Carcinoid and other Neuroendocrine Tumors

Carcinoid and other Neuroendocrine Tumors  

                                         

             PKGhatak,MD

 Definition:                                             

Carcinoid means a tumor having some but not all the features of cancer when examined under a microscope. Neuroendocrine implies a cell destined to become a nerve cell ends up as a hormone producing cell.
                                             

Even though it is known that not all of these peptide producing tumors are derived from the primitive-nerve cell, this name is still in use because of certain advantages. Neuroendocrine tumors, including carcinoids, are special tumors for several interesting reasons. Some tumors produce the same hormone/peptide even when they are located in different organs; tumors located in one organ secrete two or more hormones. Carcinoid and other neuroendocrine tumors are identical pathologically whether they are benign or malignant. Only their biological behavior makes a tumor benign or malignant. The diagnosis is often delayed because of its small size and widespread distribution. Advances in molecular biochemistry and genetics have outpaced clinical medicine, as a result, the chemical signatures and effects of these hormones on the human body are better defined than clinical diagnosis and treatment.

A simplified look in embryology is essential to comprehend the wide distribution of neuroendocrine tumors in various organs and tissues.
In a very early stage of embryo development, a sheet of cells differentiates into outer, inner and middle layers. The outer and inner layers fold into two separate tubes. The outer tube is called Neural Tube from which the brain and spinal cord develop and the inner tube is known as the Primitive Gut from it the entire gastrointestinal tract, liver, pancreas, bronchial tree and other structures develop. These two tubes lie next to each other. Some of the cells at the line of fusion of neural tube spread out like tiny wings, one on each side, called the neural crest. These cells have the potential to form many varied functions. Some of the cells of the neural crest attach to the developing primitive gut and find their way to different locations in the G-I tract and related organs.   These cells secrete potent hormones. Since these endocrine cells originated from the neural crest, they are called neuroendocrine cells.

Carcinoid Syndrome and Carcinoid tumors:

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All carcinoid tumors are capable of producing hormones and peptides but may secrete only in small quantities into circulation and tumors may remain silent for a long time. Whereas, those carcinoid tumors secrete large quantities of hormones/peptides cause severe symptoms in patients.

A patient is diagnosed as having Carcinoid Syndrome when he presents with a specific group of symptoms due to excess Serotonin.

Serotonin is produced normally in the body from an amino acid Tryptophan. The first step of this 2-step process is the conversion of tryptophan to 5-Hydroxytryptophan (5HTP), in the next step 5HTP is converted to 5-Hydroxytryptamine which is known as Serotonin (5HT). It is an amine and belongs to other potent amines like Epinephrine, Norepinephrine, and Dopamine.  5HT is stored in the cells in the secretory granules till it is released into circulation. Serotonin is taken up and stored in the platelets. In a normal situation, only about 1% of tryptophan is converted to serotonin. In carcinoid syndrome, 60% of tryptophan is diverted to 5HT production. As a result, Niacin (vitamin B3) which is also derived from Tryptophan, becomes deficient in the body and deficiency of niacin produces a condition known as Pellagra. The symptoms of pellagra are beefy red tongue, red edematous skin rash, hypersensitive to sunlight, diarrhea, and dementia.

The normal blood 5HT levels are 0.1 to 0.3 mcg/ml. In carcinoid syndrome, 5HT blood levels are 0.5 to 2.7 mcg/ml. Serotonin is degraded to 5-Hydoxyindoleacetic acid (5HIAA) and is eliminated from the body in the urine. About 75 to 700 mg of 5HIAA is excreted in the urine in 24 hours. (In normal people the range is 2 to 8mg/day). In addition, both blood and urine levels of 5HTP are usually mildly elevated.

The symptoms of carcinoid syndrome are sudden onset of flushing of the face, neck, trunk, and arms associated with a sensation of warmth or itching; profuse watery diarrhea accompanied by abdominal pain; wheezing; and cardiac problems.  These symptoms may last only a few minutes to several hours. Once symptoms are resolved by medical therapy or spontaneously, the patient remains symptom free.  Ingestion of food rich in serotonin or taking drugs that elevate blood serotonin levels may precipitate symptoms. Cardiac symptoms appear at a later stage and are due to the deposition of fibrin on the inner laying cells of the right ventricle, valves and intraventricular septum leading to valvular stenosis and incompetence and right sided heart failure.

A life-threatening situation known as a Carcinoid Crisis may occur in patients who excrete large quantities, over 200mg/day, of urinary 5HIAA.  Patients develop intense flushing, diarrhea, dehydration, hypotension, respiratory distress, cardiac rate disturbances, and death. Carcinoid crisis may happen spontaneously; often at the time of a biopsy or surgery or anesthesia.

Carcinoid tumors, like other tumors of neurological origin, produce a protein called Chromogranin and an enzyme Enolase. In carcinoids, chromogranin and enolase blood levels are high and are useful in the diagnosis but not diagnostic (normal 225ng /ml).

The incidence of Carcinoid syndrome is about 8 cases per year per million population and the incidence of carcinoid tumors is about 50 in one million population per year in the USA. Carcinoid syndrome is most frequently seen in small intestinal carcinoids and tumors are usually small and multiple.  Carcinoids also occur in the stomach, pancreas, bronchial tree, Meckel’s diverticulum, colon, rectum, appendix, ovary, and testis.  Carcinoid tumors of the appendix, colon, and rectum usually produce pain and intestinal obstruction. Carcinoid syndrome is seen in a third of the colon carcinoids and very rarely in carcinoids of the rectum and appendix. Once the tumor metastasizes to the liver it may produce carcinoid syndrome due to the direct discharge of serotonin into the bloodstream. This is also the case in ovarian carcinoid and retroperitoneal carcinoids though the incidence of carcinoid is rare in these locations.

Bronchial Carcinoid:

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Bronchial carcinoid is the second most common cause of carcinoid syndrome, even though carcinoid tumors account for less than 1% of all lung tumors. There are two subtypes – central and peripheral carcinoids. The central carcinoid tumors are located in the trachea, main bronchus, and its main branches. These tumors are slow growing and patients present with a cough and hemoptysis. Tumors are easily detected by bronchoscopy as small, fleshy, cherry red vascular tumors. Treatment can start early and patients have a better prognosis. The tumor in a later stage metastasizes to the liver.  Peripheral carcinoids are aggressive tumors that metastasize early in the regional lymph nodes and bone. Patients present with a cough, pneumonia and other signs of bronchial obstruction. CT scan of the chest detects the tumor and bronchoscopic biopsy is diagnostic.

There are certain special features of bronchial carcinoid syndrome.  Asthma attacks are common and generally last longer. Flushing is associated with increased tearing, sweating, and salivation. The flushed upper part of the body appears red in color and the flushing is intense. Diarrhea and other symptoms are like small bowel carcinoids.

Bronchial carcinoids often produce ACTH (adrenocorticotropic hormone) and growth hormone besides serotonin. Excess ACTH produces Cushing’s syndrome which is easy to diagnose by these features: central obesity, moon face, buffalo hump, wasting of muscles of upper and lower extremities, dark pigmentation, high BP, and diabetes mellitus. Acromegaly is produced by excess growth hormone-like-peptides by carcinoids. Acromegaly is also easy to recognize by very distinct clinical features: wide hands and feet, coarse facial features, protruding prominent lower jaw, large tongue, deep voice, hypertension, and cardiomegaly.

  

Somatostatin Receptors and Octeroid  Scan :

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Carcinoid tumors and other neuroendocrine tumors have receptors called Somatostatin receptors on the cell surface. There are 5 subtypes of somatostatin receptors 1 to 5(ss1 to ss5). The ss2 and ss5 bind with somatostatin most avidly. They also bind with a synthetic analog of somatostatin called Octreotide. Radioactive tagged octreotide scintigraphy (scan) is useful in localizing carcinoid tumors since ss2 and ss5 receptors are abundant in carcinoids.

Diagnosis of Carcinoid Syndrome:

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When a patient presents with symptoms of carcinoid syndrome or carcinoid crisis the clinical diagnosis is not difficult. An elevated blood level of chromogranin, 5HT and 5HPT and 24-hour urine 5HIAA should confirm the diagnosis. Localizing a small carcinoid tumor is difficult.

Routine X-Rays, CT scans, Sonograms, Endoscopy and MRI often fail to detect the tumor/ tumors.   The Octreotide scan is positive in 90 to 100 % of cases under this circumstance. It is a sensitive scan but not specific for carcinoids or other neuroendocrine tumors because the octreotide scans are also positive in granulomas like TB, sarcoid, lymphoma, wound infection and thyroid goiter.

Positron emission scans with 18F-fluoro-DOPA and 11C-5HPT scans are more sensitive scans but may not be widely available.

Once the localization of the tumor is made by an octreotide scan then a biopsy of the tumor is performed to confirm the diagnosis.

Gastric carcinoid:

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The incidence of Gastric Carcinoid is increasing.   The rise of gastric carcinoid is parallel with the increase in long term use of a potent gastric acid suppressing drug known as Proton-Pump-Inhibitor called Pantoprazole. Pantoprazole suppresses gastric acid but increases Gastrin (a hormone of the stomach) secretion. Gastrin stimulates carcinoid cellular growth and hyperplasia. High gastrin levels were seen in atrophic gastritis and pernicious anemia are also associated with an increased incidence of carcinoids. It is suspected that pantoprazole may be just one of several factors involved in the transformation of normal neuroendocrine cells into carcinoid tumors of the stomach. In MEN1 (multiple endocrine neoplasia 1) and Zollinger-Ellison syndrome, the gastrin levels are high and carcinoid tumors are part of the syndrome.  These two types of carcinoid tumors, associated with high serum gastrin levels, are multiple in number, less than 1 cm in size, invade only the submucosal layer of the stomach, and 25% of cases metastasize to the liver. A third type of gastric carcinoid not associated with high gastrin is an aggressive, large, solitary tumor and produces carcinoid syndrome, and over 60% of cases metastasize to the liver.

Some gastric carcinoids lack the DOPA-decarboxylase enzyme. Under normal conditions, this enzyme is required to convert 5HTP to 5PT.  Deficiency of this enzyme leads to accumulation of 5HTP in blood and the blood 5PT remains low or normal and urinary 5HIAA remains slightly above normal.  Kidneys can convert 5HPT to 5TP, and as a result, urinary 5TP is elevated. 

Other peptides and Hormones secreted by Carcinoid tumors:

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Many Carcinoids may not produce excess 5HT but generally, produce a number of other peptides and hormones. One tumor may produce several peptides and or hormones e.g.: -   adrenocorticotropic hormone (ACTH), insulin, calcitonin, glucagon, prostaglandins, vasoactive peptide (VAP), substance P, gastrin, ghrelin, motilin, alpha- subunit of growth hormone and others. Further discussion of these peptides/hormones will not be attempted here.

 Other Neuroendocrine Tumors:

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Of the non-carcinoid neuroendocrine tumors, pancreatic tumors are more prevalent. Other common sites are the small intestine, stomach, biliary tract, liver, ovary, and omentum. As in carcinoids these tumors may or may not secrete hormones but are capable of producing several hormones/chemicals in small quantities.

Those tumors that secrete hormones cause severe symptoms in patients but often are too small for a quick localization and treatment; whereas those do not secrete hormones grow to a large size before producing abdominal pain and by that time many tumors have metastasized and consequently the result of treatment is poor. In both instances, the usual time between the onset of symptoms and diagnosis is 5 years.

The diagnosis is strongly suggested by demonstrating elevated levels of hormone; localization of the tumor requires scanning and other methods and the final diagnosis is by a biopsy or removal of the tumor.

Only a few of these tumors will be mentioned briefly here:

Insulinoma:

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These tumors are located in the pancreas; usually multiple, and small less than 1cm in size, and only 10% are malignant. They produce insulin and proinsulin in excess amounts. The patient presents with very low fasting blood sugar levels - usually 45 mg/dl.  Because of hypoglycemia patients develop confusion, agitation, disorientation visual disturbances, and coma.

A diagnosis requires the presence of high plasma insulin, proinsulin and C-peptide levels besides severe low blood sugar in a fasting state.

Glocagonoma:

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It is also a pancreatic tumor. It produces glucagon in excessive amounts.  In normal circumstances, glucagon prevents hypoglycemia by raising blood sugar.  Patients with glucagonoma often develop a distinct skin rash around the mouth or groin or buttocks, other presenting symptoms of glucagonoma are diarrhea, weight loss, diabetes and recurrent thromboembolism.

This tumor is usually single, large 5 to 10 cm in diameter, located in the tail of the pancreas, 75% are malignant and metastasize to the liver. Diagnosis is made by the presence of high plasma levels of glucagon, over 1000ng/L. (normal less than 100 ng/L).

Gastrinoma:
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This tumor secretes gastrin in large amounts. Gastrin stimulates hydrochloric acid secretion by the parietal cells of the stomach. The patient develops severe, multiple peptic ulcers, often in unusual places, and these ulcers are registrant to treatment. Patients also have abdominal pain and diarrhea. This condition is better known as Zollinger-Ellison syndrome. The tumor usually is located in the duodenum; the next common sites are the pancreas, bile ducts, stomach, liver, and ovary. Diagnosis is made by demonstrating a basal gastrin level of over 1000ng/L, (normal 100 ng/L) and a high basal gastric acid secretion rate. Gastric pH remains below 2. In borderline cases, the Secretin Stimulation Test showing an increase in gastrin level 200ng/L over the basal gastrin level is considered diagnostic. This tumor is often malignant and metastases to the liver, bone and lymph nodes. Gastrinoma associated with MEN1 is located in the duodenum and multiple in number. 

Somatostatinoma Syndrome.

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Somatostatin is a neurotransmitter for the central nervous system and an inhibitor of all hormones in the gastrointestinal tract. It reduces gastric acid production, decreases pancreatic secretion, and decreases intestinal absorption of food. 

Tumors producing somatostatin are usually found in the head of the pancreas and small intestine. The tumor is large, about 5 cm in diameter, and often single. The liver is the main site of metastasis.

Patients present with diabetes mellitus, gallbladder disease, diarrhea and fat malabsorption.

Diagnosis requires demonstrating a high blood level of somatostatin.

Vipoma.

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Vaso-intestinal-peptide (VIP) producing tumor is called vipoma. VIP is also a neurotransmitter. It is a potent vasodilator and increases chloride secretion in the small intestine and stimulates smooth muscle contractions. Tumors are usually located in the tail of the pancreas and are usually single and large in size, and metastasize to the liver.

The presenting symptoms are watery diarrhea - over a liter a day, severe hypokalemia and vasomotor collapse. This condition is commonly known as pancreatic cholera.

Non-Functional Neuroendocrine tumors.

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The pancreas is the usual location of these tumors. The tumors are often single and over 5 cm in size, located in the head of the pancreas. Even tumors known as non-secretors, they produce very small amounts of several chemicals like chromogranin, growth hormone, and other peptides.

The patient presents with abdominal pain, jaundice, spontaneous bleeding and weight loss.

Diagnosis is often made very late in the disease and requires a biopsy.  Liver metastasis is common.

There are many other tumors under this category. In addition, some of these tumors are present as a part of groups e.g., in Multiple Endocrine Neoplasm (MENS I) and other such conditions.
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