OVERVIEW

What are neuroendocrine tumors?

Neuroendocrine tumors are heterogeneous neoplasms originating from the diffuse neuroendocrine system.

They most commonly occur in the gastrointestinal tract, where well-differentiated ones are also called carcinoids; they can also be found in the pancreas, lungs, and other organs. Despite diverse origins, the tumor cells share similar morphology, featuring specific secretory granules capable of producing biogenic amines and polypeptide hormones, hence often classified as a single tumor type.

These tumors exhibit high heterogeneity, with varying degrees of malignancy—ranging from indolent, slow-growing low-grade malignancies to highly aggressive tumors with metastatic potential. While most are benign and a minority are malignant, all neuroendocrine tumors possess malignant potential.

What are pancreatic neuroendocrine tumors?

Pancreatic neuroendocrine tumors (PNETs) are a subtype of neuroendocrine tumors, previously termed islet cell tumors. They arise from the endocrine tissue of the pancreas, unlike pancreatic adenocarcinoma, which originates from malignant transformation of acinar or ductal epithelial cells. Compared to pancreatic adenocarcinoma, PNETs generally have a lower overall malignancy.

Those originating from the digestive tract/glands are collectively termed gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs), accounting for over two-thirds of all neuroendocrine tumors.

How common are pancreatic neuroendocrine tumors? Who is at risk?

• PNETs are relatively rare overall, with an annual incidence of ≤1/100,000, representing about 1%–2% of all pancreatic tumors.
• With improved understanding and advancements in imaging and pathological techniques, the detection and diagnosis rates of PNETs are increasing.
• PNETs can occur at any age, with no significant gender preference, most commonly diagnosed between 30–60 years, and incidence rising with age.

What are the types of pancreatic neuroendocrine tumors?

Historically, the classification of neuroendocrine neoplasms (NENs) was complex and confusing, but relatively clear concepts have now been established.

• Based on differentiation, they are divided into well-differentiated neuroendocrine tumors (NETs) and poorly differentiated neuroendocrine carcinomas (NECs).
• Well-differentiated NETs and poorly differentiated NECs share neuroendocrine features, differentiation, and some histological characteristics. Though sometimes difficult to distinguish, these two NEN types are not closely related at the histogenetic or molecular level, and NETs rarely progress to NECs. In the pancreas, NETs and NECs are similarly distinguished.
• The pancreatic islets contain various hormone-secreting cells. Accordingly, PNETs can be classified, though current research shows most do not secrete their corresponding hormones and are termed non-functional; those that do and cause symptoms are called functional PNETs.

Specifically, PNETs include insulinomas, gastrinomas, glucagonomas, VIPomas, somatostatinomas, etc., each associated with distinct clinical manifestations and syndromes.

SYMPTOMS

What are the common manifestations of pancreatic neuroendocrine tumors?

When discussing clinical manifestations, it is often necessary to distinguish between functional and non-functional tumors.

• Functional tumors: Different types of functional pancreatic neuroendocrine tumors exhibit distinct clinical features. Due to their high heterogeneity, initial diagnosis is often challenging.

  • Manifestations may include: diarrhea, flushing, wheezing, shortness of breath, abdominal pain, fatigue, skin itching, heart valve lesions, edema, etc. Additionally, tumor mass effects can lead to symptoms such as bloating, abdominal pain, nausea, vomiting, loss of appetite, indigestion, jaundice, etc.

  • Common misdiagnoses include: irritable bowel syndrome, rosacea, allergies, menopause, ulcers, Crohn's disease, pneumonia, anxiety disorders, etc.

  • Insulinomas may present with the classic Whipple's triad: hypoglycemic symptoms, low blood glucose, and symptom relief after oral or intravenous glucose administration.

  • Gastrinomas may manifest as Zollinger-Ellison syndrome: diarrhea, hypergastrinemia, gastric acid hypersecretion, and peptic ulcers. VIPomas may present with Verner-Morrison syndrome: watery diarrhea, hypokalemia, and achlorhydria.

  • Glucagonomas may exhibit the 4D syndrome: necrolytic migratory erythema, diabetes mellitus, deep vein thrombosis, and depression.

  • Somatostatinomas may present with somatostatinoma syndrome: elevated somatostatin levels, diabetes mellitus, reduced gastric acid secretion, gallstones, diarrhea/steatorrhea, anemia, and weight loss.

  • Other manifestations include: acromegaly, ectopic Cushing's syndrome, etc.

• Non-functional tumors: Non-functional pancreatic neuroendocrine tumors do not exhibit hormone secretion syndromes clinically. Patients often seek medical attention due to symptoms caused by local tumor compression or advanced-stage metastasis.

  Possible manifestations include: abdominal pain, nausea, loss of appetite, weight loss; they may also lead to obstructive jaundice, intra-abdominal hemorrhage, and palpable masses upon physical examination.

CAUSES

What causes pancreatic neuroendocrine tumors?

The exact cause is unknown.

Some non-sporadic pancreatic neuroendocrine tumors may be associated with various hereditary syndromes, including multiple endocrine neoplasia type 1, von Hippel-Lindau disease, tuberous sclerosis, and neurofibromatosis type 1, suggesting a possible link to genetic factors.

What tests are needed for pancreatic neuroendocrine tumors? What is the purpose of these tests?

Routine biochemical tests and tumor marker tests alone cannot confirm a diagnosis of pancreatic neuroendocrine tumors unless the tumor causes symptoms such as jaundice or gastrointestinal obstruction, leading to secondary changes. Imaging abnormalities are often the first step in ultimately diagnosing pancreatic neuroendocrine tumors.

If initial imaging reveals abnormalities, further CT/MRI examinations are required. Conventional imaging often shows neuroendocrine tumors as hypervascular lesions, though other presentations may resemble pancreatic cysts or pancreatic cancer.

For some difficult-to-diagnose cases, additional evaluations such as endoscopic ultrasound or even biopsy under its guidance may be necessary.

Traditional imaging methods have limitations: nearly half of liver metastases may go undetected, often leading to underestimation of metastatic burden. MRI, which better visualizes liver lesions, is preferred by many physicians.

More precise techniques like DSA can provide a more accurate assessment of liver involvement but face challenges: patients may resist invasive procedures, and some lesions remain undetectable.

Recent advances in molecular imaging have significantly improved diagnostic capabilities. Somatostatin receptor imaging (SRI) techniques, such as 99mTc-OCT-SPECT and 68-Gallium-Dotatate PET/CT scans, as well as 111In-DTPA-D-Phe1-octreotide, 99mTc-HYNIC-Tyr3-OCT, and 177Lu-Dotatate, are nuclear imaging methods that use specialized molecular markers to identify the quantity and distribution of tumor cells expressing somatostatin receptors.

These tests serve a dual purpose: aiding diagnosis and identifying patients suitable for targeted receptor therapy by mapping the distribution of somatostatin receptor-expressing tumor cells.

Ultimately, however, definitive diagnosis relies on pathological examination.

DIAGNOSIS

How to Diagnose Pancreatic Neuroendocrine Tumors?

• Pathological examination is the gold standard for diagnosing neuroendocrine tumors. In addition to surgical resection for pathology, preoperative biopsies include imaging-guided percutaneous puncture and endoscopy-guided puncture.
• Immunohistochemical tests for general neuroendocrine markers, such as synaptophysin, chromogranin, and Ki-67, are mandatory. Optional markers include secretagogin, CD56, PGP9.5, and NSE.
• Beyond confirming the diagnosis, pathological examination is crucial for grading, staging, and guiding subsequent treatment.

How Are Pancreatic Neuroendocrine Tumors Graded, Staged, and Evaluated for Severity and Prognosis?

Based on mitotic count and Ki-67 index, neuroendocrine tumors are classified into G1, G2, and G3 grades. In 2017, the WHO updated the grading system, recognizing two types within G3: well-differentiated NETs and poorly differentiated NECs.

For staging, G1 and G2 neuroendocrine tumors follow site-specific TNM staging, while G3 and mixed NENs adopt the staging system for adenocarcinomas at corresponding sites.

The AJCC 8th edition adopted the staging system proposed by the European Neuroendocrine Tumor Society (ENETS). However, this system has unclear distinctions: Stage II T2N0M0 patients have a prognosis similar to Stage I, while Stage III T4N0M0 patients fare worse than those with lymph node metastasis.

Chinese researchers have developed and validated a data model proposing a new staging system that more accurately predicts patient prognosis, potentially revising future AJCC guidelines.

Which Department Should Patients with Pancreatic Neuroendocrine Tumors Consult?

Patients with this condition typically visit medical oncology or hepatobiliary-pancreatic surgery departments, with some initial cases seen in gastroenterology.

• Medical oncology focuses on chemotherapy and targeted therapy.
• Hepatobiliary-pancreatic surgery specializes in surgical treatment.
• Gastroenterology or endoscopy departments assist with endoscopic examinations and biopsies.
• Nuclear medicine departments facilitate peptide receptor radionuclide therapy.

TREATMENT

What are the treatment measures for pancreatic neuroendocrine tumors?

• In general, they include surgical treatment, tumor ablation and local therapy, drug therapy, etc.
• Drug therapy covers chemotherapy, molecular targeted therapy, and peptide receptor radionuclide therapy.

Pancreatic neuroendocrine tumors are highly heterogeneous; some are simply benign, while others have already metastasized at diagnosis.

Due to the variety of treatment methods and the higher risks and complication rates associated with certain surgical approaches, the final treatment decision requires the collective wisdom of multidisciplinary experts. A multidisciplinary team (MDT) approach is recommended.

Is surgery necessary for pancreatic neuroendocrine tumors, and under what circumstances should it be performed?

The goal of surgery is to achieve R0 resection.

In principle, pancreatic neuroendocrine tumors with a diameter >2 cm or malignant potential, whether functional or nonfunctional, are recommended for surgical resection. Adjacent organs may also be removed if necessary, along with regional lymph node dissection.

For nonfunctional tumors ≤2 cm in diameter, the need for surgical resection remains controversial. The decision should be based on tumor location, surgical risks, patient age, overall health, and potential benefits.

If somatostatin analog therapy is considered, cholecystectomy should be performed to avoid possible subsequent bile stasis.

All insulinomas should be surgically resected whenever possible: multiple lesions may exist within the gland (sometimes requiring intraoperative ultrasound localization), and complete resection can cure 85%–95% of patients.

For locally recurrent, isolated distant metastases, or initially unresectable pancreatic neuroendocrine tumors that become resectable after treatment, surgical resection should be considered.

Surgical approaches vary depending on tumor location and size, including enucleation, pancreaticoduodenectomy, distal pancreatectomy, and segmental pancreatectomy. These can be performed via open surgery, laparoscopy, or robotic surgery.

For some patients with postoperative recurrence, repeat surgery may be an option. In cases with liver or distant metastases, resection of the primary tumor may still be considered to facilitate subsequent treatments.

Selected patients with liver metastases may be candidates for liver transplantation, though these approaches remain controversial.

What ablation and local therapies are available for pancreatic neuroendocrine tumors?

Tumor ablation includes radiofrequency ablation, cryoablation, microwave ablation, etc. Ablation is commonly used for unresectable or metastatic solid tumors. For eligible surgical candidates, intraoperative ablation can also serve as an adjunct.

Ablation can be performed percutaneously, laparoscopically, or during laparotomy, with lower complication rates compared to liver resection or hepatic artery embolization. Ablation is more frequently applied to metastatic lesions, though some institutions are exploring its use for primary tumors.

Local therapies may benefit symptomatic patients with unresectable tumors or predominant liver metastases.

Transarterial therapies like hepatic artery embolization, chemoembolization, or radioembolization may provide symptom relief superior to systemic therapy alone.

While many studies confirm that transarterial therapies effectively control symptoms caused by hormone secretion or tumor burden, their survival benefits remain less clear.

Can pancreatic neuroendocrine tumors be treated with drugs? What drugs are used?

Drug therapy includes replacement therapy for pancreatic endocrine/exocrine dysfunction, immunomodulatory therapy, chemotherapy, molecular targeted therapy, and peptide receptor radionuclide therapy.

• Cytotoxic chemotherapy has proven efficacy for well-differentiated pancreatic NETs. It is recommended for patients with significant symptoms due to large tumors or rapidly progressing metastases, offering higher objective response rates.
• Somatostatin analogs (SSAs) are a common molecular targeted therapy, serving two purposes: symptom control and tumor growth inhibition. Clinical trials support SSAs as first-line treatment for nonfunctional and functional G1/G2 neuroendocrine tumors, effectively managing symptoms. Long-acting octreotide and lanreotide are commonly used, requiring strict adherence to administration guidelines.
• Novel molecular targeted therapies against PI3K, mTOR, or VEGF can prolong progression-free survival. They are suitable for adults with unresectable, locally advanced, or metastatic, well-differentiated (moderate or high-grade) progressive pancreatic neuroendocrine tumors.
• Peptide receptor radionuclide therapy (PRRT) is an internal radiation approach. It combines SSAs (e.g., lanreotide/octreotide) with radionuclides (¹¹¹In, ⁹⁰Y, ¹⁷⁷Lu) to form a targeted compound that delivers high-energy β-radiation to tumor cells expressing somatostatin receptors, thereby destroying them. Thus, PRRT is only suitable for somatostatin receptor-positive neuroendocrine tumors.

DIET & LIFESTYLE

What should patients with pancreatic neuroendocrine tumors pay attention to in daily life?

Similar to other pancreatic diseases, it is essential to strictly adhere to follow-up and re-examination schedules for necessary tests and evaluations. If undergoing SSA treatment, carefully follow the instructions for use and monitor for any significant adverse reactions during the process.

Patients should closely watch for symptoms such as flushing, venous congestion, diarrhea, and bronchospasm, as well as fatigue, loss of appetite, and weight loss. If these symptoms occur, they should seek medical attention promptly to assess potential tumor progression.

Additionally, it is important to avoid factors that may worsen pancreatic damage, primarily by adjusting dietary habits and changing unhealthy lifestyle behaviors.

Maintain a balanced diet with a mix of meat and vegetables, avoiding long-term excessive intake of high-fat and high-protein foods. At the same time, eliminate harmful habits such as alcohol consumption to prevent damage from alcohol and its metabolites, particularly acetaldehyde. Quitting smoking is also beneficial for overall health.

PREVENTION

How to prevent pancreatic neuroendocrine tumors?

Generally, it's difficult to prevent. However, understanding relevant disease knowledge, staying vigilant, and seeking timely medical attention for similar symptoms with appropriate examinations can aid in early diagnosis and treatment.