Elsevier

Human Pathology

Volume 43, Issue 11, November 2012, Pages 1964-1972
Human Pathology

Original contribution
Involvement of pelvic inflammation–related mismatch repair abnormalities and microsatellite instability in the malignant transformation of ovarian endometriosis

https://doi.org/10.1016/j.humpath.2012.02.005Get rights and content

Summary

Inflammation in the ovary, including ovulation and pelvic inflammatory disease, has been proposed to play a role in the pathogenesis of ovarian cancer. Endometriotic lesions trigger a local inflammatory reaction and have been reported to be associated with an increased risk of epithelial ovarian cancer. However, the precise molecular mechanisms of ovarian cancer arising from endometriosis are still to be elucidated. To clarify the involvement of mismatch repair (MMR) abnormalities in the inflammation-associated malignant transformation of endometriosis, the immunohistochemical expression of mismatch repair proteins (human mutL homolog 1 [hMLH1] and human mutS homolog 2 [hMSH2]) was examined in 27 cases of ovarian endometriosis, 25 cases of ovarian carcinoma accompanied by endometriosis, and 39 cases of solitary ovarian carcinoma. In addition, the relationship between mismatch repair abnormalities including the microsatellite instability, PTEN (phosphatase and tensin homolog) mutation, and clinicopathologic parameters was analyzed. The expression of mismatch repair proteins was stepwisely decreased in endometriosis, ovarian carcinoma accompanied by endometriosis, and ovarian carcinoma. Tumors harboring multiple microsatellite instability (high-frequency microsatellite instability [MSI-H]) were detected in 4 (14.8%) of 27 cases of endometriosis and 7 (30.4%) of 23 cases of ovarian carcinomas. The frequency of PTEN mutations was higher in MSI-H cases than in microsatellite instability–stable (MSI-S) cases. In 2 cases of ovarian carcinoma accompanied by endometriosis, the decreased expression of mismatch repair proteins and MSI-H was observed in both the endometriosis and carcinoma lesions. Clinicopathologically, the MSI-H cases were associated with elevated serum levels of C-reactive protein and higher white blood cell counts. These findings suggest that mismatch repair abnormalities might be involved in the malignant transformation of ovarian endometriosis and that inflammation induces mismatch repair abnormalities during ovarian carcinogenesis arising from endometriosis.

Introduction

Endometriosis is a common gynecological disease affecting approximately 10% of women of reproductive age [1]. Since Sampson [2] first suggested that ovarian cancer can arise from endometriosis in 1925, clinical analyses have shown the coexistence of endometriosis and epithelial ovarian cancer, particularly endometrioid adenocarcinoma (EAC) and clear cell carcinoma (CCC) [3], [4], [5], [6]. Recently, endometriosis has been reported to be associated with an increased risk of epithelial ovarian cancer, especially CCCs and EACs [3], [6], [7]. Endometriotic lesions trigger a local inflammatory reaction involving the activation of macrophages and cytokine release [8], and serum cytokine levels have been reported to be associated with the stage of endometriosis [9]. Inflammation in the ovary, including ovulation and pelvic inflammatory disease, has been proposed to play a role in the pathogenesis of ovarian cancer [10], [11]. These reports suggest that inflammation is involved in the carcinogenesis of ovarian cancer arising from endometriosis.

A variety of molecular events, such as p53 alterations [12], [13], PI3K (phosphoinositide-3 kinase) amplification [14], PTEN[15], [16] and K-ras mutations [17], and HNF-1β (hepatocyte nuclear factor-1 beta) amplification [18] is found in endometriosis. A recent study provided evidence of ARID1A (AT-rich interactive domein-containing protein 1A) mutation in endometriosis-associated ovarian carcinomas [19]. However, the precise molecular mechanisms of ovarian cancer arising from endometriosis are still to be elucidated. Endometriosis is characterized by the presence of endometrial tissue including endometrial epithelial cells outside the uterus. The morphological and endocrinologic characteristics of endometriosis-derived ovarian tumors suggest that the carcinogenic process responsible for the malignant transformation of endometriosis to ovarian cancer shares similarities with the carcinogenesis of endometrial carcinoma. Impaired mismatch repair (MMR) is reportedly crucial for the early stages of endometrial carcinogenesis, in which defective MMR genes, such as hMLH1 and hMSH2, induce a high frequency of replication errors as microsatellite instability (MSI) and, hence, promote tumorigenesis [20], [21]. However, the significance of MMR abnormalities in the malignant transformation of endometriosis has not been fully determined.

Therefore, in this study, the immunohistochemical expression of MMR proteins (hMLH1 and hMSH2), MSI, and mutations in the mononucleotide repeats of 5 genes (TGF-βRII [transforming growth factor beta receptor type II], PTEN, BAX [bcl-2 associated X], hMSH6 [human mutS homolog 6], and HNF-1β) were investigated in endometriosis, ovarian carcinoma accompanied by endometriosis (OCEM), and solitary ovarian carcinoma. The relationship between MSI and clinicopathologic parameters including inflammatory factors was analyzed.

Section snippets

Case selection and DNA preparation

Twenty-seven cases of ovarian endometriosis, 25 cases of OCEM, 14 cases of CCC, 12 cases of EAC, and 13 cases of high-grade serous adenocarcinoma were selected from the pathology file of Shinshu University Hospital. None of the patients had a family history of breast or ovarian cancer. All patients visited the Shinshu University Hospital between 1996 and 2008 and underwent surgery. Their tissue specimens were reviewed to confirm the histopathologic diagnosis using the standard criteria [22].

Expression of hMLH1 and hMSH2 in endometriosis

Representative immunostaining profiles for hMLH1, hMSH2, and Ki-67 are shown in Fig. 1. hMLH1 and hMSH2 staining was observed in both the cytoplasm and nucleus. We evaluated nuclear staining using a PI. All control slides yielded negative staining. The PI for hMLH1, hMSH2, and Ki-67 in normal endometrial tissue (eutopic endometria) and endometriotic tissue (ectopic endometria) is described as the mean ± SD in Fig. 2A and Table 1.

In the eutopic endometrial epithelia, the expression levels of

Discussion

In the present study, the immunohistochemical expression of hMLH1 and hMSH2 was found to decrease in the following order: ovarian endometriosis > OCEM > solitary ovarian carcinoma. Our study also demonstrated that the immunohistochemical expression levels of hMLH1 and hMSH2 in ectopic endometria were significantly decreased compared with those in eutopic endometria. The expression of hMLH1 and hMSH2 was observed in normal endometria, which is consistent with previous reports [21], [23]. The PI

Supplementary data

The following is the Supplementary data to this

Fuseya Supple Fig. Hum Pathol.

Fuseya Supple Table Hum Pathol revise.

References (35)

  • J.A. Sampson

    Endometrial carcinoma of the ovary, arising in endometrial tissue in that organ

    Arch Surg

    (1925)
  • C. Borgfeldt et al.

    Cancer risk after hospital discharge diagnosis of benign ovarian cysts and endometriosis

    Acta Obstet Gynecol Scand

    (2004)
  • H. Kobayashi et al.

    Risk of developing ovarian cancer among women with ovarian endometrioma: a cohort study in Shizuoka, Japan

    Int J Gynecol Cancer

    (2007)
  • A. Melin et al.

    Endometriosis and the risk of cancer with special emphasis on ovarian cancer

    Hum Reprod

    (2006)
  • L.L. Espey

    Current status of the hypothesis that mammalian ovulation is comparable to an inflammatory reaction

    Biol Reprod

    (1994)
  • K. Obata et al.

    Frequent PTEN/MMAC mutations in endometrioid but not serous or mucinous epithelial ovarian tumors

    Cancer Res

    (1998)
  • M. Martini et al.

    Possible involvement of hMLH1, p16(INK4a) and PTEN in the malignant transformation of endometriosis

    Int J Cancer

    (2002)
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    This work was supported by Grants-in-Aid for Scientific Research (nos. 22591850 and 22791524) from the Ministry of Education, Science and Culture, Japan.

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