Definition/General
Introduction:
Pancreatic serous cystadenoma (SCA) is a benign cystic neoplasm of the pancreas composed of glycogen-rich epithelial cells
It represents 10-16% of all pancreatic cystic neoplasms
FNAC of cyst fluid shows characteristic low cellularity with bland epithelial cells
The diagnosis is supported by low CEA levels and typical imaging features
SCA has no malignant potential and excellent prognosis.
Origin:
SCA arises from centroacinar cells or small intercalated ducts of the pancreas
The tumor consists of multiple small cysts lined by cuboidal epithelium
Central scar with stellate configuration is characteristic on imaging
Cysts contain clear, thin fluid with low protein content
Most tumors are sporadic but association with VHL syndrome exists
Growth is typically slow with doubling time of several years.
Classification:
WHO classification recognizes serous cystadenoma as benign cystic neoplasm
Subtypes include microcystic (honey-comb pattern), oligocystic (few large cysts), and solid variant
Microcystic pattern most common (70-80%)
Von Hippel-Lindau (VHL) associated tumors often multiple
Serous cystadenocarcinoma extremely rare with only few reported cases
No recognized precursor lesions for SCA.
Epidemiology:
Peak incidence in 6th-7th decades of life
Female predominance with 2:1 ratio
Most tumors are sporadic (85-90%)
VHL-associated SCAs occur in younger patients (3rd-4th decades)
Size ranges from 1-20 cm with average 4-6 cm
Location: head (45%), body/tail (40%), multifocal (15%)
Indian population shows similar demographics to Western countries.
Clinical Features
Presentation:
Many patients asymptomatic with incidental detection on imaging (50-60%)
Abdominal pain most common symptom when present
Large tumors may cause mass effect symptoms
Compression of adjacent structures in pancreatic head lesions
Jaundice rare unless very large tumors compress bile duct
Weight loss uncommon unless massive tumors.
Symptoms:
Epigastric abdominal pain in 40-50% of symptomatic patients
Pain typically dull and non-specific
Nausea and early satiety with large tumors
Back pain with retroperitoneal extension
Diabetes mellitus rarely associated
Pancreatic insufficiency extremely rare
Symptoms more common with tumors >4 cm in size.
Risk Factors:
Von Hippel-Lindau syndrome in 10-15% of cases
Family history of VHL disease
Germline VHL mutations in hereditary cases
Age over 50 years for sporadic tumors
Female gender shows slight predilection
No known environmental risk factors
No association with smoking or alcohol consumption.
Screening:
Routine screening not recommended for general population
VHL syndrome patients require pancreatic surveillance
MRI preferred imaging modality for characterization
CT shows characteristic central scar and honey-comb pattern
EUS-guided FNAC for tissue diagnosis when indicated
Cyst fluid analysis including CEA and amylase levels.
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Gross Description
Appearance:
FNAC typically yields scant cellularity with clear to slightly turbid cyst fluid
Fluid appears thin and watery consistency
Minimal debris or inflammatory cells
Epithelial cells sparse and may be difficult to identify
Background clean without significant protein or mucin
Volume of aspirated fluid variable (0.5-10 mL).
Characteristics:
Cyst fluid typically clear and colorless to pale yellow
Low viscosity compared to mucinous lesions
Minimal cellularity with few epithelial cells
No thick mucoid material or debris
Protein content low (<3 g/dL)
Specific gravity low indicating thin consistency
Chemical analysis shows low CEA levels.
Size Location:
Size ranges from 1-20 cm with most being 4-8 cm
Pancreatic head location slightly more common (45%)
Body and tail involvement in 40% of cases
Multifocal disease in 15% especially VHL-associated
Central location within pancreatic parenchyma
Relationship to main pancreatic duct typically preserved.
Multifocality:
Multiple SCAs occur in 10-15% of cases
VHL-associated tumors frequently multifocal (60-80%)
Different lesions may vary in size and imaging characteristics
Synchronous development common in genetic syndromes
Bilateral involvement possible in extensive cases
Growth rates vary among different lesions.
Microscopic Description
Histological Features:
Scant cellularity with few bland epithelial cells
Cells appear cuboidal to low columnar with clear cytoplasm
Nuclei small, round, and uniform without atypia
Glycogen-rich cytoplasm may appear vacuolated
Rare mitotic figures or nuclear pleomorphism
Background clean without inflammation or necrosis.
Cellular Characteristics:
Epithelial cells show abundant clear cytoplasm due to glycogen content
Nuclei small with fine chromatin and inconspicuous nucleoli
Nuclear-cytoplasmic ratio low due to abundant cytoplasm
Cell borders distinct in well-preserved cells
No significant nuclear atypia or pleomorphism
Cells may appear degenerated due to cyst fluid environment.
Architectural Patterns:
Cells typically present as single cells or small cohesive groups
Three-dimensional clusters rare due to scant cellularity
Honeycomb pattern may be suggested in cell blocks
No papillary formations or complex architecture
Flat epithelial sheets occasionally seen
Background lacking thick mucin or proteinaceous material.
Grading Criteria:
No grading system applicable as lesion is benign
Assessment focuses on confirming benign nature
Absence of nuclear atypia essential for diagnosis
No mitotic activity in typical cases
Cellular preservation may be poor affecting morphology
Adequate sampling important for representative evaluation.
Immunohistochemistry
Positive Markers:
Cytokeratins (CK7, CK19) positive in epithelial cells
Carbonic anhydrase II strongly positive (highly specific)
Inhibin-alpha positive in most cases
EMA positive in luminal borders
PAX6 positive (distinguishes from mucinous lesions)
Periodic acid-Schiff (PAS) positive (glycogen content).
Negative Markers:
CEA typically negative or weakly positive
MUC1 negative (distinguishes from mucinous lesions)
MUC5AC negative
Chromogranin and synaptophysin negative
TTF-1 negative
CDX2 negative
Trypsin and chymotrypsin negative (distinguishes from acinar lesions).
Diagnostic Utility:
Carbonic anhydrase II highly specific for serous lesions (85-90% positive)
Inhibin-alpha useful supporting marker
PAX6 helps distinguish from mucinous cystadenomas
Low or negative CEA in cyst fluid supports diagnosis
Immunocytochemistry rarely needed due to scant cellularity
Chemical analysis more important than morphology.
Molecular Subtypes:
VHL-associated SCAs show VHL gene mutations
Sporadic SCAs rarely show VHL mutations
mTOR pathway alterations in some cases
CTNNB1 mutations rare
No specific molecular subtypes recognized
Most tumors show stable karyotype
Chromosomal instability not characteristic feature.
Molecular/Genetic
Genetic Mutations:
VHL gene mutations in VHL syndrome-associated tumors (10-15%)
Somatic VHL mutations rare in sporadic SCAs
KRAS mutations extremely rare (distinguishes from mucinous lesions)
TP53 mutations not reported
PIK3CA mutations occasional
mTOR pathway genes occasionally altered
Overall mutation burden low.
Molecular Markers:
VHL protein expression lost in VHL-mutated tumors
HIF-1alpha accumulation in VHL-deficient cases
VEGF overexpression in some tumors
Low proliferation indices (Ki-67 <1%)
Stable microsatellites
Normal DNA ploidy in most cases
Lack of chromosomal instability pattern.
Prognostic Significance:
Excellent prognosis with no malignant potential in typical SCA
VHL-associated tumors may be multiple requiring surveillance
Growth rate typically slow (doubling time >10 years)
Size >4 cm may require surgical intervention
No risk of malignant transformation documented
Long-term survival excellent.
Therapeutic Targets:
No specific therapeutic targets due to benign nature
mTOR inhibitors theoretical consideration for VHL cases
VEGF inhibitors for symptomatic vascular lesions in VHL
Anti-angiogenic therapy not routinely used
Observation standard management for small asymptomatic lesions
Surgery for symptomatic or large tumors.
Differential Diagnosis
Similar Entities:
Mucinous cystadenoma shows thick mucoid fluid and higher CEA
Intraductal papillary mucinous neoplasm (IPMN) has duct communication
Pseudocyst lacks epithelial lining and has inflammatory history
Lymphoepithelial cyst shows dense lymphoid infiltrate
Cystic neuroendocrine tumor has neuroendocrine morphology
Simple pancreatic cyst has no epithelial cells.
Distinguishing Features:
SCA shows low CEA (<192 ng/mL) and thin watery fluid
Mucinous lesions have thick viscous fluid and high CEA (>192 ng/mL)
IPMN shows papillary epithelium and duct communication
Pseudocysts lack epithelial lining and have inflammatory cells
NET cysts show neuroendocrine morphology and markers
Simple cysts completely acellular.
Diagnostic Challenges:
Scant cellularity limits morphological assessment
Degenerated epithelial cells difficult to evaluate
Oligocystic variant may mimic mucinous lesions on imaging
Solid variant rare but may confuse diagnosis
Concurrent chronic pancreatitis complicates interpretation
Small lesions may yield insufficient material.
Rare Variants:
Oligocystic SCA has few large cysts (may mimic mucinous)
Solid SCA variant lacks typical cystic architecture
VHL-associated SCAs often smaller and multiple
Calcified SCA shows dystrophic calcification
Mixed serous-mucinous lesions extremely rare
Serous cystadenofibroma has prominent fibrous stroma.
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 aspiration of pancreatic cystic lesion, [volume] mL clear fluid obtained
Fluid Characteristics
Clear to slightly turbid fluid, low viscosity, volume [X] mL
Cytomorphological Description
Scant cellularity with few bland cuboidal epithelial cells. Clear cytoplasm and uniform small nuclei. No nuclear atypia or mitotic activity. Background clean without mucin
Chemical Analysis
CEA: [X] ng/mL (reference <192 ng/mL), Amylase: [X] U/L
Cytological Diagnosis
Consistent with serous cystadenoma (Category II - Benign)
Imaging Correlation
Findings correlate with imaging showing [microcystic pattern/central scar] characteristic of serous cystadenoma
Recommendations
Clinical correlation and imaging follow-up. Consider VHL syndrome evaluation if young age or multiple lesions
Final Diagnosis
Pancreatic serous cystadenoma - Benign cystic neoplasm with excellent prognosis