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Extrahepatic bile ducts

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Revised: 19 February 2013
Copyright: (c) 2001-2013, PathologyOutlines.com, Inc.

Normal anatomy


Reviewer: Hanni Gulwani, M.D. (see Reviewers page)
Revised: 12 February 2013, last major update September 2012
Copyright: (c) 2003-2013, PathologyOutlines.com, Inc.

Terminology
=========================================================================

Right and left hepatic ducts:
● 3-4 mm in diameter, within hepatoduodenal ligament, join to form common hepatic duct in porta hepatis (hilum of liver) within 1 cm of their exit from liver
● 10-30% have variation of 2 right sided ducts that join separately with left hepatic duct, common hepatic duct or cystic duct

Common hepatic duct:
● 2-8 mm, 1-5 cm long, joins cystic duct (1-3 cm long) to form common bile duct

Common bile duct:
● 2-9 cm long, passes posterior to first portion of duodenum, traverses the head of pancreas, enters the second part of duodenum through the ampulla of Vater and discharges gallbladder contents into duodenal lumen
● 60% have common channel for pancreatic duct and common bile duct
● Remainder have 2 ducts in parallel

Cystic duct:
● Attaches gallbladder to extrahepatic bile duct, marks division between common hepatic duct and common bile duct
● Usually 2-4 cm
● Contains spiral valves of Heister

Sacculi of Beale:
● Tiny pits that are infoldings of surface epithelium, and give mucosa a reticular macroscopic appearance

Spiral valves of Heister:
● Folds in proximal mucosa of cystic duct, supported by underlying smooth muscle fibers
● Regulates degree of gallbladder distension

Drawings
=========================================================================



Various images

Additional references
=========================================================================

Rom J Morphol Embryol 2010;51:141, Microsc Res Tech 1997;38:552



Normal histology-extrahepatic bile ducts


Reviewer: Hanni Gulwani, M.D. (see Reviewers page)
Revised: 12 February 2013, last major update September 2012
Copyright: (c) 2003-2013, PathologyOutlines.com, Inc.

Grossing
=========================================================================

● May want to submit entire specimen
● Submit margins separately, including hepatic margin (if liver tissue present)

Terminology
=========================================================================

Surface epithelium:
● Composed of tall, uniform, columnar cells
● Mucosa forms irregular pleats or small longitudinal folds

Peribiliary mucous glands:
● Considered a local progenitor cell niche in extrahepatic biliary epithelium (Liver Int 2012;32:554)
● Unevenly distributed within large intrahepatic ducts and all extrahepatic bile ducts
● Lobular architecture; are surrounded by fibroconnective tissue (important in differentiating from well differentiated carcinoma)

Subepithelial region:
● Dense, hypocellular connective tissue, few lymphocytes
● Overlies loose connective tissue with elastic fibers and smooth muscle fibers that are most prominent distally but absent or sparse proximally

Muscle layer:
● Not well defined until distal common bile duct / lower 1/3 of extrahepatic bile duct (Am J Surg Pathol 2000;24:660)
● Upper 1/3 has no muscle layer or scattered muscle fibers

Micro images
=========================================================================



Various images

Positive stains
=========================================================================

Peribiliary glands: amylase, trypsin, lipase



Extrahepatic bile duct metaplasia


Reviewer: Hanni Gulwani, M.D. (see Reviewers page)
Revised: 12 February 2013, last major update September 2012
Copyright: (c) 2003-2013, PathologyOutlines.com, Inc.

General
=========================================================================

● Pyloric gland metaplasia and less commonly intestinal metaplasia are associated with neoplasms and inflammation (Mod Pathol 2001;14:1119)

Case reports
=========================================================================

● Mucinous ductal ectasia of biliary tree secondary to mucous metaplasia (Acta Radiol 2001;42:114)

Micro images
=========================================================================



Pyloric gland metaplasia


Intestinal metaplasia


Squamous metaplasia



Congenital anomalies

Choledochal cyst


Reviewer: Hanni Gulwani, M.D. (see Reviewers page)
Revised: 15 February 2013, last major update September 2012
Copyright: (c) 2003-2013, PathologyOutlines.com, Inc.

General
=========================================================================

● Associated with other hepatobiliary tract abnormalities
● May rupture spontaneously, be associated with reflux of pancreatic enzymes into bile duct
● Associated with stones in 1-30% of cases
● Not actually a cyst, but a dilation of common bile duct which may secondarily obstruct other biliary ducts or the duodenum
● 2-8% develop biliary tract carcinoma (20x normal risk) at mean age 34 years, lower risk if surgery earlier in life (age 10 years or less), carcinoma may develop within wall of cyst, within gallbladder or bile ducts
● In Korea, usually type I or IVa (Arch Surg 2011;146:1178)

Type 1: segmental or diffuse fusiform dilation of common bile duct (50-90%)
Type 2: diverticulum of common bile duct
Type 3: dilation of intraduodenal common bile duct (choledochocele)
Type 4: multiple cysts of extrahepatic bile ducts with (4A) or without (4B) cysts of intrahepatic ducts
Type 5: one or more cysts of intrahepatic ducts (Caroliís disease)

Epidemiology
=========================================================================

● 1 per 13,000 live births in US vs. 1 per 1000 in Japan
● 75% girls
● Most common cause of obstructive jaundice in infants beyond infancy, but may be found at any age

Case reports
=========================================================================

● 11 year old boy (Hum Pathol 2003;34:99)
● 34 year old man with adenosquamous carcinoma in congenital choledochal cyst associated with pancreatico-biliary maljunction (Pathol Int 2009;59:482)
● 41 year old woman with squamous cell carcinoma arising within choledochal cyst (Dig Dis Sci 2008;53:2822)
● Type IV A choledochal cyst with cystic duct cyst (HPB (Oxford) 2010;12:285)

Treatment
=========================================================================

● Complete cyst removal with biliary reconstruction, usually with Roux-en-Y hepaticojejunostomy

Gross description
=========================================================================

● Contain 1-2 liters of bile, up to 15 cm in diameter
● Wall is fibrous, variable calcification, 2-10 mm thick

Micro description
=========================================================================

● Focal columnar epithelium (more intact in infants)
● Walls composed of dense fibrous tissue, scattered smooth muscle and elastic fibers
● Variable chronic inflammatory infiltrate (increases with age)
● Variable hyperplasia, metaplasia, dysplasia

Micro images
=========================================================================



Giant choledochal cyst



Non tumor

Extrahepatic biliary atresia


Reviewer: Hanni Gulwani, M.D. (see Reviewers page)
Revised: 15 February 2013, last major update September 2012
Copyright: (c) 2003-2013, PathologyOutlines.com, Inc.

General
=========================================================================

● Acquired sclerosing inflammatory disorder that replaces bile ducts by threadlike cord embedded in fibrous tissue of porta hepatis
● Leads progressively to loss of intrahepatic ducts and biliary cirrhosis
● Most frequent extrahepatic cause of neonatal cholestasis, causes 1/3 of all neonatal cholestasis
● 1 per 10,000 live births worldwide, 70% girls, usually from uncomplicated pregnancies

Clinical features
=========================================================================

● May be due to significantly shorter cilia with abnormal orientation (Mod Pathol 2012;25:751)
● Associated with cardiovascular defects and polysplenia (10-25%), small gallbladder
● Indication for 50% of pediatric liver transplants
● Most common cause of childhood death from liver disease

Laboratory
=========================================================================

● Persistent conjugated hyperbilirubinemia

Treatment
=========================================================================

● Kasai procedure (portoenterostomy) before 10-12 weeks may be more helpful if hilar bile ductal structures are patent with lumina 1-4 mm or greater
● Frozen section useful to determine if bile ducts in hilum are present and what their caliber is
● Liver transplantation may be curative

Gross description
=========================================================================

● Total or focal complete fibrous obliteration of major hepatic duct lumina or common bile duct

Micro description
=========================================================================

Early:
● Obstructive changes with ductular proliferation, variable portal edema, lobular cholestasis
● Neutrophils common (highlighted by CAP37, Pathol Res Pract 2010;206:314)
● Variable multinucleated giant hepatocytes

Late:
● Ductopenia

Micro images
=========================================================================



Various images

Positive stains
=========================================================================

● CD56 (may be helpful to differentiate from other causes, Am J Surg Pathol 2003;27:1454)



Non tumor

Primary sclerosing cholangitis


Reviewer: Hanni Gulwani, M.D. (see Reviewers page)
Revised: 15 February 2013, last major update September 2012
Copyright: (c) 2003-2013, PathologyOutlines.com, Inc.

General
=========================================================================

● Chronic cholestatic disorder of unknown origin (possibly autoimmune) involving entire biliary tract from ampulla of Vater to small intrahepatic bile ducts or gallbladder
● Much less common than secondary sclerosing cholangitis

Clinical features
=========================================================================

● Rule of 70ís: 70% men, 70% have chronic inflammatory bowel disease (particularly ulcerative colitis which is usually detected first; only 4% with ulcerative colitis have primary sclerosing cholangitis, which is unaffected by colectomy), 70% younger than age 45
● Also associated with chronic pancreatitis (15-25%), Riedelís thyroiditis, retroperitoneal and mediastinal fibrosis, orbital pseudotumor, Sjogrenís syndrome, angioimmunoblastic lymphadenopathy
● End stage disease is associated with hyperplasia of glands of extrahepatic bile ducts, with low incidence of dysplasia and adenocarcinoma (Am J Surg Pathol 2003;27:349)
● Bile ducts in PSC show two distinct pathways of dysplasia-carcinoma, based on differences in cell morphology, growth patterns, immunophenotypes and grade of malignancy (Histopathology 2011;59:1100)
Symptoms: fatigue, jaundice, pruritis

Complications:
● Biliary cirrhosis and liver failure in all cases with median survival 9-12 years
● Cholangiocarcinoma (10-43%), colon carcinoma

Staging:
● 1-inflammation without expansion of portal tracts or piecemeal necrosis
● 2-piecemeal necrosis or fibrosis without bridging
● 3-bridging necrosis or fibrosis
● 4-cirrhosis

Laboratory
=========================================================================

● Elevated serum alkaline phosphatase, IgM, IgG
● Variable bilirubin
● May be p-ANCA positive

Radiology
=========================================================================

Xray: beading of barium column in cholangiogram due to irregular strictures and dilations of affected bile ducts

Case reports
=========================================================================

● 17 year old boy (Diagn Cytopathol 2012;40:337)

Treatment
=========================================================================

● Liver transplant (Hum Pathol 2003;34:1127, Am J Surg Pathol 2007;31:907) since no effective medical therapy

Gross description
=========================================================================

● Periductal portal tract fibrosis, segmental stenosis of extrahepatic and intrahepatic bile ducts

Micro description
=========================================================================

● Fibrosing cholangitis of intra- and extrahepatic bile ducts with lymphocytic infiltration
● Progressive atrophy of bile duct epithelium and obliteration of the lumen, diffuse bile ductular proliferation
● ďOnion skinĒ fibrosis around affected ducts, which later disappear, leaving cord-like fibrous scar
● Remaining ducts are ectatic and inflamed
● Mild to florid hyperplasia often noted
● Recurrence after transplant exhibits bile duct structuring and nonspecific autoimmune hepatitis with variable fibrosis
● Variable portal eosinophils

Micro images
=========================================================================



Portal tract fibrosis


Bile duct with marked periductal sclerosis

Differential diagnosis
=========================================================================

● Sclerosing, well differentiated adenocarcinoma



Non tumor

Secondary sclerosing cholangitis


Reviewer: Hanni Gulwani, M.D. (see Reviewers page)
Revised: 15 February 2013, last major update September 2012
Copyright: (c) 2003-2013, PathologyOutlines.com, Inc.

General
=========================================================================

● Much more common than primary sclerosing cholangitis

Etiology
=========================================================================

● Biliary obstruction (choledochal cyst, choledocholithiasis, chronic pancreatitis, extrahepatic biliary atresia, post-operative), infection (immunodeficiency states), ischemia, malignancy, other (chronic graft vs. host disease, Langerhans cell histiocytosis, sarcoidosis, systemic mastocytosis), toxins
● Associated with hepatic lobar atrophy, bacterial infection (Postgrad Med J 2007;83:773)

Case reports
=========================================================================

● 48 year old woman with recurrent bacterial cholangitis (BMC Gastroenterol 2002;2:14)

Micro description
=========================================================================

● Fibrosis, inflammation, ulceration, foreign body granulomas

Micro images
=========================================================================



Eosinophilic cholangiopathy presenting with secondary sclerosing cholangitis

Differential diagnosis
=========================================================================

Bile duct carcinoma: infiltrating glands, often marked cytologic atypia, perineural invasion; no lobular pattern of peribiliary glands, no concentric fibrosis around peribiliary glands



Tumors

Adenoma


Reviewer: Hanni Gulwani, M.D. (see Reviewers page)
Revised: 15 February 2013, last major update September 2012
Copyright: (c) 2003-2013, PathologyOutlines.com, Inc.

General
=========================================================================

● Incidence only 10% of carcinoma
● More common in gallbladder than extrahepatic biliary tree

Treatment
=========================================================================

● Total excision

Gross description
=========================================================================

● 1-3 cm, usually in common bile duct
● Single or multiple
● Pedunculated or sessile

Micro description
=========================================================================

● Tubular, tubulovillous, villous
● Low to high grade dysplasia
● Usually lined by pseudostratified columnar epithelium and composed of intestinal type glands with goblet cells, endocrine cells, Paneth cells

Stains
=========================================================================

● Express foregut antigens (D10, 1F6, MUC6, MUC5AC, and TFF2) and secrete acid mucin (Am J Surg Pathol 2010;34:1312)



Tumors

Biliary intraepithelial neoplasia


Reviewer: Hanni Gulwani, M.D. (see Reviewers page)
Revised: 15 February 2013, last major update September 2012
Copyright: (c) 2003-2013, PathologyOutlines.com, Inc.

General
=========================================================================

● Premalignant condition divided into three subtypes (Mod Pathol 2007;20:701):

BilIN-1:
● Flat or micropapillary, basal nuclei, pseudostratification (within lower two thirds of epithelium)
● Mild nuclear abnormalities

BilIN-2:
● Flat, pseudopapillary or micropapillary architecture
● Loss of cellular polarity
● Pseudostratification (reaching the luminal surface), dysplastic nuclear changes
● Peribiliary glands are sometimes involved
● Mitoses are rare

BilIN-3:
● Pseudopapillary or micropapillary architecture
● Cytologically resembles carcinoma but no invasion
● 'Budding off' of small clusters of epithelial cells
● Severe nuclear membrane irregularities


Modified diagnostic criteria for reactive change of the biliary epithelium and biliary intraepithelial neoplasia

Micro images
=========================================================================



Various images

Differential diagnosis
=========================================================================

● Hyperplasia or regenerative change: flat or low papillae, nuclear membrane smooth with fine chromatin, intraepithelial neutrophil infiltration can be seen; variable mitotic figures



Tumors

Carcinoid tumor


Reviewer: Hanni Gulwani, M.D. (see Reviewers page)
Revised: 15 February 2013, last major update September 2012
Copyright: (c) 2003-2013, PathologyOutlines.com, Inc.

General
=========================================================================

● 0.3% of tumors in extrahepatic bile ducts
● 2/3 women, mean 50 years old, range 37-67 years
● No systemic endocrine symptoms
● Rarely associated with MEN1 and von Hippel-Lindau syndrome
● Indolent course with long survival even if nodal or hepatic metastases (Am J Surg Pathol 2000;24:1501)
● Tumor size (>2 cm) appears to be the best predictor of aggressive behavior (Arch Pathol Lab Med 2010;134:1075)

Case reports
=========================================================================

● 31 year old woman with VHL (World J Gastroenterol 2008;14:1299)
● 60 year old woman with malignant carcinoid tumor of the cystic duct (Hepatobiliary Pancreat Dis Int 2009;8:640)
● 73 year old man with clear cell carcinoid tumor of distal common bile duct (World J Surg Oncol 2007;5:6)

Gross images
=========================================================================



Clear cell carcinoid tumor of the distal common bile duct: golden yellowish polypoid mass

Micro description
=========================================================================

● Nests, cords or trabeculae of small cells with granular chromatin
● Perineural and vascular invasion is common

Micro images
=========================================================================



Various images


31 year old woman with von Hippel-Lindau syndrome

Positive stains
=========================================================================

● Chromogranin, synaptophysin, serotonin, loss of DPC4

Negative stains
=========================================================================

● p53

Electron microscopy description
=========================================================================

● Numerous membrane bound, round, neurosecretory granules



Tumors

Carcinoma of extrahepatic bile ducts


Reviewer: Hanni Gulwani, M.D. (see Reviewers page)
Revised: 15 February 2013, last major update September 2012
Copyright: (c) 2003-2013, PathologyOutlines.com, Inc.

General
=========================================================================

● Rare (1 per 100,000 in US); 90-95% of extrahepatic bile duct malignancies are adenocarcinomas (bile duct carcinoma, cholangiocarcinoma)
● Present in 0.5% of autopsies
● 2-3 times less common than gallbladder carcinoma

Clinical features
=========================================================================

● More common in Native Americans, Mexicans, Israelis, Japanese
● Present with painless, progressive jaundice; 1/3 have gallstones (10% in bile ducts themselves), 20% had prior biliary tract surgery
● Usually age 60+; rare before age 40 unless have risk factors below
● Small at diagnosis because even small tumors cause obstruction and jaundice

Risk factors:
Clonorchis sinensis and Opisthorchis viverrini infestations, primary sclerosing cholangitis, chronic ulcerative colitis, choledochal cysts, Caroliís disease, congenital hepatic fibrosis
● Also cystic fibrosis, familial polyposis coli, chronic typhoid carriers, biliary giardiasis, Thorotrast exposure, pancreaticobiliary maljunction (PBM) with bile duct dilatation (J Hepatobiliary Pancreat Surg 2008;15:15)

Spread and metastases:
● Local extension to ampulla of Vater, colon, duodenum, gallbladder, liver, omentum, pancreas, stomach
● Tumors from right or left hepatic duct usually extend proximally into liver or distally to common hepatic duct
● Tumors from cystic duct extend to gallbladder or common bile duct
● Tumors from distal common bile duct extend to pancreas, duodenum, stomach, colon, omentum
● Metastases to regional lymph nodes, liver, lungs, peritoneum

Klatskin (hilar) tumors
=========================================================================

● 70% of tumors
● Arise at confluence of right and left hepatic ducts at liver hilus
● Slow growing with infrequent distant metastases, have marked sclerosing characteristics
● Poorer prognosis since difficult to resect
● 28-89% have positive margins

Diagnosis
=========================================================================

● Tissue diagnosis is optimal because clinical diagnosis is often incorrect
● Also brushings, bile drainage cytology

Laboratory
=========================================================================

● Elevated alkaline phosphatase but normal serum bilirubin suggests location above hepatic duct bifurcation or incomplete common bile obstruction

Prognostic factors
=========================================================================

● Presence of intraepithelial spread is not an indicator of a poor prognosis, but carcinoma in situ at the bile duct stump can cause recurrence (Mod Pathol 2008;21:807)
● Mean survival 6-18 months, 2 years if resectable
● 5 year survival is only 5%, but is 60% for T1 tumors (which are rare)

Favorable:
● Low stage, papillary histology, lack of metallothionein expression (Hum Pathol 2009;40:1706), distal tumors, CDX2 and MUC2 (Am J Clin Pathol 2005;124:361)

Unfavorable:
● High grade or high stage tumors, positive surgical margins, hilar tumors, decreased expression of focal adhesion kinase (Hum Pathol 2010;41:859), IMP3 expression (Hum Pathol 2009;40:1377), nuclear KIT expression (Mod Pathol 2007;20:562)
● Presence of tumor necrosis in the nodal tumors, severe nuclear atypia of the tumor cells in lymph vessels (Hum Pathol 2005;36:655)

Case reports
=========================================================================

● 42 year old Japanese woman with obstructive jaundice (Acta Med Okayama 2010;64:63)

Treatment
=========================================================================

● Klatskin tumors require resection of hepatic duct bifurcation
● Distal tumors may require Whipple procedure

Gross description
=========================================================================

● Either firm, gray nodules within bile duct wall or diffusely infiltrative (2%)
● Often extends into adjacent structures
● Limits of tumor often difficult to detect due to desmoplasia
● Tumors may be papillary, multifocal and friable

Gross images
=========================================================================



Bile duct carcinoma

Micro description
=========================================================================

● Nodular or diffusely infiltrative tumors with marked desmoplastic response
● Sclerosing, nodular, polypoid-papillary or mixed types
● Resembles gallbladder carcinoma
● Most are well or moderately differentiated with conspicuous glands, but have extensive perineural invasion
● Even well differentiated tumors may have poorly differentiated foci deep within wall
● Mucin always present within tumor cells and glandular lumina
● Tumor cells cuboidal or columnar, with vesicular nuclei and prominent nucleoli
● Usually angiolymphatic invasion, necrosis and chronic inflammatory infiltrate
● Often adjacent intestinal and pylori metaplasia
● Dysplasia usually present
● Variants include adenosquamous, clear cell, colloid, mucoepidermoid, small cell, squamous cell, undifferentiated (pleomorphic, sarcomatoid, giant cell) carcinomas
● Pyloric gland phenotype involves younger patients, usually well differentiated tumors with characteristic stellar pattern, extensive perineural invasion, MUC6+ and MUC5AC+ (Hum Pathol 2012;43:2292)
● Diagnostically difficult cases are extremely well differentiated, but still have thickened duct wall with prominent desmoplastic response and perineural invasion

Micro images
=========================================================================



Choledochal duct adenocarcinoma


Adenocarcinoma of the gallbladder

Virtual slides
=========================================================================



Moderately differentiated adenocarcinoma

Positive stains
=========================================================================

● Mucin, CEA, CK7 (Am J Surg Pathol 2000;24:870, Arch Pathol Lab Med 2000;124:1196), P-cadherin and CD24 (Hum Pathol 2010;41:1558), EGFR (Hum Pathol 2010;41:485)

Negative stains
=========================================================================

● CK20, CD10 (Am J Surg Pathol 2012;36:101, Histopathology 2009;55:423)

Molecular
=========================================================================

● Promoter hypermethylation is important mechanism in inactivation of p16 gene (Arch Pathol Lab Med 2006;130:33)
● Telomere shortening has been observed in dysplastic epithelium and invasive adenocarcinomas of biliary tract (Mod Pathol 2006;19:772)

Differential diagnosis
=========================================================================

● Intraductal spread of hepatocellular carcinoma, cholangiocarcinoma, metastatic carcinoma
● Metastatic carcinoma: breast, colon, ovary, kidney
● Spread from adjacent tumors of ampulla, colon, duodenum, gallbladder, liver, pancreas, stomach
Sclerosing cholangitis: no perineural invasion, no random glandular infiltration



Tumors

Cystadenoma


Reviewer: Hanni Gulwani, M.D. (see Reviewers page)
Revised: 15 February 2013, last major update September 2012
Copyright: (c) 2003-2013, PathologyOutlines.com, Inc.

General
=========================================================================

● More uncommon in extrahepatic biliary system than in liver
● Extremely rare in gallbladder
● Usually women ages 42-55 years
● Resembles pancreatic cystadenoma

Case reports
=========================================================================

● 54 year old woman with extrahepatic biliary cystadenoma with mesenchymal stroma (J Gastrointestin Liver Dis 2011;20:209)
● 62 year old woman with intrahepatic cystadenoma that extended into common biliary duct (BMJ Case Rep 2012 Apr 4;2012)

Treatment
=========================================================================

● Excision, may recur or become malignant

Gross description
=========================================================================

● Unilocular or multilocular
● Well defined cystic masses with serous, mucinous, bilious, hemorrhagic or mixed fluid
● Outer fibrous wall
● Inner surface is smooth, granular or trabeculated

Gross images
=========================================================================



Multilocular cyst


With multiple tumor nodules

Micro description
=========================================================================

● Multiple locules lined by biliary-type cuboidal or columnar epithelium
● Stroma is cellular, resembling ovarian stroma in 85%, surrounded by hyalinized fibrous tissue
● 13% have dysplastic changes

Micro images
=========================================================================



Various images



Tumors

Dysplasia of extrahepatic bile ducts


Reviewer: Hanni Gulwani, M.D. (see Reviewers page)
Revised: 15 February 2013, last major update September 2012
Copyright: (c) 2003-2013, PathologyOutlines.com, Inc.

General
=========================================================================

● Spectrum from hyperplasia to high grade dysplasia to invasive adenocarcinoma exists, similar to intraductal papillary mucinous neoplasms
● High grade dysplasia at cystic duct margin is rare without invasive carcinoma (HPB (Oxford) 2011;13:865)
● Almost universally abnormally short telomeres (Mod Pathol 2006;19:772)

Micro description
=========================================================================

● May have prominent subnuclear vacuoles

Cytology images
=========================================================================



High grade dysplasia of cystic duct margin


Figures 3 and 4

Positive stains
=========================================================================

● Cell adhesion molecules (P-cadherin and CD24, Hum Pathol 2010;41:1558)

Negative stains
=========================================================================

● Usually CD10- in high grade dysplasia (Am J Surg Pathol 2012;36:101)

Differential diagnosis
=========================================================================

Papillary hyperplasia



Tumors

Giant cell tumor of extrahepatic biliary tree


Reviewer: Hanni Gulwani, M.D. (see Reviewers page)
Revised: 15 February 2013, last major update September 2012
Copyright: (c) 2003-2013, PathologyOutlines.com, Inc.

General
=========================================================================

● True histiocytic neoplasms with mixture of mononuclear and multinucleated osteoclast-like giant cells

Positive stains
=========================================================================

● Mononuclear cells: CD163 (Am J Surg Pathol 2006;30:495)
● Osteoclast-like giant cells: CD68 and HAM 56

Differential diagnosis
=========================================================================

● Anaplastic spindle and giant cell carcinoma (Case Rep Gastroenterol 2012;6:33)



Tumors

Granular cell tumor of extrahepatic bile ducts


Reviewer: Hanni Gulwani, M.D. (see Reviewers page)
Revised: 15 February 2013, last major update September 2012
Copyright: (c) 2003-2013, PathologyOutlines.com, Inc.

General
=========================================================================

● Most common benign nonepithelial tumor of extrahepatic biliary tree
● Usually young to middle-aged (mean 34 years) black (65%) women (91%)

Biliary tree sites:
● Common bile duct or cystic duct
● Also gallbladder (4%), intrahepatic ducts (4%)

Case reports
=========================================================================

● 31 year old woman with painless jaundice and pruritus (Acta Chir Iugosl 2008;55:99)

Gross description
=========================================================================

● Nonencapsulated, 85% solitary, < 3 cm, yellow-tan-white

Gross images
=========================================================================



Common hepatic duct tumor


Distal common bile duct tumor

Micro description
=========================================================================

● Large polygonal cells with abundant, eosinophilic, granular cytoplasm and central, small, dark, uniform nuclei

Micro images
=========================================================================



Large polygonal cells with eosinophilic and granular cytoplasm

Positive stains
=========================================================================

● S100, PAS+ granules, inhibin-alpha (Am J Surg Pathol 2001;25:1200)



Malignant gallbladder tumors

Intracholecystic papillary tubular neoplasm


Reviewer: Hanni Gulwani, M.D. (see Reviewers page)
Revised: 16 February 2013, last major update September 2012
Copyright: (c) 2003-2013, PathologyOutlines.com, Inc.

General
=========================================================================

● Preinavsive neoplasms at least 1 cm (Am J Surg Pathol 2012;36:1279)
● Analogous to pancreatic (IPMN) and biliary counterparts
● Show variable cellular lineages with a spectrum of dysplasia, mixture of papillary or tubular growth patterns
● Relatively indolent behavior - better prognosis than pancreatobiliary-type gallbladder carcinoma

Gross images
=========================================================================



Hilar tumor whose connective tissue contains multiple cysts, some associated with intracystic papillary or solid nodules (arrows)

Micro images
=========================================================================



A: cysts are either lined by flat epithelium or occupied by tumor; B: cyst contains intracystic papillary nodule; C/D: tumor shows papillary and tubular proliferation; E: tumor contains moderately pleomorphic adenocarcinoma cells with focal neutrophils; F: portion of cyst lined by non-neoplastic cuboidal epithelium (upper) which contrasts with carcinoma (lower)


Immunostains: CK7+, MUC1+, MUC6+, MUC5AC-



Tumors

Intraductal papillary neoplasms of biliary tract


Reviewer: Hanni Gulwani, M.D. (see Reviewers page)
Revised: 16 February 2013, last major update September 2012
Copyright: (c) 2003-2013, PathologyOutlines.com, Inc.

General
=========================================================================

● Uncommon
● Solitary, or may spread along biliary tree to cystic duct or duodenal papilla
● May resemble intrapapillary mucinous neoplasms of pancreas as both arise within a dilated duct system and demonstrate predominantly intraductal growth
● Risk factor for cholangiocarcinoma, biliary obstruction, recurring ascending cholangitis
● Are often carcinomas (HPB (Oxford) 2009;11:684)
● p21, p53, cyclin D1, DPC4 are involved in neoplastic progression (Hum Pathol 2008;39:1153)

Case reports
=========================================================================

● 67 year old woman with polypoid mass (Pathol Int 2010;60:516)

Gross description
=========================================================================

● Either polypoid, cast-like growth, superficial-spreading, or cystic type, but does not correlate with prognosis (Abdom Imaging 2011;36:438)

Micro description
=========================================================================

● Papillary fronds with fine vascular cores
● Epithelial cells are either biliary type or have gastric or intestinal differentiation with goblet cells and Paneth cells
● Production of extracellular intraductal mucin less common than papillary IPMN
● Variants have oncocytic changes or cysts (Mod Pathol 2006;19:1243)
Borderline tumor: mild to moderate nuclear atypia and nuclear pseudostratification limited to basal 2/3 of the epithelium
Carcinoma: severe cytological atypia, loss of nuclear polarity, or architectural cribriforming/papillary fusion is present

Micro images
=========================================================================



Various images

Positive stains
=========================================================================

● MUC5AC, MUC6, Claudin 18 and HepPar1
● Variable CK20 (Hum Pathol 2002;33:503)
● Tumors with oncocytic changes have gastric phenotype (Hum Pathol 2009;40:1543), express Wnt pathway proteins beta-catenin and E-cadherin (Pathology 2007;39:413)

Negative stains
=========================================================================

● p53 (Hum Pathol 2003;34:902)

Molecular description
=========================================================================

● Kras activating mutations (29%), 18q- (31%) but no loss of DPC4
● Often has microsatellite instability (Mod Pathol 2002;15:1309)



Tumors

Metastases to extrahepatic bile ducts


Reviewer: Hanni Gulwani, M.D. (see Reviewers page)
Revised: 15 February 2013, last major update September 2012
Copyright: (c) 2003-2013, PathologyOutlines.com, Inc.

General
=========================================================================

● Usually from breast, colon, kidney, lymphoma, pancreas, stomach



Tumors

Neurofibroma


Reviewer: Hanni Gulwani, M.D. (see Reviewers page)
Revised: 16 February 2013, last major update September 2012
Copyright: (c) 2003-2013, PathologyOutlines.com, Inc.

General
=========================================================================

● Very rare (Gastrointest Endosc 2010;72:895)

Case reports
=========================================================================

● 32 year old woman with obstructive jaundice (Dig Dis Sci 2005;50:1166)
● 47 year old woman with obstructive jaundice (Am J Surg 2011;202:e1)

Micro description
=========================================================================

● Fascicles of spindle cells with wavy nuclei in loose myxoid stroma

Micro images
=========================================================================



Spindle cells with adjacent myxoid areas

Positive stains
=========================================================================

● S100



Tumors

Papillary carcinoma of extrahepatic bile ducts


Reviewer: Hanni Gulwani, M.D. (see Reviewers page)
Revised: 15 February 2013, last major update September 2012
Copyright: (c) 2003-2013, PathologyOutlines.com, Inc.

General
=========================================================================

● Usually biliary phenotype, but also intestinal
● Often extends into pancreas or liver
● Papillary carcinomas confined to ductal wall have better 10 year survival than adenocarcinomas confined to ductal wall
● Better survival even if nodal metastases
● Microsatellite instability is relatively frequent in papillary neoplasms of biliary tree (Mod Pathol 2002;15:1309)
● Tumors may dedifferentiate

Micro images
=========================================================================



Exophytic and intraluminal proliferation of complex papillary structures with invasive component



Tumors

Papillomatosis


Reviewer: Hanni Gulwani, M.D. (see Reviewers page)
Revised: 16 February 2013, last major update September 2012
Copyright: (c) 2003-2013, PathologyOutlines.com, Inc.

General
=========================================================================

● Rare; multiple and recurrent papillary adenomas in biliary tract, usually involving extrahepatic bile ducts
● Also called adenomatosis
● Usually ages 50-60 years, no gender preference

Case reports
=========================================================================

● 63 year old man with intrahepatic and extrahepatic biliary papillomatosis (Arch Pathol Lab Med 1993;117:944)
● 65 year old man who received photodynamic therapy for recurrent biliary papillomatosis (World J Gastroenterol 2008;14:4234)
● 75 year old man (Ann Pathol 2004;24:364)
● 82 year old man with biliary papillomatosis of the common hepatic duct (Ann Ital Chir 2011;82:405)

Treatment
=========================================================================

● Complete excision, but local recurrence is common

Gross description
=========================================================================

● Dilated bile ducts with thick, fibrotic walls
● Entire mucosal surface may be replaced by papillary adenomas
● Intraluminal mucin common
● Adenomas are tan, soft, friable polyps without gross invasion

Micro description
=========================================================================

● Columnar or cuboidal cells with basal nuclei overlying fibrovascular core

Micro images
=========================================================================



Various images



Tumors

Rhabdomyosarcoma of extrahepatic bile ducts


Reviewer: Hanni Gulwani, M.D. (see Reviewers page)
Revised: 16 February 2013, last major update September 2012
Copyright: (c) 2003-2013, PathologyOutlines.com, Inc.

General
=========================================================================

● <1% of bile duct malignancies are sarcomas
● Most common sarcoma is embryonal rhabdomyosarcoma
● In children past infancy, #2 cause of obstructive jaundice (after choledochal cysts)
● Usually 3-4 years old with fever, weight loss, jaundice
● Usually embryonal or botyroid subtypes
● 40% have metastases, usually to regional lymph nodes, distal metastases less common
● Often extends into liver or gallbladder

Sites
=========================================================================

● Common bile duct (77%)

Case reports
=========================================================================

● 1 1/2 year old child with tumor mimicking a choledochal cyst (J Cancer Res Ther 2007;3:40)
● 3 year old boy with tumor mimicking a choledochal cyst (J Gastrointestin Liver Dis 2009;18:95)
● 3 year old with endoscopic retrograde cholangiopancreatography for diagnosis and treatment (World J Gastroenterol 2008;14:4823)

Treatment
=========================================================================

● Surgery, chemotherapy, radiation therapy may produce long term survival

Clinical images
=========================================================================



ERCP images

Gross description
=========================================================================

● Botyroid tumors have white-tan, edematous, polypoid grapelike features
● Tumor 3-14 cm

Micro description
=========================================================================

● Embryonal tumors have condensed (cambium) layer of primitive spindle cells just below surface epithelium
● Rhabdomyoblasts may be prominent with abundant eosinophilic cytoplasm
● May have relatively acellular layer with myxoid stroma

Micro images
=========================================================================



Some rhabdomyosarcoma cells have eosinophilic cytoplasm suggesting skeletal muscle differentiation but most are very undifferentiated in myxoid stroma; tumor cells are strongly myogenenin+

Positive stains
=========================================================================

● Desmin, muscle specific actin, MyoD1, variable myoglobin

Electron microscopy description
=========================================================================

● Thick and thin filaments



Tumors

Traumatic neuroma


Reviewer: Hanni Gulwani, M.D. (see Reviewers page)
Revised: 16 February 2013, last major update September 2012
Copyright: (c) 2003-2013, PathologyOutlines.com, Inc.

General
=========================================================================

● Usually post-operative, at stump of cystic duct
● May cause postcholecystectomy pain or obstructive jaundice

Case reports
=========================================================================

● 70 year old man with polypoid mass (Korean J Gastroenterol 2008;52:32)
● 73 year old patient with obstructive jaundice (G Chir 2006;27:31)
● 88 year old man with markedly fibrotic gallbladder but no prior surgery (Hum Pathol 1985;16:1168)
● Arising from injury during cholecystectomy (Hum Pathol 1984;15:287)
● Arising in gallbladder (Arch Pathol Lab Med 1985;109:574)

Micro images
=========================================================================



Various images



Tumors

TNM staging for Extrahepatic bile duct carcinoma


Reviewer: Hanni Gulwani, M.D. (see Reviewers page)
Revised: 15 February 2013, last major update September 2012
Copyright: (c) 2003-2013, PathologyOutlines.com, Inc.

Staging of Perihilar Bile Duct tumors

General
=========================================================================

● Classification excludes sarcomas and carcinoid tumors
● Divided into perihilar (proximal) and distal bile duct tumors

Primary tumor (T) - perihilar bile duct tumors
=========================================================================

TX: Primary tumor cannot be assessed
T0: No evidence of primary tumor
Tis: Carcinoma in situ
T1: Tumor confined to the bile duct, with extension up to the muscle layer or fibrous tissue
T2a: Tumor invades beyond the wall of the bile duct to surrounding adipose tissue
T2b: Tumor invades adjacent hepatic parenchyma
T3: Tumor invades unilateral branches of the portal vein or hepatic artery
T4: Tumor invades main portal vein or its branches bilaterally; or the common hepatic artery; or the second-order biliary radicals bilaterally; or unilateral second-order biliary radicals with contralateral portal vein or hepatic artery involvement

Regional lymph nodes (N) - perihilar bile duct tumors
=========================================================================

NX: Regional lymph nodes cannot be assessed
N0: No regional lymph node metastasis
N1: Regional lymph node metastasis (including nodes along the cystic duct, common bile duct, hepatic artery and portal vein)
N2: Metastases to periaortic, pericaval, superior mesenteric artery or celiac artery lymph nodes

Distant metastasis (M) - perihilar bile duct tumors
=========================================================================

M0: No distant metastasis
M1: Distant metastasis

Stage grouping - perihilar bile duct tumors
=========================================================================

0: Tis N0 M0
I: T1 N0 M0
II: T2a-b N0 M0
IIIA: T3 N0 M0
IIIB: T1-3 N1 M0
IVA: T4 N0-1 M0
IVB: any T N2 M0 or any T any N M1


Staging of Distal Bile Duct tumors

General
=========================================================================

● Classification excludes sarcomas and carcinoid tumors
● Divided into perihilar (proximal) and distal bile duct tumors
● Bile duct wall is more precisely defined as occurring between the mucosa and the outermost boundary of dense fibromuscular tissue, without consideration of the presence or absence of blood vessels and nerve fibers (Am J Surg Pathol 2006;30:744)
● Primary tumor/vessel tumor/nodal tumor classification is better instead of current TNM classification for extrahepatic bile ductcarcinoma (Hum Pathol 2008;39:37)

Primary tumor (T) - distal bile duct tumors
=========================================================================

TX: Primary tumor cannot be assessed
T0: No evidence of primary tumor
Tis: Carcinoma in situ
T1: Tumor confined to the bile duct histologically
T2: Tumor invades beyond the wall of the bile duct
T3: Tumor invades the gallbladder, pancreas, duodenum or other adjacent organs without involvement of the celiac axis or the superior mesenteric artery
T4: Tumor invades the celiac axis or the superior mesenteric artery

pT2 and pT3
● Extrahepatic biliary tree histology varies along its length, with little smooth muscle in wall of proximal ducts compared to distal bile duct, rendering assessment of depth of tumor invasion difficult
● Inflammatory changes in bile ducts and desmoplastic stromal response to tumor may also cause distortion
● To overcome these difficulties, recommended by some (but not widely adopted) to measure depth of tumor invasion from basal lamina of normal epithelium to the point of deepest tumor invasion
● The current pT3 stage of distal EBD carcinomas can be subdivided into superficial (pT3a) and deep pancreatic invasion (pT3b, Mod Pathol 2005;18:969)

Regional lymph nodes (N) - distal bile duct tumors
=========================================================================

NX: Regional lymph nodes cannot be assessed
N0: No regional lymph node metastasis
N1: Regional lymph node metastasis

● Proposed to classify as N1 (metastasis in 1-4 regional lymph nodes) or N2 (metastasis in 5+ regional lymph nodes, Am J Surg Pathol 2005;29:1177)

Distant metastasis (M) - distal bile duct tumors
=========================================================================

M0: No distant metastasis
M1: Distant metastasis

Stage grouping - distal bile duct tumors
=========================================================================

0: Tis N0 M0
IA: T1 N0 M0
IB: T2 N0 M0
IIA: T3 N0 M0
IIB: T1-3 N1 M0
III: T4 any N M0
IV: any T any N M1



Table - Stage groupings

Drawings
=========================================================================





Various images

Additional references
=========================================================================

Arch Pathol Lab Med 2010;134:e8, CAP protocol



Tumors

Features to report


Reviewer: Hanni Gulwani, M.D. (see Reviewers page)
Revised: 15 February 2013, last major update September 2012
Copyright: (c) 2003-2013, PathologyOutlines.com, Inc.

General
=========================================================================

● Bile duct wall thickness, external surface, obstruction, stones
● Tumor size and location
● Tumor histologic type, pattern and grade
● Depth of invasion
● Number and size of tumor nodules
● Tumor extension to adjacent structures
● Status of resection margins
● Regional lymph nodes: number identified, number with tumor
● Angiolymphatic invasion
● Perineural invasion
● Presence of carcinoma in situ or dysplasia

Additional references
=========================================================================

Arch Pathol Lab Med 2000;124:26, Arch Pathol Lab Med 2010;134:e8, CAP protocol

End of Extrahepatic bile ducts > Superpage


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