Carcinoid Tumors

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8 Interesting Facts of Carcinoid Tumors

  1. Carcinoids are rare, slow-growing neuroendocrine tumors that originate primarily in enterochromaffin cells, especially in the lungs and gastrointestinal tract
  2. Most cases are subclinical and diagnosed incidentally on investigation for an unrelated complaint
    • Symptomatic patients may present with nonspecific symptoms that resemble those of asthma (pulmonary carcinoids) or irritable bowel syndrome (gastrointestinal carcinoids)
    • In 10% to 15% of cases, tumor-generated vasoactive substances enter the general circulation to produce carcinoid syndrome (eg, flushing, wheezing, palpitations, diarrhea)
  3. Suspected cases are initially evaluated with 24-hour urinary 5-hydroxyindoleacetic acid and serum chromogranin A levels
  4. Tumors are assessed and staged with CT or MRI and somatostatin receptor imaging; biopsy is required to confirm histopathologic diagnosis and classification
  5. Management depends on anatomic site and size of tumor, histopathologic classification, presence of local or distant metastasis, secretory profile, and general status of patient
  6. Surgical resection is the mainstay of treatment in most cases; and is the only potentially curative treatment
  7. Therapy with somatostatin analogues (octreotide or lanreotide) may be indicated to suppress tumor proliferation, manage symptoms of carcinoid syndrome, and prevent complications such as carcinoid crisis and carcinoid heart disease
  8. Other options to delay progression in advanced disease include peptide receptor radionuclide therapy, hepatic regional therapies for liver metastases, and molecular targeted therapy

Pitfalls

  • Carcinoid heart disease is a severe complication with high rates of mortality and morbidity; it occurs in patients with longstanding elevations of 5-hydroxyindoleacetic acid level 
  • Order echocardiographic screening for all patients with carcinoid syndrome or significantly elevated serotonin or 5-hydroxyindoleacetic acid levels 

Carcinoid tumors are a heterogenous group of slow-growing neoplasms arising in the neuroendocrine cells of the gastrointestinal tract, lung, or thymus 

Once considered rare, the incidence of carcinoid tumors has increased significantly over the past few decades, possibly as a result of earlier detection 

Carcinoid tumors are neoplasms that arise from enterochromaffin cells. Today, a more common term for these tumors is neuroendocrine tumors (NETs) .

They are classified according to their site of origin, as foregut carcinoids (bronchus, stomach, duodenum, bile ducts, pancreas), midgut carcinoids (jejunum, ileum, appendix, cecum, ascending colon), or hindgut carcinoids (transverse and descending colon, rectum).

Pulmonary NETs are still commonly referred to as carcinoids, but when they occur elsewhere, the term NET , as proposed by the World Health Organization (WHO) is preferred. Less commonly, NETs can develop in the ovaries, testes, prostate, kidney, breast, thymus, or skin.

Approximately 55% of NETs occur in the gastrointestinal (GI) tract, and 30% are found in the bronchopulmonary system. Malignant NETs are referred to as neuroendocrine carcinomas.

Some forms may be clinically indolent; however, many cases present with metastatic disease at diagnosis, or will progress to metastatic disease 

Typically asymptomatic unless tumor cells metastasize or tumor-generated vasoactive substances enter the general circulation to produce carcinoid syndrome, which occurs in a minority of cases 

Classification

  • By embryologic origin 
    • Foregut tumors arise in the lungs, bronchi, stomach, biliary system, or pancreas
    • Midgut tumors arise in the small intestine, appendix, or proximal colon
    • Hindgut tumors arise in the distal colon or rectum
  • By biologic activity
    • Nonfunctional tumors: most carcinoids are insidious, nonfunctional masses 
    • Functional tumors: some carcinoids hypersecrete bioactive substances (eg, serotonin, kallikrein, histamine, prostaglandins) and can cause carcinoid syndrome 
      • Most likely to occur with midgut tumors, which secrete large amounts of serotonin, causing high serum levels of serotonin and its metabolites (eg, 5-hydroxyindoleacetic acid) 
      • Less likely to present with foregut and hindgut tumors, in which serotonin levels are typically low or absent 
  • By anatomic site and subtype
    • Carcinoids can arise anywhere in the body; however, the small intestine, rectum, and respiratory tract are the most common sites 
    • Gastrointestinal carcinoids account for approximately 60% of all neuroendocrine tumors 
      • Gastric carcinoids
        • Arise from enterochromaffin-like cells of the gastric mucosa 
        • Classified into 3 types based on tumor pathophysiology 
          • Type 1
            • Most common type (68%-83% of all diagnosed gastric carcinoids) 
            • Typically present as numerous nodular or polypoid lesions smaller than 2 cm; small central ulcerations may be evident 
            • Tumor development is associated with hypergastrinemia induced by chronic atrophic gastritis 
            • Metastasis is rare (3%-5% of all cases) 
          • Type 2
            • About 5% of all diagnosed gastric carcinoids 
            • Typically present as numerous lesions smaller than 1 cm 
            • Tumor development is associated with gastrinoma-induced hypergastrinemia (Zollinger-Ellison syndrome) attributed to the inactivation of the MEN1 tumor suppressor gene (multiple endocrine neoplasia type 1) 
            • Risk for metastasis is greater than that of type 1 gastric carcinoids; regional lymphatic malignancy (30%) and liver metastases (10%) are most commonly reported 
          • Type 3
            • Also called sporadic gastric carcinoids
            • About 20% of all diagnosed gastric carcinoids 
            • Typically present as solitary lesions larger than 2 cm 
            • Tumor development is independent of gastrin levels 
            • Relatively invasive tumor type; regional lymphatic malignancy (55%) and liver metastases (24%) are most commonly reported 
            • Abnormal histamine release causes atypical carcinoid syndrome in 5% to 10% of cases; characterized by a pruritic, red, blotchy rash; swollen salivary glands; and increased lacrimation 
      • Small bowel carcinoids
        • Typically present as firm nodules embedded within the intestinal mucosa or polypoid masses protruding into the lumen; most lesions are larger than 3.5 cm 
        • Relatively invasive tumor type; regional lymphatic malignancy (70% of cases) and liver metastases (more than 50% of cases) are most commonly reported 
        • Carcinoid syndrome is reported in 20% to 30% of all cases of small bowel carcinoids 
      • Appendiceal carcinoid
        • Most common type of appendiceal tumor (32%-57% of all diagnosed cases) 
        • Typically present as small lesions (less than 1 cm), usually at the distal tip of the appendix 
        • Overall rates of metastases are low (4%); metastatic disease is more likely in tumors larger than 2 cm 
      • Colonic carcinoids
        • Incidence is low (8% of all diagnosed gastrointestinal neuroendocrine tumors) 
        • Typically present as polypoid exophytic masses, usually in the ascending colon 
        • Ascending colon carcinoids are poorly differentiated and more invasive, unlike carcinoids that develop elsewhere in the colon 
      • Rectal carcinoids
        • Incidence is high (25% of all diagnosed gastrointestinal neuroendocrine tumors) 
        • Typically present as small (less than 1 cm) polypoid or intramural masses 
        • Incidence of metastatic disease is higher in tumors larger than 2 cm (67%-100%) 
    • Pulmonary carcinoids account for 25% to 33% of all neuroendocrine tumors 
      • Arise from the enterochromaffin cells of the respiratory mucosa 
      • Classified into 2 types based on tumor pathophysiology 
        • Typical pulmonary carcinoids
          • Most common form of pulmonary carcinoid 
          • Tumor development is not associated with smoking 
          • Tumors typically develop within the right lung parenchyma (59%-62% of diagnosed cases) and are generally resistant to chemotherapy 
          • Regional and distant metastases are rarely reported 
        • Atypical pulmonary carcinoids
          • Represent 11% to 24% of all diagnosed pulmonary carcinoids 
          • Tumor development is associated with smoking 
          • Relatively more aggressive and invasive than typical pulmonary carcinoids
    • Thymic carcinoids account for approximately 3% of all neuroendocrine tumors 
      • Most are asymptomatic and found incidentally
      • Distant metastases are often present at time of diagnosis
      • Associated with multiple endocrine neoplasia type 1 in approximately 25% of cases 

Do carcinoid tumors cause any other humoral syndromes?

  • Carcinoids may also secrete corticotropin-releasing factor (CRF) or corticotropin (adrenocorticotropin [ACTH]), causing Cushing’s syndrome, or growth hormone–releasing factor (GRF), causing acromegaly. These syndromes have been reported mainly with bronchial and pancreatic carcinoid tumors.

Clinical Presentation

History

  • Carcinoids are generally asymptomatic; most tumors are found incidentally during laparotomy or at autopsy 
    • Symptoms (if present) are usually nonspecific and vary by tumor site and biochemistry 
      • Pulmonary carcinoids
        • Most patients are asymptomatic; presenting complaints include cough (32%), hemoptysis (26%), wheezing, chest pain, and dyspnea 
        • Rarely, patients present with symptoms of Cushing syndrome, as tumors have been associated with ectopic production of adrenocorticotropic hormone 
      • Gastrointestinal carcinoids
        • Gastric carcinoids may be associated with vomiting, indigestion, loss of appetite, abdominal pain/discomfort, and unintentional weight loss 
        • Small bowel carcinoids may result in nonspecific symptoms such as abdominal pain/discomfort and changes in bowel habits (usually constipation) 
        • Appendiceal carcinoids may present with symptoms consistent with appendicitis, including midabdominal to lower right abdominal pain and tenderness 
        • Colorectal carcinoids may present with unintentional weight loss, rectal bleeding and pain, and constipation 
      • Thymic carcinoids
        • Patients are frequently asymptomatic until local invasion or mediastinal lymph node metastasis occurs; symptoms include cough, chest pain, dyspnea, stridor, hoarseness, and Cushing syndrome 
  • Carcinoid syndrome occurs in about 10% to 15% of cases 
    • Patients with suspected carcinoid syndrome report facial flushing (90%), diarrhea (80%), wheezing, and palpitations 
    • Symptoms are typically triggered by ingesting foods and drinks high in tyramine, especially blue cheese, chocolate, or red wine
    • Most likely to occur with metastatic midgut tumors (in the small intestine, appendix, or proximal colon) 
      • Midgut carcinoids secrete high levels of serotonin and serotonin metabolites; however, these are rapidly metabolized by liver enzymes in the portal circulation 
      • Symptoms of carcinoid syndrome usually develop only when liver metastases or retroperitoneal spread has occurred, in which case metastatic tumors release metabolic products directly into the systemic circulation 

Physical examination

  • Intermittent cutaneous flushing involving face, neck, and upper chest is a cardinal sign of carcinoid syndrome 
    • Tachycardia may also be present
  • Characteristic cushingoid appearance may be seen in some patients with pulmonary or thymic carcinoids: 
    • Moon face
    • Centripetal obesity
    • Buffalo hump
    • Hirsuitism
    • Bruising
    • Purple striae
  • Auscultation of chest
    • Wheezing (focal or diffuse) or stridor may be evident in patients with pulmonary carcinoids or carcinoid syndrome 
    • Heart murmur may occur in patients with valvular heart disease as a result of carcinoid syndrome 
  • Abdominal examination
    • Minority of patients with small and/or large bowel carcinoids have palpable abdominal masses (14% of cases) 
    • Hepatomegaly may be palpable in patients with liver metastasis 
    • Regional lymphadenopathy may be evident in patients with tumor metastasis 
      • 58% to 64% of patients have metastatic spread to either lymph nodes or liver at time of diagnosis 
    • Bowel sounds are hypoactive or absent in patients with constipation or complete bowel obstruction 
    • Hyperactive bowel sounds can be heard in patients presenting with diarrhea or with partial bowel obstruction 

Causes

  • Carcinoids arise in enterochromaffin cells of neuroendocrine system; development is sporadic, with no clear cause 

Risk factors and/or associations

Age
  • Carcinoids typically present between the ages of 50 and 60 years (if they present clinically at all) 
Sex
  • Among adults younger than 65 years, women have an overall higher incidence of carcinoids 
  • Among adults older than 65 years, overall incidence is twice as high in men 
Genetics
  • Although the MEN1 gene (multiple endocrine neoplasia type 1) has been implicated in carcinoid development, carcinoids are not considered heritable, and no genetic factors have been identified 
Ethnicity/race
  • Overall age-adjusted incidence rates are highest among African American males (4.48 per 100,000 population per year) 
  • Disease prognosis is worse in African American males, regardless of carcinoid type 
Other risk factors/associations
  • Morbid obesity is associated with a higher incidence of carcinoids; a causal relationship has not been established 
  • Pernicious anemia may increase the risk of gastric carcinoids 
  • Other associated conditions include atrophic gastritis and Zollinger-Ellison syndrome

Diagnostic Procedures

Primary diagnostic tools

  • Most carcinoids are asymptomatic and (if discovered at all during lifetime) are discovered incidentally during surgery, endoscopy, or imaging for another complaint 
  • Suspect diagnosis in patients who present with typical clinical manifestations of carcinoid syndrome or with history and physical examination findings suggestive of lung or gastrointestinal tumor
  • Biochemical evaluation is recommended as part of initial diagnostic evaluation
    • Patients with symptoms suggestive of hormone hypersecretion 
      • 24-hour urine (or plasma collection) for 5-hydroxyindoleacetic acid for patients with gastrointestinal or metastatic lung neuroendocrine tumors
      • Test for Cushing syndrome if bronchopulmonary or thymic carcinoid tumor is suspected and there are symptoms or signs of hypercortisolism
    • Patients with nonfunctioning tumors 
      • Chromogranin A levels may be elevated but should not be relied upon as a sole diagnostic test owing to low sensitivity
    • Measure serum gastrin level and gastric pH in patients with gastric carcinoids; this is necessary to determine gastric carcinoid type (ie, type 1, 2, or 3) 
  • Localize and stage tumor using imaging 
    • Multiphasic abdominal CT or MRI is recommended for most suspected gastrointestinal tumors; chest and mediastinal CT (in addition to abdominal imaging) are recommended for evaluation of suspected bronchopulmonary and thymic tumors
    • Consider somatostatin receptor–based imaging
      • PET-CT with ⁶⁸Ga-labeled DOTA-TATE has emerged as a superior modality for imaging of neuroendocrine tumors and is now recommended over somatostatin receptor scintigraphy with ¹¹¹In-labeled octreotide 
    • Additional evaluation is often appropriate and should be guided by tumor location and suspicion for metastatic disease
      • Modalities include endoscopic ultrasonography and esophagogastroduodenoscopy for gastric and duodenal tumors; CT enterography and colonoscopy for jejunal, ileal, and colonic tumors; endorectal ultrasonography for rectal tumors; and bronchoscopy for bronchopulmonary disease 
  • Obtain biopsy specimen to confirm histopathologic diagnosis and classification 
  • Stage tumor according to the American Joint Committee on Cancer TNM staging criteria for primary tumor site and assign grade according to WHO neuroendocrine tumor grading systems
  • Screen for carcinoid heart disease with echocardiogram if symptoms of carcinoid syndrome or biochemical evidence of serotonin excess are present 

Laboratory

  • 24-hour urinary 5-hydroxyindoleacetic acid level
    • Metabolite of serotonin 
    • Normal reference values range from 2 to 15 mg per 24 hours (73% specificity) 
    • Levels are elevated in patients with carcinoids
    • Elevated 5-hydroxyindoleacetic acid levels can also be attributed to: 
      • Serotonin-rich foods, including avocados, bananas, eggplants, kiwis, nuts, pineapples, plums, and tomato products
      • Medications and other substances, including acetaminophen, antihistamines, antihypertensives, antipsychotics, caffeine, cough suppressants, diazepam, muscle relaxants, nicotine, and warfarin
    • Foods and drugs that may influence results are excluded for 3 days before and during the urine collection 
  • Plasma chromogranin A level
    • Glycoprotein is characteristically secreted by neuroendocrine tumors and is often part of diagnostics in patients who present with symptoms suggestive of gastroenteropancreatic neuroendocrine tumors 
    • Present in both nonfunctional (non–hormone secreting) and functional carcinoids 
    • Reference values are less than 31 or 32 units/L 
    • Sensitivity of 73% and specificity of 95% in meta-analysis 
    • Elevated chromogranin A levels can also be detected in patients with a history of essential hypertension, proton pump inhibitor use, chronic atrophic gastritis, heart failure, renal failure, and pheochromocytoma

Imaging

  • CT scan
    • Standard imaging mode used to stage and diagnose tumors 
    • Used to visualize extrahepatic lesions as well as nodal and hepatic metastases larger than 1 cm 
    • Optimal for imaging the thorax, abdomen, and pelvis; suboptimal for detecting small hepatic carcinoids 
  • MRI scan
    • Alternative to CT scan for diagnosis and staging 
    • Provides multiplanar images and high spatial resolution of tumors (especially small tumors and those situated deep within visceral organs) 
    • Optimal method for imaging hepatic metastases 
  • PET-CT with ⁶⁸Ga-labeled DOTA-TATE
    • Somatostatin analogue labeled with gallium-68 binds to somatostatin type 2 receptors found on cell membranes of 50% to 80% of neuroendocrine tumors, including carcinoids 
    • PET-CT from skull base to midthigh can visualize areas with uptake of radiolabeled somatostatin analogue within several hours of administration
    • Has superior sensitivity and specificity for neuroedocrine tumors compared with somatostatin receptor scintigraphy with ¹¹¹In-labeled octreotide and CT or MRI 
    • Now recommended over somatostatin receptor scintigraphy with ¹¹¹In-labeled octreotide, particularly at initial diagnosis, to identify candidates for octreotide-based peptide receptor radiotherapy, and when primary tumor location is unknown 
    • Relatively new modality in the United States and may not be available in some settings
    • An alternative agent, ⁶⁸Ga-labeled DOTA-TOC, is currently being studied but is not yet FDA approved 
  • Somatostatin receptor scintigraphy with ¹¹¹In-labeled octreotide
    • Somatostatin analogue octreotide binds to the somatostatin type 2 receptors found on the cell membranes of 50% to 80% of neuroendocrine tumors, including carcinoids 
    • Single-photon emission CT is used to visualize uptake of radiolabeled octreotide by carcinoids 24 to 48 hours after injection 
    • Highly sensitive and specific for carcinoids; however, no longer the preferred somatostatin receptor imaging modality
  • Endoscopy
    • Upper and/or lower gastrointestinal endoscopy (eg, colonoscopy, esophagogastroduodenoscopy, video capsule endoscopy) may be indicated to evaluate suspected gastric, small bowel, and colorectal carcinoids or when the primary site is unknown 
  • Endoscopic ultrasonography
    • Optimal method of direct imaging of submucosal lesions within the chest, gastrointestinal tract, and lymph nodes 
    • Provides superior diagnostic sensitivity compared with CT and MRI 
    • Useful in determining level of malignant potential based on size and level of penetration

Procedures

Tissue biopsy 
General explanation
  • Collection of tissue specimen for histopathologic examination, performed either via open surgical resection or percutaneously under CT guidance
    • Excisional biopsy: an entire lump or suspicious area is removed
    • Incisional biopsy (core biopsy): a sample of tissue is removed with preservation of the histologic architecture of the sample tissue
    • Aspiration biopsy: a sample of tissue or fluid is removed with a needle without preservation of the histologic architecture of the sample tissue
Indication
  • Obtain tissue for diagnosis, histologic classification, and identification of biomarkers
Contraindications
  • Uncontrolled bleeding diathesis
Interpretation of results
  • Tumor is classified based on anatomic site and histologic characteristics
  • Mitotic rate, level of Ki-67 (MKI67, a cell proliferation marker), and presence of nonischemic tumor necrosis are determined
  • Specific immunohistochemical markers may be used to establish neuroendocrine differentiation (eg, chromogranin A, synaptophysin, CD56) 
  • Tumor grade is assigned according to WHO neuroendocrine tumor grading systems 
    • Pulmonary neuroendocrine tumors
      • Low-grade (typical) carcinoid: fewer than 2 mitoses per 10 high-power fields and no necrosis
      • Intermediate-grade (atypical) carcinoid: 2 to 10 mitoses per 10 high-power fields and/or focal areas of necrosis
      • High-grade carcinoid (small cell carcinoma or large cell neuroendocrine carcinoma): more than 10 mitoses per 10 high-power fields
    • Gastroenteropancreatic neuroendocrine tumors
      • Grade 1 carcinoid (low grade, well differentiated)
        • Mitotic count: fewer than 2 mitoses per 10 high-power fields
        • Ki-67 index: 3% or less
      • Grade 2 carcinoid (intermediate grade, moderately differentiated)
        • Mitotic count: 2 to 20 mitoses per 10 high-power fields
        • Ki-67 index: 3% to 20%
      • Grade 3 carcinoid (high grade, poorly differentiated)
        • Mitotic count: more than 20 mitoses per 10 high-power fields
        • Ki-67 index: greater than 20%
  • Tumor stage is assigned according to the American Joint Committee on Cancer TNM staging criteria for primary tumor site
Complications
  • Hematoma formation

Differential Diagnosis

Most common

Carcinoids are typically asymptomatic; clinical manifestations often become apparent only if carcinoid syndrome or metastatic disease develops

Differential diagnosis of carcinoid syndrome

  • Intermittent flushing
  • Menopause or perimenopause 
  • Pheochromocytoma

Treatment Goals

  • Eradicate or control tumors
  • Normalize levels of vasoactive substances to prevent carcinoid heart disease and alleviate carcinoid syndrome symptoms

Admission criteria

  • Admit patients with complications requiring surgery or inpatient management 
  • Admit patients for whom resection of tumor is planned

Recommendations for specialist referral

  • Refer patients to specialist center for diagnosis, staging, treatment, and counseling 
  • Management requires multidisciplinary approach including specialists in neuroendocrine tumors (eg, gastroenterologist, pulmonologist, oncologist, endocrinologist), surgeons, nuclear medicine specialists, radiologists, and histopathologists 

Treatment Options

Overview

  • Management depends on anatomic site and size of tumor, presence of local or distant metastasis, secretory profile, and general status of patient. Resection is the primary treatment approach for locoregional disease 
    • Local or locoregional disease
      • Management depends on tumor size, primary site, stage, and general condition of patient. Resection is the primary treatment approach for locoregional disease 
        • Some carcinoids arising in stomach, duodenum, or rectum may be managed with endoscopic resection and surveillance (eg, type 1 and 2 gastric carcinoids; small, nonfunctional nonampullary duodenal carcinoids; and rectal carcinoids 2 cm or smaller) 
          • Other forms require more extensive open surgical resection (eg, type 3 gastric carcinoids; duodenal or rectal carcinoids larger than 2 cm) 
        • Most localized carcinoids of the jejunum, ileum, and colon are treated with bowel resection with regional lymphadenectomy 
          • The entire bowel should be examined as multiple synchronous primary tumors are commonly present 
        • Localized appendiceal carcinoids are managed differently according to tumor size 
          • A simple appendectomy is recommended if tumor is 2 cm or smaller 
          • Larger tumors require a right hemicolectomy 
        • Localized carcinoids in the lung are treated with lobectomy or another form of anatomic resection with mediastinal lymph node dissection 
          • Locoregionally advanced lung carcinoids may be treated with adjuvant chemotherapy with or without radiotherapy
        • Carcinoids involving the thymus are surgically resected; radiotherapy with or without cytotoxic chemotherapy may be considered in cases with incomplete resection or positive margins 
    • Unresectable locoregional and/or metastatic carcinoids
      • Resection of asymptomatic, stable primary gastrointestinal tumors is not usually necessary in patients with unresectable metastases 
        • However, in some cases, patients with limited hepatic or other metastases can undergo complete resection of primary tumor and metastasis with curative intent 
        • Noncurative debulking surgery of the primary lesion may also be considered, especially if patient experiences symptoms owing to tumor bulk or hormone production 
      • Resection of hepatic metastases of gastrointestinal carcinoids should be undertaken when feasible, for symptomatic control and improved survival 
      • Treatment with somatostatin analogues (octreotide or lanreotide) is indicated for: 
        • Symptom control in patients with carcinoid syndrome 
        • Control of tumor growth in patients with significant tumor burden or progressive disease (recommended even in patients with negative somatostatin-receptor expression on imaging) 
        • Treatment or prevention of carcinoid crisis before, during, or after procedures such as surgery or embolization 
      • Additional options for palliation in patients with unresectable progressive disease include: 
        • Hepatic regional therapy for liver metastases (eg, arterial embolization, chemoembolization, radioembolization, radiofrequency ablation, cryoablation)
        • Everolimus
        • Interferon alfa (only if no other treatment options available) 
        • Peptide receptor radionuclide therapy
          • Uses radiolabeled somatostatin analogues such as 177Lu-DOTA-TATE 
        • Conventional cytotoxic chemotherapy (benefits are modest and some experts believe toxicity does not warrant widespread use) 
          • Agents such as temozolomide, capecitabine, streptozocin, 5-fluorouracil, dacarbazine, and oxaliplatin may be used in patients with progressive metastatic gastrointestinal carcinoids when there are no other treatment options 
          • Options for lung/thymic carcinoids include temozolomide, cisplatin-etoposide, or carboplatin-etoposide (may be used with or without radiotherapy) 
    • Carcinoid syndrome
      • Somatostatin analogues (octreotide or lanreotide) are first line agents for symptom control 
        • May also be used for treatment or prevention of carcinoid crisis before, during, or after procedures such as surgery or embolization
      • Telotristat may be added for treatment of persistent diarrhea in patients treated with somatostatin analogues; not useful for treatment of flushing 
      • Consider hepatic artery embolization with or without cytoreductive surgery for hepatic-predominant disease 
      • Regular surveillance for carcinoid heart disease is recommended 

Rationale

  • Surgical resection eradicates tumors and/or reduces tumor burden
  • Treatment with somatostatin analogs controls symptoms and may delay progression of disease
  • Other forms of therapy have potential to delay progression in advanced disease

Outcomes

  • Surgical resection is the mainstay of treatment in most cases, and is the only potentially curative treatment 
    • Provides a survival advantage in patients with localized, regional, and metastatic disease 
    • Removal of primary tumor or reduction of tumor bulk and resection of hepatic metastases may improve progression-free survival and symptom control
  • Treatment with somatostatin analogues is recommended to manage the symptoms of carcinoid syndrome and may delay progression in advanced disease
    • Improved progression-free survival has been demonstrated in patients with advanced midgut carcinoids, neuroendocrine tumors of the pancreas, midgut, hindgut, or unknown primary location 
    • Overall survival benefit has not been established 
  • Peptide receptor radionuclide therapy has emerged as a promising treatment option in advanced disease 
    • Earlier studies reported progression-free and overall survival similar to that of somatostatin analogues in patients with gastrointestinal carcinoids, with promising results also seen in patients with lung carcinoids 
    • A recent study reported treatment with 177Lu-DOTA-TATE resulted in a significantly higher response rate and a longer progression-free survival than high-dose long-acting octreotide in patients with advanced midgut carcinoid tumors 

Drug therapy

  • Somatostatin analogues
    • Octreotide (subcutaneous)
      • Octreotide Acetate Solution for injection; Adults: 100 mcg to 600 mcg/day subcutaneously, given in 2 to 4 divided doses, for the first 2 weeks. The mean dosage is 300 mcg/day; some patients may require doses up to 1500 mcg/day.
    • Octreotide (intramuscular)
      • Octreotide Acetate Suspension for injection; Adults: In adults with a response to subcutaneous use of octreotide, give 20 mg IM depot injection intra-gluteally every 4 weeks for 2 months. Continue the previous subcutaneous dosage for up to 2 weeks after initiating depot injections (some may require up to 4 weeks), as otherwise the patient may have symptom exacerbation. After 2 months, if response inadequate, may increase to 30 mg IM every 4 weeks. For maintenance, give a trial of 10 mg IM every 4 weeks if the patient responded to the initial dose. If increased symptoms occur, increase the dose. Max: 30 mg IM every 4 weeks. Dosing intervals greater than 4 weeks are not recommended. Some patients may require temporary management with subcutaneous octreotide for periodic symptom exacerbations, which may be halted once symptoms resolve.
    • Lanreotide
      • Lanreotide Solution for injection; Adults: 120 mg by deep subcutaneous injection every 4 weeks.
  • Tryptophan hydroxylase inhibitor
    • Telotristat
      • Telotristat ethyl Oral tablet; Adults: 250 mg PO three times daily. If taking with short-acting octreotide, administer telotristat ethyl at least 30 minutes before short-acting octreotide.
  • Molecular targeted agents 
    • Everolimus (mTOR inhibitor)
  • Chemotherapy agents 
    • Alkylating agents
      • Dacarbazine
      • Temozolomide
      • Streptozocin
    • Platinum-based agents
      • Oxaliplatin
      • Cisplatin
    • Antimetabolites
      • Capecitabine
      • 5-fluorouracil
    • Topoisomerase inhibitors
      • Etoposide

Nondrug and supportive care

Antidiarrheal or bile salt–sequestering agents for diarrhea caused by carcinoid syndrome 

Radiotherapy with or without chemotherapy may have a role in management of lung and thymic carcinoids

  • Adjuvant radiotherapy may be used following resection of lung carcinoids if there is residual disease or mediastinal lymphadenopathy, and for thymic carcinoids 
  • Radiotherapy can be used to treat unresectable primary lung carcinoids 
  • May be used for palliation of symptomatic bone and brain metastases arising from any primary tumor 
Procedures
  • Surgical management is individualized based on anatomic site and tumor type; may also include complete excision or debulking of hepatic metastases
    • Prophylactic cholecystectomy may be performed at time of surgery to prevent cholelithiasis in patients who are anticipated to receive somatostatin analogs (octreotide or lanreotide) 

Monitoring

  • Most patients with resected tumors of the gastrointestinal tract, lung, and thymus require reevaluation at 3 to 12 months after surgical resection, then every 12 to 24 months for up to 10 years 
    • Evaluation consists of history and physical examination, plus the following if suspicion warrants (eg, symptoms suggestive of carcinoid syndrome): 
      • Abdominal/pelvic CT or MRI 
        • If initial scan findings are negative, less frequent imaging can be considered
        • For high-grade tumors, consider more frequent imaging
      • Chest CT
        • For lung or thymic carcinoids, include chest CT at regular follow-up
      • Biochemical evaluation based on preresection findings
        • Serum chromogranin A level
        • Urinary 5-hydroxyindoleacetic acid level
    • Recommendations for specific cases 
      • Rectal tumors smaller than 1 cm with negative margins have excellent prognosis and require no follow-up
        • If margins are indeterminate with residual disease or intermediate grade, follow-up as clinically indicated
      • Rectal tumors 1 to 2 cm
        • Follow up with endoscopy and rectal MRI or endoscopic ultrasonography at 6 to 12 months, then as clinically necessary
      • Appendiceal tumors 2 cm or smaller without aggressive features
        • Follow-up as clinically indicated (low risk for recurrence)
      • Type 1 and 2 gastric tumors
        • Follow up with endoscopy every 6 to 12 months for 3 years, then annually
        • Imaging studies if clinically indicated
  • Patients at risk for carcinoid heart disease require regular surveillance; however, there is lack of consensus regarding whom should be screened and how often 
    • Recommendations generally include patients with advanced midgut neuroendocrine tumors, carcinoid syndrome, or significantly elevated serotonin or 5-hydroxyindoleacetic acid levels 
    • Echocardiography is the usual screening modality; may be performed annually or every 2 to 3 years (if well controlled) and with/without N-terminal pro–brain natriuretic peptide 

Complications

  • Carcinoid heart disease
    • Heart valve fibrosis with subsequent dysfunction occurs in 40% to 50% of patients with carcinoid syndrome 
      • Right-sided heart disease is most commonly reported and is characterized by tricuspid insufficiency, pulmonary stenosis, and ensuing pulmonary hypertension 
      • Left-sided heart disease is reported in 10% of patients and is characterized by coronary vasospasm and angina 
  • Pellagra (niacin deficiency) 
  • Carcinoid crisis 
    • Potentially fatal condition caused by an abnormally large release of bioactive amines
    • Characterized by intense flushing, hypotension, confusion, and dyspnea
    • Can be triggered by tumor manipulation (ie, biopsy, resection), stress, or anesthesia
  • Cushing syndrome
    • Due to ectopic secretion of corticotropin by some pulmonary carcinoids 
  • Bowel obstruction 
    • Can result from small bowel tumor growth or intussusception secondary to mesenteric fibrosis and contraction
  • Secondary malignancies 
    • Patients with carcinoids have higher risk 
    • Occur in 52% of patients with small bowel carcinoids (most commonly adenocarcinoma of the colon) 

Prognosis

  • Prognosis varies according to primary site, histologic classification, and stage at diagnosis; and has improved over time 
    • Overall 5-year survival rate for all carcinoids (any site and any stage) is approximately 70% to 80% 
    • 5-year survival rate in localized disease is 93% 
    • 5-year survival rate in distant metastatic disease is 20% to 30% 
  • Gastric carcinoids
    • 5-year survival rates
      • Type 1: 98%; the potential for recurrence is high if hypergastrinemia is not resolved 
      • Type 2: 70% to 90%, relative to gastrinoma prognosis 
      • Type 3: 50% overall and 10% for patients with distant metastasis 
  • Colonic and small bowel carcinoids 
    • Colonic carcinoids are associated with a poor prognosis, with most patients presenting with an average tumor size of 5 cm and over 65% having nodal and/or distant metastases
    • Small bowel and colonic carcinoids have 5-year survival ranging from 33% to 75%
    • Jejunal-ileocecal neuroendocrine tumors have 5-year survival as follows:
      • Stage I: 100%
      • Stage II: 100%
      • Stage III: 91%
      • Stage IV: 72%
  • Appendiceal and rectal carcinoids
    • Patients with appendiceal and rectal carcinoids have a 5-year survival rate of better than 62%, depending on size of primary lesion 
    • Rectal tumors smaller than 1 cm have excellent prognosis
  • Pulmonary carcinoids 
    • 5-year postoperative survival rates for typical pulmonary carcinoids are 92% to 100%
    • 5-year postoperative survival rates for atypical pulmonary carcinoids are 69% to 78%
    • Postoperative recurrence rates are 5% to 30%; distal recurrence is 4 to 5 times more likely

Sources

Modlin IM et al: Gastrointestinal neuroendocrine (carcinoid) tumours: current diagnosis and management. Med J Aust. 193(1):46-52, 2010 Reference

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