Pancreatic Neuroendocrine Tumor: Anatomy, Epidemiology, Types, Pathogenesis, Symptoms, Diagnosis, Staging and Treatment

Pancreatic Neuroendocrine Tumors (PNETs)

~Introduction

Pancreatic Neuroendocrine Tumors (PNETs) are a rare and distinct group of neoplasms arising from the neuroendocrine cells of the pancreas, which are part of the endocrine system. Unlike pancreatic ductal adenocarcinoma, which originates from the exocrine pancreas and is highly aggressive, PNETs tend to grow more slowly and often have a better prognosis. However, their clinical behavior can vary widely, ranging from indolent tumors to highly malignant forms.

PNETs account for 1–2% of all pancreatic tumors, but their incidence has increased in recent years due to improved imaging techniques and increased awareness. These tumors may be functional, producing excess hormones, or non-functional, producing no clinically significant hormones. This article discusses the epidemiology, classification, pathogenesis, clinical features, diagnosis, staging, treatment, prognosis, and recent advances related to Pancreatic Neuroendocrine Tumors.

~Anatomy and Physiology of the Endocrine Pancreas

The endocrine pancreas consists of clusters of specialized cells known as the Islets of Langerhans, which are scattered throughout the pancreas.

Major Cell Types

• Alpha cells – secrete glucagon

• Beta cells – secrete insulin

• Delta cells – secrete somatostatin

• PP cells – secrete pancreatic polypeptide

PNETs arise from these hormone-producing cells and retain some of their secretory functions.

~Epidemiology

• PNETs are rare compared to exocrine pancreatic cancers.

• Occur most commonly between 40–60 years of age.

• Affect males and females almost equally.

• Increasing incidence due to better detection of small, asymptomatic tumors.

• Around 10–20% of PNETs are associated with inherited genetic syndromes.

~Classification of Pancreatic Neuroendocrine Tumors

1. Functional PNETs

These tumors secrete hormones that cause specific clinical syndromes.

a. Insulinoma

• Most common functional PNET

• Excess insulin secretion

• Causes hypoglycemia

• Usually benign

b. Gastrinoma

• Secretes gastrin

• Causes Zollinger–Ellison syndrome

• Severe peptic ulcer disease

c. Glucagonoma

• Secretes glucagon

• Causes diabetes, weight loss, and necrolytic migratory erythema

d. VIPoma

• Secretes vasoactive intestinal peptide (VIP)

• Causes watery diarrhea, hypokalemia, and achlorhydria (WDHA syndrome)

e. Somatostatinoma

• Secretes somatostatin

• Causes diabetes, gallstones, and steatorrhea

2. Non-Functional PNETs

• Do not produce hormone-related symptoms

• Present late due to mass effect or metastasis

• Account for 60–70% of PNETs

• Often malignant at diagnosis

~Genetic and Molecular Pathogenesis

PNETs are biologically different from pancreatic adenocarcinoma.

Common Genetic Alterations

• MEN1 gene mutation (most common)

• DAXX and ATRX mutations

• mTOR pathway activation

Inherited Syndromes

• Multiple Endocrine Neoplasia type 1 (MEN1)

• Von Hippel–Lindau disease

• Neurofibromatosis type 1

• Tuberous sclerosis

These mutations lead to uncontrolled neuroendocrine cell proliferation.

~Clinical Features

Clinical presentation depends on whether the tumor is functional or non-functional.

Symptoms of Functional PNETs

• Hypoglycemia (insulinoma)

• Recurrent peptic ulcers (gastrinoma)

• Chronic diarrhea (VIPoma)

• Weight loss and skin rash (glucagonoma)

Symptoms of Non-Functional PNETs

• Abdominal pain

• Palpable abdominal mass

• Weight loss

• Jaundice (rare)

• Symptoms of metastasis (liver involvement)

~Diagnosis

1. Biochemical Tests

• Serum hormone levels (insulin, gastrin, glucagon, VIP)

• Chromogranin A (general neuroendocrine marker)

• Fasting blood glucose and insulin ratio

2. Imaging

• Contrast-enhanced CT or MRI

• Endoscopic ultrasound (EUS)

• Somatostatin receptor imaging (Ga-68 DOTATATE PET/CT)

3. Histopathology

• Well-differentiated neuroendocrine cells

• “Salt and pepper” chromatin

• Immunohistochemistry positive for chromogranin A and synaptophysin

~Grading and Staging

WHO Grading (Based on Ki-67 Index)

• Grade 1 (G1): Low grade

• Grade 2 (G2): Intermediate grade

• Grade 3 (G3): High grade

Staging

• Based on TNM classification

• Liver is the most common site of metastasis

~Treatment

Treatment depends on tumor type, grade, stage, and functional status.

1. Surgery

• Primary treatment for localized disease

• Curative in early-stage tumors

• Enucleation or pancreatic resection

2. Medical Management

• Somatostatin analogs (octreotide, lanreotide)

• Control hormone-related symptoms

• Slow tumor growth

3. Targeted Therapy

• Everolimus (mTOR inhibitor)

• Sunitinib (tyrosine kinase inhibitor)

4. Chemotherapy

• Used for high-grade or metastatic tumors

• Agents include streptozocin, temozolomide, capecitabine

5. Peptide Receptor Radionuclide Therapy (PRRT)

• Uses radiolabeled somatostatin analogs

• Effective in advanced disease

~Prognosis

PNETs have a much better prognosis than pancreatic adenocarcinoma.

• 5-year survival:

  • Localized disease: >80%

  • Metastatic disease: 30–50%

• Prognosis depends on:

  • Tumor grade

  • Stage

  • Functional status

~Complications

• Hormone-related metabolic disturbances

• Liver metastasis

• Malnutrition

• Treatment-related side effects

~Recent Advances and Research

• Improved molecular profiling

• Use of PRRT

• Liquid biopsy research

• Combination targeted therapies

~Conclusion

Pancreatic Neuroendocrine Tumors are rare, heterogeneous neoplasms with diverse clinical presentations. Early diagnosis and accurate classification are essential for effective management. Unlike pancreatic ductal adenocarcinoma, PNETs often have a favorable prognosis when detected early. Advances in imaging, molecular biology, and targeted therapies have significantly improved outcomes. A multidisciplinary approach involving surgery, medical oncology, endocrinology, and nuclear medicine is crucial for optimal patient care.