Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on sleep in brain health

LIVE: Thursday 2nd May 2024, 18:00-19:30 (CEST)

Quality sleep is essential for health. But what happens to our brains when sleep patterns are disturbed? Join our experts to explore the interplay between sleep disruption and neurological diseases, and the questions that you need to be asking your patients to help you prevent the harmful effects of sleep deprivation.
ADVANCED SEARCH
Log in
Top
Diagnostic Pathology
Published in: Diagnostic Pathology 1/2021

Open Access 01-12-2021 | Research

Mismatch repair deficiency is associated with specific morphologic features and frequent loss of ARID1A expression in ovarian clear cell carcinoma

Authors: Huijuan Ge, Yaoxin Xiao, Guangqi Qin, Yanzi Gu, Xu Cai, Wenhua Jiang, Xiaoyu Tu, Wentao Yang, Rui Bi

Published in: Diagnostic Pathology | Issue 1/2021

Login to get access

Abstract

Background

Ovarian clear cell carcinoma (OCCC) is the second subtype of ovarian epithelial carcinoma reported to be closely related to Lynch syndrome (LS). ARID1A mutation is an important pathogenetic mechanism in OCCC that leads to loss of ARID1A expression in approximately half of OCCCs. However, the correlation of MMR status and ARID1A deficiency is unclear. The current study aimed to identify the clinical and histopathological characteristics of OCCC associated with dMMR and to further explore the association between dMMR and ARID1A deficiency.

Methods

A cohort of 176 primary OCCC patients was enrolled and review included histological characteristics (nuclear atypia, necrosis, mitosis, stromal hyalinization, and background precursors) and host inflammatory response (tumor-infiltrating lymphocytes, peritumoral lymphocytes, intratumoral stromal inflammation and plasma cell infiltration). Immunohistochemical staining of MLH1, PMS2, MSH2, MSH6 and ARID1A was performed using tissue microarrays.

Results

dMMR was detected in 10/176 tumors (6 %), followed by MSH2/MSH6 (6/176), MLH1/PMS2 (3/176), and MSH6 (1/176). The average age of patients with dMMR was younger than that of patients with intact MMR (46 y vs. 53 y). Tumors with diffuse intratumoral stromal inflammation remained significantly associated after multivariate analysis. ARID1A expression was absent in 8 patients with dMMR (8/10), which is a significantly higher frequency than that observed in patients with intact MMR (80 % vs. 43.2 %).

Conclusions

Our study indicates that diffuse intratumoral stromal inflammation of OCCCs is associated with dMMR, with loss of MSH2/MSH6 expression being most frequent. dMMR is strongly associated with the loss of ARID1A expression in OCCC.
Literature
1.
Boyd J. Molecular genetics of hereditary ovarian cancer. Oncology (Williston Park). 1998;12(3):399–406. discussion 409 – 10, 413.
2.
Ligtenberg MJ, Kuiper RP, Geurts van Kessel A, et al. EPCAM deletion carriers constitute a unique subgroup of Lynch syndrome patients. Fam Cancer. 2013;12(2):169–74.
3.
Helder-Woolderink JM,  Blok EA, Vasen HF, et al. Ovarian cancer in Lynch syndrome; a systematic review. Eur J Cancer. 2016;55:65–73.
4.
Nakonechny QB, Gilks CB. Ovarian Cancer in Hereditary Cancer Susceptibility Syndromes. Surg Pathol Clin. 2016;9(2):189–99.CrossRef
5.
Lu KH, Dinh M, Kohlmann W, et al. Gynecologic cancer as a “sentinel cancer” for women with hereditary nonpolyposis colorectal cancer syndrome. Obstet Gynecol. 2005;105(3):569–74.
6.
Baglietto L, Lindor NM, Dowty JG, et al. Risks of Lynch syndrome cancers for MSH6 mutation carriers. J Natl Cancer Inst. 2010;102(3):193–201.
7.
Pal T, Permuth-Wey J, Sellers TA. A review of the clinical relevance of mismatch-repair deficiency in ovarian cancer. Cancer. 2008;113(4):733–42.CrossRef
8.
Watson P, Vasen HFA, Mecklin JP, et al. The risk of extra-colonic, extra-endometrial cancer in the Lynch syndrome. Int J Cancer. 2008;123(2):444–9.
9.
Chui MH, Ryan P, Radigan J, et al. The histomorphology of Lynch syndrome-associated ovarian carcinomas: toward a subtype-specific screening strategy. Am J Surg Pathol. 2014;38(9):1173–81.
10.
Rambau PF, Duggan MA, Ghatage P, et al. Significant frequency of MSH2/MSH6 abnormality in ovarian endometrioid carcinoma supports histotype-specific Lynch syndrome screening in ovarian carcinomas. Histopathology. 2016;69(2):288–97.
11.
Matias-Guiu X, Stewart CJR. Endometriosis-associated ovarian neoplasia. Pathology. 2018;50(2):190–204.CrossRef
12.
Garg K, Leitao MM, Jr, Kauff ND, et al. Selection of endometrial carcinomas for DNA mismatch repair protein immunohistochemistry using patient age and tumor morphology enhances detection of mismatch repair abnormalities. Am J Surg Pathol. 2009;33(6):925–33.
13.
Shia J, Black D, Hummer AJ, et al. Routinely assessed morphological features correlate with microsatellite instability status in endometrial cancer. Hum Pathol. 2008;39(1):116–25.
14.
Bi R,Tu XY, Xiao YX, et al. Expression of DNA mismatch repair protein in endometrial carcinomas and its correlation with clinicopathologic features. Zhonghua Bing Li Xue Za Zhi. 2016;45(5):302–7.
15.
Bennett JA, Morales-Oyarvide V, Campbell S, et al. Mismatch repair protein expression in clear cell carcinoma of the ovary: incidence and morphologic associations in 109 cases. Am J Surg Pathol. 2016;40(5):656–63.
16.
Wiegand KC, Shah SP, Al-Agha OM, et al. ARID1A mutations in endometriosis-associated ovarian carcinomas. N Engl J Med. 2010;363(16):1532–43.
17.
Jones S, Wang TL, Shih Ie M, et al. Frequent mutations of chromatin remodeling gene ARID1A in ovarian clear cell carcinoma. Science. 2010;330(6001):228–31.
18.
Chandler RL, Damrauer JS, Raab JR, et al. Coexistent ARID1A-PIK3CA mutations promote ovarian clear-cell tumorigenesis through pro-tumorigenic inflammatory cytokine signalling. Nat Commun. 2015;6:6118.
19.
Ye S,Yang J, You Y, et al. Clinicopathologic significance of HNF-1beta, AIRD1A, and PIK3CA expression in ovarian clear cell carcinoma: a tissue microarray study of 130 cases. Medicine. 2016;95(9):e3003.
20.
Huang HN, Lin MC, Huang WC, et al. Loss of ARID1A expression and its relationship with PI3K-Akt pathway alterations and ZNF217 amplification in ovarian clear cell carcinoma. Mod Pathol. 2014;27(7):983–90.
21.
Mutch DG, Prat J. 2014 FIGO staging for ovarian, fallopian tube and peritoneal cancer. Gynecol Oncol. 2014;133(3):401–4.CrossRef
22.
Hecht JL, Kotsopoulos J, Gates MA, et al. Validation of tissue microarray technology in ovarian cancer: results from the Nurses’ Health Study. Cancer Epidemiol Biomarkers Prev. 2008;17(11):3043–50.
23.
Katagiri A, Nakayama K, Rahman MT, et al. Loss of ARID1A expression is related to shorter progression-free survival and chemoresistance in ovarian clear cell carcinoma. Mod Pathol. 2012;25(2):282–8.
24.
 Sepulveda AR,  Hamilton SR,  Allegra CJ, et al. Molecular Biomarkers for the Evaluation of Colorectal Cancer: Guideline From the American Society for Clinical Pathology, College of American Pathologists, Association for Molecular Pathology, and American Society of Clinical Oncology. Arch Pathol Lab Med. 2017;141(5):625–57.
25.
Longacre TA,  Broaddus R,  Chuang LT, et al. Template for reporting results of biomarker testing of specimens from patients with carcinoma of the endometrium. Arch Pathol Lab Med. 2017;141(11):1508–12.
26.
Graham RP, Kerr SE, Butz ML, et al. Heterogenous MSH6 loss is a result of microsatellite instability within MSH6 and occurs in sporadic and hereditary colorectal and endometrial carcinomas. Am J Surg Pathol. 2015;39(10):1370–6.
27.
Therasse P, Arbuck SG, Eisenhauer EA, et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst. 2000;92(3):205–16.
28.
Bennett JA,Arbuck SG, Eisenhauer EA, et al. Incidence of mismatch repair protein deficiency and associated clinicopathologic features in a cohort of 104 ovarian endometrioid carcinomas. Am J Surg Pathol. 2019;43(2):235–43.
29.
 Zannoni GF,  Santoro A,  Angelico G, et al. Clear cell carcinoma of the endometrium: an immunohistochemical and molecular analysis of 45 cases. Hum Pathol. 2019;92:10–7.
30.
Parra-Herran C, Bassiouny D, Lerner-Ellis J, et al. p53, mismatch repair protein, and POLE abnormalities in ovarian clear cell carcinoma: an outcome-based clinicopathologic analysis. Am J Surg Pathol. 2019;43(12):1591–9.
31.
Ferguson SE, Aronson M, Pollett A, et al. Performance characteristics of screening strategies for Lynch syndrome in unselected women with newly diagnosed endometrial cancer who have undergone universal germline mutation testing. Cancer. 2014;120(24):3932–9.
32.
Jensen KC, Mariappan MR, Putcha GV, et al. Microsatellite instability and mismatch repair protein defects in ovarian epithelial neoplasms in patients 50 years of age and younger. Am J Surg Pathol. 2008;32(7):1029–37.
33.
Helder-Woolderink JM, Blok EA, Vasen HF, et al. Ovarian cancer in Lynch syndrome; a systematic review. Eur J Cancer (Oxford, England: 1990). 2016;55:65–73.
34.
 Ryan NAJ, Evans DG, Green K, et al. Pathological features and clinical behavior of Lynch syndrome-associated ovarian cancer. Gynecol Oncol. 2017;144(3):491–5.
35.
Ketabi Z, Bartuma K, Bernstein I, et al. Ovarian cancer linked to Lynch syndrome typically presents as early-onset, non-serous epithelial tumors. Gynecol Oncol. 2011;121(3):462–5.
36.
Soliman PT, Broaddus RR, Schmeler KM, et al. Women with synchronous primary cancers of the endometrium and ovary: do they have Lynch syndrome? J Clin Oncol. 2005;23(36):9344–50.
37.
Kobel M, Tessier-Cloutier B, Leo J, et al. Frequent mismatch repair protein deficiency in mixed endometrioid and clear cell carcinoma of the endometrium. Int J Gynecol Pathol. 2017;36(6):555–61.
38.
 Aysal A, Karnezis A, Medhi I, et al. Ovarian endometrioid adenocarcinoma: incidence and clinical significance of the morphologic and immunohistochemical markers of mismatch repair protein defects and tumor microsatellite instability. Am J Surg Pathol. 2012;36(2):163–72.
39.
Lowery WJ, Schildkraut JM, Akushevich L, et al.Loss of ARID1A-associated protein expression is a frequent event in clear cell and endometrioid ovarian cancers. Int J Gynecol Cancer. 2012;22(1):9–14.
40.
Xiao W, Awadallah A, Xin W. Loss of ARID1A/BAF250a expression in ovarian endometriosis and clear cell carcinoma. Int J Clin Exp Pathol. 2012;5(7):642–50.PubMedPubMedCentral
41.
Yamamoto S, Tsuda H, Takano M, 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. 2012;25(4):615–24.
42.
Chou A, Toon CW, Clarkson A, et al. Loss of ARID1A expression in colorectal carcinoma is strongly associated with mismatch repair deficiency. Hum Pathol. 2014;45(8):1697–703.
43.
Wang K, Kan J, Yuen ST, et al. Exome sequencing identifies frequent mutation of ARID1A in molecular subtypes of gastric cancer. Nat Genet. 2011;43(12):1219–23.
44.
Bosse T, ter Haar NT, Seeber LM, et al. Loss of ARID1A expression and its relationship with PI3K-Akt pathway alterations, TP53 and microsatellite instability in endometrial cancer. Mod Pathol. 2013;26(11):1525–35.
45.
Allo G, Bernardini MQ, Wu RC, et al. ARID1A loss correlates with mismatch repair deficiency and intact p53 expression in high-grade endometrial carcinomas. Mod Pathol. 2014;27(2):255–61.
46.
Shen J, Peng Y, Wei L, et al. ARID1A deficiency impairs the DNA damage checkpoint and sensitizes cells to PARP inhibitors. Cancer Discov. 2015;5(7):752–67.
47.
Shen J, Ju Z, Zhao W, et al. ARID1A deficiency promotes mutability and potentiates therapeutic antitumor immunity unleashed by immune checkpoint blockade. Nat Med. 2018;24(5):556–62.
48.
Stewart CJ, Bowtell DD, Doherty DA, et al. Long-term survival of patients with mismatch repair protein-deficient, high-stage ovarian clear cell carcinoma. Histopathology. 2017;70(2):309–13.
Metadata
Title
Mismatch repair deficiency is associated with specific morphologic features and frequent loss of ARID1A expression in ovarian clear cell carcinoma
Authors
Huijuan Ge
Yaoxin Xiao
Guangqi Qin
Yanzi Gu
Xu Cai
Wenhua Jiang
Xiaoyu Tu
Wentao Yang
Rui Bi
Publication date
01-12-2021
Publisher
BioMed Central
Published in
Diagnostic Pathology / Issue 1/2021
Electronic ISSN: 1746-1596
DOI
https://doi.org/10.1186/s13000-021-01071-w

Other articles of this Issue 1/2021

Diagnostic Pathology 1/2021 Go to the issue

Commentary

Hypoproteinemia predicts disease severity and mortality in COVID-19: a call for action

Research

Clinicopathological features of tumor mutation burden, Epstein-Barr virus infection, microsatellite instability and PD-L1 status in Chinese patients with gastric cancer

Case Report

COVID-19 in pregnancy: placental pathological patterns and effect on perinatal outcome in five cases

Case Report

Pancreatic medullary carcinoma developed on a pancreatic intraductal papillary mucinous neoplasm with loss of MSH2 and MSH6 expression: a case report

Case Report

Danon disease: a case report and literature review

Review

The many faces of solitary fibrous tumor; diversity of histological features, differential diagnosis and role of molecular studies and surrogate markers in avoiding misdiagnosis and predicting the behavior