Gastrinoma։ What patients should know about

Causes and Risk Factors of Gastrinoma

The risk factors for developing gastrinoma include:

1. Multiple Endocrine Neoplasia Type 1 (MEN1):
   • Approximately 25-30% of gastrinomas are associated with MEN1, an inherited genetic disorder characterized by the development of tumors in hormone-producing glands.
   • Individuals with MEN1 have a higher risk of developing gastrinomas, as well as other neuroendocrine tumors.
2. Family History:
   • Children of adults with MEN1 are at a greater risk of developing gastrinomas.
   • A family history of gastrinoma or other neuroendocrine tumors may increase the likelihood of developing these tumors.
3. Genetic Factors:
   • Gastrinomas can develop sporadically for unknown reasons, but there may be genetic links that predispose certain individuals to these tumors.
   • Genetic mutations or alterations may play a role in the development of gastrinomas in some cases.
4. Age and Gender:
   • Gastrinomas are more common in men, particularly those aged 30 to 50 years old.
   • While gastrinomas can occur at any age, they are more frequently diagnosed in adults.

Understanding these risk factors is essential for identifying individuals who may be at a higher risk of developing gastrinomas and may benefit from early screening and monitoring for these rare neuroendocrine tumors.

Symptoms of Gastrinoma

The symptoms of gastrinoma, a rare neuroendocrine tumor that originates from G cells in the pancreas, stomach, or small intestine, can be asymptomatic or present with signs and symptoms related to the excessive production of gastrin and the resulting increase in stomach acid. Common symptoms include:

1. Abdominal pain
2. Nausea
3. Vomiting
4. Weight loss
5. Diarrhea
6. Steatorrhea (fatty stools)
7. Gastroesophageal reflux
8. Gastrointestinal bleeding
9. Peptic ulcers

Tumor can lead to a rare condition known as Zollinger-Ellison syndrome, characterized by severe, recurrent, and multiple peptic ulcers in the small intestine. The excess gastrin secreted by the tumor cells can cause the stomach to produce far too much acid, leading to symptoms similar to those caused by peptic ulcers, including pain and bleeding.

Diagnosis of Gastrinoma

Gastrinoma is typically diagnosed through a combination of laboratory tests, imaging studies, and tissue biopsy. The key steps in diagnosing tumor include:Fasting serum gastrin levels:

• Elevated fasting serum gastrin levels, usually over 150 pg/mL (72 pmol/L), are the most reliable diagnostic test for tumors.
• Markedly elevated levels of over 1000 pg/mL (480 pmol/L) in a patient with compatible clinical features and gastric acid hypersecretion of over 15 mEq/hour establish the diagnosis.

Secretin stimulation test:

• In cases where fasting serum gastrin levels are inconclusive, a secretin stimulation test may be performed.
• Secretin is a hormone that stimulates the release of gastrin from gastrinoma cells, causing a rise in serum gastrin levels.

Imaging studies:

• Various imaging techniques are used to locate the gastrinoma and assess for metastatic disease.
• These include computed tomography (CT), magnetic resonance imaging (MRI), endoscopic ultrasound, somatostatin receptor scintigraphy, and positron emission tomography (PET) scans.
• However, tumors can be small and difficult to visualize on imaging.

Frequent locations of pNETs: anatomical imaging. A gastrinoma is typically located in the “gastrinomas triangle” (yellow dotted triangle). Extrapancreatic nodule measuring 10 mm located in the gastrinomas triangle with homogeneous arterial (right), and portal contrast enhancement (middle). b Insulinoma is more often localized in the pancreas head. This case shows a 25-mm nodule with arterial (right), and portal contrast hyperenhancement (middle). The report should always include the absence of vascular and perineural involvements (as well as distal metastases) in order to confirm the resectability. This image is taken from researchgate.net

Tissue biopsy:

• In some cases, a tissue biopsy may be performed to confirm the diagnosis and assess for malignancy.
• A biopsy can provide evidence of G cell proliferation and help rule out other potential causes of hypergastrinemia.

The diagnosis of gastrinoma is suspected when a patient presents with symptoms of aggressive peptic ulcers that are refractory to standard acid suppression therapy. A combination of elevated fasting serum gastrin levels, a positive secretin stimulation test, and imaging findings consistent with a tumor is typically required to establish the diagnosis.

Treatment of Gastrinoma

The treatment options for tumor, a type of neuroendocrine tumor that produces excessive levels of the hormone gastrin, include:

1. Surgical Resection:
   • Surgical removal of the tumor is the treatment of choice for localized disease, especially for primary pancreatic neuroendocrine tumors (PNETs).
   • Resection aims to remove the tumor completely and is associated with increased survival rates.
   • Surgical resection can lead to a complete cure without recurrence in a significant percentage of patients with gastrinomas.
2. Chemotherapy:
   • Chemotherapy is indicated for patients with metastatic disease or those who are not candidates for surgery.
   • Chemotherapy can reduce tumor size and improve symptoms secondary to metastatic effects of the tumor.
   • A combination of streptozocin, 5-fluorouracil, and doxorubicin has been used with a reported response rate of up to 65%.
3. Targeted Therapies:
   • Targeted therapies, such as somatostatin analogs like Sandostatin LAR, interferon, and targeted radiotherapy, may be considered for patients who are not candidates for chemotherapy.
   • Treatment with targeted somatostatin-based radiotherapy, such as [90Y-DOTA]-TOC or [177Lu-DOTA]-TOC, has been shown to improve overall survival in patients with metastasized gastrinoma.
4. Medical Management:
   • Medications to reduce stomach acid levels, such as proton pump inhibitors, are commonly used to control symptoms related to excessive gastric acid production.
   • High doses of proton pump inhibitors are often prescribed to reduce acid levels in the stomach.
5. Consultations:
   • Consultations with specialists like gastroenterologists, endocrinologists, oncologists, and surgeons are essential for the comprehensive management of tumor.
6. Long-Term Monitoring:
   • Follow-up care for patients with resected tumors focuses on monitoring for recurrence and managing any recurrent disease promptly.
   • Long-term acid suppression and chemotherapy may be used to manage metastatic disease.

These treatment options aim to control symptoms, reduce tumor burden, and improve the overall quality of life for patients with gastrinoma. The choice of treatment depends on factors such as tumor size, location, extent, and the presence of metastasis.

Prognosis and Survival

The prognosis and survival rates for patients with gastrinoma vary based on several factors, including the presence of metastases, tumor size, and whether the tumor can be completely surgically removed.

General Survival Rates

Almost 85% of people survive for 5 years or more after diagnosis, and 65% survive for 10 years or more. These statistics are derived from a Dutch study that looked at 63 people diagnosed with gastrinoma between 1990 and 2014.

MEN1 Patients

For patients with multiple endocrine neoplasia type 1 (MEN1) who have gastrinomas, the 5- and 10-year overall survival (OS) rates are 83% and 65%, respectively. Prognostic factors associated with overall survival in MEN1 patients include initial fasting serum gastrin (FSG) levels, pancreatic NET size ≥2 cm, synchronous liver metastases, gastroduodenoscopy suspicion for gastric NETs, and multiple concurrent NETs.

Surgical Outcomes

If the tumor is completely surgically removed, people have a greater than 90% chance of surviving 5 to 10 years. However, if the tumor is not completely removed, the 5-year survival rate drops to 43%, and the 10-year survival rate to 25%.

MEN1 with Small Gastrinomas

Survival in patients with MEN1 with gastrinomas smaller than 2.5 cm in size has been reported to be 100% at 15 years. In contrast, if metastatic disease is present, the survival rate at 15 years is 52%.

Factors Affecting Survival

Metastasis

The presence of hepatic metastases significantly impacts prognosis. Patients with hepatic metastases might have a remaining lifespan of one year with a five-year survival rate of 20-30%. In contrast, patients with localized tumor or localized lymph spread have a five-year survival rate of 90%

Tumor Size and Location

Pancreatic gastrinomas are larger than their duodenal counterparts and may have different survival outcomes. The size of the tumor and its location (pancreatic vs. duodenal) can influence the prognosis

Treatment Options

The choice of treatment, including surgery, medication, and potentially chemotherapy, can affect survival outcomes. Surgical resection offers the possibility of cure in some cases, especially if the tumor is localized and can be completely removed

MEN1 Association

Gastrinomas associated with MEN1 syndrome may follow a different clinical course compared to sporadic gastrinomas. MEN1-associated gastrinomas are often multiple and may present at an earlier age

Conclusion

The prognosis for patients with gastrinoma is influenced by a variety of factors, including the presence of metastases, tumor size, surgical outcomes, and association with MEN1 syndrome. While the general survival rates are encouraging, especially with complete surgical removal, the presence of metastatic disease or association with MEN1 can significantly impact long-term survival. Continuous monitoring and tailored treatment strategies are essential for managing patients with gastrinoma effectively.

Challenges and Considerations

1. Misdiagnosis

• Gastrinoma is often misdiagnosed due to its relative rarity and lack of specific symptoms.
• Typical symptoms include abdominal pain, secretory diarrhea, esophagitis, and hypercalcemia, which can be mistaken for other conditions.

2. Differential Diagnosis:

• Peptic ulcers caused by gastrinoma should be distinguished from other conditions like annular pancreas, which can lead to similar symptoms.
• Compression from the annulus to the duodenum may result in peptic ulcers, emphasizing the need for accurate diagnosis and differentiation.

3. Diagnostic Challenges:

• Tumor diagnosis relies on serum gastrin levels, which can significantly exceed normal limits in affected individuals.
• Hypergastrinemia may also be observed in other conditions, necessitating a comprehensive diagnostic approach for accurate identification.

4. Imaging and Localization

• Locating tumors prior to surgery is crucial for effective management.
• While ultrasonography is a common diagnostic tool, its sensitivity is limited, necessitating the use of additional imaging techniques like CT, MRI, and somatostatin receptor scintigraphy for accurate localization.

5. Surgical Management

• Surgical excision remains the primary curative treatment for gastrinoma, but challenges exist in locating and removing the tumor effectively.
• Recent advancements have improved the ability to find and excise gastrinomas, enhancing the chances of successful treatment and cure.

During Treatment

The most common side effects during treatment for gastrinoma, include: