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

The pathophysiology of carcinoid tumor depends on the histological subtype. genes in the pathogenesis of carcinoid tumor are β-catenin, NF1, and MEN1. Carcinoid tumors originate from neuroendocrine cells. On microscopic histopathological analysis, gastrointestinal carcinoid syndrome is characterized by solid or small trabecular clusters of neuroendocrine cells with uniform nuclei and abundant granular or faintly staining (clear) cytoplasm.

Pathophysiology

• Carcinoid syndrome (CS) is a paraneoplastic syndrome associated with the secretion of several humoral factors such as polypeptides, vasoactive amines, and prostaglandins from the well-differentiated neuroendocrine tumors

• The primary marker is serotonin (5-HT) 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 carcinoids
2. Pelvic or retroperitoneal involvement by metastatic or locally invasive small bowel carcinoids
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 GI 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 histamin and serotonin.

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. Mitral and aortic insufficiency.
4. Cardiac dysrhythmias

Mesentric fibrosis

• Serotonin and TGF-beta secreted by neuroendocrine tumours appears to play a central role in the development of mesentric fibrosis.

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 cacinoid 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.

Associated Conditions

Goblet cell carcinoid is considered to be a hybrid between an exocrine and endocrine tumor derived from crypt cells of the appendix. They behave in a more aggressive manner than do classical appendiceal carcinoids. Spread is usually to regional lymph nodes, peritoneum, and particularly the ovary. They do not produce sufficient hormonal substances to cause the carcinoid or other endocrine syndromes. In fact, they more closely resemble exocrine than endocrine tumors. The term 'crypt cell carcinoma' has been used for them, and though perhaps more accurate than considering them carcinoids, has not been a successful competitor.

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 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.

Terminal ileal carcinoid gross pathology

Ovarian Carcinoid

Lesions can markedly vary in size. Metastatic carcinoids are nearly always bilateral with scattered tumor deposits present throughout both ovaries. Primary carcinoids of the ovary are invariably unilateral. They form a solid nodule within a cystic teratoma, or form a pure solid hypervascular mass. They can be indistinguishable from other solid neoplasms of the ovary. Lesions can markedly vary in size. Metastatic carcinoids are nearly always bilateral with scattered tumor deposits present throughout both ovaries.

Microscopic Pathology

Goblet Cell Carcinoid of Appendix

Histologically, globet cell carcinoid forms clusters of goblet cells containing mucin with a minor admixture of paneth cells and endocrine cells. The growth pattern is distinctive, typically producing a concentric band of tumor nests interspersed among the muscle and stroma of the appendiceal wall extending up the shaft of the appendix. This makes the lesion difficult to suspect grossly and difficult to measure. Small tumor nests may be camouflaged amongst the muscle or in periappendiceal fat, cytokeratin preparations best demonstrate the tumor cells, mucin stains are also helpful in identifying them.

Gastric or Intestinal Carcinoid

Neuroendocrine cells have uniform nuclei and abundant granular or faintly staining (clear) cytoplasm, and are present as solid or small trabecular clusters, or are dispersed among other cells, which may make them difficult to recognize in sections stained with hematoxylin and eosin, immunostaining enables their exact identification. At the ultrastructural level, neuroendocrine cells contain cytoplasmic membrane-bound dense-cored secretory granules (diameter >80 nm) and may also contain small clear vesicles (diameter 40–80 nm) that correspond to the synaptic vesicles of neurons.

Hepatic Carcinoid

Histologically, the tumor has features of classic carcinoid (i.e. trabecular and pseudoglandular pattern) and dense core granules demonstrated by electron microscopy or by immunohistochemistry (i.e. positive staining by chromogranin antibody).

Lung Carcinoid

• Nests of cells

• Stippled chromatin
• Moderate cytoplasm

• No necrosis
• Low mitotic rate

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  Lung carcinoid low magnitude

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  Lung carcinoid intermediate magnitude

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  Lung carcinoid very high magnitude

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  Lung carcinoid high magnitude

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