Gastrinoma

Gastrinoma is a very rare neuroendocrine tumor (NET) that starts in the neuroendocrine cells that make the hormone gastrin ¹. There are neuroendocrine cells in most organs of your body, including the small bowel (duodenum) and pancreas. Most gastrinomas start in the small bowel (duodenum) and the pancreas. All gastrinomas are cancers. Some gastrinomas grow slowly and don’t spread to other parts of the body. Others can spread to other parts of the body (metastases).

Gastrinomas make large amounts of the hormone gastrin. Gastrin controls the amount of acid in your stomach, which helps to digest food. Too much acid can cause ulcers in the stomach and the small bowel (duodenum).

The combination of high levels of gastrin, too much acid and stomach or small bowel ulcers is called Zollinger Ellison syndrome.

Only between 1 and 2 people in every million develop a gastrinoma every year. With improved techniques for tumor detection, the annual incidence has increased. About 80% to 90% of these tumors arise in the so-called “gastrinoma triangle,” an anatomical area in the abdomen with boundaries formed superiorly by the confluence of the cystic and common bile ducts, inferiorly by the second and third portions of the duodenum, and medially by the neck of the pancreas ².

Around 70 out of every 100 gastrinomas (70%) start in the duodenum. Tumors that start in the duodenum are usually small (often less than 1 cm across). They are called duodenal gastrinomas.

About 25 out of every 100 gastrinomas (25%) start in the pancreas. Pancreatic gastrinomas usually start in the widest part of the pancreas (the head). The head of the pancreas is the part closest to the duodenum. Pancreatic gastrinomas are often bigger than duodenal gastrinomas.

More rarely gastrinomas can start in the:

• stomach
• liver
• bile duct
• ovary
• heart
• lungs

Gastrinomas that start in the pancreas are more likely to spread to other parts of the body, than gastrinomas that start in the duodenum:

• up to 35 out of every 100 pancreatic gastrinomas (35%) spread to the liver
• up to 10 out of every 100 duodenal gastrinomas (10%) spread to the liver

Gastrinomas can also spread to the nearby lymph nodes.

Gastrinoma causes

Gastrinomas along with other pancreatic endocrine tumors are thought to originate from endodermal pluripotent cells. Gastrinomas can be either sporadic (75% to 80%) or associated with multiple endocrine neoplasia type 1 (MEN-1) syndrome, an autosomal dominant inherited disorder (20% to 30%). MEN1 is caused by germline mutations in the tumor suppressor MEN1 gene located on chromosome 11q13. It has been proposed that the tumors arise in susceptible patients as a result of multiple independent second-hit mutations in the MEN1 gene ³.

Gastrinoma symptoms

Gastrinoma usually starts in the duodenum (small bowel) or pancreas. Gastrinoma symptoms can be vague. Gastrinomas make large amounts of the hormone gastrin. Gastrin controls the amount of acid in your stomach, which helps to digest food. You usually have symptoms caused by the increase in the amount of stomach acid. See your your doctor if you are worried.

Pain in the abdomen

This is usually caused by a stomach or duodenal ulcer. Between 70 and 100 out of every 100 people with gastrinoma (70 to 100%) have abdominal pain.

Diarrhea

Diarrhea means having more than 3 watery poop (stools) in a 24 hour period. You might also have diarrhea at night and problems controlling your bowels (incontinence).

Between 30 and 70 out of every 100 people with gastrinoma (30 to 70%) have diarrhea.

Indigestion (heartburn)

Heartburn is burning chest pain or discomfort after eating. It happens when acid from the stomach goes back up into the food pipe (esophagus) or if the stomach is inflamed or irritated.

Between 40 and 60 out of every 100 people with gastrinoma (40 to 60%) have symptoms of indigestion.

Bleeding

Gastrinomas can cause bleeding. You may not be able to see any blood if it’s a small amount. Or you may see blood in your vomit or poo. Over time, bleeding reduces the number of red blood cells in your blood (anemia).

Speak to your doctor if you see blood in your poop or if your stools are back or sticky.

Between 40 and 70 out of every 100 people with gastrinoma (40 to 70%) have bleeding.

Feeling or being sick

You may feel or be sick. Between 10 and 30 out of every 100 people with gastrinoma (10 to 30%) have sickness.

Losing weight

You might lose a lot of weight (even if you’re not dieting). Between 7 and 50 out of every 100 people with gastrinoma (7 to 50%) lose weight.

Zollinger-Ellison syndrome

Zollinger-Ellison syndrome is the name given to the collection of symptoms caused by high levels of the hormone gastrin. Zollinger-Ellison syndrome often causes:

• stomach or small bowel ulcers (peptic ulcer disease)
• acid reflux (gastro esophageal reflux or GER for short)

Gastrinoma diagnosis

Due to the elusive nature of gastrinoma, the diagnosis is based on the following 3 criteria ⁴:

1. Fasting hypergastrinemia is present (>150 pg/mL with levels >100,000 pg/mL in some patients; a serum gastrin level >1,000 pg/mL in the appropriate clinical setting is virtually diagnostic of Zollinger-Ellison syndrome).
2. Basal acid output is greater than 10 mEq/h.
3. Results from a secretin stimulation test are positive.

Fasting serum gastrin measurement is discussed as follows:

• This is the most sensitive test for the diagnosis of Zollinger-Ellison syndrome.
• This screening test is indicated for patients strongly considered to have a gastrinoma (see History).
• Stop histamine 2 (H2) blockers 1 day or omeprazole 6 days prior to performing the study.
• The reference range for fasting serum gastrin usually is 50-60 pg/mL, with an upper limit as high as 150 pg/mL.
• Levels higher than 1000 pg/mL with acid hypersecretion are highly suggestive of Zollinger-Ellison syndrome.

Because low gastric acid output (eg, in atrophic gastritis, pernicious anemia, or postvagotomy state) can lead to hypergastrinemia, check patients for the following:

• A gastric pH level higher than 3.0 excludes gastrinoma.
• A basal acid output of greater than 15 mEq/h and even as high as 150 mEq/h is indicative of gastrinoma.

In patients with intermediate gastrin levels (150-1000 pg/mL) and acid secretion, the secretin stimulation test can help diagnose the presence of gastrinoma. Intravenous secretin (2 U/kg) raises the serum gastrin levels to higher than 200 pg/mL within 2 minutes and, virtually always, within 10 minutes in patients with gastrinomas.

Imaging studies

Imaging studies are helpful in localizing the gastrinoma tumor. They also are helpful for assessing surgical resectability by helping reveal liver metastasis.

Somatostatin receptor scintigraphy is very useful to identify the primary lesions preoperatively. Somatostatin receptor scintigraphy is the most sensitive noninvasive method for localizing the primary tumors and metastases. It also is helpful for detecting the presence of liver or bone metastasis. The findings from this technique can be used to differentiate small liver metastases from small liver hemangiomas. Occasionally, false-positive somatostatin receptor scintigraphy localization results can occur.

Endoscopic ultrasonography has also been found to be useful in helping to detect the primary tumor, with a reported overall sensitivity and accuracy greater than 90% for intrapancreatic gastrinomas. For extrapancreatic gastrinomas in the duodenal wall, endoscopic ultrasound is useful but somewhat less sensitive.

Computed tomography (CT) scanning and selective angiogram also are helpful in detecting gastrinoma.

Magnetic resonance imaging (MRI) can be used as an adjunct to the imaging studies already discussed. MRI has great value in identifying liver metastases but has not been shown to be useful in detecting extrahepatic tumors less than 1 cm in diameter.

Because of the large proportion of primary gastrinomas in the proximal duodenum, upper endoscopy may also be a useful tool in the localization of tumors in these patients.

Other tests

Selective arterial secretin injection, involving the gastroduodenal, splenic, and superior mesenteric arteries, with assessment of the hepatic vein serum gastrin concentrations is one among several diagnostic procedures proposed for helping identify gastrinomas. However, this test has been shown to be of value primarily in localizing gastrinomas in the head of the pancreas and proximal duodenum and, therefore, is infrequently recommended.

The calcium infusion test, calcium gluconate, is infused intravenously over 180 minutes with serum gastrin levels obtained at set intervals. In most patients with gastrinomas, this should substantially increase serum gastrin levels (>400 pg/mL increase).

Levels of serum chromogranin A (CgA), a nonspecific marker for neuroendocrine tumors, do not appear to have any value in the diagnosis of gastrinomas compared with alpha-amidated gastrin levels ⁵. In a separate study that compared the sensitivity, specificity, and positive/negative predictive values of plasma chromogranin A levels with a polymerase chain reaction (PCR) assay based on a 51-transcript signature to detect neuroendocrine tumors, the PCR (polymerase chain reaction)-based assay was not only significantly superior to chromogranin A on all performance metrics, but it was also not affected by proton pump inhibitor therapy ⁶.

Gastrinoma treatment

The treatment you have for gastrinoma depends on a number of things such as where the tumour is, its size and whether it has spread (the stage).

Surgery is the main treatment for gastrinoma and it’s usually the only treatment that can cure it. But surgery isn’t always possible. Some gastrinomas may have already started to spread when they are diagnosed. You might have treatment to control your symptoms if you can’t have surgery to try to cure your gastrinoma.

Deciding which treatment you need

A team of doctors and other professionals will discuss your treatment, its benefits and the possible side effects with you. They are called a multidisciplinary team.

The treatment you have depends on:

• where the gastrinoma is and its size
• whether you have 1 or more tumors
• whether the gastrinoma has spread to other parts of the body
• your general health
• whether you have an inherited syndrome called multiple endocrine neoplasia 1 (MEN1)

Surgery

Surgery is the main treatment for gastrinoma. The type of surgery you have depends on whether the gastrinoma started in the small bowel (duodenum) or the pancreas. Some of these are major operations and there are risks with having these types of surgery. But if the aim is to try to cure your gastrinoma, you might feel it is worth some risks. Talk to your doctor about the risks and benefits of your surgery.

You usually have open surgery. This means having a large cut in your tummy (abdomen). You also have an ultrasound scan during your operation to check for other tumors. Your surgeon might also remove the nearby lymph nodes.

Surgery for gastrinomas in the small bowel (duodenum)

• You might have an operation called duodenectomy. Your surgeon makes a cut (incision) in your tummy to open the small bowel and remove the tumor.

Surgery for pancreatic gastrinoma

You usually have an operation to remove just the pancreatic gastrinoma. This is called a tumor enucleation. You have this if the gastrinoma is in the widest part of the pancreas (the head).

If your cancer is near the pancreatic duct, you have an operation to remove:

• the widest part of the pancreas (head), the duodenum, gallbladder and part of the bile duct (pylorus preserving pancreaticoduodenectomy or PPPD for short)
• the narrowest part of the pancreas (tail) and the body of the pancreas called distal pancreatectomy

For certain people, doctors may suggest an operation called Whipple’s procedure. This is the same as a pylorus preserving pancreaticoduodenectomy, but the surgeon also removes part of your stomach. You may have a Whipple’s operation if you have large tumors that can’t be removed by tumour enucleation.

If the gastrinoma has spread to the liver, you might be able to have the liver tumor removed at the same time you have the main surgery. Your surgeon may remove just the tumor, or part of the liver too.

Drugs to control the amount of stomach acid

Gastrinomas make large amounts of the hormone gastrin, which increases the amount of acid in your stomach. So you usually have treatment to stop your stomach from making too much acid.

The main treatment to stop you from making too much acid are drugs called proton pump inhibitors (PPIs). You usually have 1 of the following drugs:

• omeprazole
• lansoprazole
• pantoprazole
• esomeprazole

Treatment for advanced gastrinomas

Gastrinomas can spread to other parts of the body or can come back after surgery. This is advanced cancer. One of the most common places where gastrinoma can spread to is the liver.

For advanced gastrinomas, you might have:

Chemotherapy

Chemotherapy uses anti cancer (cytotoxic) drugs to destroy tumor cells. You may have chemotherapy if the gastrinoma cancer has spread to your liver or to other parts of your body.

The most common chemotherapy drugs used are:

• streptozotocin or temozolomide
• fluorouracil or capecitabine
• doxorubicin

Somatostatin analogues

Somatostatin is a protein made naturally in the body. It does several things including slowing down the production of hormones. Somatostatin analogues are man made versions of somatostatin.

You may have somatostatin analogues to try to slow down the tumour and help with symptoms. The most common drugs used are:

• octreotide (Sandostatin)
• lanreotide (Somatuline)

Somatostatin analogues don’t help everyone with gastrinoma. This treatment only helps about 10 in every 100 people (10%) with gastrinoma.

Radiofrequency ablation

Radiofrequency ablation (RFA) uses heat made by radio waves to kill tumor cells. You might have this if the gastrinoma cancer has spread to the liver.

Trans arterial embolization

You might have trans arterial embolization (TAE) if the gastrinoma cancer has spread to the liver.

Trans arterial embolization also called hepatic artery embolization, means having a substance such as a gel or tiny beads to block the blood supply to the liver gastrinoma cancer.

You may also have a chemotherapy drug to the liver at the same time. This is called trans arterial chemoembolisation (TACE). But doctors don’t know for sure whether adding chemotherapy is better than having embolization alone for gastrinoma cancers that have spread to the liver.

Embolization and chemoembolization work in two ways:

1. it reduces the blood supply to the tumor and so starves it of oxygen and the nutrients it needs to grow
2. it gives high doses of chemotherapy to the tumour without affecting the rest of the body

Targeted drugs

Cancer cells have changes in their genes (DNA) that make them different from normal cells. These changes mean that they behave differently. Targeted drugs work by ‘targeting’ the differences that a cancer cell has and destroying them.

You may have 2 types of targeted drugs called everolimus and sunitinib.

Interferon

Interferon is also called interferon alfa. You may have it if the gastrinoma has spread to other parts of the body. And other treatments have stopped working.

You may have interferon alone or together with somatostatin analogues.

Radiotherapy

You may have a type of internal radiotherapy called peptide receptor radionuclide therapy (PRRT). Internal radiotherapy means having radiotherapy from inside the body (as a drip into your bloodstream).

Peptide receptor radionuclide therapy uses a radioactive substance called lutetium-177 or yttrium-90 attached to a somatostatin analogue.

You may have peptide receptor radionuclide therapy if:

• your gastrinoma cancer has spread to other parts of the body
• you can’t have surgery
• your gastrinoma cancer has receptors on the outside of them called somatostatin receptors (you have special scans called octreotide or gallium PET scans to check for this)

Liver transplant

You may have a liver transplant if the gastrinoma cancer has only spread to the liver and you’re fit and healthy. But a liver transplant might not be possible even if your doctor thinks you can have it. This is because you need a donor liver that is a close match to yours.

A liver transplant is a major operation and it has many risks. It is rarely used as a treatment for gastrinoma cancers.

Clinical trials

For some patients, taking part in a clinical trial may be the best treatment choice. Clinical trials are part of the cancer research process. Clinical trials are done to find out if new cancer treatments are safe and effective or better than the standard treatment.

Many of today’s standard treatments for cancer are based on earlier clinical trials. Patients who take part in a clinical trial may receive the standard treatment or be among the first to receive a new treatment.

Patients who take part in clinical trials also help improve the way cancer will be treated in the future. Even when clinical trials do not lead to effective new treatments, they often answer important questions and help move research forward.

Information about clinical trials is available from the National Cancer Institute website (https://www.cancer.gov/about-cancer/treatment/clinical-trials/search). Use the National Cancer Institute clinical trial search to find National Cancer Institute-supported cancer clinical trials that are accepting patients. You can search for trials based on the type of cancer, the age of the patient, and where the trials are being done.

Gastrinoma prognosis

Patients with liver metastases may have a remaining life span of less than 1 year; the 5-year survival rate is 20-30%.

In patients with localized disease or metastasis to local lymph nodes without liver metastasis, the 5-year survival rate may be 90%.

Surgical resection of localized disease leads to a complete cure without any recurrence in 20-25% of patients with gastrinomas.

Mortality and morbidity

With the advent of anti-ulcer medications, the number of deaths secondary to ulcer complications has decreased significantly. The primary determinants of survival for patients with gastrinomas are the size of the primary tumor and the occurrence of tumor metastasis.

Gastrinoma survival rate

Gastrinoma is a type of neuroendocrine tumour (NET) that starts in the neuroendocrine cells of the pancreas or the small bowel (duodenum).

Survival for gastrinomas depends on many factors. It depends on the stage and grade of the gastrinoma when it was diagnosed. The stage describes the size of the tumour and whether it has spread. The grade means how abnormal the cells look under a microscope. Another factor is how well you are overall. So no one can tell you exactly how long you will live.

Doctors usually work out the outlook for a certain disease by looking at large groups of people. Because gastrinomas are rare tumors, the survival for this disease is harder to estimate than for other, more common cancers.

These are general statistics based on small groups of people. Remember, they can’t tell you what will happen in your individual case. Your doctor can give you more information about your own outlook (prognosis).

Study looked at the survival of people with gastrinomas that had or had not spread to the liver at the time of diagnosis.

Survival for gastrinomas that hasn’t spread to the liver

• Most people with a gastrinoma that hasn’t spread to the liver have surgery to try to cure their cancer.
• More than 90 out of every 100 people (95%) survive for 5 years or more. And around 90 out of every 100 people (90%) survive for 10 years or more.

Survival for gastrinomas that has spread to the liver

• Most people with a gastrinoma that has spread to the liver have treatment to try to control the growth of their cancer.
• More than 50 out of every 100 people (50%) survive 5 years or more. And around 30 out of every 100 people (30%) survive for 10 years or more.

The term 1 year, 5 year and 10 year survival does not mean that you will only live for 1, 5 or 10 years. They relate to the number of people who are still alive 1 year, 5 years or 10 years after their diagnosis.

Some people live much longer than 10 years.

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