Carcinoid syndrome overview

# Overview
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 -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.

# Historical Perspective
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.

# Classification
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).

# Pathophysiology
The pathophysiology of carcinoid tumor depends on the histological subtype. Genes involved in the pathogenesis of carcinoid tumor are -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.

# Causes
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).

# Differentiating Carcinoid Syndrome from other Diseases
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.

# Epidemiology and Demographics
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.

# Risk Factors
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.

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

# Natural History, Complications and Prognosis
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%.

# Diagnosis

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

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

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

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

## Chest X Ray
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.

## CT
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.

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

## Echocardiography or Ultrasound
There are no echocardiography findings associated with carcinoid syndrome.

## Other Imaging Findings
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.

## Other Diagnostic Studies

# Treatment

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

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

## Primary Prevention
There is no established method for prevention of carcinoid syndrome.

## Secondary Prevention
There are no secondary preventive measures available for carcinoid syndrome.

## Cost-Effectiveness of Therapy

## Future or Investigational Therapies