Carcinoid Tumors and Syndrome

Carcinoid tumors are small, well-differentiated, slow-growing neuroendocrine tumors (NET). Carcinoid syndrome describes the signs and symptoms associated with unregulated vasoactive hormone production by neuroendocrine tumors. Carcinoid tumors are most commonly found in the GI and bronchopulmonary tracts. Vasoactive substances produced by NET of the GI tract do not cause carcinoid syndrome until the tumors metastasize to the liver. Symptoms of carcinoid syndrome include flushing, diarrhea, and wheezing. Treatment consists primarily of surgical tumor resection and therapy with somatostatin analogs. Prognosis depends on the tumor location, aggressiveness, and overall disease burden.

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Overview

Definition

Carcinoid tumor is a neuroendocrine tumor arising from enterochromaffin cells, typically in the GI and bronchopulmonary tracts.

Epidemiology

  • Rare, but rising incidence, likely due to improved detection
  • The reported annual incidence is 4.7/100,000.
  • Black patients have a higher annual rate of incidence than whites.
  • Presents in all age groups; greater incidence in the elderly (50–70 years)
  • No clear gender predominance
  • Carcinoid syndrome occurs in approximately 5% of carcinoid tumors

Etiology

  • Exact cause is unknown.
  • Several risk factors have been identified:
    • Genetics:
      • Approximately 10% of GI carcinoids are associated with multiple endocrine neoplasia type 1 (MEN1).
      • Other associations: neurofibromatosis type 1, Von-Hippel-Lindau (VHL) syndrome, tuberous sclerosis complex
    • Race:
      • GI carcinoids are more common in Blacks.
      • Lung carcinoids are more common in whites.
    • Pernicious anemia: stomach carcinoids

Mnemonic

The rule of 1/3s can be used to recall the characteristics of carcinoid tumors:

  • 1/3 of carcinoid tumors metastasize.
  • 1/3 of carcinoid tumors present with 2nd malignancy.
  • 1/3 of carcinoid tumors are multiple.

Pathophysiology

Carcinoid tumors

Biological behavior:

  • Low-grade indolent tumors
  • Part of the spectrum for neuroendocrine tumors, ranging from low- and intermediate-grade (carcinoids) to high-grade tumors (small-cell lung cancer)

Classification based on embryonic origin:

  • Foregut carcinoids:
    • Stomach:
      • Type 1 (70%–80%): associated with chronic atrophic gastritis
      • Type 2: associated with Zollinger-Ellison syndrome and MEN1
      • Type 3: sporadic (most aggressive type)
    • Bronchial
  • Midgut (90% of all GI carcinoids):
    • Jejunoileal
    • Appendix:
      • Most common appendiceal tumor
      • Discovered incidentally in 1/300 appendectomies
  • Hindgut:
    • Colon
    • Rectum
    • Genitourinary tract (very rare)
  • Other uncommon sites:
    • Ovary
    • Liver
    • Gallbladder
    • Cystic duct
    • Thymus
    • Middle ear

Carcinoid syndrome

  • Carcinoid tumors sometimes secrete several substances:
    • Stomach carcinoids: histamine
    • Lung/bronchial carcinoids: 
      • Serotonin
      • Gastrin
      • Adrenocorticotropic hormone
      • Histamine
  • Classic carcinoid syndrome is associated with midgut tumors metastatic to liver:
    • Associated mostly with serotonin production
    • Serotonin is produced from tryptophan and converted in the body to 5-hydroxyindoleacetic acid (HIAA).
    • Effects of serotonin:
      • Vasodilation
      • ↑ Platelet aggregation
    • No symptoms appear while the tumor confined to the gut, as serotonin is metabolized by the liver.
  • Other substances contributing to clinical symptoms:
    • Histamine
    • Kallikrein
    • Tachykinins
    • Prostaglandins

Clinical Presentation

Symptoms of primary tumor

  • Many individuals are asymptomatic and discovered incidentally on imaging.
  • Presentation depends on location:
    • Gastric: asymptomatic, discovered on endoscopy
    • Small bowel:
      • Asymptomatic
      • Nonspecific abdominal pain
      • Small bowel obstruction/intussusception
    • Appendix: 
      • Usually asymptomatic
      • Most commonly discovered incidentally on appendectomy
    • Colon:
      • Asymptomatic until large (> 5 cm)
      • Symptoms similar to colon cancer when present (pain, bleeding, obstruction)
    • Rectum: 
      • Mostly asymptomatic
      • Rarely cause rectal bleeding, pain, change in bowel habits

Carcinoid syndrome

  • Specific symptoms depend on substances that are produced.
  • Hindgut tumors are mostly nonsecretory.
  • Typical carcinoid syndrome:
    • Metastatic small bowel and appendiceal carcinoids
    • Symptoms:
      • Episodic skin flushing (85% of patients)
      • Venous telangiectasia (late finding)
      • Diarrhea
      • Bronchospasm
      • Cardiac valvular lesions (deposits of fibrous tissue)
      • Retroperitoneal fibrosis
      • Muscle wasting
      • Niacin deficiency (from diversion of tryptophan synthesis to serotonin synthesis)
  • Atypical (variant) syndromes:
    • Gastric tumors:
      • Associated with histamine secretion
      • Patchy, well-demarcated flushing with pruritus
    • Lung/bronchial tumors:
      • Specific mediator unclear, possibly histamine
      • Severe and prolonged flushing
      • Disorientation/anxiety
      • Tremors
      • Periorbital edema
      • Lacrimation/salivation
      • Hypotension/tachycardia
      • Diarrhea
      • Asthma/dyspnea
      • Edema
      • Oliguria
  • Carcinoid crisis:
    • Rare life-threatening form of carcinoid syndrome
    • Massive release of bioactive compounds
    • Triggered by:
      • Tumor manipulation (surgery/biopsy)
      • Anesthesia

Clinical presentation of carcinoid syndrome

Image: “Carcinoid syndrome presentation” by Mikael Häggström. License: CC0 1.0, edited by Lecturio.

Diagnosis

History

  • Chronic and severe diarrhea
  • Flushing
  • Family history/presence of genetic conditions (MEN1, VHL syndrome, NF1)

Laboratory studies

  • 24-hour urine to determine 5-HIAA:
    • About 90% sensitivity and specificity for serotonin-producing midgut tumors
    • Does not pick up foregut or hindgut tumors, as they rarely produce serotonin
  • Plasma chromogranin A levels:
    • Elevated levels associated with carcinoids
    • Low specificity
    • Should not be used as initial screening test
    • May be used as tumor marker for patients with an established diagnosis
  • Blood serotonin: high rate of false positives
  • Blood 5-HIAA levels:
    • Relatively new test
    • Needs to be validated

Imaging

  • CT abdomen with contrast:
    • Useful in detecting liver metastases
    • Small bowel and appendiceal carcinoids are usually small and may not be detected.
    • Colon carcinoids can be seen, but cannot be distinguished from other colonic tumors.
  • MRI: more sensitive than CT for detection of liver metastases
  • Somatostatin receptor scintigraphy:
    • Most carcinoids express somatostatin receptors.
    • Whole-body imaging

Somatostatin receptor scintigraphy of pulmonary carcinoids:
Most carcinoid tumors express somatostatin receptors. Using scintigraphy, a detailed whole-body scan can be performed to identify masses.

Image: “The value of somatostatin receptor imaging with In-111 octreotide and/or Ga-68 DOTATATE in localizing ectopic adrenocorticotropic hormone-producing tumors” by Özkan ZG, Kuyumcu S, Balköse D, Ozkan B, Aksakal N, Yılmaz E, Sanlı Y, Türkmen C, Aral F, Adalet I. License: CC BY 2.5, edited by Lecturio.

Endoscopy with biopsy

  • Upper and lower endoscopy should be performed for metastases with unknown primary.
  • Bronchoscopy for lung/bronchial lesions (can miss peripheral tumors)

Management

Primary tumors

Surgical resection is the definitive treatment for non-metastatic tumors.

  • Small bowel: resection of involved segment and mesentery
  • Appendix:
    • Simple appendectomy for tumors < 2 cm confined to the appendix
    • Right hemicolectomy:
      • Tumor > 2 cm 
      • Presence of mesoappendiceal invasion
  • Colon: partial colectomy with lymphadenectomy similar to colonic adenocarcinoma
  • Rectum: 
    • Endoscopic excision usually feasible for small tumors
    • Low anterior or abdominoperineal resection required for tumors > 2 cm or with invasion of muscularis propria
  • Stomach:
    • Types 1 and 2: 
      • Endoscopic resection is adequate for tumors < 2 cm
      • Followed by endoscopic surveillance every 6–12 months
    • Type 3: wedge resection with lymphadenectomy usually recommended
  • Lung/bronchial: surgical resection

Carcinoid syndrome and metastatic disease

Medical management of carcinoid syndrome focuses on the use of somatostatin analogs to inhibit serotonin secretion. 

  • Therapy with somatostatin analogs:
    • About 80% of GI carcinoids express somatostatin receptors
    • Octreotide and lanreotide:
      • Bind to somatostatin receptors
      • Inhibit serotonin release
      • Provide symptomatic relief (50%–70% of patients) and inhibit proliferation of tumor cells
  • Additional therapy for refractory symptoms:
    • Telotristat: tryptophan hydroxylase inhibitor (decreases serotonin production)
    • Interferons
    • Anti-diarrheal medications (loperamide, diphenoxylate-atropine)
  • Hepatic resection:
    • Can be curative for resectable liver lesions
    • Can also serve as palliation for carcinoid syndrome
    • Performed if > 90% of tumor can be resected/ablated
  • Hepatic transarterial embolization: for unresectable liver-dominant disease

Computed tomography scan showing multiple metastatic carcinoid lesions of the liver before hepatic artery embolization (1A) and after (significant reduction in total liver volume and confluence of metastases (1B))

Image: “Local treatment in unresectable hepatic metastases of carcinoid tumors: Experiences with hepatic artery embolization and radiofrequency ablation” by Meij V, Zuetenhorst JM, van Hillegersberg R, Kröger R, Prevoo W, van Coevorden F, Taal BG. License: CC BY 2.0

Prognosis

  • Depends on the site of tumor, stage, histological grade, and overall tumor burden
  • Midgut tumors tend to metastasize more than foregut and hindgut tumors; however, once metastatic, the tumors tend to progress slowly.
  • Overall 5-year survival: from 41.8% (colon) to 78% (rectum)
  • 5-year survival with metastatic disease:
    • Lowest for colon: 4.1%
    • Highest for small bowel: 32.4%

Differential Diagnosis

  • Gastrinoma: a gastrin-secreting tumor that causes Zollinger-Ellison Syndrome. Tumors can arise from the pancreas, stomach, duodenum, jejunum, and/or even lymph nodes and can be malignant, with metastases to the liver and regional lymph nodes. Symptoms include refractory peptic ulcers and diarrhea. Diagnosis is established based on fasting gastrin levels. Treatment includes surgical resection and symptomatic management.
  • VIPoma: 3rd most common neuroendocrine tumor of the pancreas (after insulinoma and gastrinoma). VIPomas are associated with MEN1 and release large amounts of vasoactive intestinal peptide (VIP), which causes chronic diarrhea and flushing.
  • Celiac disease: a malabsorption syndrome, which is also known as gluten-sensitive enteropathy or nontropical sprue. Celiac disease presents with chronic diarrhea and weight loss. Diagnosis is established histologically. The mainstay of management is a gluten-free diet.
  • Irritable bowel syndrome (IBS): a condition affecting the colon. Other terminologies include spastic bowel, nervous colon, and spastic colon. Cellular/anatomical disruption is not observed (e.g., histological findings appear normal). Irritable bowel syndrome commonly presents with alternating diarrhea and constipation, and is often a diagnosis of exclusion.

References

  1. Strosberg, J.R. (2020). Staging, treatment, and posttreatment surveillance of nonmetastatic, well-differentiated gastrointestinal tract neuroendocrine (carcinoid) tumors. Retrieved January 22, 2021, from https://www.uptodate.com/contents/staging-treatment-and-posttreatment-surveillance-of-nonmetastatic-well-differentiated-gastrointestinal-tract-neuroendocrine-carcinoid-tumors
  2. Strosberg, J.R. (2019). Clinical features of carcinoid syndrome. Retrieved January 21, 2021, from https://www.uptodate.com/contents/clinical-features-of-carcinoid-syndrome
  3. Strosberg, J.R. (2020). Treatment of the carcinoid syndrome. Retrieved January 21, 2021, from https://www.uptodate.com/contents/treatment-of-the-carcinoid-syndrome
  4. Strosberg, J.R. (2019). Clinical characteristics of well-differentiated neuroendocrine (carcinoid) tumors arising in the gastrointestinal and genitourinary tracts. Retrieved January 21, 2021, from https://www.uptodate.com/contents/clinical-characteristics-of-well-differentiated-neuroendocrine-carcinoid-tumors-arising-in-the-gastrointestinal-and-genitourinary-tracts
  5. Tebbi, C.K. (2019). Carcinoid tumor. Retrieved January 21, 2021, from https://emedicine.medscape.com/article/986050-overview
  6. Santacroce, L. (2019). Malignant carcinoid syndrome. Retrieved January 21, 2021, from https://emedicine.medscape.com/article/282515-overview

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