Carcinoid syndrome pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [2]Associate Editor(s)-in-Chief: Parminder Dhingra, M.D. [3]

Overview

Carcinoid syndrome (CS) is a paraneoplastic syndrome caused by the secretion of serotonin(5-hydroxytrptamine) but can be caused by secretion of histamine, kallikrein, prostaglandins, and tachykinins..Carcinoid syndrome is most commonly caused by neuroendocrine tumors of midgut.70% of tryptophan is converted into serotonin which leads to secondary deficiency of niacin.Serotonin metabolizes into 5-hydroxy indoleacetic acid (5-HIAA) by aldehyde dehydrogenase, which is eliminated into the urine.Deficiency of niacin results in Pellagra which manifests as dermatitis, dementia, and diarrhea. Carcinoid tumors arising in the bronchi reach the systemic circulation before passing through the liver and may be associated with bronchoconstriction and manifestations of carcinoid syndrome without liver metastases. Bronchospasm leading to wheezing is caused by release of histamine and serotonin. 5-HT2B is the receptor of serotonin in the cardiovascular system that may be involved in fibrogenesis. Fibrosis leads to Tricuspid and pulmonic regurgitation, pulmonary stenosis and cardiac arrhythmias. Serotonin and TGF-beta secreted by neuroendocrine tumors and appears to play a central role in the development of mesenteric fibrosis. Carcinoid tumors are normally found throughout the gastrointestinal tract from mouth to anus, with the highest concentration of cells in the appendix and small intestine. Lung is the second most common site for neuroendocrine tumours . In the gastric or intestinal wall, carcinoids may occur as firm white, yellow, or gray nodules and may be intramural masses or may protrude into the lumen as polypoid nodules. NETs arise from enterochromaffin cells which refers to the ability to stain with potassium chromate (chromaffin), a feature of cells that contain serotonin.

Pathophysiology

• Carcinoid syndrome (CS) is a paraneoplastic syndrome associated with the secretion of several humoral factors.

• The primary marker is serotonin (5-hydroxytrptamine) but can be caused by secretion of histamine, kallikrein, prostaglandins, and tachykinins.

• Carcinoid syndrome is most commonly caused by neuroendocrine tumors of midgut.
• Serotonin and kallikrein are inactivated in the liver and manifestations of carcinoid syndrome do not occur until there are metastases to the liver.
• Exceptions include circumstances in which venous blood draining from a carcinoid tumor enters directly into the systemic circulation which are followings:

1. Primary pulmonary or ovarian carcinoid
2. Pelvic or retroperitoneal involvement by metastatic or locally invasive small bowel carcinoid.
3. Extensive bone metastases

• Only 1% of dietary tryptophan is converted into serotonin. However, in a patient with neuroendocrine tumors, up to 70% of tryptophan is converted into serotonin.
• Serotonin undergoes oxidative reaction and leads to the formation of 5-hydroxy indoleacetic acid (5-HIAA) by aldehyde dehydrogenase, which is eliminated into the urine.
• Serotonin causes increased motility and secretions resulting in diarrhea.
• As most of the body's tryptophan is diverted to serotonin formation pathway by neuroendocrine tumors, it leads to a deficiency of tryptophan which is needed for synthesis of niacin.
• Deficiency of niacin results in Pellagra which manifests as dermatitis, dementia, and diarrhea.
• Prostaglandins also mediate increased intestinal motility and fluid secretion in gastrointestinal tract causing diarrhea.
• The flushing results from secretion of kallikrein, the enzyme that catalyzes the conversion of kininogen to lysyl-bradykinin.
• Lysyl-bradykinin is further converted to bradykinin, a strong vasodilator.
• Large amounts of serotonin produces pellagra-like features including diarrhea.

Lung Carcinoid Tumor

• Carcinoid tumors arising in the bronchi reach the systemic circulation before passing through the liver and may be associated with bronchoconstriction and manifestations of carcinoid syndrome without liver metastases.
• Bronchospasm leading to wheezing is caused by release of histamine and serotonin.
• Episodes of flushing and related manifestations are particularly prolonged or severe if carcinoid syndrome is caused by a lung neuroendocrine tumour.

Carcinoid Heart Disease

• 5-HT2B is the receptor of serotonin in the cardiovascular system that may be involved in fibrogenesis.
• Activation of the 5-HT2B receptor triggers distinct intracellular signaling pathways, which in turn may result in a stronger inflammatory response and release of cytokines including TNF-alpha, activation of the MAPK signaling pathway and hyperexpression of TGF-beta leading to to cardiac fibrosis.
• Fibrosis leads to thickening of mural and valvular endothelial surfaces of right-sided cardiac structures.
• Fibrosis leads to

1. Tricuspid and pulmonic regurgitation.
2. Pulmonary stenosis.
3. Cardiac arhythmias.

Mesentric fibrosis

• Serotonin and TGF-beta secreted by neuroendocrine tumours appears to play a central role in the development of mesenteric fibrosis.
• It is another complication of uncontrolled carcinoid syndrome.
• There is a fibrotic and desmoplastic reaction around metastatic mesenteric lymph nodes.
• Mesenteric fibrosis is a pathognomonic radiological sign of midgut NET, which can be observed on computerized tomography and nuclear magnetic resonance images.
• Mesenteric fibrosis can lead to ischemia of vessels and intestinal obstruction.
• Vascular ischemia can lead to bowel congestion and result in decreased absorption of nutrients and can also cause ascites and more severe cases of mesenteric ischemia.

Genetics

• Gastrointestinal carcinoids occur in association with inherited syndromes, such as multiple endocrine neoplasia type 1 and neurofibromatosis type 1.
• Multiple endocrine neoplasia type 1 is caused by alterations of the MEN1 gene located at chromosomal region 11q13.
• Most carcinoids associated with multiple endocrine neoplasia type 1 appear to be of foregut origin.
• Neurofibromatosis type 1 is an autosomal dominant genetic disorder caused by alteration of the NF1 gene at chromosome 17q11.
• Carcinoids in patients with neurofibromatosis type 1 appear to arise primarily in the periampullary region.
• A hereditary form of small intestinal carcinoid tumour has been found which is caused by mutation in the IPMK gene leads to higher risk of developing carcinoid tumors in the small intestine.
• The most frequently reported mutated gene in gastrointestinal carcinoids is β-catenin (CTNNB1).

Embryology

• Carcinoid tumors originate from neuroendocrine cells (enterochromaffin or amine precursor uptake and decarboxylase [APUD] cells) which are derived from neural crest cells embrologically.
• Gastrointestinal carcinoids derive from cells that migrate from the neural crest to the foregut, midgut and hindgut.

Location

Carcinoid tumors are normally found throughout the gastrointestinal tract from mouth to anus, with the highest concentration of cells in the appendix and small intestine. The pancreas contains a large number of these cells, the biliary tree only a few and the liver normally contains none. Fibrotic lesions are found on endocardium, particularly on the right side of the heart.

Gross Pathology

Gastrointestinal Carcinoid

In the gastric or intestinal wall, carcinoids tumors may occur as firm white, yellow, or gray nodules and may be intramural masses or may protrude into the lumen as polypoid nodules. The overlying gastric or intestinal mucosa may be intact or have focal ulceration.

• Well-differentiated neuroendocrine tumors of the tubular gastrointestinal tract are often well-circumscribed round lesions in the submucosa or extending to the muscular layer.
• The cut surface appears red to tan, reflecting the abundant microvasculature, or sometimes yellow because of high lipid content.

Terminal ileal carcinoid gross pathology

Neuroendocrine tumours of the lung

• Pulmonary neoplasms that are characterized by neuroendocrine differentiation and relatively indolent clinical behavior.
• Lung is the second most common site for neuroendocrine tumor.
• Lung neuroendocrine tumors are classified on the basis of histology:

1. Typical neuroendocrine tumor :well-differentiated, low-grade, slowly growing neoplasms that seldom metastasize to extrathoracic structures and localized.
2. Poorly differentiated and high-grade neuroendocrine carcinomas, as typified by small cell lung cancer and large cell carcinomas which behaves aggressively, with rapid tumor growth and early distant dissemination.
3. Atypical neuroendocrine tumor, which are of intermediate grade and differentiation, is intermediate between typical neuroendocrine tumor and small cell lung cancer.

• Based on the location:

Carcinoid tumor of the lung may be classified based on the location into two subtypes:

1. Bronchial carcinoid tumors: central lesions
2. Peripheral pulmonary carcinoid tumors: peripheral lesions

• Carcinoid syndrome is encountered uncommonly and most often with tumors of large size (>5 cm).

Left upper lobe": A lung lobe 185x110x55mm with bronchovascular remnants up to 25mm. Arising in the hilum and involving the bronchus is a rubbery tan-pink tumor 21x20x19mm. The tumor is 6mm from the bronchovascular margins and 3mm from the hilar margin. 26mm from the tumor and 1mm from the pleura there is a firm white nodule 6mm. Peripheral to the tumor is an area where the lung shows dilated bronchi up to 12mm in diameter which lie 2mm from the pleura.Source: Radiopedia

Microscopic Pathology

• Neuroendocrine tumor arise from enterochromaffin (neuroendocrine) cells of the gastrointestinal tract.
• The term enterochromaffin refers to the ability to stain with potassium chromate (chromaffin), a feature of cells that contain serotonin.
• On electron microscopy ,the cells in tumors are found to contain membrane-bound secretory granules with dense-core granules in the cytoplasm.

  

  Typical carcinoid histopathology-The nuclei of the tumor cells are uniform with a stippled chromatin pattern. There is no mitotic activity or necrosis. https://commons.wikimedia.org/wiki/File:Typical_carcinoid_(3931156341).jpg source Case courtesy of Dr Yale Rosen, from wikicommons

  The most recent nomenclature for neuroendocrine tumors of the digestive system from the World Health Organization (WHO) distinguishes two broad subgroups:
• Well-differentiated neuroendocrine tumor: which are further subdivided according to proliferative rate:

1. Low grade
2. Intermediate grade.(Intermediate-grade neuroendocrine tumor arising in the lung (but not elsewhere) are referred to as atypical carcinoid.

• Poorly differentiated neuroendocrine carcinomas
• They are high-grade carcinomas that resemble small cell carcinoma or large cell neuroendocrine carcinoma of the lung.
• Histoloigically, well-differentiated neuroendocrine tumor have characteristic "organoid" arrangements of tumor cells, with solid/nesting, trabecular, gyriform, or sometimes, glandular patterns.
• The cells are relatively uniform, and they have round to oval nuclei, coarsely stippled chromatin, and finely granular cytoplasm.
• The cells produce abundant neurosecretory granules, as reflected in the strong and diffuse immunohistochemical expression of neuroendocrine markers such as synaptophysin, neuron-specific enolase and chromogranin.
• Well-differentiated neuroendocrine tumor of the midgut (ileum in particular) also have a very characteristic pattern of solid or cribriform nests punctuated by sharply outlined luminal spaces with peripheral nuclear palisading and granular eosinophilic cytoplasm.
• Poorly differentiated neuroendocrine carcinomas (NECs) less closely resemble nonneoplastic neuroendocrine cells and have a more sheet-like or diffuse architecture, irregular nuclei, and less cytoplasmic granularity. Immunohistochemical expression of neuroendocrine markers is generally more limited in extent and intensity.

References

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