The precursor lesions of invasive adenocarcinoma of the gallbladder have recently been recognized as those of in­testinal metaplasia, dysplasia and carcinoma in situ. The adenoma-carcinoma sequence occurs only in a minority of cases. Recognition of these lesions is, therefore, important when removing gallbladders for cholecystitis or cholelithia­sis.

Some gallbladder adenocarcinomas are immunoreactive for alpha-fetoprotein. No such case occurred in our se­ries.

The bcl-2 gene product is an integral membrane protein located in the inner mitochondrial membrane and princi­pally exerts its effect on the cell cycle as a suppressor of apop- tosis. Bcl-2 protein expression is linked to long term survival in female breast carcinomas. In our series, no such linkage could be established because all cases were immunonegative to Bcl-2 staining.

Our study showed moderate to strong staining patterns of CEA in both the in situ and invasive components. Such pat­terns were also associated with low mean survival rates. The pattern of CEA distribution in the gallbladder is similar to that of the rest of the digestive tract. Normal epithelial cells contain small quantities of CEA that are always distributed along the apical cytoplasm. At least three CEA-related macromolecules, glycoprotein types I, II and III, are found in normal bile. Type I occurs in normal bile and is similar to CEA but lacks the tumour-associated antigenic determi­nants. In inflammatory and tumorous conditions, type I is re­placed with types II and III, the latter being immunologically similar to CEA. The amount of CEA progressively increases in dysplasia, in situ lesions and invasive carcinomas. In addi­tion to a stronger staining, CEA can also be seen within the cytoplasm and even within the gland secretions in the inva­sive components. It is possible that serological assess­ment of CEA may be of value in the close follow-up of such precursor lesions . Such altered CEA staining pattern seems to reflect an early event in the progression of the disease as reflected by increased staining in both in situ and invasive components of the tumour in the majority of cases. Cases with negative staining in the frankly invasive components further demonstrate that cellular antigens are both devel­oped and lost during the process of neoplastic transformation of the gallbladder.

P53 expression was different from that of the CEA, with a dominant staining pattern being confined to the invasive component of the tumour. Mutations in the p53 gene (tumour suppresser oncogene) are the most common genetic lesion found in human cancers. These mutations play a key role in the multistep process that leads to carcinogenesis. These mutations are generally thought to alter the func­tional capabilities of the molecule, rendering the cell devoid of the restraint engendered by normal p53. Most p53 muta­tions described are missense mutations resulting in an abnor­mal protein that accumulates in cells by virtue of an increased half-life. Such intranuclear accumulations are eas­ily detected by immunohistochemical methods. Overexpres- sion of p53 is found in gallbladder dysplasias and invasive carcinomas. The mean survival of 8.8 months in p53 immunopositivity of the invasive components suggests that p53 positivity is associated with a worse clinical outcome.

The strong to moderate staining seen in the in situ component in 11 cases, however, clearly suggests that p53 gene mutations may play a key role in the multiple step evo­lution of disease progression in gallbladder carcinoma. It probably exerts its major effect via its antiapoptosis effect, thereby promoting cellular immortilization and ongoing ge- nomic instability with resultant acquisition of secondary chromosomal aberrations.
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CONCLUSIONS

Our study shows that altered expressions of p53 and CEA are detectable by immunohistochemical methods in de novo gallbladder carcinomas. Tumours with increased expression of p53 and CEA of a strong to moderate staining were associ­ated with poor clinical outcomes as evidenced by their short mean survival. Trends of strong to moderate staining in both the in situ and the invasive components suggest a pathoge- netic basis for ongoing disease progression. However, that p53-negative tumours were not associated with statistically longer survival indicates that p53 immunoreactivity alone is not an independent prognostic marker. These observations are based on a small number of cases, and larger series of cases with complete follow-up are required.

Category: Cancer / Tags: Alpha-fetoprotein, Bcl-2, Carcinoembryonic antigen, Gallbladder carcinoma, P53

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