Diseases of the Gallbladder and Bile Ducts - part 2 potx

34 Section 1: Anatomy, pathophysiology, and epidemiology of the biliary system seen in both obstruction and PSC. However, in large duct ob- struction from other causes, loss of interlobular bile ducts and atrophic changes in ductal epithelium do not occur. The presence of numerous eosinophils in the portal infl amma- tory infiltrate also favors PSC. In pediatric patients with PSC, overlap of clinical and his- topathologic features with autoimmune hepatitis may occur [56]. Although alkaline phosphatase is usually elevated in adults with PSC, normal alkaline phosphatase levels may be seen in children with the disease; in one study of 32 children with PSC, 15 had normal alkaline phosphatase levels at pre- sentation [56]. Most pediatric patients with PSC will also have ulcerative colitis (55%), although this fi gure is less than the commonly quoted 70% in adults. The cholangiogram may show very subtle irregularity of bile ducts, without overt stricture formation, and predominance of intrahepatic dis- ease is common in childhood PSC. Concentric periductal fi - brosis is rarely seen in biopsies from children; instead, the most notable feature is the loss of interlobular bile ducts, which often seem to vanish without a trace. The portal tracts may contain a dense mononuclear infl ammatory infiltrate, with piecemeal necrosis and scattered plasma cells, further resembling autoimmune hepatitis. A high index of suspicion on the part of the gastroenterologist and the pathologist is often necessary to make the diagnosis of PSC in the pediatric patient. Secondary sclerosing cholangiopathies Other causes of biliary strictures are intrahepatic artery chemo- therapy, immunodefi ciency syndromes,andLangerhans’ cell his- tiocytosis. Hepatic artery infusion of floxuridine for treatment of hepatic metastases from colorectal carcinoma has been associated with a sclerosing cholangitis-like lesion resulting in hepatic failure. The etiology of these changes may be isch- emic rather than toxic, as the bile ducts are supplied by the hepatic artery [57]. Although treatment regimens now at- tempt to minimize the risk of this complication, one study re- ported a 1-year rate of sclerosing cholangitis of 25% [58]. Langerhans’ cell histiocytosis may present with isolated hepatic involvement or with involvement of other organ systems, most commonly lymph node and skin. In one study, 7 of 9 cases demonstrated injury to small and medium intra- hepatic bile ducts by infiltrating Langerhans’ cells [59]. Con- centric periductal fibrosis similar to that of primary sclerosing cholangitis was a feature of most cases, and bile ductular pro- liferation was often prominent. Of note, two cases with a PSC-like pattern of injury had no detectable Langerhans’ cells in the liver, and the diagnosis was established by biopsy of extrahepatic sites. Infectious cholangiopathies may also mimic PSC. The most common infectious agents associated with this pattern of he- patic injury are cytomegalovirus and cryptosporidium, seen primarily in the AIDS population. Microsporidial species, Cyclospora, and mycobacterial avium complex are also bili- ary pathogens in this setting [60] and may be identified in biopsy or cytologic samples. Periampullary small bowel biopsies, bile duct brushings, or biopsies of the common bile duct are commonly used for diagnosis. Clinical presentation of AIDS-related cholangiopathies is variable, ranging from asymptomatic to severe right upper quadrant pain. Many pa- tients will also have diarrhea as the infectious agents are also enteric pathogens. Some children with primary immunodeficiency develop sclerosing cholangitis. While many of these cases are un- doubtedly related to persistent biliary tract infections, in others no infectious agent has been demonstrated. In one re- port of 56 children with PSC, eight (14%) had a primary im- munodeficiency syndrome, associated with cryptosporidial infection in three, cytomegalovirus in three, and no demon- strable organisms in two [61]. In our practice, we have seen PSC-like lesions in two children with immunodeficiency: one with severe combined immunodeficiency treated with bone marrow transplantation, and one with common vari- able immunodeficiency. Fibropolycystic diseases Cystic diseases of the liver may be broadly divided into the categories of infectious cystic lesions, which are of course not cysts as they lack an epithelial lining, and true epithelial cysts. Epithelial cysts may be further subdivided into muci- nous cystic neoplasms, and non-neoplastic cysts. The non- neoplastic cysts include sporadic simple cysts, which are generally clinically silent and discovered incidentally. These are typically solitary and are lined by a single layer of colum- nar or fl attened biliary-type epithelium. Also included in lists of sporadic hepatic cysts is the ciliated hepatic foregut cyst, considered developmental in origin. These rare lesions are lined by pseudostratified columnar epithelium with mucus cells; the underlying fibrous wall contains smooth muscle fi - bers [62]. Perihilar cysts arise from periductal glands in the hepatic hilum and may be found in a variety of conditions. They probably represent retention cysts from blockage of drainage of these periductal glands. Generally asympto- matic, large perihilar cysts occasionally cause large duct obstruction. Table 2.5 Staging of primary sclerosing cholangitis. Source: Wiesner et al. [55]. Stage Designation Features 1 Portal Duct abnormalities 2 Periportal Ductular proliferation 3 Septal Bridging fibrous septa 4 Cirrhosis Nodular architecture Chapter 2: Pathology of the intrahepatic and extrahepatic bile ducts and gallbladder 35 The disorders known collectively as fi bropolycystic diseases of the liver are characterized by dilatation and varying degrees of fibrosis of different levels of the intrahepatic biliary tree. These disorders include congenital hepatic fibrosis, Caroli’s disease, Caroli’s syndrome, multiple von Meyenburg com- plexes, and polycystic liver disease; these may occur singly or in various combinations. The essential precursor of the he- patic lesions is the failure of bile ductal plate remodeling dur- ing embryogenesis. This ductal plate malformation may occur at different levels in the biliary tree, from small inter- lobular bile ducts to large segmental ducts, thus leading to a spectrum of clinicopathologic entities [63]. Features in com- mon include association with various cystic diseases of the kidney, mendelian inheritance patterns, and increased risk of cholangiocarcinoma. Congenital hepatic fibrosis This disorder is usually inherited in an autosomal recessive fashion, in most cases associated with autosomal recessive polycystic kidney disease (ARPKD), but in some cases para- doxically associated with autosomal dominant polycystic kidney disease. It is characterized by persistence of the em- bryologic ductal plate, with dilatation of the residual duct- like structures around the periphery of the portal tract (Fig. 2.10). Normal interlobular bile ducts may or may not be pres- ent. Extensive portal–portal bridging fibrosis is usually pres- ent and may lead to an erroneous diagnosis of cirrhosis. However, in contrast to cirrhosis, the hepatic parenchymal architecture is normal, without evidence of regeneration. Four forms of congenital hepatic fibrosis are described, based on clinical presentation: portal hypertensive, cholangitic, mixed, and latent. In young children with ARPKD, the renal symp- toms may predominate and the hepatic lesion may be discov- ered only upon investigation. The most common mode of presentation of the liver disease is portal hypertension, with patients presenting as teenagers with splenomegaly or bleed- ing from esophageal varices. The isolated cholangitic form of congenital hepatic fibrosis is uncommon. Many patients, as in th is case, have the latent for m of congenital hepatic fibro- sis, found incidentally in later life. The natural history of the disorder is often dominated by the renal disease [64]. Pa- tients with portal hypertension may have normal growth and hepatic function. Those with the cholangitic form are at greater risk for hepatic dysfunction. Caroli’s disease and Caroli’s syndrome These disorders are both characterized by the presence of multiple saccular dilatations of the larger segmental intrahe- patic bile ducts. Caroli’s syndrome combines this cyst forma- tion in large ducts with congenital hepatic fibrosis, and is thus thought to represent a sustained insult to development of the intrahepatic biliary system. In contrast, Caroli’s disease af- fects only segmental bile ducts, and may be a result of an he- reditary factor acting at a particular point in the development of the biliary tree [63]. The dilated ducts (Fig. 2.11) are sub- ject to bile sludging and predispose to multiple bouts of chol- angitis. Continued obstruction may lead to secondary biliary cirrhosis. Approximately 15% of cases involve only a portion of the liver, most commonly the left lobe; such cases are ame- nable to surgical resection. An increased risk of cholangio- carcinoma is reported, and amyloidosis may occur as a result of chronic infection. von Meyenburg complexes These small lesions, also called bile duct hamartomas, are generally asymptomatic and are often diagnosed during in- traoperative frozen section consultation or at autopsy. When multiple, they may represent the forme fruste of polycystic liver disease. The von Meyenburg complex consists of dilated biliary channels, sometimes containing inspissated bile, Figure 2.10 Congenital hepatic fibrosis. The hepatic parenchyma is distorted by fibrous expansion of portal tracts containing numerous abnormal biliary channels. These dysmorphic anastomosing biliary channels are arranged around the perimeter of the enlarged portal tracts. Adjacent liver is noncirrhotic. 36 Section 1: Anatomy, pathophysiology, and epidemiology of the biliary system embedded in fibrous stroma at the periphery of a portal tract (Fig. 2.12). Although it was previously thought that von Meyenburg complexes did not communicate directly with the biliary tree, recent studies have shown their continuity with the intrahepatic bile ducts, thus supporting an origin from the ductal plate. The lesion probably represents a slowly involuting remnant of the ductal plate of a small peripheral interlobular bile duct [63]. Multiple von Meyenburg com- plexes are found in polycystic liver disease, and give rise to the macroscopic cysts of that disorder. Polycystic liver disease Patients with polycystic liver disease usually have ADPKD, although isolated polycystic liver disease also occurs. In both disorders, liver cysts are not present at birth but develop over time as fl uid accumulates in the dilated biliary spaces of von Meyenburg complexes. Up to 30% of young adults will have liver cysts; this prevalence increases to 90% in older patients. Multiple unilocular cysts resembling simple biliary cysts and ranging in size from a few millimeters to over 10 cm in diam- eter are scattered diffusely throughout the liver (Fig. 2.13). The cysts usually do not compromise hepatic function but may produce hepatomegaly and abdominal discomfort. Women are more likely to be symptomatic from the cysts, and morbidity is related to number of pregnancies, use of oral contraceptives, and severity of renal involvement [65]. Pathogenesis The currently favored theory for the pathogenesis of the fibropolycystic disorders is that a single gene defect causes maturational arrest of biliary and renal tubular epithelial cells. Approximately 95% of autosomal dominant polycystic kidney disease has been linked to mutations in one of two genes. PKD1, located on chromosome 16 and mutated in 85% Figure 2.11 Caroli’s disease. (A) Involvement of large intrahepatic bile ducts by the ductal plate malformation process gives rise to congenital dilatation of bile ducts in Caroli’s disease. The lesion may be confined to one lobe of the liver, generally the left lobe, and may thus be amenable to resection. (B) The dilated cuts are predisposed to bile stasis, stone formation, and infection. (A) (B) Chapter 2: Pathology of the intrahepatic and extrahepatic bile ducts and gallbladder 37 Figure 2.12 The von Meyenberg complex, or biliary microhamartoma, consists of dilated biliary channels associated with a portal tract. These, when single or few in number, are generally incidental findings, but when multiple are considered part of the spectrum of ductal plate malformation disorders. The adjacent liver in this example is steatotic. Figure 2.13 Polycystic liver disease. (A) Multiple unilocular cysts of varying sizes are found in the liver in polycystic liver disease. In this example, the noncystic portion of the liver is also involved by metastatic pancreatic carcinoma. (B) The cysts are lined by a simple cuboidal to low columnar biliary type epithelium. von Meyenberg complexes (arrow) are frequently found in the vicinity of the cysts and probably give rise to them by progressive accumulation of fluid. (A) (B) 38 Section 1: Anatomy, pathophysiology, and epidemiology of the biliary system of patients with ADPKD, encodes an integral membrane glycoprotein, polycystin-1. The second gene implicated in ADPKD, PKD2, is responsible for 5 to 10% of cases and is lo- cated on chromosome 4. PKD2 also encodes an integral mem- brane protein, known as polycystin-2. Patients with PKD2 mutations are similar clinically to patients with PKD1 muta- tions, but present later in life with renal disease [66]. Germ- line mutations in these genes are inactivating. While ADPKD is inherited in a dominant fashion, it is believed that the dis- ease is recessive on a cellular level, in that loss of the wild- type allele in renal or hepatic epithelial cells (the second hit hypothesis) is necessary for cyst formation. Mice with targeted mutations of either gene die in embryogenesis, sug- gesting that these genes are required for normal fetal devel- opment. Polycystin-1 is involved in cell–cell or cell–matrix interactions with other proteins. Polycystin-2 is thought to function as a subunit of an ion channel whose activity is reg- u l a t e d b y p o l y c y s t i n -1 . I t i s p o s t u l a t e d t h a t p o l y c y s t i n - 2 f o r m s complexes with itself, polycystin-1, or some unknown pro- tein to function as an ion channel [66]. In view of this hypothesis, it is interesting that the coexistence of cystic fibro- sis and ADPKD appears to reduce or delay formation of renal and hepatic cysts [67]. The interaction of polycystin-1 and polycystin-2 may serve to explain the nearly identical shared phenotype associated with mutations in these genes. Abnormally elevated expression of the proto-oncogenes c-myc, c-fos, and c-Ki-ras h a s b e e n de m o n s t r at e d i n c y s t e pi t h e - lium in polycystic kidneys. This altered expression may re- flect a maturational arrest in renal tubulo-epithelial cells, with loss of polarization and increased proliferative capacity. Defective remodeling of the ductal plate probably results in the distinctive hepatic lesions, although the dominant role of the portal vein branches in development of the biliary tree must also be considered, and it is likely that mesenchyme– epithelial cell interaction also plays a role in the pathogenesis of these lesions. Further clarifi cation of these disorders will depend on genetic studies. Isolated polycystic liver disease is associated with muta- tions in the PRKCSH gene, which encodes hepatocystin, a protein involved in regulation of glycosylation and fibroblast growth factor signaling [65]. Choledochal cyst Cystic dilatation of the common bile duct, or choledochal cyst (Fig. 2.14), is generally considered a congenital disorder, although refl ux of pancreatic juices into the bile duct because of an anomalous pancreaticobiliary junction has also been implicated. Classifi cation is based on anatomic location and extent [68] (Table 2.6). Microscopically, the cyst wall is fibrotic and variably infl amed. The biliary epithelial lining is often denuded; goblet cell metaplasia and squamous meta- plasia have been described. Complications include biliary ob- struction, cholangitis, cirrhosis, and cholangiocarcinoma. Complete surgical excision is the treatment of choice. Biliary disorders of childhood Cholestasis is a common finding in pediatric liver disease, and the list of diagnostic possibilities is extensive. Extrahe- patic biliary atresia is the most common cause of large bile duct disease in children. Small duct disorders in the pediatric age group are represented by the group of disorders known as paucity of intrahepatic bile ducts, characterized by a decrease in the number of interlobular bile ducts. Neonatal hepatitis, not further considered here, is a heterogeneous group of dis- orders characterized by hepatocellular injury, cholestasis, and giant cell transformation of hepatocytes, without biliary obstruction or injury to small bile ducts, although bile ductu- lar proliferation is sometimes seen in expanded portal tracts. Extrahepatic biliary atresia Extrahepatic biliary atresia is a progressive fibroinfl ammato- ry obliteration of all or part of the extrahepatic bile ducts, with eventual involvement of small intrahepatic biliary radi- cals. It is thought to be acquired, for the condition is rare in neonates and stillborns, but the etiology remains unknown. An infectious agent has long been suspected, based on the progressive infl ammatory changes in the biliary system and the rarity of the condition in newborns and premature in- fants. Although efforts have focused on the possible role of such viruses as cytomegalovirus, human papilloma virus, rotavirus, and reovirus 3 [69] as etiologic agents in extra- hepatic biliary atresia, results remain inconclusive. Other proposed etiopathologic mechanisms include a defect in morphogenesis of the extrahepatic biliary tree, disorders of immune response, exposure to environmental toxins, and interruption of the vascular supply to the biliary tree [69]. In approximately 20% of cases, other congenital anomalies such as polysplenia and intestinal malrotation are found; these cases are considered by some investigators to be an embryonic or fetal type of biliary atresia. These infants have Table 2.6 Classification of choledochal cysts. Source: Matsumoto et al. [68]. Type Features Comments I Segmental or diffuse dilatation Most common form of common bile duct II Diverticulum, usually of lateral wall III Choledochocele, usually in Usually lined by duodenal duodenal wall mucosa IV-A Multiple extrahepatic duct In association with intrahepatic cysts cysts (Caroli’s disease) IV-B Multiple extrahepatic duct Without associated cysts intrahepatic cysts Chapter 2: Pathology of the intrahepatic and extrahepatic bile ducts and gallbladder 39 earlier onset of cholestasis than those with the more com- mon perinatal type of biliary atresia [70]. Morphologic features At exploratory surgery, the extrahepatic bile ducts are par- tially or totally replaced by a fibrous atretic cord, and the gall- bladder is often shrunken and fibrotic. On microscopic examination, at least a portion of the extrahepatic bile duct is often completely obliterated by fibrous tissue. In less severely affected areas, the bile duct lumen is narrowed by edematous fi brous tissue containing mononuclear infl ammatory cells, neutrophils, and occasional eosinophils (Fig. 2.15A). The ductal epithelium is sloughed or degenerative. The liver shows changes of extrahepatic obstruction including portal enlargement and edema, canalicular cholestasis, bile ductu- lar proliferation, and portal infl ammation (Fig. 2.15B). Oc- casional hepatocyte giant cells are found in some cases, but these are generally not as numerous as in neonatal cholesta- sis, and lobular changes are not as prominent in biliary atre- sia. Even early in the course of the disease the interlobular bile ducts show subtle signs of injury such as angulated out- lines, irregular spacing of epithelial cell nuclei, and pyknosis and degenerative changes in epithelium. In some cases, ab- normal ductal structures suggestive of ductal plate malfor- mation are present. As the disease progresses, destruction of intrahepatic bile ducts continues, resulting in loss of interlob- ular bile ducts. The time course is variable, but bridging portal fibrosis eventually progresses to cirrhosis. Residual in- trahepatic bile ducts may become cystically dilated. The size of ductal remnants in the porta hepatis at the time of hepatoportoenterostomy is considered by some investiga- tors to be an indicator of the likelihood of restoration of bile flow. A diameter of 150 to 200 µm for residual biliary structures (preferably bile ducts lined by columnar Figure 2.14 Choledochal cyst. (A) This fusiform dilatation of the common bile duct is classified as a Type I large choledochal cyst (left). The gallbladder is on the right. (B) The choledochal cyst is usually lined by biliary-type epithelium, although squamous metaplasia may be seen in the setting of inflammation. (A) (B) 40 Section 1: Anatomy, pathophysiology, and epidemiology of the biliary system epithelium, not peribiliary glands) is considered desirable, although correlation of size of draining radicals with good outcome is not perfect [71]. Poor outcome has been asso- ciated with severe injury to intrahepatic ducts, lack of ducts in the hepatic hilum, coexistence of associated congenital anomalies, and the presence of cirrhosis on the initial biopsy. Recurrent bouts of bacterial cholangitis following hepatopor- toenterostomy are also associated with poor outcome [72]. Syndromic and nonsyndromic paucity of intrahepatic bile ducts Pediatric conditions characterized by decreased numbers of intrahepatic bile ducts are generally subdivided into syn- dromic and nonsyndromic categories. Syndromic paucity of intrahepatic bile ducts is synonymous with Alagille’s syn- drome, characterized by chronic cholestasis, distinctive fa- cies, cardiac murmur, vertebral abnormalities, and ocular abnormalities [73]. Nonsyndromic reduction in the number of intrahepatic bile ducts is a heterogeneous group of disor- ders, with varying etiologies such as congenital infection, metabolic disorders, and chromosomal abnormalities. The term “nonsyndromic paucity of intrahepatic bile ducts” is generally reserved for those cases in which no specific etiology can be found. In Alagille’s syndrome, the characteristic lesion is the loss of interlobular bile ducts, recognized by finding hepatic ar- tery branches that are not accompanied by a bile duct (Fig. 2.16). Evaluation of a liver biopsy should include a count of the numbers of bile ducts and the numbers of portal triads available for evaluation. Since the normal ratio of bile ducts to portal triads is approximately 1.0 to 1.8, a ratio of less than 0.5 or 0.4 is considered indicative of ductopenia. The portal triads are often small and inconspicuous and lack a signifi - cant infl ammatory infiltrate. The degree of portal fibrosis is Figure 2.15 Extrahepatic biliary atresia. (A) The extrahepatic bile duct is virtually obliterated by edematous fibrous tissue in this example. Only a small residual lumen is identified. (B) The portal tracts are enlarged by fibrous tissue, with early bile ductular proliferation around the perimeter. (A) (B) Chapter 2: Pathology of the intrahepatic and extrahepatic bile ducts and gallbladder 41 variable, however, and late changes include portal–portal bridging fibrosis; cirrhosis develops in a minority of patients, estimated as 15% [73]. Chronic cholestasis generally occurs, but the lobular changes are often mild. Biopsy specimens taken early, before 3 months of age, may not show the charac- teristic reduction in the number of bile ducts. Such biopsies usually show degenerative changes in bile ducts, and bile ductular proliferation may lead to confusion with extrahe- patic biliary atresia. The gene responsible for about 70% of cases of Alagille’s syndrome, JAG1 (Jagged1), has been identified [74]. This gene is located on chromosome 20p12 and encodes a ligand for the Notch transmembrane receptor. Described mutations in this gene result in translational frameshifts and gross al- teration of the protein; haploinsufficiency of JAG1 appears to be sufficient to produce clinical manifestations of Alagille’s syndrome. The Jagged/Notch signaling pathway mediates cell fate decisions in early development, and abnormalities in this pathway may explain the multisystem developmental abnormalities found in Alagille’s syndrome. Cytomegalovirus infection is probably the most common congenital infection associated with a reduction in the num- ber of interlobular bile ducts; characteristic viral inclusions m ay b e f ou nd i n b i le duc t ep it he l ia l c el l n uc le i i n r esi du a l b i le ducts [75], but inclusions may also be scarce. Chromosomal abnormalities associated with paucity of bile ducts include trisomy 18 and trisomy 21. A number of metabolic disorders may also be associated with decreased numbers of interlobu- lar bile ducts; these include α-1-antitrypsin deficiency, with increased α-1-antitrypsin accumulation in periportal hepa- tocytes on PAS or immunoperoxidase stain, and Zellweger’s syndrome, which shows reduction in hepatocyte peroxi- somes by electron microscopy. Rarely, cystic fibrosis may present as paucity of intrahepatic bile ducts. Duct paucity may also be seen in Byler’s syndrome (progressive familial intrahepatic cholestasis); in some cases, the biopsy shows features of both neonatal hepatitis and paucity of intrahepat- ic bile ducts. The relationship between idiopathic adulthood ductope- nia (IAD) and nonsyndromic paucity of intrahepatic bile ducts in children remains unclear. Liver changes in IAD are those of chronic cholestasis with loss of interlobular bile ducts, essentially the same changes seen in pediatric patients with the nonsyndromic form of paucity of intrahepatic bile ducts. In Alagille’s syndrome, the liver typically shows less cholestatic changes, and less portal fibrosis and bile ductular proliferation. Availability of genetic testing for the human Jagged 1 gene implicated in Alagille’s syndrome may expand our knowledge of the spectrum of abnormalities in this disorder. Neoplasms of the biliary system Benign neoplasms Bile duct adenoma The bile duct adenoma is an innocuous lesion, usually an in- cidental finding at autopsy or in the resected liver. It is not clear that the bile duct adenoma is a true neoplasm, and it is regarded by some investigators as hamartoma of peribiliary glands [76]. These lesions are usually solitary and if subcap- sular may be discovered at surgery, where they may be mis- taken for metastatic adenocarcinoma. Bile duct adenomas generally measure 1 cm or less, although larger ones, up to 4 cm, have been reported. Microscopically they consist of a dense proliferation of bland ductular structures in a variably dense stroma. Cytologic atypia is lacking and mitotic fi gures are rare (Fig. 2.17). The bile duct adenoma may be confused with the biliary microhamartoma, or von Meyenburg com- plex. The biliary microhamartoma represents failure of the ductal plate to involute and is made up of dilated bile Figure 2.16 Paucity of intrahepatic bile ducts. Most portal triads are devoid of interlobular bile ducts in this example of Alagille’s syndrome. The portal tract is not enlarged by fibrous tissue, and there is no inflammatory infiltrate. 42 Section 1: Anatomy, pathophysiology, and epidemiology of the biliary system duct-like structures, occasionally containing bile, located adjacent to a portal tract (Fig. 2.12). The biliary structures are usually more angulated than the densely packed ducts of the bile duct adenoma. Biliary cystadenoma The biliary cystadenoma is an uncommon hepatic neoplasm occurring predominantly in women. Extrahepatic tumors involving the common hepatic duct have also been reported [77]. Biliary cystadenomas are large, multiloculated cysts histologically similar to mucinous cystic tumors arising in the pancreas [78]. The cysts are lined by mucin-secreting cells similar to bile duct epithelium, ranging from flattened cuboidal to tall columnar; occasional goblet cells are seen and scattered endocrine cells can be identified in some cases by immunostaining for chromogranin [79]. The epithelial lining is usually simple, although areas of nuclear pseu- dostratifi cation and crowding may be seen. In tumors from men, the supporting stroma is composed of dense fibrous tis- sue; in women, the stroma may be densely cellular and re- semble ovarian stroma (Fig. 2.18). The biliary cystadenoma should be distinguished from the simple biliary cyst, which is unilocular and lacks a distinctive supporting stroma. Malignant neoplasms Cholangiocarcinoma Cholangiocarcinoma, the second most frequent primary he- patic malignancy, after hepatocellular carcinoma, makes up from 5 to 30% of malignant hepatic tumors. Although sever- al classifi cation schemes for these malignant bile duct tumors have been proposed, the most widely accepted divides these lesions into two broad categories: intrahepatic (peripheral), the most common type worldwide [80]; and hilar (central). This division is supported by the different clinical presenta- tions and surgical strategies associated with these locations. Figure 2.17 The bile duct adenoma is composed of tightly packed small bile duct-like structures. These lesions are small, non-infiltrative, and lack significant nuclear atypia. Figure 2.18 The multilocular cysts of the biliary cystadenoma are lined by columnar to cuboidal cells resembling biliary epithelium. In women, a distinctive mesenchymal ovarian-type stroma is often present in the cyst wall just beneath the epithelium. Chapter 2: Pathology of the intrahepatic and extrahepatic bile ducts and gallbladder 43 The ter m “c hola ng ioloc arci nom a” i s re ser ved by s ome i nve s- tigators for intrahepatic tumors confined to the liver and not involving the extrahepatic biliary tree. Hilar tumors, the ma- jority of surgically treated cholangiocarcinomas in most se- ries from the United States [81], are further subdivided based on the duct involved, or the position of the neoplasm along the common bile duct. An alternative proposed classifi cation based on anatomy and preferred surgical treatment divides cholangiocarcinomas into intrahepatic, perihilar, and distal tumors. In this classification, perihilar tumors involve the hepatic duct bifurcation. Distal tumors involve the distal ex- trahepatic or intrapancreatic portion of the common bile duct. Central/hilar (perihilar) cholangiocarcinoma These tumors share many etiologic associations, such as pri- mary sclerosing cholangitis and ulcerative colitis, fibropoly- cystic liver diseases, and parasite infestation, with intrahepatic cholangiocarcinoma. The incidence of cholan- giocarcinoma in patients with primary sclerosing cholangitis is estimated at 7 to 10% [82]. In contrast to most patients with intrahepatic cholangiocarcinoma, patients with perihi- lar tumors usually present with jaundice and other evidence of large bile duct obstruction. Gross and microscopic features The typical gross appearance of perihilar cholangiocarcinomas is dense white scar infiltrat- ing the hepatic hilum and extending into the adjacent paren- chyma (Fig. 2.19A). In cases of sclerosing cholangitis, the presence of tumor on gross examination may be obscured by dense fibrosis. The bile duct may be encircled and thickened by dense desmoplastic tumor. In some cases, the tumor is papillary and protrudes into the lumen of the bile duct. In general, the microscopic appearance is similar to that of Figure 2.19 Perihilar cholangiocarcinoma. (A) The gross appearance of perihilar cholangiocarcinoma is that of an ill-defined, densely fibrotic infiltrating mass lesion. It may be indistinguishable grossly from hilar fibrosis in primary sclerosing cholangitis. (B) The typical cholangiocarcinoma forms small tubular to cribriform glands, and the tumor cells closely resemble biliary epithelium. A dense desmoplastic stroma usually accompanies the tumor. (A) (B) [...]... Gastroenterology 19 92; 1 02: 1980 2 Diseases of the Gallbladder and Bile Ducts: Diagnosis and Treatment, Second Edition Edited By Pierre-Alain Clavien, John Baillie Copyright © 20 06 by Blackwell Publishing Ltd SEC T ION 2 Diagnostic and therapeutic approaches for the biliary tree and gallbladder Diseases of the Gallbladder and Bile Ducts: Diagnosis and Treatment, Second Edition Edited By Pierre-Alain Clavien,... cholesterolosis and are composed of lipid-laden foamy macrophages Often they are less than 10 mm in diameter and are attached to the mucosa by a stalk They can be solitary, but often multiple polyps are detected in an ultrasonography examination They can Chapter 3: Epidemiology of diseases of the bile ducts and gallbladder be distinguished from stones by their fixed position in the gallbladder and by the lack of. .. 20 01; 129 :704–13 121 Roa I, Araya JC, Shiraishi T, et al DNA content in gallbladder carcinoma: a flow cytometric study of 96 cases Histopathology 1993 ;23 :459–64 122 Suzuki T, Takano Y, Kakita A, et al An immunohistochemical and molecular biological study of c-erbB -2 amplification and prognostic relevance in gallbladder cancer Pathol Res Pract 1993;189 :28 3– 92 Diseases of the Gallbladder and Bile Ducts: Diagnosis and. .. adenomatosis and polyps of the gallbladder Cholesterolosis is an excessive accumulation of lipid in the gallbladder mucosa It can be diffuse or in the form of small polyps In autopsy studies, the prevalence of cholesterolosis is 5 to 20 % The disorder is more common with increasing age and in women The cause of the accumulation of cholesterol esters and triglycerides in the gallbladder mucosa is unknown [ 52] The. .. Hepatol 20 02; 37:806–13 96 Taylor-Robinson SD, Toledano MB, Arora S, et al Increase in mortality rates from intrahepatic cholangiocarcinoma in England and Wales 1968–1998 Gut 20 01;48:816 20 Chapter 3: Epidemiology of diseases of the bile ducts and gallbladder 67 97 Mouzas IA, Dimoulios P, Vlachonikolis IG, et al Increasing incidence of cholangiocarcinoma in Crete 19 92 20 00 Anticancer Res 20 02; 22: 3637–41... thickening of the bile duct wall is appreciated Lesions of the confluence of the hepatic bile duct and upper common hepatic duct account for over half of cases of extrahepatic biliary cancer [88] Lesions involving the middle third of the common bile duct account for approximately 20 %, as do cases involving the lower third of the common bile duct Over 95% of these tumors are Table 2. 7 Staging of perihilar... immunohistochemical, and molecular pathology study of 12 cases Am J Surg Pathol 20 01 ;25 :595–601 117 Albores-Saavedra J, Henson DE, Klimstra DS Tumors of the gallbladder, extrahepatic bile ducts, and ampulla of Vater In: Rosai J, Sobin LH, eds Atlas of tumor pathology, 3rd series, fascicle 27 Washington, D.C.: Armed Forces Institute of Pathology, 20 01, pp 123 –41 118 Henson DE, Albores-Saavedra J, Corle D Carcinoma of the. .. N Am 1990;70:1419 28 109 Tazuma S, Kajiyama G Carcinogenesis of malignant lesions of the gallbladder The impact of chronic inflammation and gallstones Langenbecks Arch Surg 20 01;386 :22 4–9 110 Washington K, Gottfried MR Expression of p53 in adenocarcinoma of the gallbladder and bile ducts Liver 1996;16: 99–104 111 Duarte I, Llanos O, Domke H, et al Metaplasia and precursor lesions of gallbladder carcinoma:... bilirubinate in the gallbladder Not surprisingly, black pigment stone formation is typically associated with chronic hemolysis and cirrhosis [22 ] Brown pigment stones are formed in the gallbladder and in the biliary tree and are, in general, associated with bacterial colonization of the biliary tree and ascending cholangitis Chapter 3: Epidemiology of diseases of the bile ducts and gallbladder 59 Table... Prevalence of gallstones in selected sonographic surveys Geographic population Age range Sample size Prevalence male % Prevalence female % Mean % Ref Europe Denmark England France Italy Italy Italy Italy Italy Norway Poland 30–60 25 –69 >30 18–65 15–65 30–69 30–64 30–69 20 –70 16–70 3608 1896 528 1911 1804 24 61 25 30 29 739 1371 10133 2 13 5– 12 5 22 4 22 1–11 0–17 2 11 6 2 19 5–37 8 3 27 0 25 5 20 15 7– 32 6–41 . disease af- fects only segmental bile ducts, and may be a result of an he- reditary factor acting at a particular point in the development of the biliary tree [63]. The dilated ducts (Fig. 2. 11). count of the numbers of bile ducts and the numbers of portal triads available for evaluation. Since the normal ratio of bile ducts to portal triads is approximately 1.0 to 1.8, a ratio of less. paucity of bile ducts include trisomy 18 and trisomy 21 . A number of metabolic disorders may also be associated with decreased numbers of interlobu- lar bile ducts; these include -1 -antitrypsin