Endometriosis-assEndometriosis-associated ovarian tumors: morphological and immunohistochemical features

Background. In 2016, the World Health Organization published an updated version of the Histological Classification for ovarian tumors presenting a new category of endometriosis-associated tumors. The predictors of malignant transformation of endometriosis have not been clearly defined so far.

Purpose. The search for histological and immunohistochemical markers of endometriosis-associated malignancy.

Materials and methods. 28 female patients with endometrioid ovarian cancer and 11 patients with clear cell ovarian carcinoma were enrolled. Histological and immunohistochemical studies were carried out using conventional techniques. Immunohistochemistry was applied to determine the hormone receptor status: expression of steroid hormone receptors, BAF250a (ARID1A), PTEN, P-catenin, MSH6, PMS2, р-53, WT-1, proliferative index (Ki-67). Microsatellite instability (MSI) testing was conducted according to the standard protocol.

Results. In all cases of ovarian cancer, histological examination showed one of the endometriosis features. Atypical endometriosis was found in 39 % (11 / 28) of endometrioid tumors and in 9% (1/ 11) of clear cell carcinomas. Endometrioid ovarian cancer was found to be ER (74±7,8%) — and PR (67±5,4%) — positive; Ki-67 index was 68,2±3,7 %; loss of BAF250a (ARID1A) expression was observed in 14% (4/ 28), loss of PTEN expression in 29 % (8 / 28), nuclear expression of P-catenin in 32% (9/28) of cases. Loss of MMR expression was detected in 7% (2/28) of cases. MSI was found in one case only, which was also associated with loss of expression of BAF250a (ARID1A) and MSH6. Clear cell carcinoma of the ovary showed histological criteria for endometriosis; however, there were no changes immunohistochemical markers expression that were typical for endometriosis-associated malignancies. It could be due to a small number of patients in the group so further research is needed.

Conclusion. Atypical endometriosis may be a morphological precursor of endometrioid and clear cell carcinoma of the ovary. Comprehensive assessment of a marker panel consisting of BAF250a (ARID1A), P-catenin, PTEN, p53, Ki-67 index, PMS2 and MSH6 will allow improving the diagnosis of atypical endometriosis and endometriosis-associated ovarian cancer.

1. Kurman R.J., Shih I.M. The dualistic model of ovarian carcinogenesis revisited, revised, and expanded // Am. J. Pathol. American Society for Investigative Pathology, 2016. Vol. 186, № 4. P. 733-747.

2. Storey D.J. et al. Endometrioid epithelial ovarian cancer: 20 years of prospectively collected data from a single center // Cancer. 2008. Vol. 112, № 10. P. 2211-2220.

3. Prat J., D'Angelo E., Espinosa I. Ovarian carcinomas: at least five different diseases with distinct histological features and molecular genetics // Hum. Pathol. 2018. Vol. 80. P. 11-27.

4. Catasus L. et al. Molecular genetic alterations in endometrioid carcinomas of the ovary: Similar frequency of beta-catenin abnormalities but lower rate of microsatellite instability and PTEN alterations than in uterine endometrioid carcinomas // Hum. Pathol. 2004. Vol. 35, № 11. P. 1360-1368.

5. Wu R. et al. Mouse Model of Human Ovarian Endometrioid Adenocarcinoma Based on Somatic Defects in the Wnt/ P-Catenin and PI3K/Pten Signaling Pathways // Cancer Cell. 2007. Vol. 11, № 4. P. 321-333.

6. Willner J. et al. Alternate molecular genetic pathways in ovarian carcinomas of common histological types // Hum. Pathol. 2007. Vol. 38, № 4. P. 607-613.

7. Catasus L. et al. PIK3CA mutations in the kinase domain (exon 20) of uterine endometrial adenocarcinomas are associated with adverse prognostic parameters // Mod. Pathol. 2008. Vol. 21, № 2. P. 131-139.

8. Wiegand K.C. et al. ARID1A Mutations in Endometriosis-Associated Ovarian Carcinomas // N. Engl. J. Med. 2010. Vol. 363, № 16. P. 1532-1543.

9. Guan B. et al. Roles of deletion of Aridla, a tumor suppressor, in mouse ovarian tumorigenesis // J. Natl. Cancer Inst. 2014. Vol. 106, № 7. P. 9-12.

10. Yamamoto S. et al. Loss of ARID1A protein expression occurs as an early event in ovarian clear-cell carcinoma development and frequently coexists with PIK3CA mutations // Mod. Pathol. Nature Publishing Group, 2012. Vol. 25, № 4. P. 615-624

11. Stamp J.P. et al. BAF250a Expression in Atypical Endometriosis and Endometriosis-Associated Ovarian Cancer // Int.J. Gynecol. Cancer. 2016. Vol. 26, № 5. P. 825-832.

12. Mayr D. et al. KRAS and BRAF mutations in ovarian tumors: A comprehensive study of invasive carcinomas, borderline tumors and extraovarian implants // Gynecol. Oncol. 2006. Vol. 103, № 3. P. 883-887.

13. Liu J. et al. Microsatellite instability and expression of hMLHl and hMSH2 proteins in ovarian endometrioid cancer // Mod. Pathol. 2004. Vol. 17, № 1. P. 75-80.

14. Rambau P.F. et al. Significant frequency of MSH2 / MSH6 abnormality in ovarian endometrioid carcinoma supports histotype-specific Lynch syndrome screening in ovarian carcinomas // Histopathology. 2016. Vol. 69, № 2. P. 288-297.

15. Shen J. et al. checkpoint blockade. 2018. Vol. 24, № 5. P. 556-562.

16. Kaspar H.G., Crum C.P. The utility of immunohistochemistry in the differential diagnosis of gynecologic disorders // Arch. Pathol. Lab. Med. 2015. Vol. 139, № 1. P. 39-54.

17. Chui M.H. et al. The Histomorphology of Lynch Syndrome — associated. 2014. Vol. 38, № 9. P. 1173-1181.

18. Howitt B.E. et al. Clear cell ovarian cancers with microsatellite instability: A unique subset of ovarian cancers with increased tumor-infiltrating lymphocytes and PD-1/PD-L1 expression // Oncoimmunology. Taylor & Francis, 2017. Vol. 6, № 2. P. 1-4.

19. Stewart C.J. R. et al. Long-term survival of patients with mismatch repair protein-deficient, high-stage ovarian clear cell carcinoma // Histopathology. 2017. Vol. 70, № 2. P. 309-313.

20. Anglesio M.S. et al. Clear cell carcinoma of the ovary: A report from the first Ovarian Clear Cell Symposium, June 24th, 2010 // Gynecol. Oncol. Elsevier Inc., 2011. Vol. 121, № 2. P. 407-415.

21. Bennett J.A. et al. Clear cell carcinoma of the ovary: Evaluation of prognostic parameters based on a clinicopathological analysis of 100 cases // Histopathology. 2015. Vol. 66, № 6. P. 808-815.

22. Oda K. et al. Genomics to immunotherapy of ovarian clear cell carcinoma: Unique opportunities for management // Gynecol. Oncol. Elsevier Inc., 2018. № xxxx.

23. Kurman R.J., Shih I.M. Seromucinous tumors of the ovary. What»s in a name? // Int. J. Gynecol. Pathol. 2016. Vol. 35, № 1. P. 78-81.

24. Hauptmann S. et al. Ovarian borderline tumors in the 2014 WHO classification: evolving concepts and diagnostic criteria // Virchows Arch. Virchows Archiv, 2017. Vol. 470, № 2. P. 125-142.

25. Rambau P.F. et al. Morphologic reproducibility, genotyping, and immunohistochemical profiling do not support a category of seromucinous carcinoma of the ovary // Am.J. Surg. Pathol. 2017. Vol. 41, № 5. P. 685-695.

26. Taylor J., Glenn McCluggage W. Ovarian seromucinous carcinoma: Report of a series of a newly categorized and uncommon neoplasm // Am. J. Surg. Pathol. 2015. Vol. 39, № 7. P. 983-992.

27. Bairamova N.N. et al. Atypical Endometriosis of the Urinary Bladder: Review of the Literature and a Clinical Case // Doctor. Ru. 2018. Vol. 6, № 150. P. 61-66. (in Russ.).