Definition/General

Introduction:
-Pancreatic ductal adenocarcinoma (PDAC) is the most common pancreatic malignancy, representing 85-90% of pancreatic cancers
-It has one of the worst prognoses among solid tumors with 5-year survival <10%.
Origin:
-Arises from pancreatic ductal epithelium through progressive accumulation of genetic alterations
-Develops through PanIN (Pancreatic Intraepithelial Neoplasia) precursor lesions.
Classification:
-WHO Classification includes conventional ductal adenocarcinoma, variants (adenosquamous, undifferentiated, colloid, hepatoid), and mixed tumors
-Molecular subtypes based on transcriptomic profiling.
Epidemiology:
-Fourth leading cause of cancer death
-Peak incidence 60-80 years
-Slight male predominance
-Higher incidence in developed countries
-Strong association with smoking and diabetes.

Clinical Features

Presentation:
-Abdominal pain radiating to back
-Painless jaundice (head tumors)
-Weight loss
-New-onset diabetes
-Acute pancreatitis
-Courvoisier sign (palpable gallbladder).
Symptoms:
-Epigastric pain (85%)
-Jaundice (70% head tumors)
-Weight loss (85%)
-Fatigue
-Loss of appetite
-Steatorrhea
-Thrombophlebitis (Trousseau sign).
Risk Factors:
-Smoking (strongest modifiable risk factor)
-Chronic pancreatitis
-Diabetes mellitus
-Family history
-BRCA1/2 mutations
-Lynch syndrome
-Peutz-Jeghers syndrome.
Screening:
-No effective screening for general population
-CA 19-9 elevated (not specific)
-CT/MRI for imaging
-ERCP for biliary obstruction
-Tissue diagnosis required.

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Gross Description

Appearance:
-Firm, gray-white mass with irregular margins
-Ill-defined borders
-Gritty consistency due to desmoplasia
-May obstruct pancreatic or bile ducts.
Characteristics:
-Size typically 2-5 cm at diagnosis
-Poor demarcation from surrounding pancreas
-Central necrosis uncommon
-Extensive fibrosis characteristic.
Size Location:
-Head of pancreas (70%)
-Body and tail (30%)
-May involve multiple anatomic sites
-Ductal dilatation proximal to tumor.
Multifocality:
-Usually unifocal
-Multicentric growth pattern possible
-Skip lesions along pancreatic duct
-Associated PanIN lesions in adjacent pancreas.

Microscopic Description

Histological Features:
-Infiltrating ductal structures in dense desmoplastic stroma
-Variable gland formation
-Nuclear pleomorphism
-Perineural invasion characteristic (>80% of cases).
Cellular Characteristics:
-Enlarged hyperchromatic nuclei
-High nuclear-to-cytoplasmic ratio
-Prominent nucleoli
-Moderate to abundant eosinophilic cytoplasm
-Mitotic activity variable.
Architectural Patterns:
-Glandular (most common)
-Cribriform
-Solid areas
-Single-cell infiltration
-Squamous differentiation (adenosquamous variant)
-Abundant desmoplastic stroma.
Grading Criteria:
-Well differentiated (>95% glands)
-Moderately differentiated (50-95% glands)
-Poorly differentiated (<50% glands)
-Based on gland formation and nuclear features.

Immunohistochemistry

Positive Markers:
-CK7 positive (100%)
-CK19 positive
-CEA positive
-CA 19-9 positive
-MUC1 positive
-MUC5AC positive (ductal phenotype).
Negative Markers:
-CK20 usually negative
-TTF-1 negative
-CDX2 negative
-Chromogranin negative
-Synaptophysin negative
-Trypsin negative.
Diagnostic Utility:
-CK7+/CK20- pattern helps distinguish from colorectal metastases
-Loss of SMAD4/DPC4 in 50% of cases (poor prognosis marker).
Molecular Subtypes:
-Classical subtype (majority)
-Basal-like subtype (worse prognosis)
-SMAD4-intact vs SMAD4-lost tumors
-Mismatch repair proficient (>95%).

Molecular/Genetic

Genetic Mutations:
-KRAS mutations (90-95%)
-TP53 mutations (70%)
-CDKN2A/p16 mutations (90%)
-SMAD4/DPC4 mutations (50%)
-BRCA1/2 mutations (5-10%).
Molecular Markers:
-Four driver mutations: KRAS, TP53, CDKN2A, SMAD4
-Homologous recombination deficiency in BRCA-mutated tumors
-Chromosomal instability high.
Prognostic Significance:
-SMAD4 loss associated with worse prognosis
-BRCA mutations predict PARP inhibitor response
-Overall prognosis remains poor regardless of molecular features.
Therapeutic Targets:
-PARP inhibitors for BRCA-mutated tumors
-KRAS G12C inhibitors for specific mutation
-Immune checkpoint inhibitors limited efficacy
-Targeted therapy options limited.

Differential Diagnosis

Similar Entities:
-Chronic pancreatitis
-Autoimmune pancreatitis
-Metastatic adenocarcinoma
-Pancreatic neuroendocrine tumor
-Acinar cell carcinoma
-Cholangiocarcinoma.
Distinguishing Features:
-PDAC: CK7+, ductal phenotype, KRAS mutations
-Chronic pancreatitis: benign ducts, inflammation
-NET: Chromogranin+, Synaptophysin+
-Acinar: Trypsin+.
Diagnostic Challenges:
-Distinction from chronic pancreatitis in small biopsies
-Recognition of well-differentiated tumors
-Differentiating from metastatic adenocarcinoma.
Rare Variants:
-Adenosquamous carcinoma (4%)
-Undifferentiated carcinoma (2%)
-Colloid carcinoma (1-3%)
-Signet-ring cell variant
-Foamy gland variant
-Large duct type.

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

Pancreaticoduodenectomy specimen

Tumor Location

Tumor located in [head/body/tail] of pancreas

Tumor Size

Tumor measures [X] x [Y] x [Z] cm

Histologic Type

Ductal adenocarcinoma, [conventional/variant] type

Histologic Grade

[Well/Moderately/Poorly] differentiated

Extent of Invasion

Tumor extends into [peripancreatic soft tissue/adjacent organs] (pT[X])

Resection Margins

Pancreatic margin: [negative/positive], Bile duct margin: [negative/positive], Duodenal margin: [negative/positive]

Lymph Nodes

[X] of [Y] lymph nodes involved (pN[X])

Perineural Invasion

Perineural invasion: [Present/Absent]

Lymphovascular Invasion

Lymphovascular invasion: [Present/Absent]

SMAD4 Status

SMAD4/DPC4: [Retained/Lost] (if performed)

TNM Staging

pT[X]N[X]M[X], Stage [I/II/III/IV]

Final Diagnosis

Final diagnosis: Pancreatic ductal adenocarcinoma, [grade], pT[X]N[X]M[X], Stage [X]