Definition/General
Introduction:
Pancreatic neuroendocrine tumors (PanNETs) are relatively uncommon neoplasms arising from pancreatic islet cells, representing 1-5% of all pancreatic tumors
FNAC plays a crucial role in diagnosis, especially for small tumors and metastatic disease
The cytological diagnosis relies on characteristic neuroendocrine morphology and confirmatory immunocytochemistry
PanNETs show wide spectrum of biological behavior from indolent to highly aggressive.
Origin:
PanNETs arise from pancreatic islet cells (alpha, beta, delta cells) distributed throughout the pancreas
Most tumors are non-functional (60-80%) and do not produce clinical hormone excess
Functional tumors include insulinomas, gastrinomas, VIPomas, and somatostatinomas
Location varies with insulinomas predominantly in body/tail and gastrinomas in head
Sporadic tumors account for 85% while 15% are associated with genetic syndromes.
Classification:
WHO 2019 classification uses Ki-67 proliferation index and mitotic count for grading
Grade 1 (G1): Ki-67 <3%, <2 mitoses per 10 HPF
Grade 2 (G2): Ki-67 3-20%, 2-20 mitoses per 10 HPF
Grade 3 (G3): Ki-67 >20%, >20 mitoses per 10 HPF
Well-differentiated NETs retain neuroendocrine morphology
Poorly differentiated neuroendocrine carcinomas show high-grade features.
Epidemiology:
PanNETs show slight female predominance (1.5:1)
Peak incidence in 5th-6th decades
Hereditary syndromes include MEN-1 (40% develop PanNETs), VHL syndrome (10-15% develop PanNETs), and NF-1
Functional tumors present earlier due to hormone excess symptoms
Non-functional tumors often detected incidentally on imaging
Indian population shows increasing detection with improved imaging.
Clinical Features
Presentation:
Non-functional tumors present with mass effect symptoms (60-80%)
Abdominal pain most common symptom in non-functional tumors
Functional tumors present with specific hormone excess syndromes
Insulinomas cause Whipple triad (hypoglycemic symptoms, low glucose, symptom relief with glucose)
Gastrinomas cause Zollinger-Ellison syndrome
Weight loss in advanced cases.
Symptoms:
Abdominal pain and discomfort in non-functional tumors
Hypoglycemic episodes in insulinomas (weakness, sweating, confusion)
Peptic ulcer disease and diarrhea in gastrinomas
Watery diarrhea and hypokalemia in VIPomas
Diabetes mellitus and steatorrhea in somatostatinomas
Facial flushing and diarrhea in carcinoid syndrome (rare).
Risk Factors:
Family history of MEN-1 syndrome (mutations in MEN1 gene)
Von Hippel-Lindau syndrome (VHL gene mutations)
Neurofibromatosis type 1 (NF1 gene mutations)
Tuberous sclerosis complex
Previous history of other neuroendocrine tumors
Age over 40 years for sporadic tumors
No strong environmental risk factors identified.
Screening:
Biochemical screening for functional tumors (insulin, gastrin, chromogranin A)
Imaging with contrast-enhanced CT or MRI
Octreotide scintigraphy (68Ga-DOTATATE PET/CT preferred)
EUS-guided FNAC for tissue diagnosis and grading
Genetic testing for hereditary syndromes in young patients
Family screening for MEN-1 syndrome patients.
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Gross Description
Appearance:
FNAC specimens typically show good cellularity with cohesive cell clusters
Tissue fragments appear tan to gray-brown colored
Background usually clean with minimal blood contamination
Well-differentiated tumors show uniform cellular morphology
Poorly differentiated tumors may show increased single cells and necrosis.
Characteristics:
Cellular yield generally good due to high cellularity of NETs
Tissue fragments show cohesive cellular arrangements
Background typically clean without significant necrosis
Blood contamination minimal in most cases
May show extracellular matrix material
High-grade tumors show increased debris and necrosis.
Size Location:
Size ranges from <1 cm (microadenomas) to >10 cm
Small tumors (<2 cm) often functional (insulinomas)
Large tumors (>4 cm) usually non-functional
Pancreatic head location common for gastrinomas
Body and tail predominant for insulinomas
Multiple tumors in MEN-1 syndrome patients.
Multifocality:
Multiple tumors occur in 15-20% of sporadic cases
MEN-1 syndrome shows multiple tumors in 80-90% of cases
Different tumors may show different hormone production
Synchronous tumors may have different grades
Microadenomatosis pattern in some hereditary cases
Metachronous development common in genetic syndromes.
Microscopic Description
Histological Features:
Uniform neuroendocrine cells arranged in nested, trabecular, or ribbon-like patterns
Cells show characteristic salt-and-pepper chromatin pattern
Nuclei typically round to oval with fine chromatin
Cytoplasm finely granular and eosinophilic to amphophilic
Nuclear molding may be present
Minimal pleomorphism in well-differentiated tumors.
Cellular Characteristics:
Cells demonstrate uniform size and shape in Grade 1-2 tumors
Nuclei show fine, evenly distributed chromatin (salt-and-pepper pattern)
Nuclear-cytoplasmic ratio moderately increased
Cytoplasm shows fine granularity due to neurosecretory granules
Cell borders indistinct with tendency to mold around each other
Nucleoli typically small and inconspicuous.
Architectural Patterns:
Characteristic nested (Zellballen) pattern most common
Trabecular arrangements with ribbon-like formations
Rosette-like structures may be present
Plasmacytoid morphology in some cases
Single cells scattered in background
High-grade tumors show loss of cohesion and sheet-like growth.
Grading Criteria:
Grade 1: Uniform cells, fine chromatin, rare mitoses, Ki-67 <3%
Grade 2: Mild pleomorphism, coarse chromatin, occasional mitoses, Ki-67 3-20%
Grade 3: Marked pleomorphism, irregular nuclei, frequent mitoses, Ki-67 >20%
Necrosis more common in high-grade tumors
Assessment of proliferation index essential for grading.
Immunohistochemistry
Positive Markers:
Chromogranin A positive in 80-90% of PanNETs
Synaptophysin positive in 95-100% of cases
CD56 positive in majority of tumors
Neuron-specific enolase (NSE) positive but less specific
Specific hormones positive in functional tumors (insulin, gastrin, somatostatin)
Somatostatin receptor 2A positive in most cases.
Negative Markers:
Cytokeratins (CK7, CK19) typically negative or weakly positive
CEA negative in most cases
TTF-1 negative (distinguishes from lung NET)
CDX2 negative (distinguishes from GI NET)
Trypsin and chymotrypsin negative (distinguishes from acinar tumors)
p63 and CK5/6 negative.
Diagnostic Utility:
Chromogranin A and synaptophysin confirm neuroendocrine differentiation
Ki-67 proliferation index essential for WHO grading
Hormone markers identify functional tumor types
Somatostatin receptor expression predicts response to somatostatin analogs
p53 overexpression rare in well-differentiated NETs
Rb protein loss in poorly differentiated carcinomas.
Molecular Subtypes:
Well-differentiated NETs retain neuroendocrine markers
Poorly differentiated carcinomas may lose chromogranin A
Mixed neuroendocrine-non-neuroendocrine neoplasms (MiNENs) show dual differentiation
Alpha cell tumors: glucagon positive
Beta cell tumors: insulin positive
Delta cell tumors: somatostatin positive
PP cell tumors: pancreatic polypeptide positive.
Molecular/Genetic
Genetic Mutations:
MEN1 gene mutations in 40% of sporadic PanNETs
DAXX and ATRX mutations in 25-30% of PanNETs
mTOR pathway alterations (TSC1, TSC2, PTEN)
VHL gene mutations in VHL-associated tumors
CDKN1B mutations in some cases
TP53 and RB1 mutations rare in well-differentiated NETs but common in carcinomas.
Molecular Markers:
Alternative lengthening of telomeres (ALT) phenotype in ATRX/DAXX mutated tumors
mTOR activation in many PanNETs
Loss of ARID1A expression in subset of tumors
PIK3CA pathway activation
Chromatin remodeling gene alterations
DNA repair pathway defects rare.
Prognostic Significance:
Grade is most important prognostic factor
ATRX/DAXX mutations associated with longer survival despite metastases
mTOR pathway activation predicts response to everolimus
High Ki-67 index associated with aggressive behavior
Chromogranin A levels correlate with tumor burden
Functional tumors may have better prognosis when hormone excess controlled.
Therapeutic Targets:
Somatostatin analogs for somatostatin receptor positive tumors
mTOR inhibitors (everolimus) for advanced NETs
VEGF inhibitors (sunitinib) for progressive NETs
Peptide receptor radionuclide therapy (PRRT) for metastatic disease
Temozolomide-based chemotherapy for Grade 3 tumors
Targeted therapy based on molecular profiling.
Differential Diagnosis
Similar Entities:
Pancreatic ductal adenocarcinoma with neuroendocrine features
Acinar cell carcinoma with neuroendocrine differentiation
Solid pseudopapillary neoplasm in young patients
Metastatic neuroendocrine tumor from other sites
Pancreatoblastoma in pediatric patients
Chronic pancreatitis with islet cell hyperplasia.
Distinguishing Features:
PanNETs show characteristic salt-and-pepper chromatin pattern
Ductal adenocarcinoma shows coarse chromatin and marked pleomorphism
Acinar tumors show enzyme-positive granules and lack neuroendocrine markers
SPN shows characteristic nuclear grooves and beta-catenin positivity
Metastatic NETs require careful IHC workup for primary site
Pancreatoblastoma shows squamoid nests.
Diagnostic Challenges:
Distinguishing Grade 2 NET from Grade 3 requires accurate Ki-67 assessment
Small biopsy samples may not be representative for grading
Crush artifact can obscure characteristic chromatin pattern
Mixed tumors (MiNEN) require recognition of both components
Poorly differentiated carcinomas may lose neuroendocrine markers
Functional status cannot be determined from morphology alone.
Rare Variants:
Mixed neuroendocrine-non-neuroendocrine neoplasms (MiNEN) show dual differentiation
Oncocytic variant shows abundant mitochondria-rich cytoplasm
Clear cell variant may mimic renal cell carcinoma
Pseudoglandular pattern may mimic adenocarcinoma
Spindle cell variant rare but reported
Composite tumors with multiple neuroendocrine cell types.
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
EUS-guided fine needle aspiration of pancreatic [location] mass, [number] passes performed
Specimen Adequacy
Adequate for evaluation - contains diagnostic neuroendocrine cells
Cytomorphological Description
Cohesive clusters of uniform neuroendocrine cells with characteristic salt-and-pepper chromatin. Nested arrangement pattern. Finely granular cytoplasm. Minimal nuclear pleomorphism
Cytological Diagnosis
Neuroendocrine tumor, WHO Grade [1/2/3] (Category V - Suspicious for malignancy or Category VI - Malignant)
Immunocytochemistry
Chromogranin A: Positive, Synaptophysin: Positive, Ki-67 index: [X]%, consistent with WHO Grade [1/2/3]
WHO Grading
WHO Grade [1/2/3] based on Ki-67 proliferation index of [X]%
Clinical Correlation
Correlate with biochemical markers [chromogranin A, specific hormones] and imaging findings
Recommendations
Endocrinology and surgical consultation. Octreotide scan for staging. Consider genetic testing if young age or multiple tumors
Final Diagnosis
Pancreatic neuroendocrine tumor, WHO Grade [1/2/3] - [Functional/Non-functional] type