Tissue Microarray Immunohistochemical Expression Analysis of Mismatch Repair (hMLH1 and hMSH2 Genes) in Endometrial Carcinoma and Atypical Endometrial Hyperplasia: Relationship with Microsatellite Instability

Aim Endometrial cancer is the most common cancer of the female genital tract. No effective biomarkers currently exist to allow for an efficient risk classification of endometrial carcinoma. Human epididymis protein 4 (HE4) overexpression is first observed in ovarian cancer tissue and subsequent research has shown that the HE4 overexpression has also been observed in patients with endometrial carcinoma. To our knowledge, this marker was evaluated in small number of research studies in cases of endometrial carcinoma versus hyperplasia. This has inspired us to test for immunohistochemical expression of HE4 in endometrial endometrioid carcinoma and hyperplastic endometria and to correlate HE4 expression with various prognostic pathological parameters including International Federation of Gynecology and Obstetrics (FIGO) grading and staging. Methods Immunohistochemical staining for HE4 was performed on paraffin-embedded sections of forty cases of endometrial endometrioid carcinoma and thirty cases of endometrial hyperplasia: including 15 cases of non-atypical hyperplasia and 15 cases of atypical hyperplasia. A histochemical score was used to evaluate HE4 expression by the tumor cells. Results In this study, HE4 overexpression level was significantly higher in endometrial endometrioid carcinoma than endometrial hyperplasia and significantly higher than non-atypical endometrial hyperplasia (P<0.05). HE4 strong expression was detected in 20% of atypical endometrial hyperplasia, but no statistical significance was detected between atypical hyperplasia and endometrial carcinoma. HE4 overexpression showed statistically significant positive correlation with FIGO grading, FIGO staging, and depth of myometrial invasion. Conclusion: During interpretation of endometrial biopsies of atypical hyperplasia, HE4 strong expression might raise the possibility of the presence of coexisting adenocarcinoma not biopsied or even warning of a near future malignant transformation. Also, strong expression of HE4 by tissue biopsy of adenocarcinoma should be reported as this might predict higher grade and stage of the tumor, a point that should be considered by surgeons while performing hysterectomy. These results should be further confirmed by extending the study on a large scale, correlation of HE4 expression with the molecular classification of Tumor Cancer Genome Atlas and long term follow up are required to establish the prognostic significance of HE4 expression in endometrial carcinoma and atypical hyperplasia. Keywords: Endometrial carcinoma, Endometrial hyperplasia, HE4, Immunohistochemistry.

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Mismatch Repair Proteins (MLH1, MSH2, MSH6, and PMS2) Immunohistochemical Expression and Microsatellite Instability in Endometrial Carcinoma

Open Access Macedonian Journal of Medical Sciences ◽

10.3889/oamjms.2020.4300 ◽

2020 ◽

Vol 8 (A) ◽

pp. 306-310

Author(s):

Nour El Hoda S. Ismael ◽

Hala M. Naguib ◽

Suzan Mohamed Talaat ◽

Rasha F. Bakry

Keyword(s):

Endometrial Cancer ◽

Microsatellite Instability ◽

Endometrial Carcinoma ◽

Mismatch Repair ◽

Tumor Grade ◽

Clinicopathological Parameters ◽

Small Subset ◽

Immunohistochemical Expression ◽

Mismatch Repair Proteins ◽

Mmr Proteins

BACKGROUND: Endometrial cancer (EC) is the fourth most common female cancer worldwide constituting 7% of cancer in women. It is a disease of older, postmenopausal women. The most of these patients have an identifiable source of excess estrogen, while in a small subset the pathogenesis is related to mismatch repair abnormality and lynch syndrome (LC). Mismatch repair behave as tumor suppressors and the most clinically relevant include MLH1, MSH2, MSH6, and PMS2. mutations in mismatch repair (MMR) results in a strong mutator phenotype known as microsatellite instability, which is a hallmark of LC-associated cancers. AIM: The aim of the study was to study microsatellite instability in endometrial cancer using the immunohistochemical expression of mismatch repair proteins (MLH1, MSH2, MSH6 and PMS2). MATERIAL AND METHODS: Sixty EC cases were studied using MLH-1, MSH-2, MSH-6, and PMS-2 immunohistochemistry and their expression was correlated with different clinicopathologic parameters. RESULTS: A statistically significant relationship exists between MMR immunohistochemistry (IHC) proteins and tumor grade. Intact MMR proteins profile was associated with the lower tumor grade (31.3% were Grade 1 and 46.9% were Grade 2). Combined loss of MLH1/PMS2, combined loss of MSH2/MSH6, and isolated loss of PMS2 were also associated with the lower tumor grade while isolated loss of MSH6 was associated with the high tumor grade. However, no statistically significant correlation was found between MMR IHC proteins expression and the age of patients; tumor histopathological types, or FIGO stage. CONCLUSION: A statistically significant correlation between the tumor grade of EC cases and the MMR IHC proteins was found. Further studies are recommended to assess correlation between MMR proteins defect and different clinicopathological parameters of endometrial carcinoma.

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