Biliary tract tumors
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1 Short Course 2010 Annual Fall Meeting of the Korean Society for Pathologists Biliary tract tumors Joon Hyuk Choi, M.D., Ph.D. Professor, Department of Pathology, Yeungnam Univ. College of Medicine, Daegu, Korea
2 I wish you pathologists would find a way to tell us surgeons whether a growth is cancer or not while the patient is still on the table. William Mayo, 1905
3 Case 1 Female, aged 57, epigastric pain and discomfort Abdomen CT: Multiple stones in the dilated left intrahepatic duct, gallbladder, and common bile duct Left lobectomy was performed
4 Dilated bile duct, fibrous ductal wall, and inflammatory cells infiltrate
5 Dysplastic nuclei reaching the luminal surface and pseudostratification
6 Nuclear hyperchromasia with pseudostratification
7 Hyperplasia of peribiliary glands
8 Immunohistochemistry (+): MUC5AC (-): MUC1, MUC2, CDX-2 MUC1 MUC5AC CDX-2
9 case 1: Biliary intraepithelial neoplasia (BilIN)-2 in hepatolithiasis Diagnostic criteria 1. Increased cellularity 2. Structural atypia: loss of polarity, nuclei reaching luminal surface 3. Nuclear atypia (evident but not enough for carcinoma): nuclear enlargement, hyperchromasia, irregularity of nuclear membrane
10 WHO histologic classification of tumors of the liver and intrahepatic bile ducts (2000) Benign epithelial tumors Malignant epithelial tumors Intrahepatic bile duct adenoma Intrahepatic bile duct cystadenoma Biliary papillomatosis Intrahepatic cholangiocarcinoma Bile duct cystadenocarcinoma Combined hepatocellular and cholangiocarcinoma Undifferentiated carcinoma Bile duct abnormalities Hyperplasia (bile duct epithelium and peribiliary glands) Dysplasia (bile duct epithelium and peribiliary glands) Intraepithelial carcinoma (carcinoma in situ)
11 Diagnostic approach of biliary tract lesions Biliary tract lesions First: clinical data, gross and microscopic features Second: immunohistochemistry, EM, molecular genetics, etc. Non-neoplastic lesion Neoplasm Line of differentiation Epithelial Non-epithelial Nuclear atypia (-) Invasion (-) Nuclear atypia (+) Invasion (-) Nuclear atypia (+) Invasion (+) Nuclear atypia, atypical mitosis, necrosis Absent Present Benign Premalignant (dysplasia) Malignant (primary vs. metastatic) Benign Malignant (primary vs. metastatic)
12 Familiarity with the normal histology of the biliary tract is important Small intrahepatic bile ducts Large bile ducts Canals of Hering Diameter (um) Bile ductules <15 Interlobular bile ducts Septal bile ducts Area ducts Segmental ducts Rt & Lt hepatic ducts > >800 Cuboidal Lower columnar Lower columnar Columnar Columnar Columnar Peribiliary glands (Prog Histochem Cytochemistry 2007; 42: )
13 Normal large intrahepatic bile duct A single layer of columnar cells with basally oriented nuclei
14 Normal small intrahepatic bile duct Canal of Hering Canal of Hering CK19 Interlobular bile ducts and bile ductules in portal tract, and canal of Hering
15 Normal peribiliary glands Peribiliary glands composed of cuboidal cells in lobular arrangement
16 Grading of biliary intraepithelial neoplasia (dysplasia) based on the degree of structural and nuclear atypia Consensus proposal (Zen, et al 2007) 3 grading system 2 grading system BilIN-1 (corresponding to low grade) Mild dysplasia BilIN-2 (corresponding to high grade) Moderate dysplasia Low grade dysplasia BilIN-3 (corresponding to carcinoma in situ) Severe dysplasia High grade dysplasia
17 Classification of biliary intraepithelial neoplasia (BilIN) Biliary epithelium Assess cellularity, structural atypia, nuclear atypia (nuclear enlargement, irregular nuclear membrane, hyperchromasia) Cellularity: slightly increased Structural atypia: (-) or mild Nuclear atypia (-) Cellularity: increased Structural atypia (+) Nuclear atypia (+) Hyperplasia or reactive atypia BilIN Cellularity: increased Structural atypia: pseudostratification, nuclei within lower 2/3 of epithelium Nuclear atypia: mild, uniform nuc. size and shape Cellularity: increased Structural atypia: loss of polarity (not diffuse), nuclei reaching luminal surface Nuclear atypia: evident, but not enough for carcinoma Cellularity: increased structural atypia: loss of polarity (diffuse), nuclei reaching and piling on luminal surface Nuclear atypia: severe, overt carcinoma BilIN-1 BilIN-2 BilIN-3 (Mod Pathol 2007; 20: )
18 Hyperplasia or reactive change Slightly increased cellularity and slightly enlarged nuclei with fine chromatin
19 BilIN-1 Mild nuclear atypia, pseudostatification, nuclei in lower two thirds of epithelium
20 BilIN-2 Enlarged, hyperchromatic nuclei reaching the luminal surface
21 BilIN-3 Diffuse loss of polarity and severe nuclear atypia
22 Practical points: evaluation of BilIN (dysplasia) Three-grade system of BilIN has been commonly used The identical diagnostic criteria of BilIN could be used in the intrahepatic and extrahepatic bile duct lesions irrespective of the preceding biliary diseases Any consensus criteria for premalignant lesions in gallbladder and peribiliary glands have been not established The diagnostic criteria of BilIN would be applicable to gallbladder and peribiliary gland lesions (Mod Pathol 2007; 20: ) (Pathol Int 2010; 60: )
23 Morphologic changes of biliary tracts in hepatolithiasis Non-neoplastic - Bile duct fibrosis and inflammatory cells infiltration - Necroinflammatory and degenerative change of peribiliary glands - Cystic dilatation of peribiliary glands - Metaplasia of peribiliary glands - Hyperplasia (or reactive change) of bile duct epithelium - Hyperplasia (or reactive change) of peribiliary glands Neoplastic - BilIN (dysplasia) of bile duct epithelium - Dysplasia of peribiliary glands - Intraductal papillary neoplasm of the bile duct (IPNB) - Intrahepatic cholangiocarcinoma with BilIN - Intrahepatic cholangiocarcinoma with IPNB
24 Necroinflammatory/degenerative change of peribiliary glands Peribiliary glands with acidophilic cytoplasm, inflammatory cells infiltrate
25 Cystic dilatation of peribiliary glands Cystic dilatation of peribiliary glands
26 Pyloric metaplasia of peribiliary glands Pyloric metaplasia lined by clear columnar cells
27 Hyperplasia of peribiliary glands Abundant proliferation of peribiliary glands with lobular arrangement
28 Dysplasia of peribiliary glands Peribiliary glands with dysplastic epithelium and nuclear hyperchromasia
29 Case 2 Female, aged 58, no specific symptoms Abdomen CT: Saccular dilatation of the left intrahepatic bile duct, with multiple stones and low density lesion along the dilated bile duct Left lobectomy was performed
30 Large bile ducts and adjacent bile ducts by lined by papillary epithelial cells
31 Papillary epithelial cells and mucin secretion
32 Mucin secreting cells with hyperchromatic nuclei and pseudostratification
33 Dysplastic cells with high nuclear/cytoplasmic ratio, pseduostratification
34 Immunohistochemistry (+): MUC5AC, MUC2, CDX-2 (-): MUC1 MUC1 MUC5AC CDX-2
35 Case 2: Intraductal papillary neoplasm of the bile duct with high grade dysplasia in hepatolithiasis Diagnostic criteria 1. Intraductal papillary proliferation of mucin secreting cells 2. Mucin hypersecretion 3. Dilatation of affected bile ducts 4. 4 types: intestinal, gastric pancreatobiliary, oncocytic type
36 Intraductal papillary neoplasm of the bile duct (IPNB) Definition Biliary papillary neoplasm mainly growing in the bile duct lumen resembling intraductal papillary mucinous neoplasm of the pancreas Morphology - Intraluminal papillary growth of mucin secreting epithelial cells (mucinous cells) - Mucin hypersecretion - Fibrovascular cores, dilatation of affected bile ducts - 4 histologic types of tumor cells: pancreatobiliary, intestinal, gastric, and oncocytic
37 Types of tumor cells in biliary tract tumors Tumor cells in biliary tract tumors Pancreatobiliary type Intestinal type Gastric type Oncocytic type Columnar cells Stratified tall Columnar cells Abundnat, granular with eosinophilic columnar cells with abundant eosinophlilic cytoplasm and with some intracytoplasmic cytoplasm and round nuclei goblet cells mucin round nuclei MUC1 (+) MUC1 (-) MUC1 (-) MUC1 (+) MUC2 (-) MUC2 (+) MUC2 (-) MUC2 (focal +) MUC5AC (+) MUC5AC (+) MUC5AC (+) MUC5AC (focal +) CDX-2 (-) CDX-2 (+) CDX-2 (-) CDX-2 (?)
38 A variety of terms have been used for intraductal papillary neoplasm of the bile duct (IPNB) Intraductal papillary neoplasia of the liver Intraductal papillary mucinous neoplasm Mucin hypersecreting bile duct tumor Biliary papillomatosis Mucin producing bile duct tumor Mucin-secreting bile duct adenoma Non-invasive or minimally invasive papillary carcinoma Intraductal mucosal-spreading mucin-producing peripheral cholangiocarcinoma Intraductal growth type of cholangiocarcinoma
39 Until now there is no consensus criteria for grading of IPNB 3 grading system 2 grading system IPNB with low grade dysplasia IPNB with high grade dysplasia IPNB-1 (corresponding to benign and borderline lesions of pancreatic IPMN) IPNB with carcinoma in situ IPNB-2 (corresponding to carcinoma in situ of pancreatic IPMN) (Histo Histopathol 2002; 17: )
40 Comparison of BilIN and IPNB BilIN IPNB Cause Gross Micro Malignant transformation Hepatolithiasis + + Parasites infestation + + Primary sclerosing cholangitis + - Tumor size Microscopic Macroscopic Grossly visible - + Dysplastic epithelium + + Flat + Rare Papillary proliferation - + Mucin hypersecretion - + Intestinal metaplasia - + Tubular adenocarcinoma + + Papillary adenocarcinoma + + Mucinous (colloid) carcinoma - +
41 Intraductal growth type of intrahepatic cholangiocarcinoma arising in IPNB Key morphologic findings 4 types of tumor cells 1. Pancreatobiliarry type 2. Intestinal type 3. Gastric type 4. Oncocytic type Male, aged 71, liver
42 Case 3 Female, aged 46, right upper quadrant pain for 2 days Abdomen CT: Intraductal mass with cystic dilation of the bile duct in segment 5 Segmentectomy was performed
43 Multiple papillary growing tumors in the dilated bile duct
44 Papillary structures covered by columnar cells
45 Complex papillary projections with fibrovascular stalks
46 Columnar cells with mild cytologic atypia
47 Immunohistochemistry (+): MUC5AC (-): MUC1, MUC2, CDX-2 MUC1 MUC5AC MUC2
48 Case 3: Biliary papillomatosis Diagnostic criteria 1. Multifocal or diffuse papillary proliferation covered by columnar cells with fibrovascular stalks 2. Histologically papillary (villous) adenoma features 3. No invasion and metastasis
49 Biliary papillomatosis Definition Multiple, benign papillary lesions with delicate fibrovascular stalks covered with columnar cells Site Any sites in biliary tree Morphology - Papillary (villous) adenoma features - Malignant change: Stromal invasion, marked dysplasia, loss of polarity, nuclear hyperchromasia, numerous mitoses
50 Intraductal growth type of intrahepatic cholangiocarcinoma arising in biliary papillomatosis Key morphologic findings Multiple papillary tumors located in intrahepatic and extrahepatic bile duct Papillary (villous) adenoma features Malignant change: stromal invasion Female, aged 61, liver and common bile duct Common bile duct
51 Intraductal growth type of intrahepatic cholangiocarcinoma arising in biliary papillomatosis Key morphologic findings Resection specimen for biliary papillomatosis should be entirely submitted to exclude a small focus of invasive carcinoma Female, aged 61, liver
52 IPNB and biliary papillomatosis share similar morphological features IPNB Biliary papillomatosis Clinical features Gender No predilection No predilection Biliary stone Commonly present Unknown etiologic factor Site Any sites in biliary tree Any sites in biliary tree Morphology Tumor cells Usually mucinous (mucinsecreting) cells Usually biliary columnar cells Papillary (villous) adenoma -/+ + Mucin hypersecretion + Variable Fibrovascular cores + + Multifocal occurrence -/+ + Malignant transformation + +
53 IPNB, billiary papillomatosis, and intrahepatic cholangioca. Female, aged 68 Biliary papillomatosis IPNB Intrahepatic cholangioca. Liver lesion shows the spectrum of papillary biliary neoplasms
54 IPNB, biliary papillomatosis, and intraductal papillary cholangiocarcinoma IPNB Intraductal papillary cholangiocarcinoma Biliary papillomatosis IPNB, biliary papillomatosis, and intraductal papillary cholangiocarcinoma belong to the spectrum of papillary biliary neoplasms
55 Case 4 Female, aged 53, epigastric pain for 3 months Abdomen CT: A 20-cm multilocular cystic mass in the left lobe Extended left lobectomy was performed
56 Multilocular cystic neoplasm
57 Low and high grade dysplastic cells and ovarian-type stroma, goblet cells
58 Moderately differentiated adenocarcinoma change
59 Poorly differentiated adenocarcinoma area
60 Immunohistochemistry (+): MUC2, MUC5AC, CDX-2 (-): MUC1 MUC5AC MUC1 CDX-2
61 Case 4: Bile duct cystadenocarcinoma arising in bile duct cystadenoma Diagnostic criteria 1. Cyst lined by columnar mucinous epithelium 2. Ovarian-type stroma 3. Malignant change: Stromal invasion, nuclear atypia, loss of polarity
62 Bile duct (biliary) cystadenoma and cystadenocarcinoma Definition A cystic tumor either benign (cystadenoma) or malignant (cystadenocarcinoma), lined by mucus-secreting or, less frequently serous epithelium Exclusively women in cystadenoma, but no predilection in cystadenocarcinoma Morphology - Multilocular cysts (size: 5-15 cm) - 2 histologic variants 1. Mucinous type: columnar, cuboidal cells, mucus secreting cells and ovarian-like stroma 2. Serous type: cuboidal cells with clear cytoplasm and no ovarian-like stroma
63 Bile duct cystadenocarcinoma arising in bile duct cystadenoma Key morpholgic findings Malignant change: stromal invasion, marked nuclear pleomorphism, loss of polarity, multilayring of epithelium, densely packed glands, mitotic figures Since malignant change can be focal, extensive sampling is recommended Male, aged 45, liver
64 Classification of cystic lesions of the liver Cystic lesions of the liver Assess gender, location, cystic fluid, lining epithelium, stroma, and relationship with bile ducts Epithelial cysts Non-epithelial cysts Non-neoplastic Neoplastic Simple (solitary Bile duct cystadenoma bile duct) cyst Bile duct cystadenoca. Ciliated foregut cyst Peribiliary cyst Fibropolycystic liver disease Caroli s disease Choledochal cyst Infectious cysts Parasitic cysts Echinococcus Opisthorchis Paragonimus Bacterial abscess Amebic abscess Secondary cystic degeneration or pseudocyst Neoplasms Posttraumatic Postinfarct
65 Ciliated foregut cyst Key morphologic findings A solitary unilocular cyst lined by ciliated, pseudostratified, columnar epithelium and smooth muscle bundles in the wall Usually found incidentally Arise from the embryonic foregut Male, aged 69, liver
66 Adult type (autosomal dominant) of polycystic liver disease Key morphologic findings Cysts lined by simple biliary epithelium Mutation in PKD1 gene (16q13.3) Fibropolycystic diseases A family of congenital hepatic fibrosis, Caroli s disease, von Meyenburg complex, choledochal cyst, infantile and adult type of polycystic liver disease Male, aged 54, liver
67 Biliary tract and pancreas have similar pathologic features Biliary tract Pancreas Biliary intraepithelial neoplasia (BilIN) Intraductal papillary neoplasm of the bile duct (IPNB) Bile duct cystadenoma/ cystadenocarcinoma Cholangiocarcinoma Pancreatic intraepithelial neoplasia (PanIN) Intraductal papillary mucinous neoplasia of the pancreas (IPMN) Mucinous cystic neoplasm Ductal adenocarcinoma (Pathol Int 2010; 60: )
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