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Emerging relationships between papillary proliferation of the endometrium and endometrial carcinoma: evidence from an immunohistochemical and molecular analysis

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Abstract

Papillary proliferation of the endometrium (PPE) is an uncommon lesion that frequently shows mucinous metaplasia. PPE occasionally has concurrent or preceding endometrial hyperplasia and carcinomas, but there is little molecular evidence to support the relationships between PPEs and endometrial neoplasia. In this study, we analyzed the clinicopathological and immunohistochemical features in 30 PPEs (22 simple PPEs and 8 complex papillary hyperplasia (CPH)). Hotspot mutations of KRAS, PI3KCA, AKT1, PTEN (exons 3, 5, and 7), and ARID1A (exons 1 and 14) were detected by pyrosequencing or bidirectional Sanger sequencing. We found that endometrial hyperplasia and carcinoma were more common in CPHs (4/6, 66.7%) than in simple PPEs (4/21, 19.0%) (p < 0.05). Compared with the adjacent normal endometrium, PPEs frequently showed loss of PAX2 (56.7%) and PTEN (10%) expression, diffuse p16 expression (36.7%), decreased PR expression (84.3%), and lower Ki67 labeling index (median 1%, range 1–15%). Simple PPEs and CPHs had similar immunohistochemical features (p > 0.05). KRAS mutations were identified in 14 PPEs and 1 concurrent endometrial carcinoma. The prevalence of KRAS mutations was not statistically different between simple PPEs (10/21, 45.5%) and CPHs (4/8, 50%) (p > 0.05), but was higher in PPEs displaying mucinous metaplasia (12/24, 50%) than in those without (2/6, 33.3%) (p < 0.05). One simple PPE with a KRAS mutation had an AKT1 mutation. No PPEs demonstrated mutations in PI3KCA, PTEN, and ARID1A. In conclusion, both simple PPE and CPH share some common molecular alterations with endometrial neoplasia, in which, KRAS mutations might be a driver.

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References

  1. Zaino R, Matias-Guiu X, Carinelli SG, Mutter GL, Ellenson LH, Peters III, WA EC, Sherman ME, Katabuchi H, Shi IM, Konishi I, Soslow R, Lax S, Stewart CJR (2014) Epithelial tumors and precursors. In: Kurman RJ, Carcangiu ML, Herrington CS, Young RH (eds) WHO classification of tumors of female reproductive organs, 4th edn. International Agency for Research on Cancer (IARC), Lyon, pp 125–135

    Google Scholar 

  2. Rawish KR, Desouki MM, Fadare O (2017) Atypical mucinous glandular proliferations in endometrial samplings: follow-up and other clinicopathological findings in 41 cases. Hum Pathol 63:53–62

    Article  PubMed  Google Scholar 

  3. Yoo SH, Park BH, Choi J, Yoo J, Lee SW, Kim YM, Kim KR (2012) Papillary mucinous metaplasia of the endometrium as a possible precursor of endometrial mucinous adenocarcinoma. Mod Pathol 25:1496–1507

    Article  CAS  PubMed  Google Scholar 

  4. Silverberg SG, Kurman RJ (1991) Tumors of the uterine corpus and gestational trophoblastic disease. Atlas of tumor pathology, 3rd series, fascicle 3. Armed Forces Institute of Pathology, Washington DC, pp 200–204

    Google Scholar 

  5. Lehman MB, Hart WR (2001) Simple and complex hyperplastic papillary proliferations of the endometrium: a clinicopathologic study of nine cases of apparently localized papillary lesions with fibrovascular stromal cores and epithelial metaplasia. Am J Surg Pathol 25:1347–1354

    Article  CAS  PubMed  Google Scholar 

  6. Ip PP, Irving JA, McCluggage WG, Clement PB, Young RH (2013) Papillary proliferation of the endometrium: a clinicopathologic study of 59 cases of simple and complex papillae without cytologic atypia. Am J Surg Pathol 37:167–177

    Article  PubMed  Google Scholar 

  7. Stewart CJR, Bigby S, Giardina T, Grieu-Iacopetta F, Amanuel B (2018) An immunohistochemical and molecular analysis of papillary proliferation of the endometrium. Pathology 50:286–292

    Article  CAS  PubMed  Google Scholar 

  8. Ogino S, Kawasaki T, Brahmandam M, Yan L, Cantor M, Namgyal C, Mino-Kenudson M, Lauwers GY, Loda M, Fuchs CS (2005) Sensitive sequencing method for KRAS mutation detection by pyrosequencing. J Mol Diagn 7:413–421

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Guan B, Mao TL, Panuganti PK, Kuhn E, Kurman TJ, Maeda D, Chen E, Jeng YM, Wang T, Shih IM (2011) Mutation and loss of expression of ARID1A in uterine low-grade endometrioid carcinoma. Am J Surg Pathol 35:625–632

    Article  PubMed  PubMed Central  Google Scholar 

  10. Hayes MP, Wang H, Espinal-Witter R, Douglas W, Solomon GJ, Baker SJ, Ellenson LH (2006) PIK3CA and PTEN mutations in uterine endometrioid carcinoma and complex atypical hyperplasia. Clin Cancer Res 12:5932–5935

    Article  CAS  PubMed  Google Scholar 

  11. Jovanovic AS, Boynton KA, Mutter GL (1996) Uteri of women with endometrial carcinoma contain a histopathological spectrum of monoclonal putative precancers, some with microsatellite instability. Cancer Res 56:1917–1921

    CAS  PubMed  Google Scholar 

  12. Nicolae A, Preda O, Nogales FF (2011) Endometrial metaplasias and reactive changes: a spectrum of altered differentiation. J Clin Pathol 64:97–106

    Article  PubMed  Google Scholar 

  13. Nucci MR, Prasad CJ, Crum CP, Mutter GL (1999) Mucinous endometrial epithelial proliferations: a morphologic spectrum of changes with diverse clinical significance. Mod Pathol 12:1137–1142

    CAS  PubMed  Google Scholar 

  14. He M, Jackson CL, Gubrod RB, Breese V, Steinhoff M, Lawrence WD, Xiong J (2015) KRAS mutations in mucinous lesions of the uterus. Am J Clin Pathol 143(6):778–784

    Article  CAS  PubMed  Google Scholar 

  15. Alomari A, Abi-Raad R, Buza N, Hui P (2014) Frequent KRAS mutation in complex mucinous epithelial lesions of the endometrium. Mod Pathol 27:675–680

    Article  CAS  PubMed  Google Scholar 

  16. Park CK, Yoon G, Cho YA, Kim HS (2016) Clinicopathological and immunohistochemical characterization of papillary proliferation of the endometrium: a single institutional experience. Oncotarget 7:39197–39206

    PubMed  PubMed Central  Google Scholar 

  17. Robboy SJ, Kurita T, Baskin L, Cunha GR (2017) New insights into human female reproductive tract development. Differentiation 97:9–22

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Zhai QJ, Ozcan A, Hamilton C, Shen SS, Coffey D, Krishnan B, Truong LD (2010) PAX-2 expression in non-neoplastic, primary neoplastic, and metastatic neoplastic tissue: a comprehensive immunohistochemical study. Appl Immunohistochem Mol Morphol 18:323–332

    Article  CAS  PubMed  Google Scholar 

  19. Monte NM, Webster KA, Neuberg D, Dressler GR, Mutter GL (2010) Joint loss of PAX2 and PTEN expression in endometrial precancers and cancer. Cancer Res 70:6225–6232

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Shukla A, Thomas D, Roh MH (2013) PAX8 and PAX2 expression in endocervical adenocarcinoma in situ and high-grade squamous dysplasia. Int J Gynecol Pathol 32:116–121

    Article  CAS  PubMed  Google Scholar 

  21. Rabban JT, McAlhany S, Lerwill MF, Grenert JP, Zaloudek CJ (2010) PAX2 distinguishes benign mesonephric and mullerian glandular lesions of the cervix from endocervical adenocarcinoma, including minimal deviation adenocarcinoma. Am J Surg Pathol 34:137–146

    Article  PubMed  Google Scholar 

  22. Maiques O, Santacana M, Valls J, Pallares J, Mirantes C, Gatius S, García Dios DA, Amant F, Pedersen HC, Dolcet X, Matias-Guiu X (2014) Optimal protocol for PTEN immunostaining; role of analytical and preanalytical variables in PTEN staining in normal and neoplastic endometrial, breast, and prostatic tissues. Hum Pathol 45:522–532

    Article  PubMed  Google Scholar 

  23. Salvesen HB, Stefansson I, Kretzschmar EI, Gruber P, MacDonald ND, Ryan A, Jacobs IJ, Akslen LA, Das S (2004) Significance of PTEN alterations in endometrial carcinoma: a population-based study of mutations, promoter methylation and PTEN protein expression. Int J Oncol 25:1615–1623

    CAS  PubMed  Google Scholar 

  24. Zielinski GD, Snijders PJ, Rozendaal L, Daalmeijer NF, Risse EK, Voorhorst FJ, Jiwa NM, van der Linden HC, de Schipper FA, Runsink AP, Meijer CJ (2003) The presence of high-risk HPV combined with specific p53 and p16INK4a expression patterns points to high-risk HPV as the main causative agent for adenocarcinoma in situ and adenocarcinoma of the cervix. J Pathol 201:535–543

    Article  CAS  PubMed  Google Scholar 

  25. Chekmareva M, Ellenson LH, Pirog EC (2008) Immunohistochemical differences between mucinous and microglandular adenocarcinomas of the endometrium and benign endocervical epithelium. Int J Gynecol Pathol 27:547–554

    Article  PubMed  Google Scholar 

  26. Yemelyanova A, Ji H, Shih IM, Wang TL, Wu LS, Ronnett BM (2009) 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 33:1504–1514

    Article  PubMed  Google Scholar 

  27. Bennecke M, Kriegl L, Bajbouj M, Retzlaff K, Robine S, Jung A, Arkan MC, Kirchner T, Greten FR (2010) Ink4a/Arf and oncogene-induced senescence prevent tumor progression during alternative colorectal tumorigenesis. Cancer Cell 18:135–146

    Article  CAS  PubMed  Google Scholar 

  28. Abe K, Suda K, Arakawa A, Yamasaki S, Sonoue H, Mitani K, Nobukawa B (2007) Different patterns of p16INK4A and p53 protein expressions in intraductal papillary-mucinous neoplasms and pancreatic intraepithelial neoplasia. Pancreas 34:85–91

    Article  CAS  PubMed  Google Scholar 

  29. Bos JL (1989) Ras oncogenes in human cancer: a review. Cancer Res 49:4682–4689

    CAS  PubMed  Google Scholar 

  30. Enomoto T, Weghorst CM, Inoue M, Tanizawa O, Rice JM (1991) K-ras activation occurs frequently in mucinous adenocarcinomas and rarely in other common epithelial tumors of the human ovary. Am J Pathol 13:777–785

    Google Scholar 

  31. Cohen Y, Shalmon B, Korach J, Barshack I, Fridman E, Rechavi G (2010) AKT1 pleckstrin homology domain E17K activating mutation in endometrial carcinoma. Gynecol Oncol 116:88–91

    Article  CAS  PubMed  Google Scholar 

  32. van der Putten LJM, van Hoof R, Tops BBJ, Snijders MPLM, van den Berg-van Erp SH, van der Wurff AAM, Bulten J, Pijnenborg JMA, Massuger LFAG (2017) Molecular profiles of benign and (pre)malignant endometrial lesions. Carcinogenesis 38:329–335

    Article  CAS  PubMed  Google Scholar 

  33. Werner HMJ, Berg A, Wik E, Birkeland E, Krakstad C, Kusonmano K, Petersen K, Kalland KH, Oyan AM, Akslen LA, Trovik J, Salvesen HB (2013) ARID1A loss is prevalent in endometrial hyperplasia with atypia and low-grade endometrioid carcinomas. Mod Pathol 26:428–434

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

We also thank Mrs. Caiyun Zhou, Department of Surgical Pathology, Women’s Hospital, School of Medicine, Zhejiang University, and Dr. Yanfeng Bai, Department of Pathology & Pathophysiology, School of Medicine, Zhejiang University, for their excellent technical support.

Funding

This work is supported by grants from Department of Health, Zhejiang Province, China [2013KYB149], Zhejiang Health and Family Planning Commission, China [JSW2013-A013], and Natural Science Foundation of China [81202067].

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LQ, Wu Q, YM, and LB researched and analyzed data, and wrote the manuscript. SH and LB edited and reviewed the manuscript. LB conceived and designed the study. All authors gave final approval for publication. LB takes full responsibility for the work as a whole, including the study design, access to data, and the decision to submit and publish the manuscript.

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Correspondence to Bingjian Lu.

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This study was conducted with the approval of the Institutional Review Board of Women’s Hospital, School of Medicine, Zhejiang University (IRB 20170135).

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The authors declare that they have no conflict of interest.

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Liu, Q., Wu, Q., Yu, M. et al. Emerging relationships between papillary proliferation of the endometrium and endometrial carcinoma: evidence from an immunohistochemical and molecular analysis. Virchows Arch 475, 201–209 (2019). https://doi.org/10.1007/s00428-019-02589-7

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