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-Jeghers^22,23 or Gardner syndrome^24,25 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 gallbladder^18–20 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 tumors^28,29), 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.