Skip to main content

Advertisement

Log in

Expression Pattern of Estrogen Receptor Alpha and Progesterone Receptor in Gallbladder Carcinoma and Their Association with Clinicopathological Parameters and Overall Survival

  • Research
  • Published:
Journal of Gastrointestinal Cancer Aims and scope Submit manuscript

Abstract

Background

Gallbladder cancer (GBC) is a highly aggressive malignant tumor with a poor prognosis. Despite being first described two centuries ago, there are no targeted therapies available beyond conventional cytotoxic therapy. Epidemiological studies have shown that the incidence of gallbladder cancer is higher in females than males. This suggests that the gallbladder may be a female sex hormone-responsive organ, and these hormones might be involved in the pathogenesis of gallbladder cancer. Therefore, we aimed to analyze the expression of ERα and PR in GBC and correlate their expression with clinicopathological variables and overall survival.

Patients and Methods

A total of 235 histopathologically diagnosed GBC cases were included in this hospital-based cross-sectional study. Clinicopathological data were collected, and the expression of ERα and PR was evaluated by immunohistochemistry.

Results

The mean age of this study population was 55.47 ± 8.45 with range 28–87 years. Females were predominated over male with a male-to-female ratio of 1:3.5. Positive nuclear expression of the ERα and PR was found in 13 (5.5%) and eight (3.4%) cases, respectively. Apart from nuclear staining, cytoplasmic expression of ERα and PR was found in three (1.2%) and 31 (13.2%) cases, respectively. Higher percentage of positive nuclear expression of ER was found in < 50 years age (p value = 0.04), parity > 4 (p value = 0.02), advanced pT stage (T3) (p value = 0.01), lymphovascular invasion (p value = 0.02), and liver invasion (p value = 0.04) which were statistically significant. Higher percentage of PR expression was also observed in < 50 years age (p value = 0.01), and tumor associated with gallstone (p value = 0.04). There was no significant correlation between cytoplasmic expression of ER, PR, and clinicopathological variables. In multivariate analysis, there was no significant correlation between ER or PR positive expression and overall survival.

Conclusion

Although nuclear expression of ERα was significantly associated with progressive disease factors but the positive expression was found in very small percentage of GBC cases. So anti-hormone therapy might be an option in patient with ER α positive gallbladder carcinoma.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

Data Availability

No datasets were generated or analysed during the current study.

References

  1. Sung H, Ferlay J, Siegel RL, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021;71(3):209–49. https://doi.org/10.3322/caac.21660.

    Article  CAS  PubMed  Google Scholar 

  2. Unisa S, Jagannath P, Dhir V, Khandelwal C, Sarangi L, Roy TK. Population-based study to estimate prevalence and determine risk factors of gallbladder diseases in the rural Gangetic basin of North India. HPB (Oxford). 2011;13:117–25. https://doi.org/10.1111/j.1477-2574.2010.00255.x.

    Article  PubMed  Google Scholar 

  3. Rout N, Hota SK, Dash S, Samantaray S, Mallik RN, Agrawal O. Diagnostic utility of ultrasound-guided fine-needle aspiration cytology in gall bladder lesions: an experience from a tertiary care cancer center in Eastern India. J Cytol. 2021;38:145–50. https://doi.org/10.4103/JOC.JOC_166_20.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Roa JC, García P, Kapoor VK, Maithel SK, Javle M, Koshiol J. Gallbladder cancer Nat Rev Dis Primers. 2022;8:69. https://doi.org/10.1038/s41572-022-00398-y.

    Article  PubMed  Google Scholar 

  5. Canale M, Monti M, Rapposelli IG, et al. Molecular targets and emerging therapies for advanced gallbladder cancer. Cancers (Basel). 2021;13:5671. https://doi.org/10.3390/cancers13225671.

    Article  CAS  PubMed  Google Scholar 

  6. Barreto SG, Haga H, Shukla PJ. Hormones and gallbladder cancer in women. Indian J Gastroenterol. 2009;28:126–30. https://doi.org/10.1007/s12664-009-0046-8.

    Article  PubMed  Google Scholar 

  7. Gabbi C, Kim HJ, Barros R, Korach-Andrè M, Warner M, Gustafsson JA. Estrogen-dependent gallbladder carcinogenesis in LXRbeta-/- female mice. Proc Natl Acad Sci U S A. 2010;107:14763–8. https://doi.org/10.1073/pnas.1009483107.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Srivastava A, Sharma KL, Srivastava N, Misra S, Mittal B. Significant role of estrogen and progesterone receptor sequence variants in gallbladder cancer predisposition: a multi-analytical strategy. PLoS ONE. 2012;7: e40162. https://doi.org/10.1371/journal.pone.0040162.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Hammond ME, Hayes DF, Dowsett M, et al. American Society of Clinical Oncology/College of American Pathologists guideline recommendations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer. J Clin Oncol. 2010;28:2784–95. https://doi.org/10.1200/JCO.2009.25.6529.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Hryciuk B, Pęksa R, Bieńkowski M, et al. Expression of female sex hormone receptors, connective tissue growth factor and HER2 in gallbladder cancer. Sci Rep. 1871;2020:10. https://doi.org/10.1038/s41598-020-58777-y.

    Article  CAS  Google Scholar 

  11. Cohen DA, Dabbs DJ, Cooper KL, et al. Interobserver agreement among pathologists for semiquantitative hormone receptor scoring in breast carcinoma. Am J Clin Pathol. 2012;138:796–802. https://doi.org/10.1309/AJCP6DKRND5CKVDD.

    Article  CAS  PubMed  Google Scholar 

  12. Sachidananda S, Krishnan A, Janani K, et al. Characteristics of gallbladder cancer in South India. Indian J Surg Oncol. 2012;3(3):228–30. https://doi.org/10.1007/s13193-012-0150-6.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Saranga Bharathi R, Singh R, Gupta R, et al. Female sex hormone receptors in gallbladder cancer. J Gastrointest Cancer. 2015;46(2):143–8. https://doi.org/10.1007/s12029-015-9698-z.

    Article  CAS  PubMed  Google Scholar 

  14. Nakamura S, Muro H, Suzuki S. Estrogen and progesterone receptors in gallbladder cancer. Jpn J Surg. 1989;19:189–94. https://doi.org/10.1007/BF02471584.

    Article  CAS  PubMed  Google Scholar 

  15. Yamamoto M, Nakajo S, Tahara E. Immunohistochemical analysis of estrogen receptors in human gallbladder. Acta Pathol Jpn. 1990;40:14–21. https://doi.org/10.1111/j.1440-1827.1990.tb01524.x.

    Article  CAS  PubMed  Google Scholar 

  16. Ko CY, Schmit P, Cheng L, Thompson JE. Estrogen receptors in gallbladder cancer: detection by an improved immunohistochemical assay. Am Surg. 1995,61:930–3. https://pubmed.ncbi.nlm.nih.gov/7668471/

  17. Malik IA, Abbas Z, Shamsi Z, et al. Immuno-histochemical analysis of estrogen receptors on the malignant gallbladder tissue. J Pak Med Assoc. 1998,48:123–6. https://pubmed.ncbi.nlm.nih.gov/9813971/

  18. Sumi K, Matsuyama S, Kitajima Y, Miyazaki K. Loss of estrogen receptor beta expression at cancer front correlates with tumor progression and poor prognosis of gallbladder cancer. Oncol Rep. 2004,12:979–84. https://pubmed.ncbi.nlm.nih.gov/15492781/

  19. Baskaran V, Vij U, Sahni P, Tandon RK, Nundy S. Do the progesterone receptors have a role to play in gallbladder cancer? Int J Gastrointest Cancer. 2005;35:61–8. https://doi.org/10.1385/IJGC:35:1:061.

    Article  CAS  PubMed  Google Scholar 

  20. Shukla PJ, Barreto SG, Gupta P, et al. Is there a role for estrogen and progesterone receptors in gall bladder cancer? HPB (Oxford). 2007;9:285–8. https://doi.org/10.1080/13651820701481489.

    Article  CAS  PubMed  Google Scholar 

  21. Albores-Saavedra J, Henson DE, Moran-Portela D, Lino-Silva S. Cribriform carcinoma of the gallbladder: a clinicopathologic study of 7 cases. Am J Surg Pathol. 2008;32:1694–8. https://doi.org/10.1097/PAS.0b013e3181706237.

    Article  PubMed  Google Scholar 

  22. Park JS, Jung WH, Kim JK, et al. Estrogen receptor alpha, estrogen receptor beta, and progesterone receptor as possible prognostic factor in radically resected gallbladder carcinoma. J Surg Res. 2009;152:104–10. https://doi.org/10.1016/j.jss.2008.01.032.

    Article  CAS  PubMed  Google Scholar 

  23. Gupta P, Agarwal A, Gupta V, Singh PK, Pantola C, Amit S. Expression and clinicopathological significance of estrogen and progesterone receptors in gallbladder cancer. Gastrointest Cancer Res. 2012,5:41–7. https://pubmed.ncbi.nlm.nih.gov/22690257/

  24. Zhang LQ, Xu XS, Wan Y, et al. Prognostic implications of estrogen receptor 1 and vascular endothelial growth factor A expression in primary gallbladder carcinoma. World J Gastroenterol. 2015;21:1243–50. https://doi.org/10.3748/wjg.v21.i4.1243.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Wang L, Yang M, Guo X, et al. Estrogen-related receptor-α promotes gallbladder cancer development by enhancing the transcription of Nectin-4. Cancer Sci. 2020;111(5):1514–27. https://doi.org/10.1111/cas.14344.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Beltjens F, Molly D, Bertaut A, et al. ER-/PR+ breast cancer: A distinct entity, which is morphologically and molecularly close to triple-negative breast cancer. Int J Cancer. 2021;149:200–13. https://doi.org/10.1002/ijc.33539.

    Article  CAS  PubMed  Google Scholar 

  27. Welsh AW, Lannin DR, Young GS, et al. Cytoplasmic estrogen receptor in breast cancer. Clin Cancer Res. 2012;18:118–26. https://doi.org/10.1158/1078-0432.CCR-11-1236.

    Article  CAS  PubMed  Google Scholar 

  28. Ebata A, Suzuki T, Shoji-Harada N, et al. Immunolocalization of cytoplasmic ER in ER-negative breast carcinoma as a potent favorable prognostic predictor. Acta Histochem Cytochem. 2023;56:59–66. https://doi.org/10.1267/ahc.23-00016.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Piasecka D, Składanowski AC, Kordek R, Romańska HM, Sądej R. Aspekty regulacji aktywności receptora progesteronu (PR) - znaczenie w progresji raka gruczołu piersiowego [Aspects of progesterone receptor (PR) activity regulation - impact on breast cancer progression]. Postepy Biochem. 2015,61:198–6. https://pubmed.ncbi.nlm.nih.gov/26689013/

  30. Cuzick J, Sestak I, Cawthorn S, et al. Tamoxifen for prevention of breast cancer: extended long-term follow-up of the IBIS-I breast cancer prevention trial. Lancet Oncol. 2015;16(1):67–75. https://doi.org/10.1016/S1470-2045(14)71171-4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Funding

This research received funding from ICMR in the form of ICMR-Senior Research fellowship (Fellowship no: No.3/2/2/14/2018/Online Onco Fship/NCD-III).

Author information

Authors and Affiliations

Authors

Contributions

S.D.; Conceptualization, Lab work, writing-original draft preparation, statistical analysis. S.S. M.N. & N.R.; analysis the clinical samples, writing-review and editing. M.R.R. supervision and editing. All authors have read and approved the final manuscript.

Corresponding author

Correspondence to Sashibhusan Dash.

Ethics declarations

Ethics Approval and Consent to Participate

This study was approved by the Institutional Ethics Committee, Acharya Harihar Post-Graduate Institute of Cancer, Cuttack, Odisha (IEC-AHRCC-066/03.07.2018). All patients provided written informed consent.

Competing Interest

The authors declare no competing interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Dash, S., Nayak, M., Samantaray, S. et al. Expression Pattern of Estrogen Receptor Alpha and Progesterone Receptor in Gallbladder Carcinoma and Their Association with Clinicopathological Parameters and Overall Survival. J Gastrointest Canc (2024). https://doi.org/10.1007/s12029-024-01045-3

Download citation

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s12029-024-01045-3

Keywords

Navigation