Research Article
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Investigation of the association of immunohistochemical mismatch repair (MMR) protein expression with prognostic parameters in endometrial carcinomas

Year 2023, Volume: 62 Issue: 1, 41 - 47, 15.03.2023

Gürdeniz Serin Pınar Savaş Necmettin Özdemir Osman Zekioğlu Levent Akman

https://doi.org/10.19161/etd.1262422

Abstract

Aim: The most crucial development in endometrial carcinomas has been molecular classification in recent years. In this classification, tumors were divided into: 1-POLE mutant group, 2-Microsatellite instable (MSI) group, 3-High copy number group (P53 mutation), 4-Low copy number group. Among these groups, POLE and MSI groups stand out with their better prognosis and potential to benefit from immune-checkpoint inhibitors. We aimed to compare the prognostic parameters of cases with and without nuclear expression loss in
MMR proteins (MLH-1, PMS-2, MSH-2, MSH-6) by immunohistochemically (IHC).
Materials and Methods: In our department, 80 patients diagnosed with endometrial carcinoma in hysterectomy materials between 2017 and 2020 and whose MMR proteins were evaluated by IHC
were included. Cases with and without MMR loss were compared in tumor size, histological grade (HG), myometrial invasion depth, lymphovascular invasion (LVI), and cervical involvement.
Results: There was a loss of any MMR proteins in 46.3% (37/80) of the cases. When the cases were compared in terms of loss of MMR protein expression, the histological grade was III in 45.9% (17/37) of cases with loss and 27.9% (12/43) of cases without a loss (p:0.03). There was no difference between the two groups regarding myometrium 1/2 external invasion, cervical stromal involvement, and LVI.
Conclusion: Loss of the MMR proteins was found in approximately half of the cases in our study. The most common loss was MLH1 and PMS2. HG of patients with loss of nuclear expression in MMR
proteins tends to be significantly higher than cases without loss.

Keywords

Endometrium Cancer Mismatch repair Microsatellite instability

References

  • Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer J Clin. 2015 Jan-Feb;65(1):5-29. doi: 10.3322/caac.21254. Epub 2015 Jan 5. PMID: 25559415.
  • Hoang LN, McConechy MK, Köbel M, et al. Histotype-genotype correlation in 36 high-grade endometrial carcinomas. Am J Surg Pathol. 2013 Sep; 37 (9): 1421-32. doi: 10.1097/PAS.0b013e31828c63ed. PMID: 24076778.
  • Cancer Genome Atlas Research Network, Kandoth C, Schultz N, Cherniack AD, et al. Integrated genomic characterization of endometrial carcinoma. Nature. 2013 May 2;497(7447):67-73. doi: 10.1038/nature12113. Erratum in: Nature. 2013 Aug 8; 500 (7461): 242. PMID: 23636398; PMCID: PMC3704730.
  • Stelloo E, Nout RA, Osse EM, et al. Improved Risk Assessment by Integrating Molecular and Clinicopathological Factors in Early-stage Endometrial Cancer-Combined Analysis of the PORTEC Cohorts. Clin Cancer Res. 2016 Aug 15; 22 (16): 4215-24. doi: 10.1158/1078-0432.CCR-15-2878. Epub 2016 Mar 22. PMID: 27006490.
  • Talhouk A, McConechy MK, Leung S, et al. Confirmation of ProMisE: A simple, genomics-based clinical classifier for endometrial cancer. Cancer. 2017 Mar 1; 123 (5): 802-13. doi: 10.1002/cncr.30496. Epub 2017 Jan 6. PMID: 28061006.
  • Wortman BG, Bosse T, Nout RA, et al.; PORTEC Study Group. Molecular-integrated risk profile to determine adjuvant radiotherapy in endometrial cancer: Evaluation of the pilot phase of the PORTEC-4a trial. Gynecol Oncol. 2018 Oct; 151 (1): 69-75. doi:10.1016/j.ygyno.2018.07.020. Epub 2018 Aug 3. PMID: 30078506.
  • van den Heerik ASVM, Horeweg N, Nout RA, et al. PORTEC-4a: international randomized trial of molecular profile-based adjuvant treatment for women with high-intermediate risk endometrial cancer. Int J Gynecol Cancer. 2020 Dec; 30 (12): 2002-07. doi: 10.1136/ijgc-2020-001929. Epub 2020 Oct 12. PMID: 33046573; PMCID: PMC7788476.
  • Kommoss S, McConechy MK, Kommoss F, et al. Final validation of the ProMisE molecular classifier for endometrial carcinoma in a large population-based case series. Ann Oncol. 2018 May 1; 29 (5): 1180-8. doi: 10.1093/annonc/mdy058. PMID: 29432521.
  • Lynch HT, Snyder CL, Shaw TG, Heinen CD, Hitchins MP. Milestones of Lynch syndrome: 1895-2015. Nat Rev Cancer. 2015 Mar; 15 (3): 181-94. doi: 10.1038/nrc3878. Epub 2015 Feb 12. PMID: 25673086.
  • McConechy MK, Talhouk A, Li-Chang HH, et al. Detection of DNA mismatch repair (MMR) deficiencies by immunohistochemistry can effectively diagnose the microsatellite instability (MSI) phenotype in endometrial carcinomas. Gynecol Oncol. 2015 May; 137 (2): 306-10. doi: 10.1016/j.ygyno.2015.01.541. Epub 2015 Jan 28. PMID: 25636458.
  • de Leeuw WJ, Dierssen J, Vasen HF, Wijnen JT, et al. Prediction of a mismatch repair gene defect by microsatellite instability and immunohistochemical analysis in endometrial tumours from HNPCC patients. J Pathol. 2000 Nov;192(3):328-35. doi: 10.1002/1096-9896(2000)9999:9999<::AID-PATH701>3.0.CO;2-2. PMID: 11054716.
  • College of American Pathologists Protocol for the Examination of Specimens From Patients With Carcinoma and Carcinosarcoma of the Endometrium. 2020 [cited 2021 Dec 14]; Available from: www.cap.org/cancerprotocols.
  • Stelloo E, Jansen AML, Osse EM, et al. Practical guidance for mismatch repair-deficiency testing in endometrial cancer. Ann Oncol. 2017 Jan 1; 28 (1): 96-102. doi: 10.1093/annonc/mdw542. PMID: 27742654.
  • Buchanan DD, Rosty C, Clendenning M, Spurdle AB, Win AK. Clinical problems of colorectal cancer and endometrial cancer cases with unknown cause of tumor mismatch repair deficiency (suspected Lynch syndrome). Appl Clin Genet. 2014 Oct 6; 7: 183-93. doi: 10.2147/TACG.S48625. PMID: 25328415.
  • Buchanan DD, Tan YY, Walsh MD, et al. Reply to J. Moline et al. J Clin Oncol. 2014 Jul 20; 32 (21): 2278-9. doi: 10.1200/JCO.2014.55.8213. Epub 2014 Jun 9. PMID: 24912891.
  • Nelson GS, Pink A, Lee S, et al. MMR deficiency is common in high-grade endometrioid carcinomas and is associated with an unfavorable outcome. Gynecol Oncol. 2013 Nov; 131 (2): 309-14. doi: 10.1016/j.ygyno.2013.08.003. Epub 2013 Aug 11. PMID: 23938375.
  • Black D, Soslow RA, Levine DA, et al. Clinicopathologic significance of defective DNA mismatch repair in endometrial carcinoma. J Clin Oncol. 2006 Apr 10; 24 (11): 1745-53. doi: 10.1200/JCO.2005.04.1574. Epub 2006 Mar 20. PMID: 16549821.
  • Ruiz I, Martín-Arruti M, Lopez-Lopez E, Garcia-Orad A. Lack of association between deficient mismatch repair expression and outcome in endometrial carcinomas of the endometrioid type. Gynecol Oncol. 2014 Jul;134 (1): 20-3. doi: 10.1016/j.ygyno.2014.04.053. Epub 2014 May 9. PMID: 24814467.
  • Nagle CM, O'Mara TA, Tan Y, et al.; Australian Endometrial Cancer Study Group. Endometrial cancer risk and survival by tumor MMR status. J Gynecol Oncol. 2018 May; 29 (3): e39. doi: 10.3802/jgo.2018.29.e39. Epub 2018 Feb 23. PMID: 29533022.
  • Moroney MR, Davies KD, Wilberger AC, et al. Molecular markers in recurrent stage I, grade 1 endometrioid endometrial cancers. Gynecol Oncol. 2019 Jun; 153 (3): 517-20. doi: 10.1016/j.ygyno.2019.03.100. Epub 2019 Mar 22. PMID: 30910249.
  • Bosse T, Nout RA, McAlpine JN, et al. Molecular Classification of Grade 3 Endometrioid Endometrial Cancers Identifies Distinct Prognostic Subgroups. Am J Surg Pathol. 2018 May;42(5):561-8. doi: 10.1097/PAS.0000000000001020. PMID: 29505428.
  • Raffone A, Travaglino A, Mascolo M, et al. Histopathological characterization of ProMisE molecular groups of endometrial cancer. Gynecol Oncol. 2020 Apr;157(1):252-9. doi: 10.1016/j.ygyno.2020.01.008. Epub 2020 Jan 10. PMID: 31932106.
  • Colombo N, Preti E, Landoni F, Carinelli S, Colombo A, Marini C, Sessa C; ESMO Guidelines Working Group. Endometrial cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2013 Oct; 24 Suppl 6: vi33-8. doi: 10.1093/annonc/mdt353. PMID: 24078661.
  • Lucas E, Chen H, Molberg K, et al. Mismatch Repair Protein Expression in Endometrioid Intraepithelial Neoplasia/Atypical Hyperplasia: Should We Screen for Lynch Syndrome in Precancerous Lesions? Int J Gynecol Pathol. 2019 Nov; 38 (6): 533-42. doi: 10.1097/PGP.0000000000000557. PMID: 30383610.
  • Le DT, Uram JN, Wang H, et al. PD-1 Blockade in Tumors with Mismatch-Repair Deficiency. N Engl J Med. 2015 Jun 25; 372 (26): 2509-20. doi:10.1056/NEJMoa1500596. Epub 2015 May 30. PMID: 26028255.
  • Howitt BE, Shukla SA, Sholl LM, et al. Association of Polymerase e-Mutated and Microsatellite-Instable Endometrial Cancers With Neoantigen Load, Number of Tumor-Infiltrating Lymphocytes, and Expression of PD-1 and PD-L1. JAMA Oncol. 2015 Dec; 1 (9): 1319-23. doi:10.1001/jamaoncol.2015. 2151.

Endometrium karsinomlarında immünohistokimyasal olarak yanlış-eşleşme onarım (MMR) protein ekspresyonunun prognostik parametreler ile ilişkisinin araştırılması

Year 2023, Volume: 62 Issue: 1, 41 - 47, 15.03.2023

Gürdeniz Serin Pınar Savaş Necmettin Özdemir Osman Zekioğlu Levent Akman

https://doi.org/10.19161/etd.1262422

Abstract

Amaç: Endometrium karsinomlarında son yıllardaki en önemli gelişme moleküler sınıflama olmuştur. Bu sınıflamada tümörler dört gruba ayrılmıştır: 1-POLE mutant grup, 2-Mikrosatellit instabil (MSİ) grup, 3-Yüksek kopya sayısı grubu (P53 mutasyonu), 4-Düşük kopya sayısı grubu. Bu gruplardan POLE ve MSİ grup daha iyi prognoza sahip olması ve immün-kontrol inhibitör tedavisinden fayda görebilme potansiyelleri ile öne çıkmaktadır. Çalışmamızda immünohistokimyasal (İHK) yöntemle MMR proteinlerinde (MLH-1, PMS-2, MSH-2,
MSH-6) nükleer ekspresyon kaybı olan ve olmayan olguların prognostik paramaterelerinin karşılaştırılması amaçlanmıştır.
Gereç ve Yöntem: Bölümümüzde 2017-2020 yılları arasında histerektomi materyalinde endometrium karsinomu tanısı almış ve İHK olarak MMR proteinlerinin değerlendirildiği 80 hasta çalışmaya
alınmıştır. MMR kaybı olan ve olmayan olgular tümör boyutu, histolojik derece (HD), myometrial invazyon derinliği, lenfovasküler invazyon (LVİ) ve servikal tutulum açısından karşılaştırılmıştır.
Bulgular: Olguların 37’sinde (%46,3) MMR proteinlerinin herhangi birinde kayıp mevcutken, 43’ünde (%53,7) kayıp izlenmemiştir. MMR protein nükleer ekspresyon kaybı açısından olgular
karşılaştırıldığında, kayıp saptanan olguların %45,9'da (17/37), kayıp saptanmayan olguların ise %27,9'da (12/43) histolojik derece III'tü (p:0,03). Myometrium 1/2 dış invazyon, servikal stromal tutulum ve LVİ açısından iki grup arasında istatistiksel olarak anlamlı bir fark saptanmamıştır.
Sonuç: Çalışmamızdaki olguların yaklaşık yarısında MMR proteinlerinin en az birinde kayıp saptanmıştır. En sık kayıp MLH-1 ve PMS-2 kaybı olarak ortaya çıkmıştır. MMR proteinlerinde nükleer
ekspresyon kaybı izlenen olguların HD’si kayıp saptanmayan olgulara göre istatistiksel olarak anlamlı şekilde daha yüksek olma eğilimindedir.

Keywords

Endometrium kanseri yanlış-eşleşme tamir mikrosatellit instabilite.

References

  • Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer J Clin. 2015 Jan-Feb;65(1):5-29. doi: 10.3322/caac.21254. Epub 2015 Jan 5. PMID: 25559415.
  • Hoang LN, McConechy MK, Köbel M, et al. Histotype-genotype correlation in 36 high-grade endometrial carcinomas. Am J Surg Pathol. 2013 Sep; 37 (9): 1421-32. doi: 10.1097/PAS.0b013e31828c63ed. PMID: 24076778.
  • Cancer Genome Atlas Research Network, Kandoth C, Schultz N, Cherniack AD, et al. Integrated genomic characterization of endometrial carcinoma. Nature. 2013 May 2;497(7447):67-73. doi: 10.1038/nature12113. Erratum in: Nature. 2013 Aug 8; 500 (7461): 242. PMID: 23636398; PMCID: PMC3704730.
  • Stelloo E, Nout RA, Osse EM, et al. Improved Risk Assessment by Integrating Molecular and Clinicopathological Factors in Early-stage Endometrial Cancer-Combined Analysis of the PORTEC Cohorts. Clin Cancer Res. 2016 Aug 15; 22 (16): 4215-24. doi: 10.1158/1078-0432.CCR-15-2878. Epub 2016 Mar 22. PMID: 27006490.
  • Talhouk A, McConechy MK, Leung S, et al. Confirmation of ProMisE: A simple, genomics-based clinical classifier for endometrial cancer. Cancer. 2017 Mar 1; 123 (5): 802-13. doi: 10.1002/cncr.30496. Epub 2017 Jan 6. PMID: 28061006.
  • Wortman BG, Bosse T, Nout RA, et al.; PORTEC Study Group. Molecular-integrated risk profile to determine adjuvant radiotherapy in endometrial cancer: Evaluation of the pilot phase of the PORTEC-4a trial. Gynecol Oncol. 2018 Oct; 151 (1): 69-75. doi:10.1016/j.ygyno.2018.07.020. Epub 2018 Aug 3. PMID: 30078506.
  • van den Heerik ASVM, Horeweg N, Nout RA, et al. PORTEC-4a: international randomized trial of molecular profile-based adjuvant treatment for women with high-intermediate risk endometrial cancer. Int J Gynecol Cancer. 2020 Dec; 30 (12): 2002-07. doi: 10.1136/ijgc-2020-001929. Epub 2020 Oct 12. PMID: 33046573; PMCID: PMC7788476.
  • Kommoss S, McConechy MK, Kommoss F, et al. Final validation of the ProMisE molecular classifier for endometrial carcinoma in a large population-based case series. Ann Oncol. 2018 May 1; 29 (5): 1180-8. doi: 10.1093/annonc/mdy058. PMID: 29432521.
  • Lynch HT, Snyder CL, Shaw TG, Heinen CD, Hitchins MP. Milestones of Lynch syndrome: 1895-2015. Nat Rev Cancer. 2015 Mar; 15 (3): 181-94. doi: 10.1038/nrc3878. Epub 2015 Feb 12. PMID: 25673086.
  • McConechy MK, Talhouk A, Li-Chang HH, et al. Detection of DNA mismatch repair (MMR) deficiencies by immunohistochemistry can effectively diagnose the microsatellite instability (MSI) phenotype in endometrial carcinomas. Gynecol Oncol. 2015 May; 137 (2): 306-10. doi: 10.1016/j.ygyno.2015.01.541. Epub 2015 Jan 28. PMID: 25636458.
  • de Leeuw WJ, Dierssen J, Vasen HF, Wijnen JT, et al. Prediction of a mismatch repair gene defect by microsatellite instability and immunohistochemical analysis in endometrial tumours from HNPCC patients. J Pathol. 2000 Nov;192(3):328-35. doi: 10.1002/1096-9896(2000)9999:9999<::AID-PATH701>3.0.CO;2-2. PMID: 11054716.
  • College of American Pathologists Protocol for the Examination of Specimens From Patients With Carcinoma and Carcinosarcoma of the Endometrium. 2020 [cited 2021 Dec 14]; Available from: www.cap.org/cancerprotocols.
  • Stelloo E, Jansen AML, Osse EM, et al. Practical guidance for mismatch repair-deficiency testing in endometrial cancer. Ann Oncol. 2017 Jan 1; 28 (1): 96-102. doi: 10.1093/annonc/mdw542. PMID: 27742654.
  • Buchanan DD, Rosty C, Clendenning M, Spurdle AB, Win AK. Clinical problems of colorectal cancer and endometrial cancer cases with unknown cause of tumor mismatch repair deficiency (suspected Lynch syndrome). Appl Clin Genet. 2014 Oct 6; 7: 183-93. doi: 10.2147/TACG.S48625. PMID: 25328415.
  • Buchanan DD, Tan YY, Walsh MD, et al. Reply to J. Moline et al. J Clin Oncol. 2014 Jul 20; 32 (21): 2278-9. doi: 10.1200/JCO.2014.55.8213. Epub 2014 Jun 9. PMID: 24912891.
  • Nelson GS, Pink A, Lee S, et al. MMR deficiency is common in high-grade endometrioid carcinomas and is associated with an unfavorable outcome. Gynecol Oncol. 2013 Nov; 131 (2): 309-14. doi: 10.1016/j.ygyno.2013.08.003. Epub 2013 Aug 11. PMID: 23938375.
  • Black D, Soslow RA, Levine DA, et al. Clinicopathologic significance of defective DNA mismatch repair in endometrial carcinoma. J Clin Oncol. 2006 Apr 10; 24 (11): 1745-53. doi: 10.1200/JCO.2005.04.1574. Epub 2006 Mar 20. PMID: 16549821.
  • Ruiz I, Martín-Arruti M, Lopez-Lopez E, Garcia-Orad A. Lack of association between deficient mismatch repair expression and outcome in endometrial carcinomas of the endometrioid type. Gynecol Oncol. 2014 Jul;134 (1): 20-3. doi: 10.1016/j.ygyno.2014.04.053. Epub 2014 May 9. PMID: 24814467.
  • Nagle CM, O'Mara TA, Tan Y, et al.; Australian Endometrial Cancer Study Group. Endometrial cancer risk and survival by tumor MMR status. J Gynecol Oncol. 2018 May; 29 (3): e39. doi: 10.3802/jgo.2018.29.e39. Epub 2018 Feb 23. PMID: 29533022.
  • Moroney MR, Davies KD, Wilberger AC, et al. Molecular markers in recurrent stage I, grade 1 endometrioid endometrial cancers. Gynecol Oncol. 2019 Jun; 153 (3): 517-20. doi: 10.1016/j.ygyno.2019.03.100. Epub 2019 Mar 22. PMID: 30910249.
  • Bosse T, Nout RA, McAlpine JN, et al. Molecular Classification of Grade 3 Endometrioid Endometrial Cancers Identifies Distinct Prognostic Subgroups. Am J Surg Pathol. 2018 May;42(5):561-8. doi: 10.1097/PAS.0000000000001020. PMID: 29505428.
  • Raffone A, Travaglino A, Mascolo M, et al. Histopathological characterization of ProMisE molecular groups of endometrial cancer. Gynecol Oncol. 2020 Apr;157(1):252-9. doi: 10.1016/j.ygyno.2020.01.008. Epub 2020 Jan 10. PMID: 31932106.
  • Colombo N, Preti E, Landoni F, Carinelli S, Colombo A, Marini C, Sessa C; ESMO Guidelines Working Group. Endometrial cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2013 Oct; 24 Suppl 6: vi33-8. doi: 10.1093/annonc/mdt353. PMID: 24078661.
  • Lucas E, Chen H, Molberg K, et al. Mismatch Repair Protein Expression in Endometrioid Intraepithelial Neoplasia/Atypical Hyperplasia: Should We Screen for Lynch Syndrome in Precancerous Lesions? Int J Gynecol Pathol. 2019 Nov; 38 (6): 533-42. doi: 10.1097/PGP.0000000000000557. PMID: 30383610.
  • Le DT, Uram JN, Wang H, et al. PD-1 Blockade in Tumors with Mismatch-Repair Deficiency. N Engl J Med. 2015 Jun 25; 372 (26): 2509-20. doi:10.1056/NEJMoa1500596. Epub 2015 May 30. PMID: 26028255.
  • Howitt BE, Shukla SA, Sholl LM, et al. Association of Polymerase e-Mutated and Microsatellite-Instable Endometrial Cancers With Neoantigen Load, Number of Tumor-Infiltrating Lymphocytes, and Expression of PD-1 and PD-L1. JAMA Oncol. 2015 Dec; 1 (9): 1319-23. doi:10.1001/jamaoncol.2015. 2151.
There are 26 citations in total.

Details

Primary Language Turkish
Subjects Health Care Administration
Journal Section Research Articles
Authors

Gürdeniz Serin

Pınar Savaş

Necmettin Özdemir

Osman Zekioğlu

Levent Akman

Publication Date March 15, 2023
Submission Date April 19, 2022
Published in Issue Year 2023Volume: 62 Issue: 1

Cite

Vancouver Serin G, Savaş P, Özdemir N, Zekioğlu O, Akman L. Endometrium karsinomlarında immünohistokimyasal olarak yanlış-eşleşme onarım (MMR) protein ekspresyonunun prognostik parametreler ile ilişkisinin araştırılması. EJM. 2023;62(1):41-7.
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