Precursor lesions

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Adenomas are benign neoplasms of glandular epithelium (intraepithelial neoplasia) that are typically polypoid, single and well-demarcated. They are more common in women than in men {42}. There is a wide age range; although mostly a disease of adults rare gallbladder adenomas occur in children {1256, 2126}. They are more common in the gallbladder than in the extrahepatic bile ducts, and are found in 0.3-0.5% of gallbladders removed for cholelithiasis or chronic cholecystitis. A small proportion of adenomas progress to carcinoma {42, 909, 967}.

Adenomas are often small, asymptomatic, and usually discovered incidentally during cholecystectomy, but they can be multiple, fill the lumen of the gallbladder and be symptomatic. Occasionally, adenomas of the gallbladder occur in association with the Peutz-Jeghers syndrome {521} or with Gardner syndrome {1900, 2041}. Adenomas of the extrahep-atic bile ducts are usually symptomatic and cause biliary obstruction. These benign tumours are not associated with lithiasis.

According to their pattern of growth, they are divided into three types: tubular, papillary, and tubulopapillary. Cytologically, they are classified as: pyloric gland type, intestinal type, and biliary type. Tubular adenomas of pyloric gland type are more common in the gallbladder while intestinal type adenomas are more common in the extrahepatic bile ducts {42}.

Tubular adenoma, pyloric-gland type. A

benign tumour composed of closely packed short tubular glands that are similar to pyloric glands. Early lesions appear as well demarcated nodules embedded in the lamina propria and covered with normal biliary epithelium. They are composed of lobules that contain closely packed pyloric-type glands, some of which may be cystically dilated. The epithelial cells are columnar or cuboidal with vesicular or hyperchromat-ic nuclei and small nucleoli and variable amounts of cytoplasmic mucin. Nodular aggregates of cytologically bland spindle cells with eosinophilic cytoplasm but without keratinization or intercellular bridges known as squamoid morules {984, 1361} are present in about 10% of the cases, whereas frank squamous metaplasia is exceedingly rare. Paneth cells and endocrine cells are often present. By immunohistochemistry, serotonin and a variety of peptide hormones including somatostatin, pancreatic polypeptide, and gastrin have been detected in the cytoplasm of these cells. Smaller lesions show low-grade intraep-ithelial neoplasia, but larger adenomas may have high-grade changes or foci of invasive carcinoma. As they enlarge, most adenomas develop a pedicle and project into the lumen. Rarely, they extend into or arise from Rokitansky-Aschoff sinuses, a finding that should not be mistaken for carcinoma {42}.

Tubular adenoma, intestinal type. This benign tumour is composed of tubular glands lined by cells with an intestinal phenotype, and closely resembles colonic adenomas. It consists of tubular glands lined by pseudostratified columnar cells with elongated hyperchromatic nuclei, and high-grade dysplastic changes are frequent. The glands lack invasive properties and focally are arranged in well defined lobules. The adenomatous epithelium may extend into the Rokitansky-Aschoff sinuses, a finding that should not be confused with stromal invasion. Clusters of goblet, Paneth, and endocrine cells are usually mixed with the columnar cells. Serotonin and, less frequently, peptide hormones have been identified in the endocrine cells by immunohistochemistry. Hyperplasia of metaplastic pyloric type glands is often seen at the base of the adenomas. Papillary adenoma, intestinal type. This benign tumour consists predominantly of papillary structures lined by dysplastic cells with an intestinal phenotype. These adenomas, which usually arise in a background of pyloric gland metaplasia, may

Papillary Adenoma Gallbladder
Fig. 9.15 Papillary adenoma of gallbladder, intestinal type. A Numerous papillary structures project into lumen. B Pseudostratified columnar cells with scattered goblet and Paneth cells.

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Gallbladder Adenoma Biliary Type

Fig. 9.16 A, B Tubular adenoma of gallbladder, pyloric gland type.

occur in the gallbladder or the extrahep-atic bile ducts. In a series of five intestinal type papillary adenomas of the gallbladder, one progressed to invasive carcinoma {42}. The predominant cell is columnar with elongated hyperchromatic nuclei and little or no cytoplasmic mucin. The cells are pseudostratified, mitotically active, and indistinguishable from those of villous adenomas arising in the large intestine. Tubular glands lined by the same type of epithelium, but representing less than 20% of the tumour, may also be found. Dysplastic changes are more extensive than in pyloric-gland type adenomas. Also present are goblet, Paneth, and serotonin-containing cells. Some of the endocrine cells are immunoreactive for peptide hormones.

Papillary adenoma, biliary type. This lesion consists predominantly of papillary structures lined by cells with a biliary phenotype. It is well demarcated and consists of papillary structures lined by tall columnar cells, which except for the presence of more cytoplasmic mucin show minimal variation from normal gallbladder epithelium. Endocrine or Paneth cells are not found. Only mild dysplastic changes are noted. In situ or invasive carcinoma has not been reported in association with these adenomas. This is the rarest form of adenoma of the gallbladder; we have seen only one case. Most papillary lesions composed of normal-appearing gallbladder epithelium are examples of hyperplasia secondary to chronic cholecystitis.

Tubulo-papillary adenoma. When tubular glands and papillary structures each comprise more than 20% of the tumour, the term tubulo-papillary adenoma is applied. Two subtypes are recognized: one is composed of tubular glands and papillary structures similar to those of tubulovillous intestinal adenomas; the other subtype consists of tubular glands similar to pyloric glands and papillary structures often lined by foveolar epithelium. Paneth and endocrine cells are present in some. Rarely, tubulo-papillary adenomas arise from the epithelial invaginations of adenomyomatous hyper-plasia.

Other benign biliary lesions Biliary cystadenoma. These lesions resemble their intrahepatic counterparts (see chapter on bile duct cystadenoma and cystadenocarcinoma). Cystadeno-mas are seen predominantly among adult females and are usually symptomatic. Some of the tumours may measure up to 20 cm in diameter leading to obstructive jaundice or cholecystitis-like symptoms. More common in the extra-hepatic bile ducts than in the gallbladder, cystadenomas are multiloculated neoplasms that contain mucinous or serous fluid and are lined by columnar epithelium reminiscent of bile duct or foveolar gastric epithelium {404}. Occasionally endocrine cells are present. The cellular subepithelial stroma resembles ovarian stroma and shows immunoreactivity for estrogen and progesterone receptors {2029}. The stroma also shows variable fibrosis. Malignant transformation (cystadenocarcinoma) can occur {404}.

Papillomatosis (adenomatosis). Papillo-matosis is a clinicopathological condition characterized by multiple recurring papillary adenomas, that may involve extensive areas of the extrahepatic bile ducts and even extend into the gallbladder and intrahepatic bile ducts. The disease affects both sexes equally. Most patients are adults between 50 and 60 years. Complete excision of the multicentric lesions is difficult and local recurrence is common. The lesion consists of numerous papillary structures as well as complex glandular formations. Because severe dysplasia is often present, papillo-matosis is difficult to distinguish from papillary carcinoma. Some regard this lesion as a form of low-grade multicentric intraductal papillary carcinoma. Papil-lomatosis has a greater potential for malignant transformation than solitary adenomas.

Intraepithelial neoplasia (dysplasia)

If intraepithelial neoplasia is found, multiple sections should be taken to exclude invasive cancer. Cholecystectomy is a curative surgical procedure for patients with in situ carcinoma or with carcinoma extending into the lamina propria {35}. Epidemiology. The rate of intraepithelial neoplasia of the gallbladder reflects that of invasive carcinoma. In countries in which carcinoma of the gallbladder is endemic, the prevalence is higher than in countries in which this tumour is sporadic. Studies from different countries have shown that the incidence of highgrade dysplasia or carcinoma in situ in gallbladders with lithiasis has varied from 0.5-3% {35}. This variation in the incidence of intraepithelial neoplasia is also attributable to other factors such as lack of uniformity in morphological criteria and sampling methods.

Macroscopic features. Intraepithelial neoplasia is usually not recognized on macroscopic examination because it often occurs in association with chronic cholecystitis. The mucosa may appear granular, nodular, plaque-like, or trabec-ulated. The papillary type of intraepithe-lial neoplasia usually appears as a small, cauliflower-like excrescence that projects into the lumen and can be recognized on close inspection. However, in most cases, the gallbladder shows only a thickened and indurated wall, the result of chronic inflammation and fibrosis. Microscopic features. Microscopically two types of intraepithelial neoplasia are recognized: papillary and flat, the latter being more common. The papillary type is characterized by short fibrovascular stalks that are covered by dysplastic or neoplastic cells.

Intraepithelial neoplasia usually begins on the surface epithelium and subsequently extends downward into the Rokitansky-Aschoff sinuses and into metaplastic pyloric glands. Columnar, cuboidal, and elongated cells with variable degrees of nuclear atypia, loss of polarity, and occasional mitotic figures are characteristic. The dysplastic cells are usually arranged in a single layer, but can be pseudostratified. Later, papillary structures covered by dysplastic epithelium may form. The large nuclei of dys-plastic cells may be round, oval, or fusiform, with one or two nucleoli that are more prominent than those of normal cells.

The cytoplasm is usually eosino-philic and contains non-sulphated acid and neutral mucin. Goblet cells are found in one third of cases. An abrupt transition between normal-appearing columnar cells and intraepithelial neoplasia is seen in nearly all cases. In general, the cell population of dysplasia is homogeneous, unlike the heterogeneous cell population of the epithelial atypia of repair. Widespread involvement of the mucosa by intraepithelial neoplasia often occurs. For this reason, we have suggested that some, if not most, invasive carcinomas of the gallbladder arise from a field change within the epithelium. The cells of intraepithelial neoplasia are reactive for CEA and for the carbohydrate antigen CA19-9 {35}. Expression of p53 occurs in some lesions {2125}. Differential diagnosis. Reactive epithelial changes ('atypia of repair') differs from intraepithelial neoplasia in consisting of a heterogeneous cell population in which columnar mucus-secreting cells, low cuboidal cells, atrophic-appearing epithelium, and pencil-like cells are present. In addition, there is a gradual transition of the cellular abnormalities, in contrast with the abrupt transition seen in intraepithelial neoplasia. The extent of nuclear atypia is less pronounced in reactive changes and immunoreactivity for p53 protein is absent, while usually positive in intraep-ithelial neoplasia.

High-grade intraepithelial neoplasia and carcinoma in situ

In cases where the cells have all the cytological features of malignancy with frequent mitotic figures, nuclear crowding and prominent pseudostratification, the term carcinoma in situ may be used. Neoplastic cells first appear along the surface epithelium and later spread into the epithelial invaginations and antral-

Fig. 9.18 High-grade intraepithelial neoplasia adjacent to intestinal metaplasia with numerous mature goblet cells.

type metaplastic glands. In the late stages of carcinoma in situ, the histolog-ical picture is that of back-to-back glands located in the lamina propria but often connected with the surface epithelium. However, not all in situ carcinomas exhibit this type of growth pattern. Some show distinctive papillary features with small fibrovascular stalks lined by neoplastic cells. Not infrequently, a combination of these growth patterns is seen. The differential diagnosis between highgrade intraepithelial neoplasia (severe dysplasia) and carcinoma in situ is difficult and often impossible in many cases. This is not important because the two lesions, which vary only in degree histologically, are closely related biologically Histological variants of carcinoma in situ. An in situ carcinoma composed of goblet cells, columnar cells, Paneth cells, and endocrine cells, has been described, which may represent an in situ phase of intestinal-type adenocarcinoma {35, 41}. Another type of in situ intestinal-type carcinoma is composed of cells closely resembling those of colonic carcinomas at the light and electron microscopic lev

Fig. 9.17 High-grade intraepithelial neoplasia (carcinoma in situ) of gallbladder.

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