Adenocarcinoma of the Extrahepatic Biliary Tree

Epidemiology:

• 60s and 70s
• younger when associated with PSC
• Risk factors:
• PSC
• UC
• Cystic liver diseases (Caroli disease, choledochal cysts)
• Gallstones (debateable)
• Infections:
• Biliary tree fluke infections (Clonorchis sinensis) in Asia
• Salmonella typhi (chronic)

Common sites:

• Upper third (majority)
• proximal to the cystic duct junction, including both hepatic ducts, CBD, and cystic duct
• Klatskin tumour – arises between cystic duct junction and the confluence of the right and left hepatic ducts

Gross features:

• small (usually symptomatic)
• Firm, grey nodules within the bile duct wall
• 4 “types” described with significant overlap
• polypoid type:
• papillary
• friable
• soft
• tan
• nodular type:
• infiltrating pattern usually
• scirrhous constricting type:
• infiltrating pattern usually
• diffusely infiltrating type:
• spreads linearly along ducts
• spread to regional lymph nodes, distant sites (30-70%), or diffuse peritoneal seeding in later stages

Histologic features:

• most are pancreatobiliary type adenocarcinomas (similar to gallbladder carcinoma)
• may be mucin-secreting or not
• other types include intestinal, squamous/adenosquamous, small cell, signet ring cell, mucinous, and undifferentiated carcinomas
• abundant fibrous stroma usually
• perineural invasion often (not seen in benign conditions)
• may be deceptively benign-appearing
• nuclear atypia is not important for diagnosis
• conversely, reactive atypia may be malignant-appearing
• haphazard distribution of glands
• wider, more open luminae than benign glands
• irregular or angular contours of glands may be present
• loss of polarity may be present
• grading (same as rest of GI tract):
• grade 1 – well differentiated - > 95% glands
• grade 2 – moderately differentiated – 50-95% glands
• grade 3 – poorly differentiated - < 50% glands
• papillary adenocarcinoma:
• papillary architecture
• well-differentiated
• good prognosis
• intestinal type
• gastric foveolar type
• mucinous adenocarcinoma
• Clear cell adenocarcinoma:
• Similar to gallbladder variant
• Signet-ring cell carcinoma
• Foamy-gland variant:
• Similar to gallbladder variant
• Prominent nuclear polarity
• Distinctive microvesicular (foamy) cytoplasm
• Chromophilic condensation of apical cytoplasm
• Nuclei may be slightly irregular shape
• Grooves may be present
• Prominent nucleoli not helpful
• Lobular variant:
• Similar to gallbladder variant
• Prognostic parameters similar to gallbladder
• squamous features uncommonly
• Middle third (upper half of CBD) carcinomas:
• Perineural invasion particularly frequent

Immunophenotype:

Marker:	Sensitivity:	Specificity:
MUC1 MUC5AC (cytoplasmic) (apical membrane staining is normal)	“almost all”	Differentiate from intestinal-type adenoCA
P53	>50%
CEA (cytoplasmic) (apical membrane staining is normal)

• endocrine cells often demonstrable

Molecular features:

• mutations in codon 12 of k-ras oncogene
• loss of DPC4 (distal > proximal)

Other features:

• poor prognosis (mean survival 6-18mo.)
• usually not surgically respectable despite small size
• distal third (lower half of CBD) are most respectable (Whipple) and have best prognosis
• Well-differentiated (usually polypoid/papillary) have best prognosis
• Klatskin:
• slow-growing
• relatively infrequent distal metastases
• better prognosis elevated CEA and CA19-9
• familial syndromes:
• FAP (cases reported)
• Type 1 neurofibromatosis (rarely)
• Clinical features:
• Cholestasis
• Acanthosis nigricans
• 5% have synchronous gallbladder carcinoma

References:

• Robbins 2005
• Sternberg 2004