Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Parminder Dhingra, M.D. [2]

Carcinoid (also carcinoid tumor or carcinoid tumor) is a slow-growing but often malignant type of neuroendocrine tumor, originating in the cells of the neuroendocrine system. Carcinoid tumors are apudomas that arise from the enterochromaffin cells throughout the gut. They are most commonly found in the foregut (35.6% cases) with lungs, bronchus and trachea constituting 27.9% cases from where they rarely metastasized (except in case of pancreas). The next most common affected area is the small intestine especially the midgut (32.1% cases) with the highest proportion from the ileum at 14.9% of all cases. In cases of metastases it can lead to carcinoid syndrome. This is due to the production of serotonin, which when released into the systemic circulation leads to symptoms of cutaneous flushing, diarrhea, bronchoconstriction and right-sided cardiac valve disease. Carcinoid syndrome was first described by Siegfried Oberndorfer, a German pathologist in 1907. Endocrine related properties of carcinoid syndrome was described by Gosset and Masson in 1914. Carcinoid tumor of the gastrointestinal tract may be classified based on the location into three subtypes (foregut, midgut, or hindgut). Carcinoid tumor of the lung may be classified based on the histology into two subtypes (typical and atypical). Carcinoid tumor of the ovary may be classified into four subtypes (insular, trabecular, strumal, and mucinous type). The pathophysiology of carcinoid tumor depends on the histological subtype. Genes involved 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. Common causes of carcinoid syndrome include genetic disorders (multiple endocrine neoplasia type 1 and neurofibromatosis type 1) and genetic mutations (gains involving chromosomes 5, 14, 17, and 19 and losses involving chromosomes 11 and 18). Carcinoid syndrome must be differentiated from systemic mastocytosis, medullary thyroid carcinoma, irritable bowel syndrome, malignant neoplasms of the small intestine, benign cutaneous flushing, and recurrent idiopathic anaphylaxis. The incidence of carcinoid syndrome is estimated to be 2 cases per 100,000 individuals worldwide. Carcinoid syndrome is a disease that tends to affect the elderly population. The median age at diagnosis is 60.9 years. Females are more commonly affected with carcinoid syndrome than males. Carcinoid syndrome usually affects individuals of the Caucasian race. African American, Latin American, and Asian individuals are less likely to develop carcinoid syndrome. Common risk factors in the development of carcinoid syndrome include age (50 years or older), gender (female), multiple endocrine neoplasia type 1, neurofibromatosis type 1, atrophic gastritis, pernicious anemia, and Zollinger-Ellison syndrome. There is insufficient evidence to recommend routine screening for carcinoid tumor. If left untreated, patients with carcinoid syndrome may progress to develop flushing, diarrhea, and carcinoid heart disease (valvular heart disease and cardiac dysrythmias). Common complications of carcinoid tumor include increased risk of falls and injury (from hypotension), bowel obstruction, gastrointestinal bleeding, right-sided heart failure, and fibrosis of the tricuspid valve and pulmonary valve, and rarely the mitral valve in cases with left sided involvement. Prognosis is generally good and the 5-year survival rate of patients with carcinoid syndrome is approximately 69.7%. According to The American Joint Committee on Cancer (AJCC), there are four stages of carcinoid syndrome based on the TNM staging sysytem. Symptoms of carcinoid tumor include flushing, diarrhea, wheezing, abdominal cramps, wheezing, and cough. Common physical examination findings of carcinoid syndrome include tachycardia, flushing, hypertension, hirsutism, pallor, cervical lymphadenopathy, wheezing, systolic or diastolic murmur, and lower limb edema. Laboratory findings consistent with the diagnosis of carcinoid syndrome include an elevated urinary 5-hydroxyindoleacetic acid (5-HIAA) and plasma levels of CgA levels. On ECG, carcinoid syndrome is characterized by high frequency of low-voltage qrs complexes. On chest x-ray, bronchial carcinoid tumor is characterized by the presence of round or oval opacities with sharp and notched margins, whereas thymic carcinoid tumor often demonstrates focal areas of necrosis or punctate calcifications. Chest CT scan may be helpful in the diagnosis of carcinoid tumor. On high-resolution CT scan of the chest, peripheral pulmonary carcinoid tumor is characterized by a solitary and round pulmonary nodule with a lobulated margin, whereas bronchial carcinoid tumor is characterized by a single well-defined, round or ovoid, hilar or perihilar mass with marked homogenous enhancement. On CT scan of the neck, thymic carcinoid tumor is characterized by a mass with heterogeneous attenuation. Abdominal MRI scan may be performed to detect metastases of carcinoid syndrome to liver and mesentery. There are no echocardiography findings associated with carcinoid syndrome. Other imaging studies for carcinoid tumor include somatostatin scintigraphy with 111Indium-octreotide, bone scintigraphy with 99mTc-methylene diphosphonate (99mTcMDP), 123 I-metaiodobenzylguanidine (MIBG) scintigraphy, capsule endoscopy (CE), enteroscopy, and angiography. The predominant therapy for carcinoid syndrome is surgical resection. Supportive therapy for carcinoid syndrome includes somatostatin analogs, interferons, and radionuclides. Surgery is the mainstay of treatment for carcinoid tumor. The feasibility of surgery depends on the stage of carcinoid tumor at diagnosis. There is no established method for prevention of carcinoid syndrome. There are no secondary preventive measures available for carcinoid syndrome.

Carcinoid syndrome was first described by Siegfried Oberndorfer, a German pathologist in 1907. Endocrine related properties of carcinoid syndrome was described by Gosset and Masson in 1914.

Carcinoid tumor of the gastrointestinal tract may be classified based on the location into three subtypes (foregut, midgut, or hindgut). Carcinoid tumor of the lung may be classified based on the histology into two subtypes (typical and atypical). Carcinoid tumor of the ovary may be classified into four subtypes (insular, trabecular, strumal, and mucinous type).

The pathophysiology of carcinoid tumor depends on the histological subtype. Genes involved 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.

Common causes of carcinoid syndrome include genetic disorders (multiple endocrine neoplasia type 1 and neurofibromatosis type 1) and genetic mutations (gains involving chromosomes 5, 14, 17, and 19 and losses involving chromosomes 11 and 18).

Carcinoid syndrome must be differentiated from systemic mastocytosis, medullary thyroid carcinoma, irritable bowel syndrome, malignant neoplasms of the small intestine, benign cutaneous flushing, and recurrent idiopathic anaphylaxis.

The incidence of carcinoid syndrome is estimated to be 2 cases per 100,000 individuals worldwide. Carcinoid syndrome is a disease that tends to affect the elderly population. The median age at diagnosis is 60.9 years. Females are more commonly affected with carcinoid syndrome than males. Carcinoid syndrome usually affects individuals of the Caucasian race. African American, Latin American, and Asian individuals are less likely to develop carcinoid syndrome.

Common risk factors in the development of carcinoid syndrome include age (50 years or older), gender (female), multiple endocrine neoplasia type 1, neurofibromatosis type 1, atrophic gastritis, pernicious anemia, and Zollinger-Ellison syndrome.

There is insufficient evidence to recommend routine screening for carcinoid tumor.

If left untreated, patients with carcinoid syndrome may progress to develop flushing, diarrhea, and carcinoid heart disease (valvular heart disease and cardiac dysrythmias). Common complications of carcinoid tumor include increased risk of falls and injury (from hypotension), bowel obstruction, gastrointestinal bleeding, right-sided heart failure, and fibrosis of the tricuspid valve and pulmonary valve, and rarely the mitral valve in cases with left sided involvement. Prognosis is generally good and the 5-year survival rate of patients with carcinoid syndrome is approximately 69.7%.

According to The American Joint Committee on Cancer (AJCC), there are four stages of carcinoid syndrome based on the TNM staging sysytem.

Symptoms of carcinoid tumor include flushing, diarrhea, wheezing, abdominal cramps, wheezing, and cough.

Common physical examination findings of carcinoid syndrome include tachycardia, flushing, hypertension, hirsutism, pallor, cervical lymphadenopathy, wheezing, systolic or diastolic murmur, and lower limb edema.

Laboratory findings consistent with the diagnosis of carcinoid syndrome include an elevated urinary 5-hydroxyindoleacetic acid (5-HIAA) and plasma levels of CgA levels.

On ECG, carcinoid syndrome is characterized by high frequency of low-voltage qrs complexes.

On chest x-ray, bronchial carcinoid tumor is characterized by the presence of round or oval opacities with sharp and notched margins, whereas thymic carcinoid tumor often demonstrates focal areas of necrosis or punctate calcifications.

Chest CT scan may be helpful in the diagnosis of carcinoid tumor. On high-resolution CT scan of the chest, peripheral pulmonary carcinoid tumor is characterized by a solitary and round pulmonary nodule with a lobulated margin, whereas bronchial carcinoid tumor is characterized by a single well-defined, round or ovoid, hilar or perihilar mass with marked homogenous enhancement. On CT scan of the neck, thymic carcinoid tumor is characterized by a mass with heterogeneous attenuation.

Abdominal MRI scan may be performed to detect metastases of carcinoid syndrome to liver and mesentery.

There are no echocardiography findings associated with carcinoid syndrome.

Other imaging studies for carcinoid tumor include somatostatin scintigraphy with 111Indium-octreotide, bone scintigraphy with 99mTc-methylene diphosphonate (99mTcMDP), 123 I-metaiodobenzylguanidine (MIBG) scintigraphy, capsule endoscopy (CE), enteroscopy, and angiography.

The predominant therapy for carcinoid syndrome is surgical resection. Supportive therapy for carcinoid syndrome includes somatostatin analogs, interferons, and radionuclides.

Surgery is the mainstay of treatment for carcinoid tumor. The feasibility of surgery depends on the stage of carcinoid tumor at diagnosis.

There is no established method for prevention of carcinoid syndrome.

There are no secondary preventive measures available for carcinoid syndrome.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Parminder Dhingra, M.D. [2]

The term Carcinoid was given by Siegfried Oberndorfer, a German pathologist at the University of Munich in 1907. Enterochromaffin cell, the cell of origin of carcinoid tumour had been identified as early as 1897 by N. Kulchitsky.

• Theodor Langhans (1839–1915) was the first to describe the histology of a carcinoid tumor in 1867.
• The term Carcinoid was given by Siegfried Oberndorfer, a German pathologist at the University of Munich in 1907.
• Siegfried Oberndorfer referred the carcinoid tumor as “benign carcinomas” as they had distinct clinical entities and named them “karzinoide”(carcinoma-like).
• Karzinoide or “carcinoma-like” describes the unique feature of behaving like a benign tumor despite resembling a carcinoma microscopically.
• Rapport and colleagues isolated and named serotonin (5-HT), initially identified as a vasoconstrictor substance in the serum.^[1]
• Enterochromaffin cell,the cell of origin of carcinoid tumour had been identified as early as 1897 by N. Kulchitsky (1856-1925).
• In 1953, F. Lembeck established that enterochromaffin cells synthesizes and secretes serotonin, the major hormone responsible for carcinoid syndrome.^[2][3]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Anum Gull M.B.B.S.[2]Parminder Dhingra, M.D. [3]

Gastroenteropancreatic neuroendocrine tumors are classified based on their origin from the embryonic divisions of the alimentary tract into foregut (bronchial, stomach), midgut (small intestine, appendix, cecum) and hindgut (distal colon, rectum, genitourinary) tumours.

• Gastroentero–pancreatic neuroendocrine tumors are classified based on their origin from the embryonic divisions of the alimentary tract:

1. Foregut (bronchial, stomach)
2. Midgut (small intestine, appendix, cecum)
3. Hindgut (distal colon, rectum, genitourinary)

• Gasroenteropancreatic- neuroendocrine tumor produce a number of secretory products, resulting in a wide range of clinical symptoms.^{[1] [2][3]}
• Midgut gastrointestinal tract neuroendocrine tumors produce serotonin and other vasoactive substances that causes the manifestations of typical carcinoid syndrome.
• Lung neuroendocrine tumors produce less quantities of serotonin.
• Carcinoid syndrome is caused less commonly by lung neuroendocrine tumor and most often by tumors of large size (>5 cm).

Gastroenteropancreatic neuroendocrine tumors

	Foregut	Midgut	Hindgut
Location	Stomach Duodenum Bronchus Thymus	Jejunum Ileum Appendix Ascending colon	Transverse colon Descending colon Sigmoid colon Rectum Genitourinary
Hormones produced	5-hydroxytryptophan Histamine Multiple polypeptides	Serotonin Prostaglandins Polypeptides	Variable
Possibility of carcinoid syndrome	Rare, and atypical when it occurs	Classic	Rare

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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]

Carcinoid syndrome (CS) is a paraneoplastic syndrome caused by the secretion of serotonin (5-hydroxytrptamine) but can be caused by the secretion of histamine, kallikrein, prostaglandins, and tachykinins..Carcinoid syndrome is most commonly caused by neuroendocrine tumors of midgut. In patients with carcinoid syndrome, 70% of tryptophan is converted into serotonin which leads to secondary deficiency of niacin. Serotonin is metabolized 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. 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 are secreted by neuroendocrine tumors and appear 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. Neuroendocrine tumors arise from enterochromaffin cells. The name “enterochromaffin” refers to the ability to stain the cell with potassium chromate (chromaffin), a feature of cells that contain serotonin.

• Carcinoid syndrome (CS) is a paraneoplastic syndrome associated with the secretion of several hormones.^[1]

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

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

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 of the GIT resulting in diarrhea.
• As most of the body’s tryptophan is diverted to serotonin formation pathway by neuroendocrine tumors, tryptophan (which is needed for niacin synthesis) becomes deficient.
• 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.
• Skin flushing results from the 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.

• Carcinoid tumors arising in the bronchi reach the systemic circulation before passing through the liver and may be associated with bronchoconstriction and manifestations without liver metastases.
• Bronchospasm leading to wheezing is caused by the crelease of histamine and serotonin.^[2]
• Episodes of flushing and related manifestations are particularly prolonged or severe if carcinoid syndrome is caused by a lung neuroendocrine tumour.

• 5-HT2B is the receptor of serotonin in the cardiovascular system that may be involved in fibrogenesis.^[3]
• 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.^[4][5][6]
• Fibrosis leads to thickening of mural and valvular endothelial surfaces of right-sided cardiac structures.^[7][8]
• Fibrosis leads to

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

• Serotonin and TGF-beta secreted by neuroendocrine tumours appears to play a central role in the development of mesenteric fibrosis.^[9]
• 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 CT, and nuclear MRI.
• 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.^[10][11]

• Gastrointestinal carcinoids occur in association with inherited syndromes, such as multiple endocrine neoplasia type 1 and neurofibromatosis type 1.^[12]
• Multiple endocrine neoplasia type 1 is caused by alterations of the MEN1 gene located at chromosomal region 11q13.
• Most carcinoids that are 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.^[13]
• A hereditary form of small intestinal carcinoid tumour has been found which is caused by a mutation in the IPMK gene leads to higher risk of developing carcinoid tumors in the small intestine.^[14]
• The most frequently reported mutated gene in gastrointestinal carcinoids is β-catenin (CTNNB1).^[15]

• 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.^[16]

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.

In the gastric or intestinal wall, carcinoids tumors may occur as firm white, yellow, or gray nodule. The lesions 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 the high lipid content.

• 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:^[18][19]

1. Typical neuroendocrine tumor : well-differentiated, low-grade, slowly growing neoplasms that are localized and rarely metastasize to extrathoracic structures.
2. Poorly differentiated and high-grade neuroendocrine carcinomas, as typified by small cell lung cancer and large cell carcinomas which behave 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 the large size (>5 cm).

• Neuroendocrine tumor arises 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 tumor cells are found to contain membrane-bound secretory granules with dense-core granules in the cytoplasm.

The most recent nomenclature for neuroendocrine tumors of the digestive system from the World Health Organization (WHO) distinguishes two broad subgroups:^[20][21][22]

Neuroendocrine tumor: which are further subdivided according to their proliferative rate:^[23]

1. Well-differentiated :Low grade also known as typical neuroendocrine tumors.
2. Intermediate grade.(Intermediate-grade neuroendocrine tumor arising in the lung (but not elsewhere) are referred to as atypical carcinoid.

• Poorly differentiated neuroendocrine carcinomas: High grade
• 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.^[24][25]
• 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.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Parminder Dhingra, M.D. [2]

Common causes of carcinoid syndrome include genetic disorders (multiple endocrine neoplasia type 1 and neurofibromatosis type 1) and genetic mutations (gains involving chromosomes 5, 14, 17, and 19 and losses involving chromosomes 11 and 18).

• Approximately 30-40% of patients with well-differentiated neuroendocrine tumors present with carcinoid syndrome.
• Carcinoid syndrome is predominantly associated with neuroendocrine tumors (NETs) that arise from the midgut in the setting of extensive liver metastases
• Carcinoid syndrome may be present in patients with bronchial carcinoids.^[1]
• other common causes of carcinoid syndrome includes are mostly genetic:^[2]
• Genetic disorders^[3]

^[4][5]

Genetic Disorder	Tumor Location
Multiple endocrine neoplasia type 1	Carcinoids associated with multiple endocrine neoplasia type 1 appear to be of foregut origin
Neurofibromatosis type 1	Carcinoids in patients with neurofibromatosis type 1 appear to arise primarily in the periampullary region

• Genetic mutations

Type of Mutation	Chromosomes
Gains	Chromosome 5 Chromosome 14 Chromosome 17 Chromosome 19
Losses	Chromosome 11 Chromosome 18

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Parminder Dhingra, M.D. [2]

Carcinoid syndrome must be differentiated from systemic mastocytosis, medullary thyroid carcinoma, irritable bowel syndrome, malignant neoplasms of the small intestine, benign cutaneous flushing, and recurrent idiopathic anaphylaxis.

Carcinoid syndrome must be differentiated from:^[1]

• Systemic mastocytosis
• Medullary thyroid carcinoma
• Irritable bowel syndrome
• Malignant neoplasms of the small intestine
• Benign cutaneous flushing
• Recurrent idiopathic anaphylaxis

Diseases		Clinical manifestations												Para-clinical findings										Gold standard	Additional findings
		Symptoms						Physical examination
														Lab Findings			Imaging						Histopathology
		Abdominal pain	Diarrhea	Flushing	Dyspnea	Palpitations	Other symptoms	Wheezing	Telangiectasia	Hypotension	Tachycardia	Systolic murmur of tricuspid regurgitation	Other physical findings	Urinary 5-hydroxyindoleacetic acid (5-HIAA)	Serum Chromogranin A (CgA)	Other markers	Abdominal computed tomography (CT)	Abdominal MRI	Somatostatin receptor scintigraphy [SRS], or Octreoscan	Metaiodobenzylguanidine (MIBG) scintigraphy	Other diagnostic studies	Transthoracic echocardiography
Carcinoid Syndrome[2][3][4][5][6][7][8][9][10]	Neuroendocrine tumor of midgut [11][12][13][14]	+ Mild	+ Intermittent Secretory diarrhea	+	+	+	Pellagra Dermatitis Diarrhea Dementia Metastatic tumors in the liver: Right upper quadrant pain, hepatomegaly, and early satiety	+	+/-	+/-	+	+	–	+	+	NT-proBNP Screening of carcinoid heart disease Blood Serotonin levels	Neuroendocrine tumor of midgut are difficult to identify on CT because of their small size. Findings: mass-like process with soft tissue “spokes” radiating into the mesenteric fat toward the small bowel causing retraction. Liver metastases	Sensitive for detection of liver metastases	+ Localization of carcinoid tumor	+	68-Ga DOTATATE PET scan Positron emission tomography-computed tomography (PET-CT) using 18-fluoro-dihydroxyphenylalanine Ki-67 labeling index Endoscopy for metastatic Neuroendocrine tumour with an unknown primary site.	Valve thickening with retraction and reduction in the mobility of the tricuspid valve	Enterochromaffin cells stain with potassium chromate (chromaffin). On electron microscopy ,the cells in tumors are found to contain membrane-bound secretory granules with dense-core granules in the cytoplasm.	Somatostatin receptor scintigraphy [SRS], or Octreoscan Biopsy and histopathology	Mesenteric fibrosis Pathognomonic radiological sign of midgut NET.
	Neuroendocrine tumor of lung[15][16][17][18]	+	+	+	+	+	Cough Hemoptysis Chest pain Fever due to post -obstructuve pneuomnia	+	+/-	+/-	+	+	–	+	+	Immunohistochemical stains: Synaptophysin Neuron-specific enolase NT-proBNP Low serotonin content as compared to midgut tumors.	Atypical neuroendocrine tumors have a greater tendency to metastasize to liver,hypervascular, and becomies isodense relative to the liver parenchyma after contrast administration.		Sensitive for detection of liver metastases if present	+	+	Chest X ray: round or oval opacities from 2-5cm with sharp and notched margins Chest CT : Hilar or Perihilar Masses, Endobronchial Nodules,Related to bronchial Obstruction:peripheral atelectasis and postobstructive pneumonia Pulmonary funcation test Bronchoscopy 68-Ga DOTATATE PET scan Fluorodeoxyglucose PET scans for atypical lung NETs .	–	Typical low-grade:bland cells containing regular round nuclei with finely dispersed chromatin and inconspicuous small nucleoli.Mitotic figures are scarce and necrosis is absent. Intermediate-grade atypical: presence of Neuroendocrine morphology and either necrosis or 2 to 10 mitoses per 10 HPF	Biopsy and histopathology
Irritable Bowel Syndrome[19][20][21][22]		+ Perioidic	Intermittent Chronic history of diarhea alternating with constipation	–	–	–	Fibromyalgia Chronic fatigue syndrome Gastroesophageal reflux disease, Functional dyspepsia Non-cardiac chest pain, Major depression ,Anxiety	–	–	–	–	–		–	–		–	–	–	–	Bristol stool form scale should to record stool consistency Abdominal radiograph to assess for stool accumulation and determine the severity. Age-appropriate colorectal cancer screening in all patients	–	–	Rome IV criteria Recurrent abdominal pain, at least 1day/week in the last 3 months, a/s with 2 or more of the following criteria: •Related to defecation •Associated with a change in stool frequency •Associated with a change in stool form (appearance)
Malignant neoplasms of small intestine[23][24][25]		+/-	+/-	–	–	+/-	Constipation Fatigue Early satiety	–	–	+/-	–	* Abdominal mass Ascites	–	+	Abdominal CT scan may be diagnostic of small intestine cancer. Findings on CT scan suggestive of small intestine cancer include intrinsic mass with a short segment of bowel wall thickening	MRI and MRI enteroscopy are other advance modalities to diagnose and stage small intestinal cancers	–	–	Enteroscopy, capsule endoscopy and double balloon enteroscopy		Adenocarcinomas may be polypoid, infiltrating, or as annular constricting lesions is small intestine. Polyps and adenomas of small intestine are considered precursor lesions of adenocarcinoma. Lymphomas of small intestine present with suspicious growths in submucosa with normal appearing muscosa. Endoscopic evaluation may show multifocal involvement and large biopsies are required for diagnoses	Biopsy and histopathology
Crohn disease[26][27][28][29]		Right lower quadrant pain	+/-	–	–	–	Gross bloody diarrhea +/- Weight loss Fatigue	–	–	–	–	–	Weight loss Pallor Oral lesions Odynophagia Dysphagia Perianal skin tags Sinus tracts Gallstones Extraintestinal manifestations Arthritis Uveitis, Iritis, and Episcleritis Erythema nodosum and Pyoderma gangrenosum Primary sclerosing cholangitis Secondary amyloidosis Thromboembolism Renal stones Osteoporosis Vitamin B12 deficiency	–	–	CRP may be high p-ANCA and ASCA	CT enterography Small bowel inflammation by displaying mural hyperenhancement and thickening; engorged vasa recta; and perienteric inflammatory changes.		–	–	CBC Blood chemistry including electrolytes Renal function tests liver enzymes Blood glucose ESR CRP Serum iron Vitamin D & vitamin B12 levels Stool D/R and culture for ova and parasites, C. difficile toxin	–	Focal ulcerations and acute and chronic inflammation Granulomas	Colonoscopy:focal ulcerations adjacent to areas of normal appearing mucosa along with polypoid mucosal,skip lesions,pseudopolyps,
Benign cutaneous flushing[30][31][32]		–	–	+	–	–		–	–	–	–	–	–	–	–	–	–	–	–	–	–	–	–	–
Systemic mastocytosis[33][34][35][36][37][38][39]		+	+	+	+	–	Maculopapular rash Pruritus	+/-	+/-	+	–	–	Diffuse musculoskeletal pain Neuropsychiatric symptoms	–	–	Activating mutations of KIT Serum Tryptase levels			–	–
Asthma exacerbation[40][41][42][43][44][45]		–	–	–	+	+		+	–	–	+	–	Tachypnea Prolonged expiratory phase of respiration (decreased I:E ratio) Seated position with use of extended arms to support the upper chest (tripod position) +/- Pulsus paradoxus	–	–	–	—	–	–	–	Chest X ray	–	Loss of the normal pseudostratified structure of airway epithelium Increase in the proportion of goblet cells Fibrotic thickening of the sub-epithelial reticular basement membrane Increased numbers of myofibroblasts Increased vascularity Increased airway smooth muscle mass Increased extracellular matrix
Anaphylaxis[46][47][48][49][50]		+	-/+	+	+	+	Vomiting Generalized hives, Pruritus Itching	+/-	–	+	+	–	Swollen lips–tongue–uvula Periorbital edema, Conjunctival swelling	–	–	–	–	–	–	–	plasma tryptase Plasma histamine levels Take proper clinical history and medication history specially beta blockers,ACE-inhibitors,opioids Skin testing with allergen extracts enzyme-linked immunosorbent assays (ELISAs) for quantification of allergen-specific IgE levels	–	–		History of exposure to insect stings,food alllergy,rubber latex,food additives,,allergy to medications,physical factors such s excercise and cold
Histaminergic Angioedema[51][52][53][54][55][56]		+/-	+/-	+	+	+	Generalized pruritus Throat tightness Hoarse voice Difficulty swallowing	+	–	+	+	–	Urticaria Localized swelling of skin	–	–	–	Bowel wall edema Circumferential thickening of the small bowel wall with ascites or incomplete obstruction	–	–	–	CBC with differential, Electrolytes Liver function tests C-reactive protein Erythrocyte sedimentation rate Levels of the complement protein C4 Serum total tryptase Allergen-specific IgE immunoassays	–	–	–	Take proper clinical history of previous similar episodes Medication history Any allergy to insects stings , foods or any ingestion within previous 24 hours
Medullary Thyroid Carcinoma[57][58][59][60][61]		–	+/-	+/-	+/-	–	Neck pain Hoarseness Cough Difficulty swallowing Difficulty breathing Lethargy Bone pain from metastasis	–	–	–	–	–	Solitary thyroid nodule Cervical lymph node involvement Weight loss	–	–	Basal serum calcitonin concentrations Carcinoembryonic antigen (CEA) concentration Thyroid function tests: normal Germline RET testing Serum calcium Plasma fractionated metanephrines	–	–	–	–	Ultrasonography of the neck For metastasis Chest computed tomography Neck CT Three-phase contrast-enhanced liver CT Axial MRI Bone scintigraphy.	–	Immunohistochemical staining for calcitonin Spindle-shaped and frequently pleomorphic cells without follicle development	Fine-needle aspiration (FNA) biopsy TNM staging American Thyroid Association (ATA) Guidelines for Management and evaluation of Medullary Thyroid Cancer

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Parminder Dhingra, M.D. [2]

The incidence of carcinoid syndrome is estimated to be 2 cases per 100,000 individuals worldwide. Carcinoid syndrome is a disease that tends to affect the elderly population. The median age at diagnosis is 60.9 years.Females are more commonly affected with carcinoid syndrome than males. Carcinoid syndrome usually affects individuals of the caucasian race. African American, Latin American, and Asian individuals are less likely to develop carcinoid syndrome.

• Carcinoid tumors represent about 0.5% of all newly diagnosed malignancies.
• Carcinoid tumors account for 75% of all gastrointestinal endocrine tumors.
• Ovarian carcinoid tumors account for 0.3% of all ovarian tumors and 0.5% of carcinoid tumors.^[1]

• The incidence of carcinoid syndrome is estimated to be 2 cases per 100,000 individuals worldwide.^[2]
• Neuroendocrine tumors of the digestive system arising in the tubular gastrointestinal tract and the pancreas are relatively rare.
• The annual incidence in the United States is approximately 3.56 per 100,000 population.^[3]

• Carcinoid syndrome is a disease that tends to affect the elderly population.^[4]
• Ovarian carcinoid tumors are commonly seen in perimenopausal and postmenopausal women.
• The median age at diagnosis is 60.9 years.^[4]

• Females are more commonly affected with carcinoid syndrome than males.
• Males are more commonly affected with thymic carcinoid tumor than females. The male to female ratio is approximately 3 to 1.^[5]

• Carcinoid syndrome usually affects individuals of the Caucasian race.
• African American, Latin American, and Asian individuals are less likely to develop carcinoid syndrome.^[4]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Parminder Dhingra, M.D. [2]

Common risk factors in the development of carcinoid syndrome include age (50 years or older), female gender, family history of multiple endocrine neoplasia type 1 and neurofibromatosis type 1, atrophic gastritis, pernicious anemia, and Zollinger-Ellison syndrome.

Common risk factors in the development of carcinoid syndrome include:^[1]

• Age (50 years or older)
• Gender: female
• Race:African Americans
• Family history of multiple endocrine neoplasia type 1
• Family history of neurofibromatosis type 1
• Genetic syndromes such as

1. Tuberous sclerosis complex
2. Von Hippel Lindau disease
3. Familial small intestinal neuroendocrine tumor^[2]

• Risk factors for carcinoid tumours of stomach

1. Atrophic gastritis
2. Pernicious anemia
3. Zollinger-Ellison syndrome

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Parminder Dhingra, M.D. [2]

There is insufficient evidence to recommend routine screening for carcinoid tumor.

There is insufficient evidence to recommend routine screening for carcinoid tumor.^[1]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Parminder Dhingra, M.D. [2]

If left untreated, patients with carcinoid syndrome may progress to develop flushing, diarrhea, and carcinoid heart disease (valvular heart disease and cardiac dysrythmias). Common complications of carcinoid tumor include increased risk of falls and injury (from hypotension), bowel obstruction, gastrointestinal bleeding, right-sided heart failure, and fibrosis of the tricuspid valve and pulmonary valve, and rarely the mitral valve in cases with left sided involvement. Prognosis is generally good and the 5-year survival rate of patients with carcinoid syndrome is approximately 69.7%.

• If left untreated, patients with carcinoid syndrome may progress to develop flushing, diarrhea, and carcinoid heart disease (valvular heart disease and cardiac dysrythmias):^[1]
  • Pathologically, the cardiac valves become thickened because of fibrosis
  • Tricuspid and pulmonic valves are affected to a greater extent than the mitral and aortic valves
• They have a very slow growth rate compared to most malignant tumors

Common complications of carcinoid tumor include:^[2]

• Increased risk of falls and injury (from hypotension)
• Bowel obstruction
• Gastrointestinal bleeding
• Carcinoid heart disease develops in more than one-third of patients with carcinoid syndrome:^[3]
• Fibrosis of the tricuspid valve and pulmonary valve, rarely the mitral valve in cases with left sided involvement

• Tricuspid and pulmonic regurgitation (“TIPS” – Tricuspid Insufficiency, Pulmonic Stenosis)
• Pulmonary stenosis
• Mitral and aortic insufficiency
• Cardiac dysrhythmias

• Prognosis of carcinoid tumor is generally good and the 5-year survival rate of patients is approximately:^[4]

• Stomach-75.1%
• Small Intestine-76.1%
• Appendix-76.3%
• Rectum-87.5%

• Factors that determine the prognosis of patients with gastrointestinal carcinoid tumors include:^[5]

• Site of origin
• Size of the primary tumor
• Anatomical extent of disease

• Negative prognostic factors include:
  • Carcinoid heart disease
  • High concentrations of the tumor markers – urinary 5-HIAA and plasma chromogranin A
  • Metastasis to the liver
  • Carcinoid tumor in the thymus
  • Overexpression of the proliferation antigen Ki-67
  • Mutation in the p53 gene

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