Cystic lesions of the liver can be derived from a variety of pathologic processes. Several different classifications for these lesions have consequently been proposed, based variously on the pathogenesis, origin, or biliary relationship of the cysts.²⁰ A simple histologic classification separates hepatic cysts into two major categories, epithelial and infectious. The epithelial cysts can be divided into neoplastic and nonneoplastic groups. The neoplastic group primarily comprises biliary cystadenoma and cystadenocarcinoma, which are discussed in Chapter 15, and the nonneoplastic cysts, including sporadic cysts and cysts associated with fibropolycystic disease, are examined in this chapter.

The infectious cysts entail echinococcal (and other parasitic) cysts, bacterial abscesses, and so-called amebic abscesses (Chapter 8). A cyst-like appearance can also occur as a secondary feature in almost any neoplasm, either because of cystic degeneration or central necrosis (Chapter 15). Finally, hepatic pseudocysts with a granulation tissue-lining can develop after trauma or focal infarction.²⁰

Simple hepatic cysts, also known as solitary cysts, nonparasitic cysts, or benign hepatic cysts, are usually considered rare lesions, although in careful autopsy or radiographic surveys, they are found in 1% to 2.5% of individuals.⁶ They occur at all ages, though the prevalence increases with advancing age, and women are more often affected than men. Most simple cysts cause no symptoms and are discovered fortuitously. Rare examples produce abdominal discomfort or distension, cause local biliary obstruction, or develop complications such as intracystic hemorrhage, torsion, secondary infection, or rupture.^2,3

The pathogenesis of simple cysts is not known, but an developmental origin from aberrant bile ductules, possibly included within a biliary microhamartoma, is generally proposed. The lesions exhibit no consistent association with cysts in other organs or with other diseases. A connection with Peutz-Jeghers syndrome has been proffered, but this may be only a coincidental occurrence.¹⁶

Typical simple cysts are single and unilocular with diameters that range from a few millimeters to 20 cm or more. As many as five cysts can be seen on occasion, but the presence of multiple cysts should raise the possibility of autosomal dominant polycystic disease; evaluation for renal cysts and a careful family history are then warranted.²⁰ The cystic fluid is usually clear yellow, but it may appear mucoid, or, under appropriate circumstances, bloody or purulent. The inner surface is smooth and glistening.

Histologically, the cysts are lined by a single layer of cuboidal to columnar epithelium that resembles biliary epithelium (Figure 14-1). The epithelial cells contain small quantities of mucin and demonstrate weak immunostaining for epithelial membrane antigen and carcinoembryonic antigen.¹⁵ The epithelium may become attenuated, denuded, or replaced by squamous epithelium, in which case a designation such as epidermoid cyst is appropriate.¹² Surrounding the epithelial layer is a thin wall of mature fibrous tissue, sometimes containing bile ducts and large blood vessels, and a variable outer zone of compressed hepatic parenchyma. An occasional biliary microhamartoma can be present in the neighboring liver, but when they are numerous, consideration should again be given to polycystic disease.

An ominous but rare complication of simple cysts is the development of carcinoma (Figure 14-2). In most cases, this has been an adenocarcinoma, although squamous carcinoma and mixed adenosquamous (or mucoepidermoid) carcinoma have also been reported.^1,7,8,11,17

The ciliated hepatic foregut cyst is a variation on the simple cyst theme.^14,19 This unusual lesion, generally solitary and unilocular, is characterized by ciliated pseudostratified columnar epithelium with mucous cells and an underlying fibrous wall containing abundant smooth muscle. Since these features are similar to those seen in bronchial and esophageal cysts, an analogous origin from the embryonic foregut is suggested.

Periductal hilar cysts are multiple, small (1 mm to 2 cm) cystic lesions that are found along the walls of large bile ducts, both intrahepatic and extrahepatic, in the vicinity of the hepatic hilum.^4,10,18 Often occurring in a setting of cirrhosis or portal vein thrombosis, these cysts are generally considered to represent retention cysts resulting from obstructed periductal glands. They contain a watery or mucoid material and are lined by a mucinous epithelium ranging from columnar to flattened in appearance. The surrounding stroma exhibits mild chronic inflammation, variable fibrosis, and occasional obliterated veins. Usually periductal hilar cysts are an incidental finding, but on occasion, they can give rise to biliary obstruction.

Miscellaneous Cysts

Other unusual cystic lesions include endometrial cysts and alimentary duplications that extend into the liver.^5,9,13

The fibropolycystic diseases constitute a family of conditions distinguished by malformation or dilatation of the bile ducts together with associated hepatic fibrosis. Included are congenital hepatic fibrosis, autosomal recessive polycystic disease, autosomal dominant polycystic disease, Caroli's disease, and, to a lesser extent, choledochal cysts.^38,93

Although representing a heterogeneous group, these conditions often do not occur as single entities but are found in various combination, leading to problems in classification and nomenclature. In addition, they share certain other features, including Mendelian inheritance patterns, an association with various cystic disease of the kidney, and an increased risk of developing cholangiocarcinoma. These relationships all support the consideration of these disorders as part of one family.

The pathogenesis of all these conditions is generally considered to involve abnormalities in the embryogenesis or development of the biliary tract. By this view, the various disorders likely reflect alterations at different biliary levels, ranging from the small bile ducts in congenital hepatic fibrosis and autosomal recessive polycystic disease, to the large intrahepatic bile ducts in Caroli's disease, to the extrahepatic bile ducts in choledochal cyst.^38,39

An additional member of this group is the biliary microhamartoma or von Meyenberg complex. This small lesion, which discussed in detail in Chapter 15, consists of numerous irregular bile duct-like structures embedded within a fibrous stroma (Figure 14-3). It is typically an incidental finding, but constitutes the precursor lesion of autosomal dominant polycystic disease and, when multiple, is difficult to distinguish from congenital hepatic fibrosis. As with other forms of fibropolycystic disease, biliary microhamartomas have been complicated by cholangiocarcinoma.^28,37,53

Congenital hepatic fibrosis and autosomal recessive (infantile-type) polycystic disease are the two classic conditions associated with distinctive alterations in the formation and development of the small intrahepatic bile ducts. In addition to this characteristic biliary dysgenesis, both disorders are regularly associated with renal cystic diseases.²⁴ The classification and nomenclature of the biliary dysgenesis disorders is complicated and confusing, in part reflecting whether the liver or the kidney serves as the taxonomic focus, and the relationship between them remains controversial. Some consider the two disorders to be separate and distinct entities, whereas others regard them as variable expressions of the same basic disease.^25,40,66,74

Resolution of these disputes awaits a better understanding of the etiology and pathogenesis of the conditions. Nonetheless, the hepatic abnormalities are similar in both conditions, and many of the differences between them are accounted for by variations in the extent and severity of the renal manifestations. In general, the label of congenital hepatic fibrosis is applied when the hepatic manifestations predominate, and the name autosomal recessive polycystic disease is employed when renal disease is the principal feature. Because of the correspondence of the liver findings, the two disorders will be regarded, for purposes of this discussion, as a single entity with a spectrum of clinical presentations.

Clinical features. The clinical manifestations of the biliary dysgenesis disorders vary greatly. Affected patients range in age from birth to over 50 years, and males and females are equally involved. In some instances, however, the disease remains clinically silent and is discovered either incidentally or at autopsy. Although individual cases appear to occur sporadically, most pedigree studies demonstrate an autosomal recessive transmission.

The main consequence of hepatic involvement is portal hypertension. This represents the classic presentation of congenital hepatic fibrosis and typically appears in patients between five and 20 years of age, although any age group can be affected.^21,50 Variceal bleeding, hepatomegaly, and splenomegaly complicated by hypersplenism are common findings, and liver function tests are normal or only mildly elevated. Ascites, jaundice, and hepatic failure rarely develop.^45,61 In some cases associated with Caroli's disease, recurrent bacterial cholangitis can become a severe complication, occasionally leading to sepsis and death.^41,75,78 Since liver function tends to be maintained, however, the long-term prognosis is relatively favorable if variceal bleeding can be controlled by endoscopic sclerotherapy or portosystemic shunting.^21,41,62 Rare reports describe the development of complicating cholangiocarinoma.^35,90

Renal abnormalities occur in almost all cases and, particularly in infants and young children, can dominate the clinical picture and produce the prototypic setting of autosomal recessive polycystic disease. The corresponding renal alterations consist of cystic dilatation of the collecting ducts; although diffuse and distinctive in younger patients, these changes become less characteristic in older individuals.^23,25,68 In severe cases, the result is renal enlargement with progressive renal insufficiency, systemic hypertension, respiratory distress, and congestive heart failure. The early mortality rate is high, but with appropriate management, some patients survive into childhood.^48,68 In other cases, the renal involvement is less marked, although hypertension or overt renal failure can occasionally develop.

In occasional instances, the associated kidney disorder is instead represented by autosomal dominant (adult-type) polycystic kidney disease, renal dysplasia, or nephronophthisis and other forms of medullary cystic disease, and rarely the kidneys are normal.^{22,34,81,95,108} Other reported associations include various malformation syndromes including Meckel-Gruber syndrome, Zellweger's syndrome, Jeune's syndrome, Ivemark's syndrome, tuberous sclerosis, and vaginal atresia and miscellany of additional conditions such as pulmonary arteriovenous fistulas, cerebral artery aneurysms, forms of congenital heart disease, and intestinal lymphangiectasia; in some of these cases, however, the hepatic abnormality is not definitively demonstrated to be biliary dysgenesis, but may simply represent nonspecific bile ductular proliferation.^20,24,66

Pathologic features. The histologic hallmark of biliary dysgenesis is the presence of numerous abnormal biliary channels embedded within an enlarged fibrotic portal tract (Figure 14-4). These aberrant channels exhibit various elongated, branched, or angular profiles, vary in number, and are typically located along the margins of the portal tracts, often running parallel to the border. They are in continuity with the remainder of the biliary system and can become variably enlarged, but obvious cyst formation is uncommon and seen only in infants. Normal interlobular bile ducts may or may not be present.

The dysmorphic biliary structures are thought to represent the remnants of embryonic bile ducts and have been designated as the ductal plate malformation.^38,39,58 Normally the bile ducts develop from a double-layed epithelial cylinder -- the ductal plate -- that forms around the nascent portal tract. Some portions of this cylinder become incorporated into the portal mesenchyme and give rise to the interlobular ducts, and the residue then regresses and disappears. This developmental process starts during the third month of gestation at the hepatic hilum and progressively continues with smaller portal branches, finally concluding during the first postnatal month.^87,91,104 If the process is disrupted, segments of the surplus ductal plate persist and give rise to flattened, interconnected biliary sacs that are recognized on histologic sections as the ductal plate malformation (Figure 14-5).

The involved portal tracts are expanded by dense fibrosis and sharply demarcated from the adjacent parenchyma (Figure 14-6). The degree of fibrosis can remain static or slowly progress, perhaps a result of secondary complications such as focal biliary obstruction or bacterial cholangitis, and can lead to the formation of portal-portal fibrous bridges.²⁵ The lobular architecture is preserved, however, and cirrhosis by strict criteria does not develop. The portal vein branches are often small or compressed, and the hepatic arteries appear normal or hyperplastic. Inflammation is typically sparse or absent except in cases with superimposed bacterial cholangitis related to coexisting Caroli's disease. In this situation, canalicular cholestasis, bile ductular proliferation with its attendant inflammatory response, and acute cholangitis can all be prominent features. Usually the histologic changes are uniformly distributed across the liver, although localized involvement has also been noted.^21,52

In addition to Caroli's disease, biliary dysgenesis -- usually designated as congenital hepatic fibrosis -- can be associated with autosomal dominant polycystic disease or choledochal cysts.^78,97

Differential diagnosis. The diagnosis of the biliary dysgenesis disorders is generally straightforward, although because of sampling problems, the distinctive biliary alterations may be missed with needle biopsy specimens. In some instances, the appearances can be confused with cirrhosis, but the lack of nodular hyperplasia and inflammatory infiltration together with the presence of the characteristic bile channels rather than proliferated ductules permits the distinction (Figure 14-7).

Biliary microhamartomas (von Meyenberg complexes) basically represent focal lesions of biliary dysgenesis. Although they can be confused with the biliary dysgenesis disorders in biopsy specimens, they are typically an incidental and innocuous finding and are unassociated with evidence of portal hypertension.

Autosomal dominant (adult-type) polycystic liver disease is a uncommon condition characterized by the gradual development of multiple simple cysts. Occurring with an autopsy prevalence of about 0.13%, the disorder is intimately associated with polycystic kidney disease, and the two disorders are generally considered to represent a single dominantly inherited condition.^64,105

Virtually all patients with polycystic liver disease are found to have kidney involvement, although there are sporadic exceptions in which only the liver is affected.⁶⁰ Conversely, an overall 30% to 75% of patients with polycystic kidney disease have hepatic cysts in systematic radiographic surveys.^67,71,98 The hepatic cysts are more commonly found in women, especially those who have experienced pregnancy, and patients with more severe renal impairment. The prevalence also increases with advancing age; the cysts are uncommon in children, but are found in more than 60% of patients over 60 years.^47,51,72 In addition, cysts develop in the pancreas, epididymis, and spleen, and cerebrovascular aneurysms occur in up to 20% of affected patients.

Clinical features. The clinical findings primarily reflect the presence of kidney disease, including progressive renal insufficiency and systemic hypertension, and generally become evident in patients between 40 and 60 years of age. Liver involvement typically produces few manifestations other than hepatomegaly or abdominal discomfort and has little effect on the natural history.^51,71 Since the cysts do not compromise hepatic parenchyma, evidence of hepatic dysfunction does not generally evolve.⁴³ Nevertheless, with improvements in patient management and long-term survival, hepatic manifestations have become a more noticeable problem. Scattered reports describe the development of ascites, portal hypertension complicated by esophageal varices, and biliary obstruction.^84,103,107 Moreover, secondary bacterial infection of the cysts, typically by enteric bacteria, is increasingly recognized.⁹⁶ Symptomatic cysts can be treated by repeated aspiration, operative fenestration with or without hepatic resection, or, in severe cases, by liver transplantation.^92,105

Pathologic features. On gross examination, multiple unilocular cysts ranging from a few mm to over 10 cm in diameter are diffusely scattered throughout the liver. On occasion, the cysts are confined to one lobe, usually the left, or are unevenly distributed.⁵¹ The cysts are histologically similar to simple hepatic cysts (Figure 14-8). They are lined by a single layer of cuboidal or attenuated epithelium, which resembles biliary epithelium both morphologically and functionally, and are surrounded by a thin fibrous wall.⁴²

Biliary microhamartomas are frequently noted in the neighboring liver (Figure 14-9). These lesions, also known as von Meyenberg complexes, are generally considered the precursor of the cysts. Developing by progressive dilatation of the microhamartoma's bile ducts, the cysts gradually increase in size and become detached from their biliary origins, thus appearing as noncommunicating cystic lesions.^59,83

In occasional instances, polycystic liver disease is associated with biliary dysgenesis in the form of congenital hepatic fibrosis, and accompanying Caroli's disease is noted in rare cases.^34,57,70,97 Complicating cholangiocarinoma has been described in a few reports.^1,26

Caroli's disease is the eponymous designation for congenital nonobstructive dilatation of the large intrahepatic bile ducts. This condition, which was first described in 1958, is rare and incompletely delineated, and its taxonomic status remains controversial. Characteristically the large bile ducts, particularly the segmental ducts, exhibit localized saccular ectasia, producing multiple cyst-like structures of varying size. These ducts are in continuity with the remainder of the biliary tract, and as a result, are predisposed to bile stasis, bacterial cholangitis, and intrahepatic pigment stone formation.²⁹

Two forms of Caroli's disease have been described, a pure and a combined type.^29,38 The pure form is characterized exclusively by bile duct dilatation and lacks other primary histologic abnormalities. The combined form, on the other hand, is distinguished by the additional presence of biliary dysgenesis and congenital hepatic fibrosis and accounts for the preponderance of reported cases.⁷⁵ The mixture of lesions in this variant implies that pathogenetic process of ductal plate malformation has extended to involve the entire intrahepatic biliary tract.^38,78,93 The suggestion has been advanced that the term Caroli's disease be restricted to only the pure form and that the combined variant be referred to as Caroli's syndrome, but despite its merits, this proposal has not been generally adopted.²⁰

Clinical features. The disorder usually manifests during childhood or early adult life, although affected patients can be of any age, and males are slightly favored over females.^93,94 Many cases appear to be sporadic, but an autosomal recessive inheritance, consistent with the concurrent presence of congenital hepatic fibrosis, is suggested by some studies. The typical clinical features include hepatomegaly and recurrent episodes of abdominal pain, fever, and occasionally jaundice. These bouts vary in their frequency and duration, and at times, they can be complicated by the development of bacterial abscesses, pancreatitis, bacteremia, or death.⁸⁵ Findings related to portal hypertension are additionally noted in patients with the combined form of the condition. Occasional cases are associated with autosomal dominant polycystic disease or choledochal cysts, and various types of renal cystic disease are also sometimes identified.^57,97

The diagnosis is basically a radiographic one. By ultrasonography or computed tomography, the characteristic findings include cystically dilated intrahepatic ducts, sometimes with central points of enhanced contrast ("central dot sign"), and intrahepatic lithiasis. Cholangiography is the definitive means of confirming the diagnosis (Figure 14-10).^33,55,69 Medical treatment focuses on the management and prevention of bacterial cholangitis and intrahepatic stones, but the results are variable. Various forms of biliary diversion can be employed, and partial hepatectomy can be successful cases with involvement confined to one lobe. Liver transplantation remains as a final therapeutic option for patients with severe incapacitating disease.^76,94

Pathologic features. The cystically dilated ducts appear as rounded or elongated cavities ranging up to 5 cm in diameter. The cysts are typically separated by intervening segments of normal or slightly dilated bile duct.²⁹ Any portion of the intrahepatic biliary tract can be affected, and typically the involvement is distributed diffusely across the liver. On occasion, however, the disease is confined to one lobe, usually the left.²⁷ The dilated ducts are filled with a mixture of bile, biliary sludge, occasional pigment stone material, and, during episodes of bacterial cholangitis, purulent exudate.

Histologically, the ductal walls are chronically inflamed with varying degrees of ductal and periductal fibrosis and a superimposed acute inflammatory response (Figure 14-11). Proliferated mucous glands can be conspicuous in the walls of larger ducts. The biliary epithelium, although often normal in appearance, can also exhibit evidence of epithelial damage or regeneration with variable cytoplasmic eosinophilia, nuclear enlargement, inflammatory infiltration, and ulceration. These changes are primarily seen primarily in large biopsy specimens and may not be present in the usual needle specimen.²⁹

The background changes vary among cases, but, as noted above, congenital hepatic fibrosis is commonly present. In addition to the characteristic dysmorphic bile ducts, acute inflammation and ductal epithelial damage can additionally note found. Other cases show a range of alterations ranging from nonspecific portal inflammation to features of acute or chronic biliary obstruction with bile ductular proliferation, neutrophil infiltration, acute cholangitis, and periductal or portal fibrosis (Figure 14-12).

An additional but rare complication is the development of intraductal epithelial dysplasia or overt cholangiocarcinoma (Figure 14-13).^31,36,46

Differential Diagnosis. Caroli's disease is an uncommon biopsy diagnosis. The diagnostic changes are best detected radiographically, and liver biopsy often shows only nonspecific alterations and is seldom required. Nonetheless, several disorders other than Caroli's disease can demonstrate intrahepatic duct dilatation with a cystic appearance and thus becomes differential considerations. Some cases of primary sclerosing cholangitis, for instance, mimic Caroli's disease, although the distinction can usually be made by the additional presence of multifocal ductal stricturing involving the extrahepatic ducts.⁴⁹ Intrahepatic biliary cysts can similarly develop in biliary atresia, but the overall context, including the obliteration of the extrahepatic bile ducts, allows for differentiation.⁴⁴

In recurrent pyogenic cholangitis, the combination of ductal dilatation with a clinical picture of intermittent bacterial cholangitis can be especially difficult to separate from Caroli's disease; typically, however, the clinical setting is different and the ductal changes are irregularly distributed and often lack a distinct saccular configuration (Chapter 5).

Although not primarily a liver disorder, cystic dilatation of the common bile duct nonetheless represents a component of the fibropolycystic disease family, and hence a brief discussion is warranted here. These cysts are uncommon lesions, more common in the Far East than in Western countries, and their prevalence in the United States is estimated at about one in 13,000 live births.⁸⁸ The pathogenesis is not clearly understood, and more than one pathologic process might be involved.^32,79 A congenital origin involving embryologic maldevelopment has been commonly accepted, but other evidence raises the possibility of an acquired etiology. Up to 85% of affected patients have an anomalous pancreaticobiliary junction with a long common channel between the distal common duct and the pancreatic duct; this anomaly would presumably allow pancreatic secretions to reflux into the bile ducts, causing ductal damage and eventual dilatation.^73,79 Hereditary factors might additionally be involved, although no specific inheritance pattern has been identified.⁵⁶

Choledochal cysts are classified by their anatomic distribution and extent into four main groups.^100,109 Type I cysts are characterized by segmental or diffuse fusiform dilatation of the common bile duct; they are the most common variety, accounting for 75% to 95% of cases. Type II cysts represent a diverticulum of the duct, usually protruding from the lateral wall, and type III cysts represent a choledochocele that most often occurs within the duodenal wall. Type IV designates the presence of multiple extrahepatic bile duct cysts; this can be seen alone (type IV B) or in association with Caroli's-type intrahepatic biliary cysts (type IV A). On occasion, cystic dilatation of the intrahepatic bile ducts equivalent to Caroli's disease is separated delineated as type V.

Clinical Features. Most choledochal cysts become clinically evident before 10 years of age, but they can manifest at any age, and they have been demonstrated both in fetuses and octogenarians.^54,77,102 About 75% of the affected patients are female. The classic clinical presentation consists of right upper quadrant mass with intermittent abdominal pain and jaundice, but this complete triad is seen in only a minority of patients.⁷⁹ Affected infants instead exhibit a picture of prolonged neonatal cholestasis and thus enter into the spectrum of so-called infantile obstructive cholangiopathy; jaundice, acholic stools, hepatomegaly, and a palpable abdominal mass are frequently noted.⁶⁵ Some cases produce no symptoms and are discovered incidentally.⁸²

The diagnosis is generally established by radiographic imaging with ultrasonography, radionuclide scintigraphy, or computed tomography, with cholangiography through percutaneous, endoscopic, or intraoperative techniques serving as the definitive diagnostic procedure.

The clinical course of choledochal cysts varies depending on the occurrence of complications. In some cases, particularly among infants, low-grade biliary obstruction develops and can potentially result in cirrhosis and portal hypertension.⁸⁰ Other cases are complicated by bile duct perforation, biliary stone formation, bacterial cholangitis with subsequent hepatic abscess and sepsis, or the development of bile duct carcinomas. To prevent these complications, complete surgical excision of the cyst followed by Roux-en-Y choledochojejunostomy is generally advised.^79,88

Pathologic Features. Choledochal cysts range in diameter from a few centimeters to over 15 cm and typically contain one to two liters of bile. On occasion, stones are also present. The cyst wall is thickened, fibrotic, and occasionally calcified; varying degrees of chronic inflammation and scattered elastic and smooth muscle fibers are noted histologically. The biliary epithelium lining the cyst is sometimes intact, especially in infants, but it is more often damaged, attenuated, or missing (Figure 14-14). Goblet-cell metaplasia and epithelial dysplasia with nuclear hyperchromasia, irregularity, and loss of polarity have been described and may play a role in subsequent development of carcinoma.^63,86 The choledochocele (type III cyst) is usually lined by duodenal mucosa, but occasionally biliary epithelium is found.⁸⁹

Liver biopsy can appear normal or display changes of acute or chronic biliary obstruction, including bile ductular proliferation with portal neutrophilia, acute cholangitis, and fibrosis of varying portal, periductal, or bridging distribution. Progression to obstructive biliary cirrhosis can result. In infants, the histologic alterations suggest biliary atresia, and in this setting, obliteration of the distal common bile duct often accompanies choledochal cysts (Figure 14-15).⁶⁵ On occasion, coexisting congenital hepatic fibrosis with biliary dysgenesis is seen.⁴¹

The most feared complication of choledochal cysts is the development of carcinoma, usually adenocarcinoma.^30,86,99,106 In various reports, the crude prevalence of this complication varies from 2% to 18%, corresponding to roughly a five to thirty-five times increased risk, and the risk grows with advancing age. The carcinomas have been proposed to arise in a background of epithelial dysplasia, perhaps contributed to by bacterial overgrowth within the stagnant bile contained by the cyst.^63,84a,86 Although the cyst is most common site for carcinoma development, other portions of the biliary tract may also be at increased risk.¹⁰¹