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Neoplasia of gallbladder and biliary epithelium.

Neoplasms of gallbladder and biliary epithelium are relatively rare and their diagnosis can be challenging. In addition, recently, gallbladder and biliary lesions have been clinically recognized more frequently, likely because of the advances in diagnostic imaging and the widespread use of laparoscopic cholecystectomy, which exposes many surgical pathologists to these lesions. This review highlights some of the morphologic features that can help pathologists to accurately diagnose neoplastic lesions of the gallbladder and bile ducts, emphasizing their diagnostic criteria and their differential diagnosis.

METAPLASIA AND DYSPLASIA IN THE GALLBLADDER

The pathogenesis of gallbladder and biliary tract carcinoma is thought to be the result of an evolutionary sequence from metaplasia to dysplasia to carcinoma. Metaplasia tends to occur in a setting of inflammation and chronic injury and to be associated with dysplasia or carcinoma. (1,2) Two major types of metaplasia occur in the biliary tract: gastric and intestinal. (3) Gastric metaplasia is the most common type of metaplasia and is found in about 50% of gallbladders removed for chronic cholecystitis or cholelithiasis. (2) The lesion appears to begin in the base of the crypt as buds or branches. Secondary branches then occur and are arranged either in a lobular or a diffuse pattern. Gastric metaplasia recapitulates the gastric pyloric or antral mucosa. Morphologically, pyloric gland metaplasia shows small branching glands that are composed of columnar or cuboidal cells with abundant bubbly cytoplasm. Pyloric gland metaplasia can be indistinguishable from pyloric gland adenoma, except that adenoma usually forms a discrete lesion grossly. An arbitrary cutoff of 5 mm has been used to separate these 2 lesions.3 Intestinal metaplasia is noted in around 30% of gallbladders excised for cholelithiasis. (3) The incidence of intestinal metaplasia appears to increase with age and with the duration of gallstone disease. (3) The initial lesion begins as a few goblet cells at the tips of the mucosal folds rather than the base of the crypts. This is followed by a downward progression of the lesion, possibly reaching the Rokitansky-Aschoff sinuses. When fully developed, the intestinal metaplasia consists of variable amounts of goblet or columnar cells with a brush border. Paneth and endocrine cells can also be found. (3) Although metaplastic cells can show pseudostratification and mild nuclear atypia, the presence of only basal pseudostratification and the absence of significant atypia favor metaplasia over dysplasia. (3) In addition, squamous metaplasia, a rare type of metaplasia, can be seen in the gallbladder and biliary tract. (3) Squamous metaplasia tends to be associated with gallstones and can lead to squamous dysplasia or squamous cell carcinoma. (3)

Dysplasia of the biliary tract, considered as preinvasive biliary neoplasia, (1-3) has been noted in 40% to 60% of patients with invasive carcinoma, 30% of patients with sclerosing cholangitis, and incidentally in 1 to 3.5% of cholecystectomy specimens. (3-4) The mean age of the patients progressively increases with the degree of dysplasia and invasive carcinoma, from 50 years in low-grade dysplasia, to 58 years in high-grade dysplasia, and to 60 years in invasive carcinoma. (5) Unlike adenomas and papillary neoplasms, dysplasia is often unrecognizable grossly and radiographically; it does not form a mass but can appear granular or slightly thickened in the gross specimens. Microscopically, dysplasia is usually an incidental finding. It is multicentric in many cases and usually flat or forming abortive papillae (beyond the normal villiform configuration of the mucosal folds of the gallbladder). Dysplasia is characterized by an atypical disordered proliferation of cuboidal or columnar epithelium showing loss of polarity and pseudostratification. We categorize dysplasia of the gallbladder as low- or high-grade dysplasia. Low-grade dysplasia shows mild nuclear enlargement, mild nuclear pseudostratification, and only minimal nuclear irregularities (Figure 1, A). Marked nuclear enlargement and irregularity, prominent nucleoli, mitoses, nuclear hyperchromasia, and loss of polarity are characteristic features of high-grade dysplasia (Figure 1, B). Complex architecture with ductal fusion and cribriforming are considered as high-grade dysplasia. Carcinoma in situ is considered as part of the spectrum of high-grade dysplasia. However, in situ carcinoma, which can be histologically identical to high-grade dysplasia and is subject to a great degree of interobserver variability, is classified as pTis in the American Joint Committee on Cancer TNM staging system, whereas high-grade dysplasia is generally not staged (pT0). This may present a problem, particularly if dysplasia involves the resection margin. (3) Squamous cell dysplasia/squamous cell carcinoma in situ is a type of preinvasive neoplasia that can be found in the gallbladder. (3) A rare type of signet ring cell in situ carcinoma has also been reported. (3)

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The biologic behavior of gallbladder dysplasia is poorly understood, since dysplasia is often incidental and is commonly associated with invasive carcinoma. Therefore, when dysplasia is found, the gallbladder has to be extensively (if not entirely) submitted for microscopic evaluation. Patients of gallbladder dysplasia appear to be prone to develop multifocal biliary neoplasia, and should be closely followed up. (3,6) On the other hand, patients who have gallbladder dysplasia without invasive carcinoma and have an uninvolved cystic duct margin are considered essentially to be cured. (3)

The term biliary intraepithelial neoplasia, a 3-grade classification system, was proposed instead of the term biliary dysplasia, to describe the flat or the low papillary dysplastic epithelium in the bile ducts. The significance of this classification has not been demonstrated yet, and further studies are needed to resolve this issue. (7)

Differential Diagnosis of Dysplasia in the Gallbladder

Mild nuclear atypia and hyperchromasia are common in inflamed biliary epithelium, which sometimes makes distinguishing dysplasia from reactive atypia very difficult (Figure 2, A and B). The presence of acute inflammation, especially intraepithelial neutrophils, favors a reactive process; therefore, one should be cautious in diagnosing definite dysplasia in the setting of acute inflammation or ulceration. Features that can be helpful in distinguishing biliary dysplasia from reactive/ regenerative atypia are listed in Table 1.

Extension of dysplasia into Rokitansky-Aschoff sinuses of the gallbladder or into peribiliary mucous glands can mimic invasive carcinoma. Criteria to differentiate invasive carcinoma from dysplasia extending into Rokitansky-Aschoff sinuses were illustrated in a study by Albores-Saavedra et al (3) and are summarized in Table 2.

ADENOMAS AND PAPILLARY LESIONS

Adenomas have been reported in 0.3% to 0.5% of gallbladders removed for cholelithiasis or cholecystitis. They are often incidental findings. (8) They are usually asymptomatic unless they are large, multiple, or detached and obstructing the bile flow. (3) The increased use of ultrasound means that more incidental polypoid lesions are being found in the gallbladder. (3) Adenomas may occur at any age, with a mean age of 58 years, and 70% of the patients are female. (3) Adenomas are associated with cholelithiasis in 50% of the cases, and the body or the fundus of the gallbladder is the most common site of origin. (3) They are rarely associated with Gardner syndrome or Peutz-Jeghers syndrome. (3) Adenomas are usually intraluminal and form polyps or nodules. They may be pedunculated or sessile, and single or multifocal, they usually have a granular or a cauliflower-like appearance. These lesions are often smaller than 2 cm. (3) Adenomas are classified by their architecture as tubular, papillary, and tubulopapillary (when both the papillary and tubular components involve at least 20% of the entire adenoma). (3) The risk of malignant transformation increases with the size of the adenoma and with the amount of the papillary pattern. (3,9) Adenomas can also be classified by their cytoarchitectural resemblance to the different parts of the gastrointestinal tract as pyloric gland adenoma, intestinal-type adenoma, and biliary-type adenoma. (3,10-12) Pyloric gland adenoma almost always occurs in the gallbladder, where it is the most common type of adenoma, (3) and it is extremely rare in the extrahepatic biliary tract. It is composed of small, tightly packed and relatively uniform pyloric or antral-type glands (Figure 3). These glands are histologically indistinguishable from gastric pyloric glands or duodenal Brunner glands. The amount of the intervening stroma is minimal. Squamoid morules consisting of vague spindle cell whorls without keratinization are characteristic features but are not always present. Paneth cells and endocrine cells can be seen in 20% of pyloric gland adenomas. Despite the well-differentiated appearance of pyloric gland adenoma and its minimal cytologic atypia, all adenomas are regarded as dysplastic. High-grade dysplasia has been reported in 7% of pyloric gland adenomas, but these lesions are rarely associated with invasive carcinoma. (3,12,13) Pyloric gland adenomas are also usually solitary and exquisitely pedunculated, and the surrounding gallbladder mucosa is typically normal and nondysplastic. Intestinal-type adenoma closely resembles the colonic adenoma, showing mucin-depleted pseudostratified columnar epithelium. It may contain goblet cells, Paneth cells, or endocrine cells. These lesions can be tubular or papillary. The degree of dysplasia in this type of adenoma tends to be higher than the degree of dysplasia in pyloric gland adenoma. (3,9,10,12) Biliary-type adenoma is less well characterized. It shows epithelium that resembles the gallbladder epithelium, can be columnar or cuboidal, and often exhibits high-grade dysplasia. (3,9,10,14) Papillary lesions that show biliary-type epithelium can be classified as this subtype. (3) Sometimes, it is difficult to place an adenoma into a specific category. Adenomas other than pyloric gland adenomas are strongly associated with flat dysplasia elsewhere in the gallbladder epithelium. Thus, regardless of the classification, when an adenoma is recognized microscopically, one should examine the remaining gallbladder extensively, if not entirely, to rule out multifocality and the possibility of occult invasive carcinoma. Papillary neoplasms with diffuse (or even focal) high-grade dysplasia are alternatively termed intraductal (intravesical) papillary carcinoma or noninvasive papillary carcinoma.

Papillomatosis is a term that is applied to predominantly papillary lesions that are extensive and multifocal. These lesions are more common in the extrahepatic tract than the gallbladder. (3,15-19) Some of these lesions may show an intestinal morphology. (3) A high rate of recurrence and strong association with invasive carcinoma has been seen in these lesions.3 The incidence of high-grade dysplasia is high, and even in the absence of high-grade dysplasia, metastases have been reported from these lesions, likely due to undetected foci of invasion. (3) On the basis of the biology of papillomatosis, some investigators have recommended the term intraductal papillary carcinoma to more accurately reflect this process. However, when no invasive carcinoma is present, papillomatosis is usually associated with a good prognosis. (4,16,18-21)

[FIGURE 3 OMITTED]

Some authorities have proposed the term biliary intraductal papillary neoplasm to describe all papillary biliary lesions, because of the clinical and pathologic similarities of these lesions to the pancreatic intraductal papillary mucinous neoplasm. (3,7,21)

ADENOCARCINOMA OF THE BILE DUCTS AND GALLBLADDER

Biliary adenocarcinoma is classified by the location of the tumor into intrahepatic (peripheral) cholangiocarcinoma, extrahepatic adenocarcinoma of the bile ducts, and gallbladder carcinoma. (3,22,23) Adenocarcinoma of the extrahepatic bile ducts can also involve the major bile ducts in the hepatic hilum (where the distinction from hilar intrahepatic cholangiocarcinoma is largely semantic) or can arise in the nonhilar extrahepatic bile ducts. (3,22-24) Many studies (3,22) have divided extrahepatic bile duct adenocarcinomas into upper third (hilar), middle third, and lower third. Carcinomas of the bile ducts typically occur in elderly patients. Both sexes are affected equally by intrahepatic cholangiocarcinomas, whereas the extrahepatic types are more common in males. (3) Several risk factors for intrahepatic and extrahepatic carcinomas have been identified, such as primary sclerosing cholangitis, ulcerative colitis, hepatolithiasis, choledochal cyst, Caroli disease, abnormal choledochopancreatic duct junction, parasites, smoking, and Thorotrast. (3,25-27) The peripheral type often remains asymptomatic until the tumor is at a late stage, since significant biliary obstruction is not common.3,22 Patients with the extrahepatic type usually present relatively early with signs of biliary obstruction. (3,4) Histologically, intrahepatic (peripheral) cholangiocarcinoma (Figure 4, A) shows significant heterogeneity of morphologic features and degree of differentiation and can resemble adenocarcinomas originating from many different organs. A tubular or branching gland pattern is common in the early stages of the development of the tumor (ie, in smaller examples). Cribriform, micropapillary, and cordlike patterns can also be identified. Fibrous stroma, which can be extensively hyalinized rather than desmoplastic, is a characteristic feature of these tumors, usually exhibiting a fibrotic hypocellular center and cellular periphery. These tumors are often mucin negative. Bile can be seen at the periphery of the tumor as a result of native bile duct invasion, but intracellular bile is not present and would suggest the presence of hepatocellular differentiation (mixed hepatocellular-cholangiocarcinoma, for example). Hilar cholangiocarcinomas and adenocarcinomas of the extrahepatic bile ducts (Figure 4, B) display the typical morphologic features of the pancreatobiliary-type adenocarcinomas, often showing desmoplastic stroma, and are characterized by widely separated, irregular, and well-formed glands. Luminal and intracellular mucin is frequently seen. Occasionally, pseudoangiomatous and micropapillary patterns are noted.

Gallbladder carcinoma shows female predominance (female to male ratio, 3-4:1). The mean age of patients is 65 years. (3,28-31) It is more common in some Latin American countries such as Chili, Mexico, and Bolivia. In the United States, Native and Hispanic Americans have a higher rate of gallbladder cancer than other ethnic groups. (3) Gallbladder carcinomas are associated with gallstones (80%), porcelain gallbladder (20%), and abnormal choledochopancreatic duct junction. (3) Sixty percent of the gallbladder carcinomas arise in the fundus. (3,22) Histologically, most gallbladder carcinomas are pancreatobiliary-type adenocarcinomas, showing variable degrees of differentiation. Some arise in association with a noninvasive papillary neoplasm. Other histologic subtypes include adenosquamous carcinoma, squamous cell carcinoma, intestinaltype adenocarcinoma, mucinous carcinoma, clear cell carcinoma, signet ring carcinoma, undifferentiated carcinoma, lymphoepithelial-like carcinoma, and small cell carcinoma. (3,7) Well-differentiated adenocarcinoma of the gallbladder can be difficult to distinguish from Rokitansky-Aschoff sinuses, which usually do not have a lobular architecture and can be located throughout the gallbladder wall, even extending into perimuscular adipose tissue. Rokitansky-Aschoff sinuses are normally continuous, showing a perpendicular orientation to the surface, and typically have undulating, smooth contours. In contrast, adenocarcinomas show small and variably sized glands with angulated contours. Desmoplasia favors a diagnosis of carcinoma. However, a stromal desmoplastic-like reaction surrounding Rokitansky-Aschoff sinuses is not uncommon, especially when there is active cholecystitis. The malignant glands are usually densely packed and may be oriented parallel to the surface. Moreover, cytologic atypia, mitoses, and intraglandular necrosis are all features that favor a diagnosis of adenocarcinoma over benign Rokitansky-Aschoff sinuses. Adenomyomatous hyperplasia can also mimic well-differentiated adenocarcinoma of the gallbladder. However, the glands in adenomyomatous hyperplasia are usually bland cytologically; they show cystic dilatation, and they communicate with the main gallbladder lumen. The immunoprofile of gallbladder carcinoma is similar to that of bile duct carcinoma (intrahepatic and extrahepatic) and pancreatic carcinoma. Cytokeratin 7 (CK7) is almost always positive. Cytokeratin 20 (CK20) can be positive, more often in extrahepatic bile duct carcinoma than intrahepatic cholangiocarcinoma. (3) In addition, carcinoembryonic antigen-monoclonal (CEA-M), carbohydrate antigen (CA19-9), B72.3, MUC1, and MUC5AC are also positively expressed in bile ducts and gallbladder carcinoma but can be focal. (3)

[FIGURE 4 OMITTED]

ADENOCARCINOMA IN LIVER BIOPSIES: PRIMARY VERSUS METASTATIC

Metastatic adenocarcinoma to the liver from the pancreas, colon, upper gastrointestinal tract, lung, breast, and other sites can closely mimic cholangiocarcinoma histologically. The morphologic features of the tumor are sometimes suggestive of a specific primary site. For example, an adenocarcinoma with tall columnar adenoma-like epithelium and intraluminal necrosis is suggestive of a colorectal primary tumor. Moreover, the clinical history, such as a history of a prior primary tumor at another anatomic site, the age, gender, and radiographic appearance of the tumor, the presence of a solitary mass or multiple masses, and a history of smoking and exposure to other agents, can be very helpful in distinguishing primary from metastatic liver tumors and should be always considered in making this distinction. In addition, immunohistochemical stains can also be used to differentiate primary from metastatic adenocarcinomas. A panel of the following immunohistochemical stains is recommended to cover most of the differential diagnosis: CK7, CK20, CDX2, thyroid transcription factor 1 (TTF-1), and estrogen receptor/progesterone receptor (for females) or prostate-specific antigen (for males). (3) Other stains (such as trypsin and chymotrypsin for pancreatic acinar cell carcinoma, chromogranin and synaptophysin for neuroendocrine neoplasms, and others) can be included in the panel, depending on the clinical information and the morphologic appearance. Metastatic adenocarcinomas from the gallbladder, pancreas, and upper gastrointestinal tract are usually positive for CK7 and negative for other site-specific markers, showing a similar immunoprofile to cholangiocarcinoma. Table 3 shows immunophenotypes that are relatively specific for metastatic adenocarcinomas from other sites. In many cases, the tumor displays a nonspecific morphology (adenocarcinoma) and nonspecific immunohistochemistry, with positive staining for CK7 and negative staining for CK20, CDX2, TTF-1, and estrogen receptor or prostate-specific antigen. In such cases, and in the absence of a prior cancer history and radiographic evidence of current extrahepatic sites of disease, we recommend listing the potential primary sites in the pathologic report, by the gender and the histologic features (often pancreatobiliary tract, upper gastrointestinal tract, lung, and/or breast). A primary cholangiocarcinoma should be considered if the tumor is morphologically and immunophenotypically compatible and if thorough clinical and radiographic evaluations fail to identify an extrahepatic primary tumor.

THE DIFFERENTIAL DIAGNOSIS OF ATYPICAL GLANDULAR HEPATIC LESIONS

Benign biliary lesions such as bile duct hamartoma, bile duct adenoma, and reactive bile ductular proliferation can be difficult to distinguish from metastatic adenocarcinoma (from the pancreas, for example), especially on frozen section (Figure 5, A through C). However, this distinction is critical for patient management and proper staging of the disease. (3) Bile duct hamartoma or von Meyenburg complex is a type of ductal malformation that often occurs sporadically or as part of the spectrum of polycystic liver disease. (3,22) It is commonly multifocal and located in or near the periphery of portal tracts. (3,22) This lesion is usually small (<0.5 cm), gray or white, and irregularly shaped. It consists of dilated, small to medium-sized ductular structures that usually contain inspissated bile. The ductules are separated by dense collagen and lined by cuboidal to flattened epithelium that shows no or minimal cytologic atypia. Bile duct adenoma is less common than bile duct hamartoma. It is typically noted in a subcapsular location but can be seen deep in the hepatic parenchyma. (3,22) Bile duct adenomas may occur singly or as multiple lesions. This lesion is typically small (<2 cm, although examples measuring more than 2 cm can occur rarely), white or gray, and firm. (3,22) Microscopically, it consists of relatively uniform ductules lined by bland cuboidal epithelium and separated by fibrotic stroma, sometimes containing dense chronic inflammation. Mucinous differentiation and neuroendocrine cells can be found in bile duct adenomas. (22) Since they are neoplasms, bile duct adenomas can display mild nuclear enlargement and atypia, but they lack marked variation in nuclear size and shape. Bile ductular proliferation is a reactive process that occurs in noncirrhotic or cirrhotic liver (especially when cirrhosis is associated with large areas of fibrosis). It can be seen as a reaction to obstruction of bile flow, a reaction to infarction, or as a sequela of tumor ablation. (3) The reactive ductules usually show a uniform lobular architecture with bland, atrophic, flattened biliary epithelium. Acute inflammation is commonly present. Metastatic pancreatic adenocarcinoma can be difficult to differentiate from the benign biliary lesions mentioned above, especially on frozen section. Despite the dismal prognosis of pancreatic adenocarcinoma, complete surgical resection of the tumor is the best hope for survival. The presence of metastases, for which liver is a common site, is an extremely poor prognostic sign. Metastases to the liver may occur singly or as multiple lesions and are often subcapsular, which is a common location for benign biliary lesions as well. The following morphologic features have been noted to support the diagnosis of carcinoma over that of a benign biliary lesion: the presence of irregularly spaced and shaped glands, cytologic atypia with variation in nuclear size (4 to 1) and shape from cell to cell, mitoses, intracellular mucin, and the presence of desmoplastic stroma. On permanent sections, immunohistochemical stains can be helpful. Benign bile duct lesions should be negative for B72.3, monoclonal CEA, mesothelin, and p53, and should show intact nuclear staining for Dpc4 (Smad4). In contrast, adenocarcinoma is often positive for B72.3, monoclonal CEA, mesothelin, and p53 (60%) and can exhibit loss of Dpc4 nuclear staining in 55% of cases. (3)

[FIGURE 5 OMITTED]

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Nora Katabi, MD

Accepted for publication February 19, 2010.

From the Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York.

Presented in part at the Surgical Pathology of Neoplastic Diseases course, Memorial Sloan-Kettering Cancer Center, New York, New York, May 18-22, 2009.

The author has no relevant financial interest in the products or companies described in this article.

Reprints: Nora Katabi, MD, Department of Pathology, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10065 (e-mail: katabin@mskcc.org).
Table 1. Morphologic Features To Distinguish
Dysplasia From Reactive Atypia in Gallbladder

 Dysplasia Reactive
 Atypia

Acute inflammation and/or ulceration -- +
Intraepithelial neutrophils -- +
Abrupt transition between normal and
 atypical epithelium + -Fine
nuclear chromatin + -Prominent
nucleoli - /+ +
Surface maturation - /+ +
Loss of polarity + -History
of instrumentation -- +

Abbreviations: +, present;-, absent;+/-, can be present or absent.

Table 2. Morphologic Features To Distinguish
Dysplasia/In Situ Carcinoma Extending into Rokitansky-Aschoff
Sinuses From Invasive Carcinoma in Gallbladder

 Dysplasia/
 In Situ Invasive
 Carcinoma Carcinoma

Desmoplasia -- +
Connection to surface epithelium + -Small
to medium-sized glands in smooth muscle
Dilated or long elongated gland structures
Presence of luminal bile + -Mixture
of benign and atypical glands
Involvement of intermuscular connective tissue
Involvement of the muscle itself -- +
Perineural or vascular invasion -- +

Abbreviations: +, likely present;-, likely absent.

Table 3. Relatively Specific Immunophenotypes
for Metastatic Adenocarcinoma in the Liver
From Other Sites

Metastatic Tumor Immunohistochemical Stains

Colorectal CK20, CDX2
Lung TTF-1, PE10
Breast ER, PR, BRST2
Thyroid TTF-1, thyroglobulin
Pancreatic acinar cell carcinoma Trypsin, chymotrypsin
Prostate PSA, PSAP
Mullerian ER, PR, CA125, WT1
Ne roendocrine neoplasms Chromogranin, synaptophysin

Abbreviations: CA125, carbohydrate antigen 125; CK20, cytokeratin
20; ER, estrogen receptor; PR, progesterone receptor; PSA,
prostate-specific antigen;PSAP, prostate-specific acid phosphatase;
TTF-1, thyroid transcription factor 1;WT1, Wilms tumor suppressor
gene.
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Date:Nov 1, 2010
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