10 Key Symptoms of Pancreatic Neuroendocrine Tumors You Should Know

Pancreatic neuroendocrine tumors (PNETs), also known as islet cell tumors, are a rare type of cancer that originates in the hormone-producing cells of the pancreas. Unlike the more common pancreatic adenocarcinoma, neuroendocrine pancreatic cancer tends to grow more slowly and may produce various hormones that cause distinctive symptoms. These tumors account for only about 3-5% of all pancreatic cancers, but recognizing their symptoms early can significantly impact treatment outcomes and quality of life.

PNETs can be classified as either functional (hormone-producing) or non-functional (non-hormone-producing). Functional tumors cause symptoms related to excess hormone production, while non-functional tumors typically produce symptoms only when they grow large enough to affect surrounding organs. Understanding the various symptoms associated with these tumors is crucial for early detection and proper medical intervention.

1. Abdominal Pain and Discomfort

Abdominal pain is one of the most common symptoms experienced by patients with pancreatic neuroendocrine tumors, particularly when tumors are non-functional or have grown to a significant size. The pain typically manifests in the upper abdomen and may radiate to the back, creating a band-like sensation around the midsection.

This discomfort occurs because the growing tumor puts pressure on surrounding tissues, organs, and nerves in the abdominal cavity. The pancreas is located deep in the abdomen, behind the stomach, so pain from pancreatic tumors often feels deep-seated and persistent. Patients describe the sensation as a dull, aching pain that may worsen after eating or when lying flat. The pain can be intermittent initially but tends to become more constant as the tumor progresses.

The intensity of abdominal pain doesn’t always correlate with tumor size, as smaller tumors in sensitive locations can cause significant discomfort. Some patients also experience tenderness when pressure is applied to the upper abdomen during physical examination.

2. Hypoglycemia (Low Blood Sugar)

Hypoglycemia is a hallmark symptom of insulinomas, the most common type of functional pancreatic neuroendocrine tumor. These tumors produce excessive amounts of insulin, causing blood sugar levels to drop dangerously low, often during fasting periods or between meals.

Symptoms of hypoglycemia associated with insulinomas include:

• Confusion, dizziness, and difficulty concentrating
• Excessive sweating, particularly at night
• Rapid heartbeat and palpitations
• Trembling or shakiness
• Intense hunger
• Weakness and fatigue
• Blurred vision
• In severe cases, seizures or loss of consciousness

What distinguishes tumor-related hypoglycemia from other causes is the pattern known as “Whipple’s triad”: symptoms occur during fasting, documented low blood glucose levels accompany the symptoms, and symptoms resolve when blood sugar is restored. Patients often find themselves needing to eat frequently, including waking up at night to consume food to prevent dangerous drops in blood sugar.

3. Peptic Ulcers and Severe Acid Reflux

Gastrinomas, tumors that produce excessive amounts of the hormone gastrin, cause a condition known as Zollinger-Ellison syndrome. The overproduction of gastrin stimulates the stomach to produce far more acid than normal, leading to severe and recurrent peptic ulcers in the stomach and small intestine.

These ulcers are notably different from common peptic ulcers because they:

• Tend to be multiple rather than single
• Occur in unusual locations, such as the jejunum (part of the small intestine)
• Are resistant to standard ulcer treatments
• Recur quickly even after successful treatment
• May cause complications like bleeding or perforation

Patients typically experience severe heartburn, burning chest pain, and persistent indigestion that doesn’t respond well to over-the-counter antacids. The excessive stomach acid can also damage the lining of the esophagus, causing painful swallowing and chronic acid reflux. Some patients develop severe diarrhea due to the high acid content reaching the intestines and interfering with normal digestion and nutrient absorption.

4. Chronic Diarrhea

Chronic diarrhea is a prominent symptom in several types of functional pancreatic neuroendocrine tumors. VIPomas (tumors producing vasoactive intestinal peptide) cause a syndrome called WDHA (Watery Diarrhea, Hypokalemia, and Achlorhydria), characterized by profuse, watery diarrhea that can be debilitating.

The diarrhea associated with neuroendocrine pancreatic tumors has distinctive features:

• Large volume (often more than 3 liters per day in VIPomas)
• Watery consistency without blood or mucus
• Persists even when fasting
• Doesn’t respond to standard anti-diarrheal medications
• May be accompanied by abdominal cramping

This chronic diarrhea leads to significant dehydration, electrolyte imbalances (particularly low potassium levels), and weight loss. Patients may need to stay close to bathroom facilities, which can severely impact their quality of life and daily activities. The excessive fluid loss can also cause weakness, muscle cramps, and in severe cases, dangerous cardiac arrhythmias due to electrolyte disturbances.

5. Skin Rash and Flushing

Glucagonomas, rare pancreatic neuroendocrine tumors that produce excess glucagon, cause a distinctive skin condition called necrolytic migratory erythema (NME). This characteristic rash is often one of the first signs that leads to diagnosis of a glucagonoma.

The skin manifestations include:

• Red, raised patches that typically start in the groin, buttocks, and legs
• Blisters that break open, crust over, and heal, leaving darkened skin
• The rash migrates across the body, hence “migratory” in its name
• Painful or itchy lesions
• Affected areas may become infected due to skin breakdown

Additionally, some patients with carcinoid-type pancreatic neuroendocrine tumors may experience episodes of facial flushing. The flushing appears as sudden redness of the face and upper chest, often accompanied by a sensation of warmth. These episodes can be triggered by stress, alcohol consumption, certain foods, or occur spontaneously. The flushing may last from a few minutes to several hours and can be accompanied by rapid heartbeat and low blood pressure.

6. Unexplained Weight Loss

Significant, unintentional weight loss is a common symptom in patients with pancreatic neuroendocrine tumors, particularly those with non-functional tumors or advanced disease. Unlike weight loss from dieting, this occurs without trying and can be rapid and substantial.

The weight loss in neuroendocrine pancreatic cancer results from multiple factors:

• Decreased appetite due to the tumor’s effect on metabolism and digestion
• Malabsorption of nutrients when the tumor affects pancreatic function
• Increased metabolic demands as the body fights the disease
• Chronic diarrhea leading to nutrient loss (in functional tumors)
• Early satiety (feeling full quickly) when tumors press on the stomach

Patients may lose 10% or more of their body weight over a period of several months without changes to their diet or exercise routine. This weight loss is often accompanied by muscle wasting, weakness, and a general sense of declining health. Clothing becomes loose, and patients may notice their face appearing more gaunt. The weight loss can be particularly concerning because it often indicates more advanced disease or significant metabolic disruption from hormone-secreting tumors.

7. Jaundice (Yellowing of Skin and Eyes)

Jaundice occurs when pancreatic neuroendocrine tumors grow large enough to compress or block the bile duct, preventing bile from flowing normally from the liver into the intestines. This causes bilirubin, a yellow pigment, to accumulate in the blood and body tissues.

Signs of jaundice in pancreatic neuroendocrine tumors include:

• Yellowing of the skin and the whites of the eyes
• Dark, tea-colored urine
• Pale or clay-colored stools
• Intense itching all over the body, particularly at night
• Feeling of fullness or discomfort in the upper right abdomen

The itching associated with jaundice can be particularly distressing and is caused by bile salts accumulating in the skin. Patients often scratch until their skin bleeds, leading to secondary skin infections and scarring. The jaundice typically develops gradually, and patients or their family members may notice the yellowing before other symptoms become apparent. While jaundice is more common in pancreatic adenocarcinoma, it can occur with neuroendocrine tumors, especially those located in the head of the pancreas near the bile duct.

8. Diabetes or Worsening Blood Sugar Control

New-onset diabetes or sudden worsening of previously controlled diabetes can be a sign of pancreatic neuroendocrine tumors. This occurs because tumors can damage the insulin-producing beta cells in the pancreas or disrupt normal pancreatic function.

Paradoxically, while insulinomas cause low blood sugar, other types of pancreatic neuroendocrine tumors can lead to high blood sugar levels by:

• Destroying normal pancreatic tissue, reducing insulin production
• Producing hormones like glucagon or somatostatin that counteract insulin
• Interfering with the pancreas’s ability to regulate blood glucose

Patients may experience symptoms of elevated blood sugar including increased thirst, frequent urination, blurred vision, fatigue, and slow-healing wounds. In some cases, patients who have had well-controlled diabetes for years suddenly find their blood sugar levels becoming difficult to manage despite no changes in their diet, exercise, or medication. This new-onset or difficult-to-control diabetes warrants investigation, particularly in older adults without traditional risk factors for diabetes. The diabetes associated with pancreatic tumors may require higher doses of medication or insulin to control.

9. Nausea and Vomiting

Persistent nausea and vomiting are common symptoms in patients with pancreatic neuroendocrine tumors, occurring for several reasons. These symptoms can significantly impact nutritional status and quality of life.

The nausea and vomiting in neuroendocrine pancreatic cancer can result from:

• Tumor pressing on the stomach or duodenum, causing gastric outlet obstruction
• Excessive hormone production (such as gastrin) irritating the digestive system
• Tumor involvement affecting normal digestive processes
• General metabolic disturbances caused by the tumor

Patients typically experience waves of nausea that may be worse after eating, particularly after larger meals. The vomiting may contain undigested food if the stomach cannot empty properly due to tumor obstruction. Some patients develop a pattern of feeling better in the morning but progressively worse throughout the day. The persistent nausea can lead to food aversions, where patients begin avoiding foods they previously enjoyed, further contributing to weight loss and malnutrition. Unlike nausea from gastroenteritis or food poisoning, tumor-related nausea tends to be chronic and progressive rather than acute and self-limiting.

10. Palpable Abdominal Mass

In some cases, particularly with larger non-functional pancreatic neuroendocrine tumors, patients or their healthcare providers may be able to feel a mass or lump in the abdomen. This typically indicates a more advanced or larger tumor.

Characteristics of a palpable mass from pancreatic neuroendocrine tumors include:

• Usually located in the upper abdomen, either centrally or toward the left side
• Firm or hard to the touch
• May be movable or fixed, depending on tumor attachment
• Often painless initially, though may become tender
• Size can range from a few centimeters to quite large

Patients might discover the mass themselves while bathing, dressing, or resting their hand on their abdomen. In thinner individuals, the mass may be more easily detectable than in those with more abdominal adipose tissue. The presence of a palpable mass usually indicates a tumor of significant size (typically larger than 5 centimeters) and warrants immediate medical evaluation. Sometimes, what feels like a mass could also be an enlarged liver due to tumor spread (metastasis) or an enlarged spleen due to pressure on blood vessels. Healthcare providers use imaging studies to determine the exact nature, size, and location of any abdominal mass detected during examination.

Main Causes of Pancreatic Neuroendocrine Tumors

The exact causes of pancreatic neuroendocrine tumors remain largely unknown, but research has identified several risk factors and genetic conditions associated with their development:

Genetic Syndromes: Certain inherited genetic conditions significantly increase the risk of developing PNETs. Multiple Endocrine Neoplasia type 1 (MEN1) is the most common, where patients have mutations in the MEN1 gene and develop tumors in multiple endocrine glands. Von Hippel-Lindau (VHL) syndrome, Neurofibromatosis type 1 (NF1), and Tuberous Sclerosis Complex (TSC) are other hereditary conditions associated with increased PNET risk. Patients with these syndromes often develop PNETs at younger ages and may have multiple tumors.

Family History: Having a first-degree relative with pancreatic neuroendocrine tumors or related endocrine cancers increases risk, even without identified genetic syndromes. This suggests both known and yet-to-be-discovered genetic factors play a role in tumor development.

Spontaneous Genetic Mutations: Most pancreatic neuroendocrine tumors occur sporadically without inherited genetic syndromes. Random mutations in genes that control cell growth and division can accumulate over time, leading to tumor formation. These acquired mutations are not passed to offspring.

Age: PNETs can occur at any age but are most commonly diagnosed in adults between 40 and 60 years old. The risk increases with advancing age, likely due to accumulated genetic changes over time.

Race and Ethnicity: Some studies suggest slightly higher rates of pancreatic neuroendocrine tumors in African Americans compared to other racial groups, though the reasons for this difference are not fully understood.

Unlike pancreatic adenocarcinoma, lifestyle factors such as smoking, obesity, and diet have not been definitively linked to pancreatic neuroendocrine tumors, though research continues to explore potential environmental and lifestyle connections.

Prevention Strategies

Because the exact causes of most pancreatic neuroendocrine tumors are unknown, specific prevention strategies are limited. However, several approaches can help with early detection and risk management:

Genetic Counseling and Testing: Individuals with a family history of pancreatic neuroendocrine tumors or known hereditary syndromes like MEN1, VHL, NF1, or TSC should seek genetic counseling. Testing can identify mutations that increase risk, allowing for earlier and more frequent screening. Family members of affected individuals may benefit from genetic testing to determine their risk status.

Surveillance Programs: People with identified genetic syndromes should participate in regular surveillance programs. This typically includes periodic imaging studies (MRI or CT scans) and blood tests to measure hormone levels and tumor markers. Early detection through surveillance can identify tumors when they are smaller and potentially more treatable.

Maintaining Overall Health: While not specific to PNET prevention, maintaining general health through a balanced diet, regular exercise, avoiding tobacco, and limiting alcohol consumption supports overall wellbeing and may help the body better cope with various diseases. A healthy lifestyle also ensures you’re in optimal condition should treatment become necessary.

Regular Medical Check-ups: Attending routine medical appointments and promptly reporting any unusual or persistent symptoms to healthcare providers can lead to earlier diagnosis. Being proactive about health concerns and not dismissing persistent symptoms is important for catching tumors at more manageable stages.

Awareness of Symptoms: Education about the signs and symptoms of pancreatic neuroendocrine tumors, particularly for those at higher risk, can promote earlier medical consultation and diagnosis. Recognizing patterns like recurrent hypoglycemia, persistent diarrhea, or recurrent ulcers that don’t respond to treatment can prompt appropriate investigation.

Frequently Asked Questions

What is the difference between pancreatic neuroendocrine tumors and pancreatic cancer?

Pancreatic neuroendocrine tumors (PNETs) arise from the hormone-producing endocrine cells of the pancreas and typically grow more slowly than pancreatic adenocarcinoma, which arises from the exocrine cells that produce digestive enzymes. PNETs account for only 3-5% of pancreatic cancers and generally have a better prognosis. They may produce hormones causing distinctive symptoms, while adenocarcinomas typically don’t.

Are pancreatic neuroendocrine tumors always cancerous?

Pancreatic neuroendocrine tumors can be benign or malignant, though the distinction can be difficult to determine without microscopic examination. Even tumors that appear low-grade can sometimes spread to other organs. Size, growth rate, and microscopic features help determine whether a tumor is likely to behave aggressively. All PNETs require medical evaluation and monitoring.

How are pancreatic neuroendocrine tumors diagnosed?

Diagnosis typically involves a combination of blood tests to measure hormone levels, imaging studies such as CT scans, MRI, or specialized scans like octreotide scans that detect neuroendocrine cells, and endoscopic ultrasound which can provide detailed images and allow for biopsy. A tissue sample examined under a microscope confirms the diagnosis and helps determine the tumor type and grade.

Can pancreatic neuroendocrine tumors be cured?

If detected early and localized to the pancreas, pancreatic neuroendocrine tumors can potentially be cured through surgical removal. The prognosis depends on factors including tumor size, grade, whether it produces hormones, and whether it has spread to other organs. Even advanced PNETs often grow slowly, and various treatment approaches can manage the disease for extended periods.

How fast do pancreatic neuroendocrine tumors grow?

Pancreatic neuroendocrine tumors generally grow much more slowly than other pancreatic cancers, though growth rates vary. Low-grade tumors may take years to grow significantly, while high-grade tumors can grow more rapidly. The grade of the tumor, determined by how quickly cells are dividing under microscopic examination, helps predict growth rate and behavior.

Who is at highest risk for developing pancreatic neuroendocrine tumors?

Individuals with hereditary genetic syndromes including Multiple Endocrine Neoplasia type 1 (MEN1), Von Hippel-Lindau syndrome, Neurofibromatosis type 1, and Tuberous Sclerosis Complex have significantly elevated risk. People with a family history of PNETs and adults between ages 40-60 also have increased risk. However, most cases occur sporadically without identified risk factors.

What should I do if I experience symptoms of a pancreatic neuroendocrine tumor?

If you experience persistent symptoms such as unexplained abdominal pain, episodes of low blood sugar, chronic diarrhea, recurrent ulcers, unexplained weight loss, or jaundice, you should consult a healthcare provider promptly. While these symptoms can have many causes, persistent or worsening symptoms warrant medical evaluation, which may include blood tests, imaging studies, and referral to specialists if necessary.

References:

• National Cancer Institute – Pancreatic Neuroendocrine Tumors Treatment
• Mayo Clinic – Neuroendocrine Tumors
• Cancer Research UK – Pancreatic Neuroendocrine Tumours
• Johns Hopkins Medicine – Pancreatic Neuroendocrine Tumors
• NHS – Neuroendocrine Tumours