somatostatin analogs (eg, octreotide attached to a radioactive load using yttrium-90 or111 indium-labeling agents) provides promise for patients with unresectable tumors. This therapy is currently used on an experimental basis in adults and children.

  • A case of a 16-year-old female with recurrent disseminated, ganglioside positive bronchial carcinoid, successfully treated with recombinant alpha interferon with a third relapse treated with NGcGM3/VSSP Montanide ISA 51 vaccination in conjunction with rec-h lFNalpha is available.[89] The disease was stable 56 months posttherapy.

Surgical Care

If feasible, the treatment of choice is surgical excision which is associated with an excellent prognosis, especially in appendiceal tumors.[33, 90, 2, 3, 4, 45, 46, 47, 48] Surgical technique may vary according to the type or location of the tumor.

  • For pediatric age group, surgical treatment of appendiceal carcinoids can be challenging. In most appendiceal tumors, simple appendectomy is sufficient for treatment and are universally accepted.[91, 90, 2, 3, 4, 45, 46, 47, 48]  Choosing optimal treatment when lesions are greater than two centimeters, appendix is perforated, or there is involvement in the appendiceal base are challenging and can be controversial.[47, 48, 49] In intestinal carcinoids, block resection of the tumor with adjacent lymph nodes must be attempted. In the bronchial location, aggressive surgical resection, and not bronchoscopic removal, is recommended.[44, 43]

  • In localized tumors, surgical resection can result in cure, with 70% to more than 90% survival rate.

  • In rectal tumors, endoscopic resection in adults is sufficient for small tumors measuring less than 1 cm, for tumors limited to the mucosa, and in tumors resected with adequate margin at presentation. Nevertheless, resection does not guarantee prevention of metastasis at a later date.[92] In adults, surgical resection of the primary tumor is shown to provide survival advantage.[93]

  • When total resection is not possible, debulking may provide symptomatic relief.

  • For hepatic tumors, surgical ligation of the hepatic artery can potentially deprive blood supply to the tumor cells and cause necrosis while preserving most of the normal live cells. However, over time new blood vessels develop and restore circulation.

  • Intra-arterial infusion of chemotherapeutic agents with chemoembolization of the hepatic artery may also provide effective, albeit short term, relief of symptoms due to hepatic metastasis. If hepatic metastasis is present but resectable, surgical resection is preferred.

  • In selected cases, cryotherapy can be effective. Bronchoscopic cryotherapy has been successfully applied in treatment of isolated endoluminal carcinoid tumor in an adult patient.[94]

  • In patients with tumors less than 1 cm located in the appendix, appendectomy is the treatment of choice. More extensive surgery is indicated for tumors larger than 2 cm, lymphatic invasion, lymph node involvement, mesoappendix infiltration, positive resection margins, and cellular pleomorphism with a high mitotic index. For tumors larger than 2 cm, accepted treatment has been hemicolectomy; however, a survival advantage over simple appendectomy has not been demonstrated.[95] Given the relatively low malignant potential of appendiceal carcinoids, some have suggested simple appendectomy for tumors more than 2 cm diameter without affecting overall survival.[96]

 

Guidelines

Guidelines Summary

Guidelines Contributor: Evan S Ong, MD, MS Assistant Professor of Surgery, Section of Surgical Oncology, University of Arizona College of Medicine

The following organizations have issued clinical guidelines for the treatment of carcinoid tumors:

  • National Comprehensive Cancer Network (NCCN)

  • North American Neuroendocrine Tumor Society (NANETS)

  • European Neuroendocrine Tumor Society (ENETS)

  • European Society for Medical Oncology (ESM0)

  • UK and Ireland Neuroendocrine Tumour Society (UKI NETS)

Grading and Staging

Grading schemes for neuroendocrine tumors (NETs) use mitotic count; the level of the nuclear protein Ki-67, which is associated with cellular proliferation; and assessment of necrosis. The World Health Organization (WHO) and the European Neuroendocrine Tumor Society (ENETS) both incorporate mitotic count and Ki-67 proliferation for the classification of gastroenteropancreatic NETs (GEP-NETs).[97, 98, 99]

Tumors fall into one of the following three grades:

  • G1: well differentiated, low grade

  • G2: well differentiated, intermediate grade

  • G3: poorly differentiated, high grade

However, for NETs of the lungs and thymus, the WHO includes only mitotic count and assessment of necrosis.[100] In its 2015 consensus statement on best practices for pulmonary neuroendocrine tumors, the European Neuroendocrine Tumor Society (ENETS) noted that tumor grading based on a combination of KI-67, mitotic rate, and necrosis may be of clinical importance but lacks validation.[101]

Under the WHO grading scheme, pulmonary and thymic tumors fall into one of the following three grades[100] :

  • Low-grade tumors:  < 2 mitoses/10 high power field (HPF) and no necrosis
  • Intermediate tumors:  2-10 mitoses/HPF and/or foci of necrosis
  • High grade tumors:  >10 mitoses/10 HPF

The European Society for Medical Oncology (ESMO) uses only mitotic count for bronchial and thymic tumors to determining tumor grade as follows[102] :

  • Low-grade tumors:  < 10 mitoses/10 high power field (HPF) 
  • Intermediate tumors:  10-20 mitoses/10 HPF
  • High grade tumors:  >20 mitoses/10 HPF

The National Comprehensive Cancer Network (NCCN) recommends that tumor differentiation, mitotic rate, and Ki-67 rate be included in the pathology report and that the specific classification and grading scheme be noted to avoid confusion. Clinicians are advised to view histologic grade as a general guide and use clinical judgment to make treatment decisions, particularly in cases of discordance between differentiation and Ki-67 proliferation results.[103]

NCCN guidelines recommend staging according to the 7th edition of the American Joint Committee on Cancer's AJCC Cancer Staging Manual.[103]  The AJCC uses separate staging systems for carcinoids of the stomach, duodenum/ampulla/jejunum/ileum, colon/rectum, and appendix, as well as adrenal gland tumors. Bronchopulmonary carcinoids are staged using the same system as for other pulmonary malignancies, and pancreatic NETS are staged the same as for exocrine pancreatic tumors.[104]

For staging of GEP-NETs, the European Society for Medical Oncology (ESM0) guidelines, updated in 2012, utilize the tumor-node-metastasis (TNM) classification created by the ENETS and the 2010 WHO grading system.8 For staging of bronchopulmonary and thymus NETs, the ESMO prefers the AJCC system.[102] For adrenal carcinoma staging, the 2009 European Network for the Study of Adrenal Tumors (ENSAT) TNM system is recommended over the AJCC system.[105]

In 2012, the UK and Ireland Neuroendocrine Tumour Society (UKI NETS) released updated guidelines for the management of GEP-NETs. Recommendations for grading and staging are as follows[106] :

  • For grading: WHO 2010 grading system

  • For staging: 7th edition of the AJCC Cancer Staging Manual

  • Also stage NETs of the stomach, pancreas and appendix with the ENETS site-specific T-staging system

  • The TNM classification used should be specified

  • Underlying features of the T-stage classification (eg, tumor size, extent of invasion) should be documented to allow for translation between different classification systems

In 2013, the North American Neuroendocrine Tumor Society (NANETS) concluded that while the criteria differ among the various classification systems, the underlying data are similar and pathology reports should include notation of the systems and parameters used to assign the grade and stage.[36]

Gastrointestinal Tumors

Treatment for locoregional disease

NCCN guidelines recommend resection as the primary treatment for most carcinoid tumors of the gastrointestinal (GI) tract, lung, and thymus. Specific recommendations vary by tumor subtype. However, for neuroendocrine tumors at any site, cholecystectomy is recommended during surgical resection if treatment with a somatostatin analog (ie, octreotide, lanreotide) is planned, due to the increased rate of biliary problems associated with long-term use of these agents.[103]

Gastric tumors

For gastric tumors, the NCCN recommendations are as follows[103] :

  • With hypergastrinemia and tumors ≤2 cm: Endoscopic resection with biopsy or observation; or octreotide or lanreotide for patients with Zollinger-Ellison syndrome.

  • With hypergastrinemia and tumors >2 cm: Endoscopic resection, if possible, or surgical resection

  • With normal gastrin levels: Radical gastric resection and regional lymphadenectomy; endoscopic or wedge resection can be considered for tumors ≤2 cm

Gastric carcinoids can be subclassified into the following three distinct groups[107] :

  • Type I – Those associated with chronic atrophic gastritis/pernicious anemia (70-80%)

  • Type II – Those associated with Zollinger-Ellison syndrome with multiple endocrine neoplasia type I (MEN I) (5%)

  • Type III – Sporadic NETs of the stomach (15-20%)

In 2013, NANETS released updated guidelines with the following recommendations for treatment of gastric carcinoid tumors[108] :

  • Type I or II, < 1 cm: Surveillance or endoscopic removal

  • Type I, 1 cm to < 2 cm: Surveillance with repeat endoscopy every 3 years or endoscopic resection

  • Type II, 1 cm to < 2 cm: Endoscopic resection

  • Type I, ≥2 cm (≤6 polyps), or type II ≥2 cm: Endoscopic resection, if possible, or open surgical resection

  • Type I, ≥2 cm (>6 polyps): Individualized treatment required; surveillance, endoscopic resection, or surgical resection

  • Type III: Partial gastrectomy and lymph node dissection

The 2016 revised ENETS guidelines prefer conservative management strategies over surgery for type I tumors. The guidelines recommend resection of tumors ≥ 10 mm performed by experienced endoscopists in gastric tumors using either endoscopic mucosal resection (EMR) or endoscopic submucosal dissection (ESD).[109]

For type II tumors, local or limited excision can be recommended, but this should be patient tailored at multidisciplinary NET centers of excellence. Type III tumors should be treated similarly to gastric adenocarcinoma with surgery(partial or total gastrectomy with lymph node dissection). Systemic therapies is required for inoperable or stage 4 disease.[109]

Duodenal tumors

For duodenal tumors, the NCCN recommends the following treatments[103] :

  • Endoscopic resection with follow-up upper endoscopy

  • Transduodenal local excision with or without lymph node sampling

  • Pancreatoduodenectomy

ENETS guidelines provide the following recommendations for treatment of duodenal tumors[109] :

  • All localized tumors should be removed

  • Endoscopic resection for tumors ≤1 cm confined to the submucosal layer, without lymph node or distant metastasis

  • Surgical resection with lymphadenectomy for tumors in the periampullary region

  • Surgical resection for tumors >2 cm and tumors of any size with lymph node metastases

Bowel tumors

NCCN recommendations are as follows[103] :

  • Surgical resection with lymphadenectomy

  • Careful examination of the entire bowel and assessment of proximity to or involvement of the superior mesenteric artery and superior mesenteric vein

  • Prophylactic cholecystectomy if further treatment with octreotide or lanreotide is planned

The NANETS guidelines include the following recommendations[108] :

  • Tumors of the cecum: Right hemicolectomy with node dissection

  • Tumors of the jejunal or ileum: Resection with node dissection; full bowel examination required

  • Distal colon and rectum tumors < 1 cm: Endoscopic resection (polypectomy, endoscopic mucosal resection, endoscopic submucosal dissection) for mucosal or submucosal tumors

  • Distal colon and rectum tumors 1-2 cm: Transanal excision via rigid or flexible dissection; could also be considered after endoscopic resection with positive margins

  • Distal colon and rectum tumors >2 cm: Surgical resection (low anterior resection or abdominoperineal resection) for larger tumors, tumors invading muscularis propria, or those with lymphadenopathy

The ENETS guidelines provide following recommendations[110, 111] :

Rectal Tumors [110]

  • Endoscopic resection by simple polypectomy, endoscopic mucosal resection (EMR) with modified EMR band ligation, endoscopic submucosal dissection (ESD) and transanal endoscopic microsurgery (TEMS).[112]

  • For lesions < 10 mm and no involvement of the muscularis propria, EMR is adequate, but EMR band-assisted ligation may improve the number of complete resections 

  •  If EMR results in an incomplete resection, then ESD or TEMS may be indicated as salvage therapy

 Jejunum and Ileum Tumors[111]

  • Curative resection of the primary tumor and dissection of the locoregional lymph node metastasis along the superior mesenteric root and around the mesentery
  • Lymphatic mapping it is not a standardized procedure and not generally recommended 

Appendix tumors

NCCN recommendations for appendix NETs are as follows[103] :

  • Tumors ≤2 cm confined to the appendix: Appendectomy

  • Tumors ≤2 cm with lymphovascular or mesoappendiceal invasion or atypical histologic features: More aggressive treatment can be considered

  • Incomplete resection or tumors >2 cm: Staging with abdominal/pelvic CT or MRI; if no distant disease, reexploration with a right hemicolectomy

The NANETS guidelines include the following recommendations[108] :

  • Excision for tumors ≤2 cm; consider right hemicolectomy with node dissection if high- risk features are present

  • Tumors >2 cm: Right hemicolectomy with node dissection

The 2016 ENETS revised guidelines recommendations include[109] :

  • Tumors ≤2 cm: simple appendicectomy unless incompletely resected
  • Right hemicolectomy with node dissection only in rare tumors measuring 1–2 cm but with positive or unclear margins or with deep mesoappendiceal invasion (ENETS T2), higher proliferation rate (G2) and/or vascular invasion
  • Tumors >2 cm: right hemicolectomy with node dissection

Metastatic disease

NCCN recommendations for the treatment of unresectable and/or metastatic carcinoid tumors of the GI tract include the following[103] :

  • Somatostatin scintigraphy to assess sites of metastases and somatostatin receptor status if octreotide or lanreotide is considered

  • Limited hepatic metastases: Complete resection of primary tumor and metastases with curative intent; noncurative debulking surgery in select cases

  • Unresectable hepatic progressive disease: Radiofrequency ablation or cryoablation or hepatic regional therapy (arterial embolization, chemoembolization, or radioembolization)

  • Palliative small bowel resection for patients with abdominal pain from bowel obstruction or ischemia related to the primary tumor

  • Octreotide or lanreotide to control tumor growth in patients with clinically significant tumor burden or progressive disease; everolimus can be considered for advanced tumors

  • Consider capecitabine if no other options are feasible (category 3)

  • Consider interferon alfa-2b after octreotide or lanreotide failure (category 3)

  • Malignant carcinoid syndrome: Octreotide or lanreotide; cardiology consultation, and echocardiogram to assess for heart disease

  • Liver transplantation is investigational and not recommended as routine care

Note that the use of ablative techniques for hepatic disease is associated with increased infectious complications. Although the NCCN guidelines cite category 2b evidence for cryoablation and radiofrequency ablation, most centers use radiofrequency or microwave ablation. Cryoablation is generally used only in centers providing ablation for renal cell cancers, and it is associated with a small but definite risk of subsequent acute respiratory distress syndrome.[113]

Thoracic carcinoids

Thymic NETs

NCCN recommendations include the following[103] :

  • Localized disease: Surgical resection

  • Locoregional disease: Reresection; if resection is incomplete, follow with radiation therapy and/or chemotherapy

The NANETS guidelines include the following additional recommendations[108, 114] :

  • Locoregional disease: Surgical resection including mediastinal lymphadenectomy

  • Metastatic or unresectable disease: Options include radiation therapy, everolimus, interferon alpha, or temozolomide

The ESMO guidelines note that a protracted follow-up should always be performed after surgical resection because of the high rates of recurrence. For metastatic disease, although the available chemotherapy regimens have not demonstrated good effects, cisplatinum-based regimens have been of value and temozolomide-based treatment gives some benefit.[102]

Bronchopulmonary NETs

NCCN recommendations for bronchopulmonary NETs are as follows[103] :

  • Stage I, II, and IIIA: Lobectomy or wedge resection for peripheral low-grade neuroendocrine carcinoma and lymph node dissection or sampling

  • Stage IIIA low grade nonresectable tumors: Radiation therapy

  • Stage IIIA intermediate grade nonresectable tumors: Cisplatin/etoposide and radiation therapy

  • Stage IIIB (except for T4 due to multiple lung nodules): Cisplatin/etoposide with or without radiation therapy

  • Stage IIIBm (T4 due to multiple lung nodules) or stage IV: Systemic therapy; no preferred regimen; options include cisplatin/etoposide, temozolomide with or without capecitabine, sunitinib, or everolimus; consider octreotide for symptoms of malignant carcinoid syndrome

The NANETS guidelines and the ESMO guidelines are similar to those of the NCCN, with some minor variances.[108, 102] The ESMO guidelines include the following additional recommendations[102] :

  • Bronchoscopic laser excision should be considered a suboptimal treatment and be reserved for inoperable patients or performed as a preoperative disobliterating procedure

  • Lobectomy and sleeve resection are preferred for locoregional tumors and systemic nodal dissection should be performed

  • Pneumonectomy should be avoided

Additionally, NANETS suggests that interferon alpha should be considered for metastatic or unresectable disease.[108]

Neuroendocrine Tumors of the Pancreas

Treatment for locoregional disease

National Comprehensive Cancer Network (NCCN) guidelines recommend resection as the primary treatment for most localized pancreatic neuroendocrine tumors (NETs). Exceptions include patients with life-limiting comorbidities or high surgical risk. In addition, observation may be appropriate for incidentally discovered tumors < 1 cm, depending on the site.[103]

Prior to surgery, NCCN recommends that symptoms of hormonal excess be treated with octreotide or lanreotide; however, such treatment is contraindicated in patients with insulinoma because of the potential for fatal complications. Specific recommendations vary by tumor subtype. Cholecystectomy is recommended during surgical resection if treatment with octreotide or lanreotide is planned, due to the increased rate of biliary problems associated with long-term use of these agents.[103]

Nonfunctioning pancreatic tumors

For nonfunctioning pancreatic NETs, treatment recommendations are as follows:

  • Tumors ≤2 cm: Enucleation of the tumors with strong consideration of lymph node resection or pancreatectomy (Whipple type or proximal) with or without regional node resection or distal pancreatectomy with or without regional node resection/splenectomy

  • Tumors >2 cm located at the head: Whipple-type or proximal pancreatectomy with regional node resection

  • Tumors >2 cm located distally: Distal pancreatectomy with regional node resection and splenectomy

Gastrinoma

Recommendations for gastrinoma treatment include the following:

  • Manage gastric hypersecretion with proton pump inhibitors; consider octreotide or lanreotide

  • Occult tumors: Observation or exploratory surgery, including duodenotomy and intraoperative ultrasound with enucleation; local resection if tumors identified, and removal of periduodenal nodes

  • Duodenum tumors: Duodenotomy and intraoperative ultrasound with local resection or enucleation and periduodenal node dissection

  • Tumors at head of pancreas: Exophytic or peripheral tumors require enucleation and periduodenal node dissection; deeper or invasive tumors or those with proximity to the main pancreatic duct require pancreatoduodenectomy

  • Distal tumors: Distal pancreatectomy with or without splenectomy.

Insulinoma

Recommendations for insulinoma treatment include the following:

  • Stabilize glucose levels with diet and/or diazoxide; everolimus may be considered

  • Primary treatment is enucleation; consider laparoscopic resection for solitary tumors

  • Deeper or invasive tumors or those with proximity to the main pancreatic duct require pancreatoduodenectomy if located in the head and laparoscopic distal pancreatectomy if in a distal location, with preservation of the spleen for smaller tumors

Glucagonoma

Recommendations for glucagonoma treatment include the following:

  • Stabilize glucose levels with IV fluids; treat hyperglycemia and diabetes

  • Tumors located in the head of the pancreas: Pancreatectomy with resection of peripancreatic lymph nodes

  • Distal tumors: Distal pancreatectomy with splenectomy and resection of peripancreatic lymph nodes

  • Consider perioperative anticoagulation due to increased risk of pulmonary emboli

VIPoma

Recommendations for treatment of NETs that secrete vasoactive intestinal peptide (VIPomas) include the following:

  • Stabilize with IV fluids; correct electrolyte imbalance

  • Tumors located in the head of the pancreas: Pancreatectomy with resection of peripancreatic lymph nodes

  • Distal tumors: Distal pancreatectomy with splenectomy and resection of peripancreatic lymph nodes.

The North American Neuroendocrine Tumor Society (NANETS) guidelines and the European Society for Medical Oncology (ESMO) guidelines for treatment of neuroendocrine pancreatic tumors are similar to those of the NCCN, with some minor variances. The ESMO guidelines do not recommend laparoscopic resection or surgical treatment of G2 pancreatic NETs.[115]

Metastatic disease

NCCN recommendations for the treatment of unresectable and/or metastatic pancreatic tumors include the following[103] :

  • Limited hepatic metastases: Complete resection of primary tumor and metastases with curative intent; noncurative debulking surgery in select cases

  • Asymptomatic unresectable disease: For select patients with low tumor burden and stable disease, consider observation with marker assessment and imaging every 3-12 months until significant disease progression occurs; lanreotide or octreotide can be considered

  • Symptomatic unresectable disease: Octreotide or lanreotide; everolimus or sunitinib; or cytotoxic chemotherapy

  • Hepatic-directed therapies include cytoreductive surgery or ablative therapy; bland hepatic arterial embolization, radioembolization, and chemoembolization are additional options but the optimal embolization technique has not been determined

  • Liver transplantation is investigational and not recommended as routine care

The European Neuroendocrine Tumor Society (ENETS) guidelines are generally similar to those of the NCCN, with the following major variances[116] :

  • To justify surgery of liver metastases in patients with nonfunctioning tumors, reduction of at least 90% of the tumor mass should be expected

  • Liver transplantation is an option in patients without extrahepatic metastases and low proliferation rate when other options have failed

Pheochromocytoma

In 2014, The Endocrine Society (TES), the American Association for Clinical Chemistry (AACC), and the European Society of Endocrinology (ESE) released joint clinical practice guidelines for the management of pheochromocytoma and paraganglioma (referred to together as PPGL). The guidelines include recommendations (based on strong evidence) and suggestions (based on weaker evidence).[117]

In patients suspected of having PPGL, biochemical testing via measurement of plasma free metanephrines or urinary fractionated metanephrines is recommended. The use of liquid chromatography with mass spectrometry or electrochemical-detection methods is suggested over other laboratory methods. Patients with a known germline mutation that predisposes to PPGL should undergo periodic biochemical testing.[117]

The 2010 guidelines from the North American Neuroendocrine Tumor Society (NANETS) recommend biochemical testing for pheochromocytoma that includes measurements of fractionated metanephrines in plasma, urine, or both, as available, in the following cases[118] :

  • Symptomatic patients

  • Patients with an adrenal incidentaloma

  • Patients who have a hereditary risk for developing a pheochromocytoma or paraganglioma (extra-adrenal pheochromocytoma)

For imaging studies, the joint TES/AACC/ESE guidelines recommend computed tomography (CT) as first line, rather than magnetic resonance imaging (MRI). However, MRI is an option in certain patients, such as those with metastatic PPGL; those allergic to CT contrast media; and those for whom radiation exposure should be limited, such as pregnant women.[117]

For preoperative management, TES/AACC/ESE recommendations include the following:

  • Blockade of hormonally functional PPGL to prevent cardiovascular complications

  • Medical treatment to normalize blood pressure and heart rate

  • A high-sodium diet with supplemental fluid intake to prevent severe hypotension after removal of the tumor

The TES/AACC/ESE guidelines recommend minimally invasive (eg, laparoscopic) adrenalectomy for most adrenal pheochromocytomas, with open resection reserved for very large or invasive pheochromocytomas. Open resection is suggested for paragangliomas, although laparoscopic resection is an option for smaller tumors. Partial adrenalectomy is also a possibility for certain types of patients.

In the immediate postoperative period, the TES/AACC/ESE guidelines recommend monitoring of blood pressure, heart rate, and glucose levels. Postoperative measurement of plasma or urine metanephrine levels and lifelong annual biochemical testing are suggested.

For genetic testing, TES/AACC/ESE recommendations are as follows:

  • Patients with PPGLs should be engaged in shared decision-making for genetic testing

  • Patients with paraganglioma should undergo testing of succinate dehydrogenase (SDH) mutations

  • Patients with metastatic disease should undergo testing for SDHB mutations

  • Genetic testing should include pre- and posttest genetic counseling

The 2010 NANETS recommendations for treatment of advanced disease include the following[118] :

  • Surgical debulking to release tumor pressure on surrounding tissues or to decrease tumor mass

  • In select patients, radiofrequency ablation or cryoablation are options

  • Chemotherapy is preferred in patients with negative metaiodobenzylguanidine (MIBG) scintigraphy and in those with rapidly progressing tumors

  • External-beam irradiation of bone metastases or radiofrequency and cryoablation in selected cases only

Adrenal Carcinomas and Incidentalomas

Guidelines issued by the American Association of Clinical Endocrinologists (AACE) and American Association of Endocrine Surgeons (AAES) in 2009 for the management of adrenal incidentalomas recommend that evaluation of patients with an adrenal incidentaloma include clinical, biochemical, and radiographical testing for the following[119] :

  • Hypercortisolism

  • Aldosteronism (if hypertensive)

  • Pheochromocytoma or a malignant tumor

The simplest screening test for autonomous cortisol secretion from an incidentaloma is a 1-mg overnight dexamethasone suppression test. Salivary cortisol, dexamethasone suppression, and urine free cortisol testing can be used if clinical suspicion is high (eg, in patients with hypertension, obesity, diabetes mellitus, or osteoporosis).

Primary aldosteronism is confirmed by lack of aldosterone suppression on a 24-hour urine study with salt loading.

To determine the incidentaloma subtype, high-resolution computed tomography scanning should be performed in all patients. In addition, adrenal venous sampling should be performed in most patients older than 40 years.

Treatment recommendations are as follows:

  • Surgical resection should be reserved for those with worsening hypertension, abnormal glucose tolerance, dyslipidemia, or osteoporosis

  • In patients with primary aldosteronism and a unilateral source of aldosterone excess, laparoscopic total adrenalectomy is preferred over open approaches

  • Patients with bilateral idiopathic hyperaldosteronism (IHA) should be managed with selective and nonselective mineralocorticoid receptor blockers

  • Open adrenalectomy should be performed if adrenocortical carcinoma is suspected

For patients with adrenal incidentalomas who do not fulfill the criteria for surgical resection, the guidelines recommend radiographic reevaluation at 3 to 6 months and then annually for 1 to 2 years. Hormonal evaluation should be performed annually for 5 years.

National Comprehensive Cancer Network (NCCN) guidelines for treatment of adrenal carcinoma include separate recommendations for localized and metastatic disease.[103] Recommendations for localized disease are as follows:

  • Resection of primary tumor and adjacent lymph nodes

  • Open adrenalectomy recommended

  • External-beam radiation therapy and adjuvant mitotane may be considered in patients at high risk for recurrence

NCCN treatment recommendations for metastatic disease are as follows:

  • Observation for clinically indolent disease with imaging and biomarkers (if functional) every 3 months

  • Resection of primary tumor and metastases if >90% removable, particularly if functional

  • Systemic therapy, preferably within a clinical trial

The European Society for Medical Oncology (ESMO) guidelines utilize the 2005 proposed diagnostic workup of the European Network for the Study of Adrenal Tumors (ENSAT) for evaluation of possible adrenocortical carcinomas (ACC), which includes a detailed endocrine assessment and comprehensive hormonal analysis. Additional recommendations include the following[105] :

  • Open surgery with transperitoneal access for stages I-III when complete resection is possible

  • Laparoscopic adrenalectomy only for selected patients with small tumors and no evidence of invasiveness or adrenal incidentalomas

  • Margin-free complete resection of locally advanced ACC may require resection of parts of adjacent organs

  • Re-resection of ACC for recurrence, if margin-free resection is possible and the time to recurrence was >12 months

  • Adjuvant mitotane therapy in patients with incomplete/R1 or Rx resection and/or Ki67 expression in ≤10% of neoplastic cells

  • For bone metastasis, palliative radiotherapy is an option; arterial chemoembolization and radiofrequency ablation may be beneficial in selected patients

  • The National Comprehensive Cancer Network's 2013 guidelines do not provide precise criteria for the follow up and monitoring of appendiceal tumors of less than 2 cm in diameter.  For tumors greater than 2 cm., the recommended monitoring includes history and physical examination as well as imaging studies every 3 months during the first year post-resection and every 6-12 months during the next ten years and evaluation by 5-HIAA and chromogranin A.  2012 European Neuroendocrine Tumor Society (ENTS) guidelines do not suggest post appendectomy anymore for tumors less than 1 cm in diameter which are fully resected with negative margins. There is no definitive guideline for a tumor with a diameter of 1-2 cm.; however, the presence of aggravating factors such as localization of the tumor at the base, infiltration of mesoappendix >3 millimeters, infiltration of vessels, and others in cases where a simple appendectomy was performed, requires close follow up and appropriate monitoring. Specific consensus guidelines by European Neuroendocrine Tumor Society (ENETS) for standard care and follow up of neuroendocrine tumors of various locations, including surgical approach for those located in the small intestine and pancreas, jejunum and ileum, are available. [15, 120, 109, 111, 116]
 

Follow-up

Complications

The most serious complications of carcinoid tumors are carcinoid syndrome /crisis and metastasis, which is often observed in patients who have foregut tumors and high levels of 5-HIAA.[17]

Prognosis

The prognosis for patients with completely resected localized disease is excellent.[121, 122, 123, 124]  Tumors larger than 2 cm, positive lymph nodes, and atypical histologic features are often associated with a poor prognosis.[125] In patients with carcinoid tumors located in the appendix, age, primary tumor size, histologic features, lymph node involvement, and distant metastasis are significant factors in predicting survival.[126]  In one retroactive study, survival of patients with sigmoid colon was only 33% while 99% of those with appendiceal tumor had survived.[122] Second primary malignancies of gastrointestinal tract which occurred in up to 33% of cases in adults,are unusual in children and adolescents.[123]

In adult patients, factors associated with poor survival include persistence of plasma neurokinin A (NKA), urinary 50-hydroxyindolacetic acid output, age, and 5 or more liver metastases. Rise in plasma NKA appears to be independent of other prognostic factors and constitutes the strongest indication.[127]

Overall, localized carcinoid tumor which is completely resected has an excellent prognosis, the outcome for patients with metastasis, however, remains poor.

 

Questions & Answers

Overview

What are carcinoid tumors?

What is the range of clinical presentations for carcinoid tumors?

What are the signs and symptoms of carcinoid tumors?

How are carcinoid tumors classified?

What causes carcinoid tumors?

How are carcinoid tumors diagnosed?

Which imaging modalities may be used to evaluate suspected carcinoid tumors?

What endoscopic procedures may be used for biopsy and diagnosis of carcinoid tumors?

What are the treatment of options for carcinoid tumors?

What is the role of chemotherapy in the treatment of carcinoid tumors?

What are carcinoid tumors?

How are carcinoid tumors classified?

How do the features of carcinoid tumors vary by location?

What is the pathophysiology of carcinoid tumors?

What are the histologic patterns of carcinoid tumors?

How are midgut carcinoid tumors characterized?

What is the role of fibrosis in the pathophysiology of carcinoid tumors?

Which physiological products are produced by carcinoid tumors?

Which biomarkers are used for the diagnosis of classic carcinoid tumor cells?

What is the role of somatostatin receptors in the pathophysiology of carcinoid tumors?

Why do carcinoid tumors have a high potential for metastasis?

What is the prevalence of carcinoid tumor in the US?

What is the global prevalence of carcinoid tumors?

What is the prognosis of carcinoid tumors?

Presentation

How are the signs and symptoms of carcinoid tumors determined?

What is the anatomic distribution of carcinoid tumors?

What are the challenges to correctly diagnose carcinoid tumors?

What is the common clinical presentation of carcinoid tumors?

What are the less common symptoms of carcinoid tumors?

What causes carcinoid tumors?

What is the role of MEN 1 in the etiology of carcinoid tumors?

What is the role of genetics in the etiology of carcinoid tumor?

Workup

What is the role of lab studies in the diagnosis of carcinoid tumor?

Which imaging modalities are used to detect carcinoid tumors?

What is the sensitivity and specificity of PET-CT for detection of carcinoid tumors?

What is the role of CT and MRI in the workup of carcinoid tumor?

What is the role of angiography, PET scanning and scintigraphy in the diagnosis of carcinoid tumors?

What is the role of radionuclide imaging in the workup of carcinoid tumors?

Which procedures are used for biopsy of carcinoid tumors?

Treatment

How is carcinoid tumor metastasis treated?

Which chemotherapeutic agents are used for palliation of metastatic carcinoid tumors?

What is the role of octreotide in the treatment of carcinoid tumors?

What is the role of surgery in the treatment of carcinoid tumor?

Guidelines

Which organizations have issued clinical treatment guidelines for carcinoid tumors?

How are carcinoid tumors graded?

How are carcinoid tumors staged?

What are the UK and Ireland Neuroendocrine Tumour Society (UKI NETS) recommendations for grading and staging of carcinoid tumors?

What are the NCCN recommendations for the treatment of GI carcinoid tumors?

What are the NCCN recommendations for the treatment of gastric carcinoid tumors?

What are the NCCN recommendations for the treatment of duodenal carcinoid tumors?

What are the NCCN recommendations for the treatment of bowel carcinoid tumors?

What are the ENETS recommendations for the treatment of colorectal and small bowel carcinoid tumors?

What are the NCCN recommendations for the treatment of appendix carcinoid tumors?

What are the NCCN recommendations for the treatment of metastatic GI carcinoid tumors?

What are the treatment guidelines for thymic carcinoid tumors?

What are the treatment guidelines for bronchopulmonary NETs?

What are the NCCN recommendations for the treatment of localized neuroendocrine tumors of the pancreas?

What are the NCCN recommendations for the treatment of nonfunctioning pancreatic tumors?

What are the NCCN recommendations for the treatment of gastrinoma?

What are the NCCN recommendations for the treatment of insulinoma?

What are the NCCN recommendations for the treatment of glucagonoma?

What are the treatment guidelines for VIPomas?

What are the treatment guidelines for unresectable and/or metastatic pancreatic tumors?

Which organizations have issued clinical treatment guidelines for pheochromocytoma and paraganglioma?

What are the TES recommendations for diagnosis of pheochromocytoma and paraganglioma (PPGL)?

What are the NANETS recommendations for biochemical testing in suspected pheochromocytoma?

Which imaging studies are recommended by TES/AACC/ESE for diagnosis of pheochromocytoma and paraganglioma?

What are the TES/AACC/ESE recommendations for preoperative management of pheochromocytoma and paraganglioma?

What are the TES/AACC/ESE recommendations for postoperative management of pheochromocytoma and paraganglioma?

What are the TES/AACC/ESE recommendations for genetic testing in pheochromocytoma and paraganglioma?

What are the NANETS recommendations for treatment of advanced pheochromocytoma and paraganglioma?

What are the AACE/AAES joint diagnostic guidelines for adrenal incidentaloma?

What are the AACE/AAES joint treatment guidelines for adrenal incidentaloma?

What are the NCCN recommendations for the treatment of adrenal incidentaloma?

What are the ESMO guidelines for diagnosis and treatment of adrenocortical carcinomas (ACC)?

Follow-up

What is the most serious complication of carcinoid tumors?

What is the prognosis of carcinoid tumors?