Benign and Malignant Tumors of the Gallbladder and Extrahepatic Biliary Tract

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Chapter 38

Benign and Malignant Tumors of the Gallbladder and Extrahepatic Biliary Tract

N. Volkan Adsay

David S. Klimstra


Gallstones and inflammatory disorders constitute most biliary tract pathology. Neoplasms and tumorlike lesions are uncommon but form an important category with challenging diagnostic issues. Because of advances in radiographic modalities and widespread use of laparoscopic cholecystectomy, the frequency of gallbladder and biliary tumors that have come to clinical attention has increased. These techniques have also led to an increase in the diagnosis of mass-forming lesions, including “incidentalomas” such as cholesterol polyps, that would have otherwise gone undetected.

The terminology used for gallbladder and bile duct tumors and for preinvasive neoplasms has been reevaluated. This evaluation was done to standardize the approach to tumors across the entire pancreatobiliary system.

Sampling Gallbladder Specimens

A significant proportion of gallbladder carcinomas are un­apparent both clinically and grossly,4a discovered only after microscopic examination of cholecystectomy specimens performed and processed with the clinical and gross impressions of cholecystitis.19 Therefore, a sampling protocol addressing this possibility ought to be utilized routinely.1,7 Our approach is the following: The cystic duct margin is sampled en-face unopened. The serosal and hepatic surfaces of the GB are inked in different colors and the gallbladder is opened from the serosal aspect. If no overt lesions are noted, a through-and-through section, going from the fundus to the cystic duct, is taken, rolled up, and submitted in the same cassette along with the cystic duct margin. If a lymph node is present, this is also included in the same cassette.

If focal epithelial atypia (undetermined nature) or low-grade dysplasia are identified in this random sample, 4 additional blocks are obtained. If high-grade dysplasia is identified, then the entire gallbladder needs to be examined because grossly invisible invasive carcinoma is commonly associated with this and ought to be documented since the prognosis changes dramatically. Along the same lines, if a Tis or T1a or T1b carcinoma is identified, then the entire gallbladder must be examined to rule out a T2 carcinoma (invading through the tunica muscularis) since the clinical outcome of the latter is starkly worse, and it is typically undetectable grossly.9

If there is a polyp or papillary lesion, it is submitted entirely for examination. If this proves neoplastic, several (a minimum of 5) sections of the uninvolved gallbladder ought to also be examined for other dysplastic lesions. If the polyp shows high-grade dysplasia, then the entire gallbladder ought to be examined because these can be associated with invasive carcinoma in other segments of gallbladder.10

For a carcinoma of T2 or beyond, the documentation should include, in addition to the cystic duct margin, the spread to the serosal versus hepatic surfaces, respectively. Typically proper documentation of the deepest region requires at least 12 cassettes because foci of carcinoma are often grossly unapparent, unless the first set of slides already documents the highest possible stages (T3 with surface involvement).

For a high-risk lesion, such as established examples of hyalinizing cholecystitis and xanthogranulomatous chole­cystitis, which are notorious for hiding grossly unapparent carcinomas, extensive sampling ought to be performed (preferably entirely) from the beginning. Cases with a clinical history of a high risk disease for carcinoma, such as primary sclerosing cholangitis cases, may also have to be sampled more from the beginning, preferably with 3 to 4 cassettes with multiple strips during the initial random sampling.


Tumoral Intraepithelial Neoplasms

Mass-forming, preinvasive neoplastic lesions (i.e., tumoral intraepithelial neoplasms) of the gallbladder occur in two forms. Papillary or polypoid, preinvasive neoplasms known as intracholecystic papillary-tubular neoplasms, or ICPNs (i.e., adenomas, papillary neoplasms, papillomatosis, and papillary adenocarcinomas) compose the first type.10 The second is referred to as mucinous cystic neoplasms with ovarian-like stroma, and these tumors are rare.1113

These lesions represent one end of an adenoma-carcinoma sequence and can progress to more advanced degrees of dysplasia or invasive carcinoma. Although most invasive carcinomas of the gallbladder arise in the setting of non­polypoid (flat) dysplasia, approximately 6% arise from tumoral intraepithelial neoplasms.10 The incidence of malignant transformation varies. The frequency is less for certain subsets of tumors such as pyloric gland adenomas and significantly higher for entities with high-grade dysplasia (i.e., papillary adenocarcinoma).10,14,15

Intracholecystic Papillary-Tubular Neoplasms


Included in this category of tumors are all discrete, mass-forming, preinvasive neoplasms that arise in gallbladder mucosa. The ICPNs represent the gallbladder counterpart of gastrointestinal (GI) adenomas and pancreatic and biliary intraductal neoplasms (i.e., intraductal papillary mucinous neoplasms of the pancreas, pyloric gland adenomas of the pancreas, intraductal tubulopapillary neoplasms of the pancreas, and intraductal tubular and tubulopapillary neoplasms of the bile ducts), including those associated with biliary papillomatosis and tumors that once were classified as noninvasive papillary adenocarcinomas. In the 2010 World Health Organization (WHO) classification of tumors of the digestive system,16 these lesions are classified as adenoma or intracystic papillary neoplasm (Box 38.1). This distinction is presumably based on the degree of papilla formation or dysplastic transformation (both higher in the latter), although no specific criteria were established to help distinguish one from the other, which is problematic even for experts.17

The clinical and pathologic features of these lesions were not fully appreciated until recently because of the differences in terminology. For instance, many studies on adenomas discuss solely the pyloric gland type,1820 which includes small lesions that represent metaplastic micronodules of pyloric glands. In the largest studies, the mean size of adenomas ranged between 0.6 and 0.9 cm and included cases as small as 2 mm in the largest dimension. In contrast, many truly preinvasive papillary lesions with extensive high-grade dysplasia were referred to as papillary variants of adenocarcinoma.14

Pyloric gland metaplasia is common in the gallbladder, and in some cases, it may form a polypoid nodule.21 We think that most of these cases are best regarded as polypoid metaplasia. We reserve the term neoplasm for lesions that can form large (>1 cm) tumors that are distinguishable from the background mucosa or a convincingly dysplastic epithelium.10 The 1-cm cutoff point is arbitrary, and is used by clinicians as a cutoff point for cholecystectomy and for pancreatic lesions (i.e., intraductal neoplasms).16

Clinical Features

The clinical features of ICPNs depend mainly on their size. The clinically more meaningful (>1 cm) tumors have certain recognized characteristics.10 They occur in older adults, who are typically in their early 60s at the time of diagnosis. At clinical presentation, patients may have pain, or the tumor may be detected incidentally. Gallstones are less common than in other types of gallbladder tumors.

Radiologically, almost 50% of cases are perceived as cancer, whereas the others are interpreted as polypoid tumor. Approximately 10% are not detected clinically, presumably because they are mistaken for stones or sludge. Rarely, patients have Peutz-Jeghers22,23 or Gardner syndrome24,25 or an anomalous union of pancreatobiliary ducts. Some cases are associated with a cholesterol-type polyp or, rarely, with a Brunner gland hamartoma of the duodenum. There are geographic differences in the incidence, histologic types, and association with invasive carcinoma. For instance, these tumors are more common in Asia.26

Pathologic Features

Macroscopically, ICPNs are characterized by large, villous or papillary growths with a feathery or cauliflower-like pattern, or by smooth-surfaced polypoid projections that may be pedunculated or sessile (Fig. 38.1).10 The lesions can be multifocal. They occur more commonly in the body or fundus of the gallbladder and may grow as large as 7 cm in the maximum dimension.

These lesions are often friable, and by the time they reach the dissection table, pedunculated cases may become detached and may be dismissed by prosectors as debris, necrosis, or sludge. If there is a radiologic or pathologic suggestion of a polyp in a gallbladder, it is important to sample all free-floating fragments in addition to the remaining mucosa of the gallbladder.

By definition, the tumors discussed in this section are premalignant. However, some, particularly those with pyloric gland differentiation, may lack significant cytologic atypia that is characteristic of conventional dysplasia.

Microscopically, the lesions may be predominantly tubular or predominantly papillary (or villous), but a significant proportion shows a mixed tubulopapillary pattern (Fig. 38.2). The risk of malignancy is proportional to the amount of papilla formation. Various cell lineages that recapitulate the normal cell types in the GI tract (i.e., pyloric, foveolar, intestinal, and biliary) can be observed in the tumors. Although one cell type may be predominant in some cases, most exhibit a mixture of cell types.

The pyloric gland pattern constitutes an overwhelming percentage of lesions that are less than 1 cm in the largest dimension (Fig. 38.3). The literature on so-called adenomas of the gallbladder1820 is mostly based on small pyloric gland lesions, some of which may represent polypoid metaplasia rather than true neoplasms.10 Small lesions are often associated with extensive pyloric gland metaplasia in the background mucosa, further supporting the impression that they are exuberant polypoid examples of metaplasia.

ICPNs larger than 1 cm in size are more commonly of the biliary type, showing cuboidal cells with prominent nucleoli and MUC1 positivity (Fig. 38.4, A). These tumors grow in a pattern known in the past as noninvasive papillary adenocarcinoma. They are often associated with extensive high-grade dysplasia (see Fig. 38.4, B) and invasive carcinoma. Prominent lymphoplasmacytic and neutrophilic inflammation may involve the papillary cores and the epithelium. Follicular cholecystitis occurs in patients with this type of tumor. It is evident in the background mucosa in 30% of cases.

Another tumor phenotype resembles gastric foveolar or endocervical epithelium (Fig. 38.5). It is composed of tall columnar cells with abundant, pale, mucinous cytoplasm, and it shows MUC5AC positivity. Although these tumors do not seem overtly atypical, their association with invasive carcinoma is fairly high. Among the cases that are larger than 1 cm in the largest dimension, it is uncommon to see tumors composed exclusively of bland-appearing pyloric (see Fig. 38.3) or Brunner-like glands. The incidence of associated invasive carcinoma in these cases is less than 15%.

A distinctive and more common variant is characterized by a well-lobulated, complex tubular pattern of small, back-to-back, round or compressed glandular units with different degrees of lumen formation and with no intervening stroma. The glands are lined by cuboidal cells without overt intracytoplasmic mucin formation. These tumors have been referred to as pyloric gland adenoma, and the architecture of the polyps, along with MUC6-positivity, supports this designation. They may represent pyloric gland adenomas with high-grade dysplasia. However, they are seldom associated with a more conventional mucinous pyloric gland pattern within the lesion or in the uninvolved gallbladder. The overall morphology and immunophenotype of these tumors more closely resembles intraductal tubulopapillary or tubular neoplasms of the pancreas and bile ducts, and in one study, many examples of this variant were designated as such.27 We regard them as tumors with a complex pyloric gland phenotype (Fig. 38.6).10 Interestingly this variant is seldom if ever associated with invasive carcinoma. In addition many examples of this variant are associated with cholesterolosis, both within the lesion and away, and give the impression of arising in association with a cholesterol polyp.

In some examples of tumors with a complex pyloric gland phenotype, the nuclei are more elongated and show overlapping features and chromatin clearing, creating a pattern reminiscent of papillary thyroid carcinomas. Morular foci composed of squamoid spindle cells in a vague whorled pattern similar to the type of squamoid morules found in pancreatoblastoma, pulmonary blastoma, cribriform-morular thyroid carcinoma, or endometrioid adenocarcinoma are commonly seen in this variant. The nuclei in these morular areas have biotin-containing, optically clear pseudoinclusions (Fig. 38.7). Paneth cells and neuroendocrine cells are also commonly found in this variant.

Tumors with a complex pyloric gland phenotype are often large, have a thin stalk, and display a distinctive lobulated pattern in which the lobules are often covered by unremarkable gallbladder epithelium. The surrounding gallbladder is usually surprisingly free of abnormalities, including flat dysplasia or inflammation. Within the lobules, cystically dilated glands with acidophilic granular secretions are often evident. Some show amyloid-like hyalinization in the stroma.

A small percentage of ICPNs resemble intestinal adenomas (Fig. 38.8). They are characterized by pseudostratified columnar, cigar-shaped nuclei with conspicuous nucleoli, and tubular or villous architecture (often in combination). Goblet cells can be found in any type of ICPN, and their presence should not be considered evidence of intestinal differentiation. Many cases with columnar nuclei and basophilic cytoplasm lack true intestinal differentiation on immunohistochemical analysis.

Rare ICPNs may be oncocytic (Fig. 38.9), showing features similar to intraductal oncocytic papillary neoplasms of the pancreas and biliary tract. Even less common are transitional cell (urothelial-like) lesions that do not fit into any of the subtypes described previously. The clinical and biologic relevance of these subgroups has not been determined.

The 2010 WHO classification16 advocates use of one of two diagnostic categories: adenoma or intracystic papillary neoplasm. However, a study focusing on the reproducibility of international experts assigning cases to one of these two diagnostic categories revealed a very low level of agreement.17 We prefer to classify these tumors as ICPNs.10

Regardless of the term used, the most important aspect of tumor pathology is to rule out invasive carcinoma. Because invasive carcinoma is difficult to detect in the gallbladder grossly, extensive sampling is warranted. If an invasive carcinoma is identified, its type, size, and extent should be documented separately from the noninvasive component. Most invasive carcinomas that arise in these tumors are ordinary tubule-forming adenocarcinomas (pancreatobiliary type), although unusual types such as mucinous, squamous, and neuroendocrine tumors also occur.10 These unusual variants may be more common than those that arise from nontumoral (flat) dysplasia. If invasive carcinoma is not found, it is helpful to document as much as possible the amount of papillary growth, the cell types (especially biliary and foveolar types), and the extent of dysplasia, because these parameters are associated with a higher incidence of invasive carcinoma and disease progression.

Molecular Aspects

The immunophenotype of ICPNs corresponds to their line of differentiation. Most are cytokeratin 7 (CK7) positive, and many express mucin-related glycoproteins and oncoproteins, including carcinoembryonic antigen (CEA). The MUC1 response is typically confined to the apical membrane of cells in areas of biliary differentiation or high-grade dysplasia. MUC2 is expressed in intestinal, MUC5AC in foveolar, and MUC6 in pyloric or Brunner gland–like areas.10 The complex pyloric gland phenotype, which is a distinct group, also shows pyloric differentiation with diffuse MUC6 expression. Similar to other morule-forming tumors (i.e., biotin-rich, optically clear nuclei [BROCNs]–forming tumors28,29), the complex pyloric gland phenotype is commonly associated with mutations in β-catenin and expression of estrogen receptors.30 Mutation in KRAS is uncommon (<25%), similar to other gallbladder neoplasms.31,32 Tumor protein p53 (TP53) is expressed in approximately one third of cases, mostly in the biliary subtype with high-grade dysplasia.

The GNAS codon 201 mutation, which is seen in approximately 66% of pancreatic intraductal papillary mucinous neoplasms33 is rarely seen in ICPNs.27 This disparity is presumably related to the rarity of the intestinal variant, which appears to be linked with this mutation.

Differential Diagnosis

Metaplastic changes, particularly nodular pyloric gland metaplasia, can be indistinguishable from ICPNs with a pyloric or Brunner gland–like phenotype if the glandular units are interpreted solely at high-power magnification. An arbitrary size of 1 cm has been proposed as the minimum size for a tumor. Rarely, dysplastic cells that form a compact nodule less than 1 cm in diameter may be detected incidentally. We refer to these as incipient ICPNs, similar to incipient intraductal papillary mucinous neoplasms in the pancreas.

Ordinary nontumoral (flat) dysplasia of the gallbladder often has papillary structures. In some cases, these papillae may be tall and exuberant, creating a papillary adenocarcinoma pattern (Fig. 38.10, D), but these cases are not assigned to the ICPN category unless they form a distinct mass.

Recognition of the presence or absence of invasive carcinoma in or underneath polypoid tumors may be problematic because of architectural complexity and tangential sectioning. Features that favor carcinoma include wide separation of glandular units, their irregular contours (Fig. 38.11), cytologic differences from the surface lesion (including paradoxical differentiation with more abundant cytoplasm and tubule formation), foamy gland features,10,34 and cell clusters that reside in clefts. Extension of dysplastic epithelium into Rokitansky-Aschoff sinuses creates a pseudoinvasive appearance (Table 38.1).35 The distribution of the units, their spatial connection to the overlying mucosa, and the finding of remnants of normal epithelium are helpful clues in determining that the lesion is not invasive. Unlike invasive adenocarcinomas, Rokitansky-Aschoff sinuses are often flask shaped or elongated with the longitudinal axis oriented perpendicular to the surface (Fig. 38.12). Paradoxically, these sinuses often have concentric bands of loose stroma that resembles desmoplasia (Fig. 38.13). Most gallbladder adenocarcinomas do not exhibit significantly desmoplastic stroma.

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