It has previously been demonstrated that sex steroids influence the formation and growth of tumors arising from their target organs. This effect is mediated through some specific receptors on the malignant cells. In breast cancer, ER status is an important determinant of response to anti-estrogenic therapy and survival18,19. Estrogen receptors have also been demonstrated on other hormone-dependent tumors such as ovarian and endomet.rial cancer22,23. Interestingly, a variety of tumors arising from tissues not generally considered hormone-dependent also express these receptors. This includes tumors of pancreas, stonmch colon, liver, thyrnus, thyroid, brain, kidney and skin24-30. The patho-physiologic significance and clinical relevance of these receptors, however, remain uncertain31-34.
Steroid receptors have been demonstrated on benign and malignant gallbladder tissue. Singletaiy etalobserved the presence of both estrogen and progesterone receptors in the cytosolic and nuclear fractions of benign gallbladder tissue obtained from patients undergoing cholecystectomy during liver transplantation or for cholelithiasis. These were high-affinity receptors and specific for their respective ligands35. Daignault et al reported the presence of progesterone receptors in 60% of patients who had cholelithiasis36. More recently, similar results were reported by others37-38. These studies suggest that estrogen and progesterone receptors are present on the benign gallbladder tissue obtained from patients with cholelithiasis. Since estrogenic effect is required for the expression of progesterone receptors, these studies also suggest that these receptors are functional39. Veiy few studies have been performed on the malignant gallbladder tissue. Nakarnura et a! studied 21 patients with gallbladder cancer40. Immuno-histochemical analyses revealed that 58.6% of the tumors had cytoplasmic and 52.4% had nuclear ER expression. In this study, moderately-well and poorly-differentiated tumors were more often ER positive. This difference, however, was not statistically significant. Similarly, gender did not influence the receptor status. Yamamoto et al demonstrated that 23% of the patients with gallbladder cancer had ER positive tumors41. Well differentiated tumors were more often ER positive. Receptors status, however, did not influence survival. Our study demonstrates the presence of cytoplasmic estrogen receptors in 60% of patients with gallbladder cancer. These figures are similar to Nakamura et al but more frequent than the nuclear receptor positivity reported by Yamomoto et al. Variability of ER expression has been previously documented35-38. This may reflect heterogeneity in the patient population, methodology employed to determine ER status and interpretation of the histologic findings. Source of the malignant tissue for histologic examination i.e. primary site versus metastases may also play an important role. In breast carcinoma, it has been demonstrated that metastatic sites are less frequently ER positive as compared to the primary site19. All patients in our study had tissues obtained from the primary site. We utilized anti-estradiol antibiotics to demonstrate cytoplasmic receptor binidng. Although less specific than anti ER antibodies, it was the only method available at the Aga Khan University Hospital at that time. Additionally, other authors have used similar methods and demonstrated cytosolic binding36,37,40. Even the more widely used dextran-coated charcoal method demonstrates cytosolic binding35,36,38. However, using more specific monoclonal antibody against nuclear estrogenic receptors may be more advantageous. Such a study is in progress.
In this study, we observed no correlation between ER status and age, parity, menopausal status, presence of cholelithiasis, degree of differentiation of turnoror stage of the disease. Overall survival is also not influenced by the receptor status. Although these observations are similar to the previous two reports. number of patients is small. Larger studies are required to substantiate these preliminary findings.
Biologic significance of these receptors remains unknown. Only a few studies have utilized anti-estrogenic therapy in patients with tumors arising from the “non-target” organs30. In general, such trials have been negative. This may be due to several reasons. Level of ER expression in “non-target” tissues is generally low. Degree of positivity is an important detenuinant of response to anti-estrogenic therapy. It is also possible that, atleast in some cases,these receptors are not functional. This has been demonstrated in patients with melanoma42,43. Furthennore, improper selection of patients may have contributed to the poor results. Restricting the use of anti-estrogens to individuals with ER positive tumors may be more appropriate to evaluate the worth of such an approach. Anti-estrogen therapy has not been previously evaluated in patIents with gallbladder cancer. A well controlled prospective clinical trial of hormonal therapy in patients with ER positive gallbladdercancer may be the best way to evaluate the pathophysiological significance of these receptors. Such a trial is in progress at our institution.
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