Definition/General
Introduction:
Pancreatic adenocarcinoma represents the most common primary malignancy of the pancreas, accounting for 85-95% of all pancreatic cancers
FNAC plays a crucial role in diagnosis, especially for unresectable tumors requiring neoadjuvant therapy
The cytological diagnosis relies on identification of malignant ductal epithelium with characteristic morphological features
Early detection through FNAC is essential given the poor prognosis of pancreatic adenocarcinoma.
Origin:
Pancreatic ductal adenocarcinoma arises from the ductal epithelium of the pancreatic duct system
Most tumors develop through progression from pancreatic intraepithelial neoplasia (PanIN) lesions
The malignant transformation involves accumulation of genetic mutations including KRAS, TP53, CDKN2A, and SMAD4
Location varies with 65% in pancreatic head, 15% in body, and 20% in tail
Desmoplastic reaction is characteristic feature.
Classification:
WHO classification recognizes conventional ductal adenocarcinoma as the predominant type
Variants include adenosquamous carcinoma, colloid carcinoma, and hepatoid carcinoma
Grading follows standard adenocarcinoma criteria: well-differentiated (Grade 1), moderately differentiated (Grade 2), and poorly differentiated (Grade 3)
FNAC typically shows moderately to poorly differentiated morphology
TNM staging important for prognosis and treatment planning.
Epidemiology:
Pancreatic adenocarcinoma shows peak incidence in 6th-7th decades of life
Male-to-female ratio approximately 1.3:1
Risk factors include smoking, diabetes mellitus, chronic pancreatitis, and family history
Indian population shows increasing incidence with lifestyle changes
Five-year survival rate remains below 10%
Most patients present with advanced stage disease requiring palliative care.
Clinical Features
Presentation:
Epigastric abdominal pain radiating to back (80% of cases)
Painless jaundice in pancreatic head tumors (70%)
New-onset diabetes mellitus in elderly patients (30%)
Weight loss and cachexia in advanced cases
Gastric outlet obstruction in large head tumors
Thrombophlebitis (Trousseau sign) in some patients
Ascites in cases with peritoneal metastases.
Symptoms:
Abdominal pain typically dull and persistent
Jaundice progressive and associated with dark urine
Steatorrhea due to pancreatic enzyme deficiency
Nausea and vomiting from duodenal obstruction
Fatigue and weakness from cachexia
Back pain may indicate retroperitoneal invasion
Depression commonly associated with pancreatic cancer.
Risk Factors:
Cigarette smoking increases risk 2-3 fold
Diabetes mellitus present in 80% of patients
Chronic pancreatitis increases risk 15-20 fold
Family history of pancreatic cancer
BRCA1/BRCA2 germline mutations
Lynch syndrome and familial atypical multiple mole melanoma (FAMMM)
Obesity and high-fat diet
Age over 60 years.
Screening:
No effective screening for general population
High-risk individuals may undergo imaging surveillance
CA 19-9 tumor marker elevated in 70-80% of cases
EUS-guided FNAC gold standard for tissue diagnosis
CT and MRI for staging and resectability assessment
Laparoscopic staging in selected cases
Molecular profiling for targeted therapy options.
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Gross Description
Appearance:
FNAC specimens typically show low to moderate cellularity
Tissue fragments appear gray-white to tan colored
Background often bloody with necrotic debris
Desmoplastic reaction evident as fibrous tissue fragments
May show mucin-rich areas in well-differentiated tumors
Poorly differentiated tumors show increased cellularity.
Characteristics:
Cellular yield varies based on tumor differentiation and fibrosis
Well-differentiated tumors yield fewer cells due to desmoplasia
Poorly differentiated tumors more cellular with single cells
Necrotic background common in high-grade tumors
Mucin production varies with differentiation grade
Blood contamination frequent due to tumor vascularity.
Size Location:
Pancreatic head tumors most commonly sampled (65%)
Head tumors often smaller at diagnosis due to early jaundice
Body and tail tumors typically larger when detected
Size ranges from 2-8 cm at diagnosis
Relationship to major vessels affects resectability
Multifocal disease in 20% of cases at autopsy.
Multifocality:
Synchronous multifocal tumors occur in 10-20% of cases
Skip lesions may be present along pancreatic duct
Different areas may show varying differentiation grades
Sampling multiple sites increases diagnostic accuracy
Metastatic deposits may be sampled inadvertently
PanIN lesions often present in surrounding tissue.
Microscopic Description
Histological Features:
Malignant ductal epithelium arranged in glands, clusters, and single cells
Cells show marked nuclear pleomorphism with irregular nuclear contours
Prominent nucleoli and coarse chromatin pattern
Cytoplasm variable from scant to abundant
Mucin production evident in cytoplasm and lumina
Desmoplastic stroma with fibroblastic proliferation.
Cellular Characteristics:
Large pleomorphic nuclei with irregular contours and membrane thickening
Nuclear-cytoplasmic ratio markedly increased
Prominent nucleoli often multiple per nucleus
Chromatin coarse and irregularly distributed
Cytoplasm eosinophilic to amphophilic with variable mucin content
Cell borders indistinct with loss of cohesion.
Architectural Patterns:
Malignant glands with loss of normal architecture
Three-dimensional clusters with overlapping nuclei
Single cells scattered in background
Papillary formations in some areas
Cribriform pattern in moderately differentiated areas
Sheet-like arrangement in poorly differentiated tumors
Loss of basement membrane integrity.
Grading Criteria:
Grade 1 (well-differentiated): >95% gland formation with minimal nuclear atypia
Grade 2 (moderately differentiated): 50-95% gland formation with moderate atypia
Grade 3 (poorly differentiated): <50% gland formation with marked atypia
Most FNAC cases show Grade 2-3 morphology
Mitotic activity increases with higher grade
Necrosis more common in high-grade tumors.
Immunohistochemistry
Positive Markers:
Cytokeratins (CK7, CK19) positive in 90-95% of cases
CK20 positive in 70-80% of ductal adenocarcinomas
CEA positive in majority of cases (85%)
CA 19-9 positive in 70-80% when elevated in serum
MUC1 and MUC5AC frequently positive
p53 overexpression in 60-70% of cases.
Negative Markers:
CK5/6 and p63 negative (help exclude squamous differentiation)
TTF-1 negative (distinguishes from lung adenocarcinoma)
PSA and PSAP negative (excludes prostatic origin)
CDX2 usually negative (distinguishes from colorectal metastases)
Chromogranin and synaptophysin negative
Trypsin and chymotrypsin negative.
Diagnostic Utility:
IHC panel essential for confirming pancreatic ductal origin
CK7+/CK20+ pattern suggests pancreatobiliary origin
CEA and CA 19-9 useful for pancreatic primary
p53 overexpression indicates malignancy
SMAD4 loss in 55% of pancreatic adenocarcinomas
mismatch repair proteins usually intact.
Molecular Subtypes:
Squamous subtype: CK5/6 and p63 positive, p40 positive
Adenosquamous carcinoma: mixed CK7 and CK5/6 expression
Colloid carcinoma: MUC2 positive, intestinal-type mucins
Medullary carcinoma: mismatch repair protein deficiency
Undifferentiated carcinoma: loss of epithelial markers
BRCA-associated tumors may show specific patterns.
Molecular/Genetic
Genetic Mutations:
KRAS mutations present in >95% of pancreatic adenocarcinomas (most common G12D, G12V)
TP53 mutations in 70-80% of cases
CDKN2A inactivation in 90% of tumors
SMAD4 inactivation in 55% of cases
BRCA1/BRCA2 mutations in 5-10% of cases
PIK3CA mutations in 10-20% of tumors.
Molecular Markers:
KRAS G12D mutation most common driver alteration
p16 protein loss corresponds to CDKN2A inactivation
SMAD4 protein loss indicates poor prognosis
BRCA1/BRCA2 mutations predict PARP inhibitor sensitivity
Microsatellite instability rare (<5%)
PD-L1 expression variable and generally low.
Prognostic Significance:
SMAD4 loss associated with early distant metastases
BRCA mutations associated with better response to platinum chemotherapy
KRAS G12C mutations potentially targetable with specific inhibitors
High tumor mutational burden rare but may predict immunotherapy response
Homologous recombination deficiency predicts platinum sensitivity
Chromosomal instability pattern most common.
Therapeutic Targets:
KRAS G12C inhibitors (sotorasib, adagrasib) for specific mutations
PARP inhibitors for BRCA-mutated tumors (olaparib, rucaparib)
Platinum-based chemotherapy for homologous recombination deficient tumors
Immunotherapy for mismatch repair deficient tumors (<5%)
FOLFIRINOX and gemcitabine-based regimens standard therapy
Targeted agents under investigation in clinical trials.
Differential Diagnosis
Similar Entities:
Chronic pancreatitis with reactive epithelial changes
Pancreatic intraepithelial neoplasia (PanIN) high-grade lesions
Well-differentiated neuroendocrine tumors
Acinar cell carcinoma with ductal differentiation
Cholangiocarcinoma in periampullary region
Metastatic adenocarcinoma from other sites (lung, breast, GI tract).
Distinguishing Features:
Adenocarcinoma shows marked nuclear atypia and loss of cohesion
Chronic pancreatitis maintains cellular cohesion despite inflammation
PanIN lesions show intact basement membrane and preserved architecture
Neuroendocrine tumors display salt-and-pepper chromatin
Acinar carcinoma shows enzyme-positive granules
Metastatic tumors have specific IHC profiles.
Diagnostic Challenges:
Well-differentiated adenocarcinoma may mimic reactive changes
Crush artifact obscures nuclear details
Scant cellularity in desmoplastic tumors
Distinction from high-grade PanIN lesions
Differentiation from atypical ductal proliferation
Recognition of adenosquamous carcinoma variants
Sampling bias in heterogeneous tumors.
Rare Variants:
Adenosquamous carcinoma shows mixed glandular and squamous components
Colloid carcinoma demonstrates abundant extracellular mucin
Signet ring cell variant mimics gastric carcinoma
Hepatoid carcinoma resembles hepatocellular carcinoma
Medullary carcinoma shows mismatch repair deficiency
Undifferentiated carcinoma lacks glandular differentiation.
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 [head/body/tail] mass, [number] passes performed
Specimen Adequacy
Adequate for evaluation - contains diagnostic epithelial cells
Cytomorphological Description
Clusters and single malignant epithelial cells with marked nuclear pleomorphism. Irregular nuclear contours and prominent nucleoli. Coarse chromatin pattern. Cytoplasm shows mucin production. Background shows necrotic debris
Cytological Diagnosis
Malignant - consistent with adenocarcinoma (Category VI - Malignant)
Immunocytochemistry
CK7 positive, CK19 positive, CEA positive, consistent with pancreatic ductal adenocarcinoma
Clinical Correlation
Findings correlate with imaging showing [size] cm pancreatic mass with [vascular involvement/metastases]
Recommendations
Oncology consultation for staging and treatment planning. Consider molecular profiling for targeted therapy options
Final Diagnosis
Pancreatic adenocarcinoma - Primary pancreatic ductal adenocarcinoma