Benign and Malignant Biliary Tumors

Murli Krishna, MD

29.1 INTRODUCTION

Biliary neoplasms and tumor-like lesions form a diverse group of lesions in the liver, and include tumors with characteristics similar to those in the extrahepatic biliary tract, pancreas, and upper gastrointestinal tract. Primary intrahepatic biliary malignancies are far less common than metastases and should be evaluated with awareness of the clinical context, presence or absence of precursor lesions, and morphologic variability. This chapter discusses the clinicopathologic aspects of intrahepatic biliary neoplasms (Table 29.1) and selected non-neoplastic biliary lesions.

29.2 CILIATED HEPATIC FOREGUT CYST

Ciliated hepatic foregut cyst is a rare benign cystic lesion that represents a developmental anomaly. Although rare, the number of reported cases has increased dramatically in the past few decades, presumably reflecting increased detection by imaging.¹ The cyst is usually an incidental finding in adults, but they are also well described in children.² They
are isolated findings that are not associated with other developmental abnormalities. Rarely, there can be elevated serum CA19-9 levels.³

Table 29.1 Biliary epithelial neoplasms of liver

Bile duct adenoma

Serous microcystic adenoma

Biliary adenofibroma

Biliary intraepithelial neoplasia

Intraductal papillary neoplasm

Mucinous cystic neoplasm

Intrahepatic cholangiocarcinoma

Intraductal papillary neoplasm with invasive carcinoma

Mucinous cystic neoplasm with invasive carcinoma

Figure 29.1 Ciliated hepatic foregut cyst, lined by a ciliated and stratified columnar epithelium with smooth muscle and fibrosis in the wall.

Ciliated hepatic foregut cyst usually presents as solitary unilocular lesions with an average size of 7 cm and a range from subcentimeter to 19 cm.²,³ Most are located in segment IV of the liver.³ The cyst contains either clear fluid or mucoid material. Biliary communication has been observed in rare cases.²

There are two characteristic findings (Fig. 29.1). First, the cyst is lined by a ciliated, pseudostratified columnar epithelium. Second, the wall of the cyst contains smooth muscle that tends to be somewhat ill defined, growing in bundles that surround all or parts of the cyst. There can be one or two layers of smooth muscle, but a myenteric plexus is absent. In addition, there can be a thin layer of connective tissue between the muscle and an outermost later of fibrous tissue. Not all these layers in the cyst wall (smooth muscle, loose connective tissue, fibrous capsule) are seen in every case. The epithelium can occasionally show goblet cells or squamous metaplasia. The cyst fluid may contain high levels of carcinoembryonic antigen (CEA) and CA19-9, with the lining epithelium also staining positive for CEA and CA19-9 on immunohistochemistry.⁴

There is a risk for carcinoma, with about 5% of all cases reported to date having undergone malignant transformation.⁵ Squamous cell carcinomas are the most common malignancy.

29.3 SOLITARY BILE DUCT CYST

Solitary bile duct cysts are also known as simple biliary cysts. The cysts are unilocular and lined by a single layer of cuboidal to flattened biliary epithelium. The wall of the cyst is made of fibrous tissue with no muscle or ovarian-type stroma. The etiology of the cyst is unknown, and most are incidental findings in middle-aged women, with about a 10:1 female predominance.

Solitary bile duct cysts are usually single unilocular cysts, although rarely multiple cysts can be seen within the same liver, sometimes in
a small cluster. The cysts are filled with thin, clear to bilious fluid, and may be complicated by hemorrhage. The cyst lining is usually smooth and without septa. If septae are present, they are usually located at the periphery of the cyst.

Figure 29.2 Solitary bile duct cyst, lined by a single layer of cuboidal epithelium with fibrotic wall.

The epithelial lining in solitary bile duct cysts is cuboidal to flat, resembling biliary epithelium, and often shows extensive denudation (Fig. 29.2). In the areas of epithelial denudation, the cyst wall may show fibrin and mild chronic inflammation. Occasionally, there is more extensive erosion and granulation tissue reaction. In larger cysts, various types of metaplasia may be present such as intestinal, pyloric, or squamous metaplasia.

The diagnosis is usually straightforward, but differential diagnostic considerations may include mucinous cystic neoplasms and mesothelial cysts. Mucinous cystic neoplasms are lined by mucinous epithelium and have ovarian-type stroma in the cyst wall. However, in both of these cysts the diagnostic findings can be obscured by epithelial denudation and inflammation of the cyst wall, so extensive sampling is often needed. In difficult cases, the most helpful stains are for mucin, estrogen receptor, and progesterone receptor, which are positive in mucinous cystic neoplasms but negative in simple biliary cysts. Although mesothelial cyst lining can mimic bile duct cysts on hematoxylin and eosin (H&E), they are usually subcapsular, very small, and stain for markers of mesothelial differentiation, such as calretinin.

29.4 BILE DUCT HAMARTOMA

Bile duct hamartomas are also called von Meyenburg complexes and are small benign lesions composed of interanastomosing bile ducts.

Figure 29.3 Bile duct hamartoma (von Meyenburg complex), showing anastomosing bile duct structures with open lumens, bile plugs, and fibrotic stroma.

Despite being designated as a hamartoma, most sporadic cases are acquired lesions. Overall, bile duct hamartomas are more commonly found in cirrhotic livers than in noncirrhotic livers. Within cirrhotic livers, they are most commonly seen in cases of chronic hepatitis C and alcohol-related liver disease. The malignant potential of these lesions is very low, but there have been reports of cholangiocarcinomas that arose from or adjacent to von Meyenburg complexes.⁶

Bile duct hamartomas are most commonly encountered by surgeons while doing abdominal surgery for cancers of other organs. In this setting, biopsies are often submitted for frozen section to rule out metastatic disease. The diagnosis in most cases is readily made because of the lack of cytological atypia and the distinctive histological findings, as discussed below.

Bile duct hamartomas can be single or multiple, and most and usually measure less than 1 cm in size. Histologically, they are composed of bile duct structures that grow in an irregular inter-anastomosing fashion. The duct structures have open lumens, often contain bile, and are associated with either a myxoid or fibrotic stroma (Fig. 29.3). Bile duct hamartomas are distinct from bile duct adenomas, although the distinction is mostly academic, with relatively modest clinical relevance. Bile duct adenomas tend to have small, round, gland-like, or tubular structures, with small to absent lumens, and no luminal bile.

29.5 BILE DUCT ADENOMA

Bile duct adenoma is a benign lesion that is composed of small compactly arranged ducts within a fibrous stroma. It is often an incidental lesion, but can be clinically significant because it may grossly resemble
a metastasis. In this setting, bile duct adenomas are often submitted intraoperatively for frozen section evaluation.

Figure 29.4 Bile duct adenoma. The lesion is well circumscribed, and the proliferating ducts lack cytologic atypia.

Most bile duct adenomas are diagnosed in middle-aged patients, with men slightly more often affected than women. Grossly, bile duct adenomas are well circumscribed, firm, white lesions that are commonly seen in a subcapsular location. Most measure less than 1 cm in size. Histologically, the proliferating ducts are small and form tubules, embedded in a variably desmoplastic stroma.⁸ The ducts are lined by a single layer of cuboidal epithelial cells that lack atypia (Fig. 29.4). The well-delineated margin and absence of atypia distinguishes this lesion from carcinoma. Bile duct adenomas have also been called peribiliary gland hamartomas in the past, implying that it is a nonneoplastic lesion. However, the distinctive morphological features are now considered to represent a neoplastic proliferation. In addition, a recent study found BRAF V600E mutations in 53% of these lesions, further indicating that these are true neoplasms.⁹ A common differential diagnostic consideration for the bile duct adenoma is the bile duct hamartoma. The latter is usually smaller, associated with portal tracts and characterized by the presence of dilated inter-anastamosing ducts; the duct lumens often contain bile or proteinaceous debris. Similar to bile duct hamartomas bile duct adenomas have a very low proliferative rate of about 2% on Ki-67 immunostaining.⁷

29.6 CLEAR CELL BILE DUCT ADENOMA

Clear cell bile duct adenoma is a rare but distinctive subtype of bile duct adenoma.¹⁰ They are generally small, usually about 1 cm, though a larger example of about 3 cm has also been reported.¹¹ The cells grow in small nests and cords, often with no visible lumen (Fig 29.5). There can be mild nuclear atypia. Clear cell bile duct adenomas are often less well circumscribed than typical bile duct adenomas and often show extension into the adjacent hepatic parenchyma. In some cases, preexisting bile ducts in portal tracts appear to be colonized by the lesional cells. Mild chronic inflammation can also be found in the lesion, even if not present in the background liver. Although data is limited by the rarity of these tumors, clear cell bile duct adenomas have a low proliferative rate by Ki-67 immunostain.

Figure 29.5 Clear cell bile duct adenoma. Small nests of bland clear cells without recognizable lumens.

The differential diagnoses include clear cell carcinomas, including clear cell cholangiocarcinoma, clear cell hepatocellular carcinoma, and metastatic clear cell carcinoma. Clear cell bile duct adenomas stain with typical biliary markers, whereas markers of hepatic differentiation are negative. In contrast to clear cell cholangiocarcinomas, only mild cytological atypia is present and the proliferative rate is low. Clear cell bile duct adenomas can be positive for p53,¹⁰ and this finding should not be interpreted in isolation as evidence for malignancy. Metastatic clear cell carcinomas typically are larger, show more atypia, and often show necrosis. Clinical context and immunohistochemical findings are important in excluding metastatic clear cell carcinomas.

29.7 BILIARY ADENOFIBROMA

Biliary adenofibromas are rare neoplasms with some similarities to bile duct hamartomas but are larger, often show epithelial atypia, and can be associated with frank carcinoma.¹², ¹³, ¹⁴, ¹⁵ Histologically, these lesions are characterized by a tubulocystic biliary epithelial proliferation with prominent fibrotic stroma (Fig. 29.6).
There is no mucin production and the epithelium stains like typical biliary epithelium. Relatively few cases have been reported in literature, and the clinicopathologic characteristics are not well defined. Although some cases can be indolent, there is a clear association with malignancy. Complete excision with follow-up is recommended.

Figure 29.6 Biliary adenofibroma. Tubulocystic structures lined by bland biliary epithelium within fibrotic stroma.

29.8 SEROUS MICROCYSTIC ADENOMA

The serous microcystic adenoma is an exceedingly rare benign multiloculated cystic tumor of the liver. Histologically, it resembles its pancreatic counterpart, where it is more common. The locules are lined by a single layer of bland cuboidal epithelial cells with clear cytoplasm containing glycogen. They do not contain the ovarian-type stroma characteristic of mucinous cystic neoplasm¹⁶ (Fig. 29.7). Serous microcystic adenomas have a benign course. The differential diagnoses include other clear cell lesions such as metastatic renal cell carcinoma with cystic features. Rare histologically bland-appearing serous cystadenocarcinomas of the pancreas can metastasize to the liver, so correlation with imaging studies of the pancreas is important.

Figure 29.7 Serous microcystic adenoma. The locules are lined by low cuboidal epithelium with clear cytoplasm.

29.9 MUCINOUS CYSTIC NEOPLASM

Definition and etiology

Mucinous cystic neoplasm is a rare cystic neoplasm composed of variably mucinous epithelium associated with ovarian-type stroma, occurring almost exclusively in women. They occur mostly in the liver, with very rare cases reported in the extrahepatic biliary ducts and gallbladder. The etiology of these tumors is not known; however, an origin from peribiliary glands and underlying hormonal factors have been suggested in its pathogenesis.¹⁷

Epidemiology and clinical features

Mucinous cystic neoplasms are rare, accounting for less than 5% of cystic lesions of the liver, and these are seen almost exclusively in women. Benign mucinous cystic neoplasms usually present in the fifth decade, whereas mucinous cystic neoplasms associated with invasive carcinoma tend to present about a decade older. The most common symptoms include abdominal fullness and discomfort because of the mass, symptoms of biliary obstruction, ascending cholangitis, or even cyst rupture. Rarely, these tumors are discovered as an incidental radiographic finding.¹⁷

Serum CA19-9 can be elevated, especially if there is associated carcinoma; however, this marker does not reliably distinguish between benign and malignant tumors. Imaging studies reveal a multiloculated cyst with internal septations. Malignancy can be suggested by mural nodules or by irregular cyst wall thickening. The presence of multiloculation contrasts with simple biliary hepatic cysts, which are much more common than mucinous cystic neoplasms.¹⁶, ¹⁷, ¹⁸

Gross findings

Grossly the lesions are typically multiseptated cysts filled with variably mucoid or hemorrhagic fluid. There is no communication between the mucinous cystic neoplasms and the bile ducts. Mural nodules or papillary areas are uncommon, but these should be generously sampled for microscopic examination to evaluate for malignancy. These tumors can grow large, with reports of tumors approaching 30 cm. Approximately, twothirds of tumors are within the left lobe.¹⁹,²⁰

Microscopic findings

The cells lining the cyst wall and locules range from columnar mucinous cells to low cuboidal cells without mucin, resembling biliary epithelium. Intestinal-type goblet cells may be present. In most cases, the cytologic atypia is minimal to absent. The defining histologic feature is the presence of ovarian-type stroma underlying the epithelium (Fig. 29.8). The lining epithelium is immunoreactive for CK7 and CK19 in cases with a biliary phenotype, and CK20 and CDX2 in cases with an intestinal phenotype. The stroma is commonly immunoreactive for estrogen and progesterone receptors, and variably for inhibin. Although immunostaining is not necessary for diagnosis when the ovarian-type stroma is obvious, in many cases the stroma is fibrotic, attenuated, or equivocal, and immunohistochemistry is beneficial.²⁰ Secondary changes may be present, such as hemorrhage and granulation tissue reaction, and the subepithelial stroma may contain areas of dense collagen.

Practically, as is true for grading intraductal papillary mucinous neoplasms and biliaryintraepithelial neoplasia, classifying dysplasia in mucinous cystic neoplasms into low- and high-grade dysplasia is more reproducible for pathologists and clinically more useful. Some authors also recognize a category of moderate dysplasia; however, this terminology is currently not used in the World Health Organization (WHO) classification.¹⁹ Invasive adenocarcinoma arising in mucinous cystic neoplasms usually has tubular or tubulopapillary morphology. The role of fine-needle aspiration cytology for diagnosing mucinous cystic neoplasms is limited because of scant cellular yield and the risk of pleural and peritoneal dissemination.

Figure 29.8 Mucinous cystic neoplasm, characterized by mucinous lining epithelium and ovarian-type stroma. Foci of stromal hyalinization are present.

Intraoperative frozen section analysis is often used to distinguish between nonneoplastic and neoplastic cystic masses, with the aim of complete resection for neoplasms. Cystic lesions often show extensive degenerative changes including denudation of the epithelium, making this distinction difficult. In such cases, the presence of ovarian-type stroma indicates a mucinous cystic neoplasm.

Differential diagnosis

The most common differential diagnostic considerations are other cystic lesions of the liver and include intraductal papillary neoplasms, bile duct cysts, ciliated foregut cysts, peribiliary cysts and cystic endometriosis. An important distinction with these lesions is the presence of ovarian-type stroma in mucinous cystic neoplasms. Additionally, intraductal papillary neoplasms generally show a greater degree of papillary epithelial proliferation. Bile duct cysts show simple cuboidal epithelial lining. Ciliated foregut cysts are lined by ciliated epithelium and often have smooth muscle in their wall. Peribiliary cysts are small cysts, usually multifocal, located in the perihilar region closely associated with large bile ducts and lined by cuboidal epithelium.

Endometriosis shows hemorrhagic material in the lumen instead of mucin. Histologically, endometriosis shows cysts lined by glandular epithelium with underlying endometrial stroma, which tends to be less densely cellular than the ovarian stroma of mucinous cystic neoplasms. Hemorrhage can be seen along with numerous hemosiderin-laden macrophages. The endometrial epithelium can be flattened to pseudostratified, but is non-mucinous. The stroma in endometriosis is positive for CD10, whereas both the epithelium and stroma are positive for estrogen and progesterone receptors. In contrast, the epithelium of mucinous cystic neoplasms is negative for estrogen and progesterone receptors.

Treatment and prognosis

Complete surgical resection of mucinous cystic neoplasms is the optimal treatment. Tumor recurrence is common in patients with subtotal resection.¹⁶ Malignant transformation in untreated cases is estimated to occur in up to 32% of cases. Prognosis after complete resection is excellent in the absence of carcinoma. Cystadenocarcinomas arising from mucinous cystic neoplasms appear to have a better prognosis than pure cholangiocarcinomas, emphasizing the importance of this distinction.¹⁹,²¹, ²², ²³

29.10 INTRADUCTAL BILIARY LESIONS

Biliary intraepithelial neoplasia

BilINs are characterized by dysplastic change in the biliary epithelial cells, without forming a mass lesion, similar to pancreatic intraepithelial neoplasia (PanIN). The bile ducts are of normal caliber or may be dilated because of another primary cause such as hepatolithiasis. BilINs are largely seen in livers resected or explanted for an underlying chronic disease (such as primary sclerosing cholangitis) or as a noninvasive component associated with cholangiocarcinoma. The epithelium can be flat or show a micropapillary growth pattern. The lesion has been classically graded as BilIN-1, BilIN-2, and BilIN-3, corresponding to mild, moderate, and severe dysplasia/carcinoma in situ respectively. In practice, it is often preferable to classify the dysplasia as low grade (mild to moderate dysplasia) and high grade (severe dysplasia/carcinoma in situ) (Figs. 29.9, 29.10, and 29.11). Such a two-tiered classification is easier, clinically more meaningful, and follows a similar approach for noninvasive neoplasms at other sites (e.g., cervix, urinary bladder, prostate, gastrointestinal tract).²⁴,²⁶ In one study of liver explants from patients with primary sclerosing cholangitis, BilIN was seen in 83% and 36% of cases with and without cholangiocarcinoma, respectively.²⁷ Other major risk factors are hepatitis C cirrhosis and alcoholic cirrhosis.²⁸

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