Definition/General
Introduction:
Pancreatic neuroendocrine tumors (PanNETs) are neoplasms with neuroendocrine differentiation
They constitute 1-2% of all pancreatic neoplasms
They demonstrate variable clinical behavior from benign to highly malignant
They show characteristic morphology and immunoprofile
They can be functional or non-functional.
Origin:
Arise from pancreatic islet cells (beta, alpha, delta cells)
Show neuroendocrine differentiation
May originate from pluripotent stem cells
Demonstrate hormone production capabilities
Located throughout pancreatic parenchyma
Show varying degrees of differentiation.
Classification:
WHO 2019 classifies as neuroendocrine neoplasms
Well-differentiated NET Grade 1 (G1: <3 mitoses/10HPF, <3% Ki-67)
Well-differentiated NET Grade 2 (G2: 3-20 mitoses/10HPF, 3-20% Ki-67)
Well-differentiated NET Grade 3 (G3: >20 mitoses/10HPF, >20% Ki-67)
Poorly differentiated NEC (neuroendocrine carcinoma)
Mixed neuroendocrine-non-neuroendocrine neoplasms.
Epidemiology:
Peak incidence in 5th-6th decades
Equal gender distribution
Sporadic (95% of cases)
Hereditary syndromes (5%): MEN1, VHL, NF1, TSC
Non-functional (60-90%)
Functional (10-40%)
Indian population shows similar epidemiology with increasing recognition.
Clinical Features
Presentation:
Abdominal pain (most common, 40-80%)
Weight loss (30-50%)
Jaundice (if head of pancreas)
Palpable mass (large tumors)
Functional syndrome symptoms
Incidental finding on imaging (increasing).
Symptoms:
Non-functional PanNETs: Mass effect symptoms
Insulinoma: Whipple triad (hypoglycemia, symptoms, relief with glucose)
Gastrinoma: Zollinger-Ellison syndrome
Glucagonoma: Diabetes, necrolytic migratory erythema
VIPoma: Watery diarrhea, hypokalemia, achlorhydria
Somatostatinoma: Diabetes, steatorrhea, cholelithiasis.
Risk Factors:
MEN1 syndrome (20-30% develop PanNETs)
Von Hippel-Lindau syndrome (10-17% develop PanNETs)
Neurofibromatosis type 1
Tuberous sclerosis
Family history
Advanced age
Most cases are sporadic.
Screening:
Biochemical markers (chromogranin A, specific hormones)
Cross-sectional imaging (CT, MRI)
Endoscopic ultrasound
Somatostatin receptor scintigraphy
Genetic testing (familial cases)
Fine needle aspiration for tissue diagnosis.
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Gross Description
Appearance:
Well-circumscribed tan-brown mass
Firm consistency
Homogeneous cut surface
Size typically 2-5 cm
May show central necrosis (high grade)
Encapsulated or pseudoencapsulated appearance.
Characteristics:
Tan to brown color
Solid consistency
Well-demarcated from surrounding pancreas
May show hemorrhage
Cystic degeneration (rare)
Calcification may be present
Cut surface appears lobulated.
Size Location:
Size ranges from few mm to >10 cm
Pancreatic head (40%)
Body and tail (60%)
Multiple tumors (MEN1 syndrome)
Insulinomas usually small (<2 cm)
Non-functional NETs often larger at presentation.
Multifocality:
Multifocal disease (MEN1 syndrome)
Microadenomas in background pancreas
Lymph node metastases (30-40%)
Liver metastases (advanced disease)
Peritoneal seeding (rare).
Microscopic Description
Histological Features:
Organoid architecture (nests, trabeculae, ribbons)
Uniform round cells with moderate cytoplasm
Round to oval nuclei with salt-and-pepper chromatin
Inconspicuous nucleoli
Rich vascular network
Delicate fibrovascular stroma.
Cellular Characteristics:
Monotonous cell population
Moderate eosinophilic cytoplasm
Central round nuclei
Finely dispersed chromatin
Rare mitotic figures (G1 tumors)
Nuclear molding may be present
Crush artifact in small biopsies.
Architectural Patterns:
Nested (Zellballen) pattern most common
Trabecular pattern
Ribbon/linear pattern
Rosette formation (rare)
Pseudoglandular pattern
Solid pattern (high-grade tumors)
Mixed architectural patterns.
Grading Criteria:
WHO 2019 grading based on mitotic count and Ki-67
Grade 1: <3 mitoses/10 HPF, <3% Ki-67
Grade 2: 3-20 mitoses/10 HPF, 3-20% Ki-67
Grade 3: >20 mitoses/10 HPF, >20% Ki-67
Necrosis not part of grading
Vascular invasion indicates malignant potential.
Immunohistochemistry
Positive Markers:
Chromogranin A (85-100%)
Synaptophysin (90-100%)
CD56 (NCAM) (80-90%)
Neuron-specific enolase (variable)
Ki-67 (proliferation index)
Specific hormones (insulin, glucagon, somatostatin)
SSTR2A (70-80%).
Negative Markers:
Cytokeratins (usually negative or focal)
CEA (negative)
CDX2 (negative)
TTF-1 (negative)
Trypsin (negative)
Chymotrypsin (negative)
Help distinguish from ductal adenocarcinoma.
Diagnostic Utility:
Chromogranin A most specific
Synaptophysin most sensitive
Ki-67 essential for grading
Hormone stains for functional classification
SSTR2A predicts somatostatin analog therapy response
Essential for differential diagnosis.
Molecular Subtypes:
Insulinomas: MEN1, DAXX/ATRX alterations
Non-functional NETs: MEN1, DAXX/ATRX, mTOR pathway
Syndromic NETs: Specific germline mutations
Sporadic NETs: Somatic alterations.
Molecular/Genetic
Genetic Mutations:
MEN1 mutations (45% sporadic, 100% MEN1 syndrome)
DAXX/ATRX mutations (25-45%)
mTOR pathway alterations (15-25%)
VHL mutations (VHL syndrome)
NF1 mutations
TSC1/TSC2 mutations
YY1 mutations (insulinomas).
Molecular Markers:
MEN1 protein (menin) loss
DAXX/ATRX loss (alternative lengthening of telomeres)
mTOR activation
p53 mutations (rare in low grade)
Rb alterations (high grade)
Chromatin remodeling alterations.
Prognostic Significance:
Grade most important prognostic factor
Size >2 cm associated with metastasis
DAXX/ATRX loss paradoxically better prognosis
Chromosome instability in higher grade
Functional status affects management
Nodal metastases worsen prognosis.
Therapeutic Targets:
Somatostatin analogs (octreotide, lanreotide)
mTOR inhibitors (everolimus)
VEGFR inhibitors (sunitinib)
PRRT (peptide receptor radionuclide therapy)
Chemotherapy (temozolomide, capecitabine)
Targeted therapy based on molecular profile.
Differential Diagnosis
Similar Entities:
Pancreatic ductal adenocarcinoma (solid variant)
Acinar cell carcinoma
Solid pseudopapillary neoplasm
Pancreatoblastoma
Metastatic neuroendocrine carcinoma
Lymphoma.
Distinguishing Features:
PanNET: Chromogranin/synaptophysin positive
PanNET: Organoid architecture
PDAC: CK19, CEA positive
Acinar cell: Trypsin positive
SPN: Beta-catenin nuclear
Pancreatoblastoma: Squamoid corpuscles
Metastatic: Clinical history.
Diagnostic Challenges:
Distinguishing grade 2 vs grade 3 NET
Well-differentiated vs poorly differentiated
Primary pancreatic vs metastatic NET
Functional vs non-functional
Small biopsy specimens
Crush artifacts.
Rare Variants:
Clear cell NET
Oncocytic NET
Lipid-rich NET
Melanotic NET
Gangliocytic paraganglioma (duodenal)
Mixed ductal-neuroendocrine carcinoma
Microadenoma.
Sample Pathology Report
Template Format
Sample Pathology Report
Complete Report: This is an example of how the final pathology report should be structured for this condition.
Specimen Information
Pancreatoduodenectomy/distal pancreatectomy from [location], measuring [dimensions]
Diagnosis
Pancreatic Neuroendocrine Tumor (PanNET)
WHO Grade
WHO Grade: [1/2/3] (Well-differentiated NET)
Microscopic Features
Shows organoid architecture with uniform cells and neuroendocrine morphology
Size and Location
Size: [X] cm; Location: [head/body/tail] of pancreas
Grading Parameters
Mitotic count: [X] per 10 HPF; Ki-67 index: [X]%
Margins
Margins: [involved/uninvolved], closest margin [X] mm
Lymphovascular Invasion
Lymphovascular invasion: [present/absent/suspicious]
Lymph Node Status
Lymph nodes: [X] positive out of [X] examined
Immunohistochemistry
Chromogranin A: [positive/negative]; Synaptophysin: [positive/negative]; Ki-67: [X]%
Functional Status
Hormone production: [insulin/glucagon/gastrin/non-functional/clinical correlation needed]
TNM Staging
pT[X]N[X]: [staging based on size, invasion, nodes]
Final Diagnosis
Pancreatic Neuroendocrine Tumor, WHO Grade [1/2/3], [size] cm, pT[X]N[X]