Endometrial Küretaj Olgularında p16 Ekspresyonunun İmmünohistokimyasal Olarak İncelenmesi
Yıl 2024,
Cilt: 46 Sayı: 5, 759 - 769, 12.09.2024
Aslıhan Yurtkal
,
Müjde Canday
,
Hatice Beşeren
Öz
Çalışmamız, hücre döngüsünde yer alan ve endometrium kanseri gelişiminde rol oynayan P16 molekülünün normal epitel, endometrial polip ve prekürsör lezyonlardaki immünohistokimyasal ekspresyonunu araştırmayı amaçlamaktadır. Çalışmaya 2020-2021 yılları arasında Kafkas Üniversitesi Tıp Fakültesi Kadın Hastalıkları ve Doğum Anabilim Dalı’nda çeşitli nedenlerle endometriyal örnekleme yapılan 68 hasta dahil edildi. Seçilen vakalar dört gruba ayrıldı: proliferatif endometriyum, atipisiz endometrial hiperplazi, atipik endometrial hiperplazi/endometrioid intraepitelyal neoplazi ve endometrial polip. Çalışmamızda endometrial tümör tanısı alan olguya rastlanmadı. Tüm hastaların patoloji örnekleri yeniden değerlendirildi ve doku örneklerine P16 immünohistokimyası uygulandı. Atipik endometriyal hiperplazi tanısı alan hastaların %72,7’sinde orta derecede P16 protein ekspresyonu, %18,2’sinde düşük ekspresyon ve %9,1’inde yüksek protein ekspresyonu gösterdi. Atipik endometrial hiperplazi tanısı alan hasta sayısı çalışma popülasyonunda çok düşük bir sıklığa sahipti. Endometriyal polip tanısı alan hastaların %50,0’ı orta derecede P16 protein ekspresyonu gösterdi, %20,0’ı düşük protein ekspresyonu gösterdi ve %30,0’ı yüksek protein ekspresyonu gösterdi. Literatürde yüksek P16 ekspresyonunun endometrium kanseri ile anlamlı derecede ilişkili olduğu bildirilmektedir. P16 ekspresyonu kanser öncesi lezyonlarda ve kanser gelişiminin aşamalarında önemlidir. Bu konuda daha büyük ölçekli, daha fazla olgu içeren çalışmalara ihtiyaç vardır.
Kaynakça
- 1. Silverberg SG. Problems in the differential diagnosis of endometrial hyperplasia and carcinoma. Mod Pathol. 2000;13(3):309-27.
- 2. Allison KH, Reed SD, Voigt LF, Jordan CD, Newton KM, Garcia RL. Diagnosing endometrial hyperplasia: why is it so difficult to agree? Am J Surg Pathol. 2008;32(5):691-8.
- 3. Kim KR, Peng R, Ro JY, Robboy SJ. A diagnostically useful histopathologic feature of endometrial polyp: the long axis of endometrial glands arranged parallel to surface epithelium. Am J Surg Pathol. 2004;28(8):1057-62.
- 4. Beşeren H, Yurtkal A, Canday M. The Relationship of Endometrial hyperplasia and Endometrial Polyps with P16 Stromal Expression: Review. Caucasian Journal of Science. 2022;9(2):168-74.
- 5. O'Neill CJ, McCluggage WG. p16 expression in the female genital tract and its value in diagnosis. Adv Anat Pathol. 2006;13(1):8-15.
- 6. Sharpless NE. INK4a/ARF: a multifunctional tumor suppressor locus. Mutat Res. 2005;576(1-2):22-38.
- 7. Keating JT, Cviko A, Riethdorf S, Riethdorf L, Quade BJ, Sun D, et al. Ki-67, cyclin E, and p16INK4 are complimentary surrogate biomarkers for human papilloma virus-related cervical neoplasia. Am J Surg Pathol. 2001;25(7):884-91.
- 8. Klaes R, Benner A, Friedrich T, Ridder R, Herrington S, Jenkins D, et al. p16INK4a immunohistochemistry improves interobserver agreement in the diagnosis of cervical intraepithelial neoplasia. Am J Surg Pathol. 2002;26(11):1389-99.
- 9. Chiesa-Vottero AG, Malpica A, Deavers MT, Broaddus R, Nuovo GJ, Silva EG. Immunohistochemical overexpression of p16 and p53 in uterine serous carcinoma and ovarian high-grade serous carcinoma. Int J Gynecol Pathol. 2007;26(3):328-33.
- 10. Yemelyanova A, Ji H, Shih Ie M, Wang TL, Wu LS, Ronnett BM. Utility of p16 expression for distinction of uterine serous carcinomas from endometrial endometrioid and endocervical adenocarcinomas: immunohistochemical analysis of 201 cases. Am J Surg Pathol. 2009;33(10):1504-14.
- 11. D'Angelo E, Prat J. Uterine sarcomas: a review. Gynecol Oncol. 2010;116(1):131-9.
- 12. Gannon BR, Manduch M, Childs TJ. Differential immunoreactivity of p16 in leiomyosarcomas and leiomyoma variants. Int J Gynecol Pathol. 2008;27(1):68-73.
- 13. Carlson JW, Mutter GL. Endometrial intraepithelial neoplasia is associated with polyps and frequently has metaplastic change. Histopathology. 2008;53(3):325-32.
- 14. Marotti JD, Glatz K, Parkash V, Hecht JL. International Internet-based assessment of observer variability for diagnostically challenging endometrial biopsies. Arch Pathol Lab Med. 2011;135(4):464-70.
- 15. Romagosa C, Simonetti S, Lopez-Vicente L, Mazo A, Lleonart ME, Castellvi J, et al. p16(Ink4a) overexpression in cancer: a tumor suppressor gene associated with senescence and high-grade tumors. Oncogene. 2011;30(18):2087-97.
- 16. Makker V, MacKay H, Ray-Coquard I, Levine DA, Westin SN, Aoki D, et al. Endometrial cancer. Nat Rev Dis Primers. 2021;7(1):88.
- 17. Nees LK, Heublein S, Steinmacher S, Juhasz-Boss I, Brucker S, Tempfer CB, et al. Endometrial hyperplasia as a risk factor of endometrial cancer. Arch Gynecol Obstet. 2022;306(2):407-21.
- 18. Gallos ID. Risk of relapse of endometrial hyperplasia is high and long-term treatment and follow up are recommended. BJOG. 2016;123(9):1520.
- 19. McCluggage WG. My approach to the interpretation of endometrial biopsies and curettings. J Clin Pathol. 2006;59(8):801-12.
- 20. Liu Y, Alqatari M, Sultan K, Ye F, Gao D, Sigel K, et al. Using p16 immunohistochemistry to classify morphologic cervical intraepithelial neoplasia 2: correlation of ambiguous staining patterns with HPV subtypes and clinical outcome. Hum Pathol. 2017;66:144-51.
- 21. Murali R, Davidson B, Fadare O, Carlson JA, Crum CP, Gilks CB, et al. High-grade Endometrial Carcinomas: Morphologic and Immunohistochemical Features, Diagnostic Challenges and Recommendations. Int J Gynecol Pathol. 2019;38 Suppl 1(Iss 1 Suppl 1):S40-S63.
- 22. Negri G, Vittadello F, Romano F, Kasal A, Rivasi F, Girlando S, et al. p16INK4a expression and progression risk of low-grade intraepithelial neoplasia of the cervix uteri. Virchows Arch. 2004;445(6):616-20.
- 23. Safwan-Zaiter H, Wagner N, Wagner KD. P16INK4A-More Than a Senescence Marker. Life (Basel). 2022;12(9).
- 24. Cherniack AD, Shen H, Walter V, Stewart C, Murray BA, Bowlby R, et al. Integrated Molecular Characterization of Uterine Carcinosarcoma. Cancer Cell. 2017;31(3):411-23.
- 25. Uglietti A, Buggio L, Farella M, Chiaffarino F, Dridi D, Vercellini P, et al. The risk of malignancy in uterine polyps: A systematic review and meta-analysis. Eur J Obstet Gynecol Reprod Biol. 2019;237:48-56.
- 26. Gunduz R, Agacayak E, Okutucu G, Alabalik U, Evsen MS. Evaluation of definitive histopathological results of patients diagnosed with endometrial polyps: a tertiary care center experience. Afr Health Sci. 2022;22(1):125-32.
- 27. Murphy N, Heffron CC, King B, Ganuguapati UG, Ring M, McGuinness E, et al. p16INK4A positivity in benign, premalignant and malignant cervical glandular lesions: a potential diagnostic problem. Virchows Arch. 2004;445(6):610-5.
- 28. Kuhn E, Ayhan A, Bahadirli-Talbott A, Zhao C, Shih Ie M. Molecular characterization of undifferentiated carcinoma associated with endometrioid carcinoma. Am J Surg Pathol. 2014;38(5):660-5.
- 29. Dal Cin P, Wanschura S, Kazmierczak B, Tallini G, Dei Tos A, Bullerdiek J, et al. Amplification and expression of the HMGIC gene in a benign endometrial polyp. Genes Chromosomes Cancer. 1998;22(2):95-9.
- 30. Chen W, Husain A, Nelson GS, Rambau PF, Liu S, Lee CH, et al. Immunohistochemical Profiling of Endometrial Serous Carcinoma. Int J Gynecol Pathol. 2017;36(2):128-39.
- 31. Onat T, Demir ÇM, Şahin S, Aytekin B, Başer E, Aydoğan KD, et al. The Evaluation of Endometrial Biopsy Histopathological Results According to Age Groups. Bozok Tıp Dergisi. 2021;11(1):98-103.
- 32. Matrai CE, Pirog EC, Ellenson LH. Despite Diagnostic Morphology, Many Mixed Endometrial Carcinomas Show Unexpected Immunohistochemical Staining Patterns. Int J Gynecol Pathol. 2018;37(5):405-13.
- 33. Yoon G, Koh CW, Yoon N, Kim JY, Kim HS. Stromal p16 expression is significantly increased in endometrial carcinoma. Oncotarget. 2017;8(3):4826-36.
- 34. Matson DR, Accola MA, Henderson L, Shao X, Frater-Rubsam L, Horner VL, et al. A "Null" Pattern of p16 Immunostaining in Endometrial Serous Carcinoma: An Under-recognized and Important Aberrant Staining Pattern. Int J Gynecol Pathol. 2022;41(4):378-88.
- 35. Stewart CJ, Bharat C, Crook M. p16 immunoreactivity in endometrial stromal cells: stromal p16 expression characterises but is not specific for endometrial polyps. Pathology. 2015;47(2):112-7.
- 36. Baker-Rand H, Kitson SJ. Recent Advances in Endometrial Cancer Prevention, Early Diagnosis and Treatment. Cancers (Basel). 2024;16(5).
Immunohistochemical Investigation of P16 Expression in Curettage Biopsies
Yıl 2024,
Cilt: 46 Sayı: 5, 759 - 769, 12.09.2024
Aslıhan Yurtkal
,
Müjde Canday
,
Hatice Beşeren
Öz
Our study aims to investigate the immunohistochemical expression of the P16 molecule, which is involved in the cell cycle and plays a role in developing endometrial cancer in normal epithelium, endometrial polyp, and precursor lesions. A total of 68 patients underwent endometrial sampling for various reasons at the Department of Obstetrics and Gynecology, Faculty of Medicine, Kafkas University, between 2020 and 2021 were included in the study. The selected cases were categorized into four groups: proliferative endometrium, endometrial hyperplasia without atypia, atypical hyperplasia / endometrioid intraepithelial neoplasia (AH / EIN) and endometrial polyp. There were no cases with a diagnosis of endometrial tumors in our study. All patients’ pathology samples were re-evaluated, and P16 immunohistochemistry was applied to tissue samples. Among patients diagnosed with atypical endometrial hyperplasia, 72.7% exhibited moderate P16 protein expression, 18.2% had low expression, and 9.1% had high protein expression. The number of patients diagnosed with AH / EIN had a very low frequency in the study population. Among patients diagnosed with endometrial polyps, 50.0% showed moderate P16 protein expression, 20.0% exhibited low protein expression, and 30.0% had high protein expression. High P16 expression has been reported to be significantly associated with endometrial cancer in the literature. P16 expression is significant in precancerous lesions and stages of cancer development. Larger-scale studies with more cases are needed in this regard.
Etik Beyan
The study was received ethical approval from the Faculty of Medicine Ethics Committee, Kafkas University, with reference number 80576354-050-99/231, on November 23, 2021.
Teşekkür
We would like to express our gratitude to Dr. Yalçın Polat for his supervision in the evaluation of pathological data and to Barış Yıldız for his contributions to the statistical analysis of the data in our study.
Kaynakça
- 1. Silverberg SG. Problems in the differential diagnosis of endometrial hyperplasia and carcinoma. Mod Pathol. 2000;13(3):309-27.
- 2. Allison KH, Reed SD, Voigt LF, Jordan CD, Newton KM, Garcia RL. Diagnosing endometrial hyperplasia: why is it so difficult to agree? Am J Surg Pathol. 2008;32(5):691-8.
- 3. Kim KR, Peng R, Ro JY, Robboy SJ. A diagnostically useful histopathologic feature of endometrial polyp: the long axis of endometrial glands arranged parallel to surface epithelium. Am J Surg Pathol. 2004;28(8):1057-62.
- 4. Beşeren H, Yurtkal A, Canday M. The Relationship of Endometrial hyperplasia and Endometrial Polyps with P16 Stromal Expression: Review. Caucasian Journal of Science. 2022;9(2):168-74.
- 5. O'Neill CJ, McCluggage WG. p16 expression in the female genital tract and its value in diagnosis. Adv Anat Pathol. 2006;13(1):8-15.
- 6. Sharpless NE. INK4a/ARF: a multifunctional tumor suppressor locus. Mutat Res. 2005;576(1-2):22-38.
- 7. Keating JT, Cviko A, Riethdorf S, Riethdorf L, Quade BJ, Sun D, et al. Ki-67, cyclin E, and p16INK4 are complimentary surrogate biomarkers for human papilloma virus-related cervical neoplasia. Am J Surg Pathol. 2001;25(7):884-91.
- 8. Klaes R, Benner A, Friedrich T, Ridder R, Herrington S, Jenkins D, et al. p16INK4a immunohistochemistry improves interobserver agreement in the diagnosis of cervical intraepithelial neoplasia. Am J Surg Pathol. 2002;26(11):1389-99.
- 9. Chiesa-Vottero AG, Malpica A, Deavers MT, Broaddus R, Nuovo GJ, Silva EG. Immunohistochemical overexpression of p16 and p53 in uterine serous carcinoma and ovarian high-grade serous carcinoma. Int J Gynecol Pathol. 2007;26(3):328-33.
- 10. Yemelyanova A, Ji H, Shih Ie M, Wang TL, Wu LS, Ronnett BM. Utility of p16 expression for distinction of uterine serous carcinomas from endometrial endometrioid and endocervical adenocarcinomas: immunohistochemical analysis of 201 cases. Am J Surg Pathol. 2009;33(10):1504-14.
- 11. D'Angelo E, Prat J. Uterine sarcomas: a review. Gynecol Oncol. 2010;116(1):131-9.
- 12. Gannon BR, Manduch M, Childs TJ. Differential immunoreactivity of p16 in leiomyosarcomas and leiomyoma variants. Int J Gynecol Pathol. 2008;27(1):68-73.
- 13. Carlson JW, Mutter GL. Endometrial intraepithelial neoplasia is associated with polyps and frequently has metaplastic change. Histopathology. 2008;53(3):325-32.
- 14. Marotti JD, Glatz K, Parkash V, Hecht JL. International Internet-based assessment of observer variability for diagnostically challenging endometrial biopsies. Arch Pathol Lab Med. 2011;135(4):464-70.
- 15. Romagosa C, Simonetti S, Lopez-Vicente L, Mazo A, Lleonart ME, Castellvi J, et al. p16(Ink4a) overexpression in cancer: a tumor suppressor gene associated with senescence and high-grade tumors. Oncogene. 2011;30(18):2087-97.
- 16. Makker V, MacKay H, Ray-Coquard I, Levine DA, Westin SN, Aoki D, et al. Endometrial cancer. Nat Rev Dis Primers. 2021;7(1):88.
- 17. Nees LK, Heublein S, Steinmacher S, Juhasz-Boss I, Brucker S, Tempfer CB, et al. Endometrial hyperplasia as a risk factor of endometrial cancer. Arch Gynecol Obstet. 2022;306(2):407-21.
- 18. Gallos ID. Risk of relapse of endometrial hyperplasia is high and long-term treatment and follow up are recommended. BJOG. 2016;123(9):1520.
- 19. McCluggage WG. My approach to the interpretation of endometrial biopsies and curettings. J Clin Pathol. 2006;59(8):801-12.
- 20. Liu Y, Alqatari M, Sultan K, Ye F, Gao D, Sigel K, et al. Using p16 immunohistochemistry to classify morphologic cervical intraepithelial neoplasia 2: correlation of ambiguous staining patterns with HPV subtypes and clinical outcome. Hum Pathol. 2017;66:144-51.
- 21. Murali R, Davidson B, Fadare O, Carlson JA, Crum CP, Gilks CB, et al. High-grade Endometrial Carcinomas: Morphologic and Immunohistochemical Features, Diagnostic Challenges and Recommendations. Int J Gynecol Pathol. 2019;38 Suppl 1(Iss 1 Suppl 1):S40-S63.
- 22. Negri G, Vittadello F, Romano F, Kasal A, Rivasi F, Girlando S, et al. p16INK4a expression and progression risk of low-grade intraepithelial neoplasia of the cervix uteri. Virchows Arch. 2004;445(6):616-20.
- 23. Safwan-Zaiter H, Wagner N, Wagner KD. P16INK4A-More Than a Senescence Marker. Life (Basel). 2022;12(9).
- 24. Cherniack AD, Shen H, Walter V, Stewart C, Murray BA, Bowlby R, et al. Integrated Molecular Characterization of Uterine Carcinosarcoma. Cancer Cell. 2017;31(3):411-23.
- 25. Uglietti A, Buggio L, Farella M, Chiaffarino F, Dridi D, Vercellini P, et al. The risk of malignancy in uterine polyps: A systematic review and meta-analysis. Eur J Obstet Gynecol Reprod Biol. 2019;237:48-56.
- 26. Gunduz R, Agacayak E, Okutucu G, Alabalik U, Evsen MS. Evaluation of definitive histopathological results of patients diagnosed with endometrial polyps: a tertiary care center experience. Afr Health Sci. 2022;22(1):125-32.
- 27. Murphy N, Heffron CC, King B, Ganuguapati UG, Ring M, McGuinness E, et al. p16INK4A positivity in benign, premalignant and malignant cervical glandular lesions: a potential diagnostic problem. Virchows Arch. 2004;445(6):610-5.
- 28. Kuhn E, Ayhan A, Bahadirli-Talbott A, Zhao C, Shih Ie M. Molecular characterization of undifferentiated carcinoma associated with endometrioid carcinoma. Am J Surg Pathol. 2014;38(5):660-5.
- 29. Dal Cin P, Wanschura S, Kazmierczak B, Tallini G, Dei Tos A, Bullerdiek J, et al. Amplification and expression of the HMGIC gene in a benign endometrial polyp. Genes Chromosomes Cancer. 1998;22(2):95-9.
- 30. Chen W, Husain A, Nelson GS, Rambau PF, Liu S, Lee CH, et al. Immunohistochemical Profiling of Endometrial Serous Carcinoma. Int J Gynecol Pathol. 2017;36(2):128-39.
- 31. Onat T, Demir ÇM, Şahin S, Aytekin B, Başer E, Aydoğan KD, et al. The Evaluation of Endometrial Biopsy Histopathological Results According to Age Groups. Bozok Tıp Dergisi. 2021;11(1):98-103.
- 32. Matrai CE, Pirog EC, Ellenson LH. Despite Diagnostic Morphology, Many Mixed Endometrial Carcinomas Show Unexpected Immunohistochemical Staining Patterns. Int J Gynecol Pathol. 2018;37(5):405-13.
- 33. Yoon G, Koh CW, Yoon N, Kim JY, Kim HS. Stromal p16 expression is significantly increased in endometrial carcinoma. Oncotarget. 2017;8(3):4826-36.
- 34. Matson DR, Accola MA, Henderson L, Shao X, Frater-Rubsam L, Horner VL, et al. A "Null" Pattern of p16 Immunostaining in Endometrial Serous Carcinoma: An Under-recognized and Important Aberrant Staining Pattern. Int J Gynecol Pathol. 2022;41(4):378-88.
- 35. Stewart CJ, Bharat C, Crook M. p16 immunoreactivity in endometrial stromal cells: stromal p16 expression characterises but is not specific for endometrial polyps. Pathology. 2015;47(2):112-7.
- 36. Baker-Rand H, Kitson SJ. Recent Advances in Endometrial Cancer Prevention, Early Diagnosis and Treatment. Cancers (Basel). 2024;16(5).