Immunohistochemical Evaluation of Minichromosome Maintenance Protein 7 (MCM7), Topoisomerase IIα, and Ki-67 in Diffuse Malignant Peritoneal Mesothelioma Patients Using Tissue Microarray

Our plain-English summary of Immunohistochemical Evaluation of Minichromosome Maintenance Protein 7 (MCM7), Topoisomerase IIα, and Ki-67 in Diffuse Malignant Peritoneal Mesothelioma Patients Using Tissue Microarray, by M. Deraco, A. Cabras, D. Baratti, et al (Annals of Surgical Oncology, 2015).

The study

• Authors: M. Deraco, A. Cabras, D. Baratti, S. Kusamura
• Journal: Annals of Surgical Oncology
• Published: 2015;22(13):4344-51
• Cited by: 22 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Purpose: Immunohistochemistry and tissue microarray (TMA) were used to perform a prognostic analysis of markers related to cell proliferation in diffuse malignant peritoneal mesothelioma (DMPM).

Methods: Clinicopathologic data were extracted from a prospectively collected database containing cases of peritoneal mesothelioma treated with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in the National Cancer Institute of Milan from 1995 to 2013. Eighty-one DMPM patients were recruited and their tissue samples were used to construct TMAs. We evaluated the immunoexpressions of markers related to cell proliferation-topoisomerase IIα, minichromosome maintenance protein 7 (MCM7), and Ki-67-and then conducted a multivariate Cox model to identify the predictors of overall survival (OS) and progression-free survival (PFS) among the following parameters: age, sex, Eastern Cooperative Oncology Group (ECOG) performance status, baseline serum albumin, Charlson Comorbidity Index, previous systemic chemotherapy, histological subtype (epithelioid vs. biphasic/sarcomatoid), peritoneal cancer index, completeness of cytoreduction (CC), and proliferative biological markers.

Results: The rates of high/intermediate immunoreactivity were 95 % for topoisomerase IIα and 90 % for MCM7, and the median Ki-67 labeling index was 5 %. The independent predictors of OS were baseline serum albumin >3.5 g/dl, CC, and Ki-67 >5 %, whereas those for PFS were an ECOG performance status of 0, baseline serum albumin >3.5 g/dl, Charlson Comorbidity Index >3, previous systemic chemotherapy, morbidity G3-5, and Ki-67 >5 %. The remaining biological markers were not associated with outcome.

Conclusions: Ki-67 was found to be a new powerful determinant of outcome. Patients with a Ki-67 labeling index >5 % carry a very poor prognosis and do not benefit from the combined procedure. Further studies should be conducted to confirm the present data.

In plain English

This study from the National Cancer Institute of Milan, Italy, examined tumor tissue from 81 patients with diffuse malignant peritoneal mesothelioma. All were treated with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy between August 1995 and October 2013. The authors stained the tissue for three markers of cell growth (MCM7, topoisomerase IIα and Ki-67) and tested whether these were linked to survival. The article does not report on asbestos exposure. Median overall survival for the whole group was 40 months. Topoisomerase IIα and MCM7 showed intermediate staining in 94 and 87 % of cases, and neither was shown to be linked to outcome. The median Ki-67 level was 5 %, and 18 patients (22 %) were above 5 %. After adjusting for other factors, Ki-67 above 5 % was associated with a hazard ratio of 4.5 (95 % CI 2.1 to 9.5) for overall survival and 2.7 (1.3 to 5.6) for progression-free survival. These patients had a median overall survival of 11 months. The authors concluded that this tumor has low growth activity but that Ki-67 independently affected outcome. They called for outside validation and noted that no untreated comparison group was available.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Retrospective prognostic analysis of a prospectively collected single-center database, using immunohistochemistry on tissue microarrays
• Who was studied: 81 patients with diffuse malignant peritoneal mesothelioma, selected from 170 cases in the institutional database, all treated with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy at the National Cancer Institute of Milan from August 1995 to October 2013. The group was 39 men and 42 women with a median age of 56 years. By tissue type, 69 were epithelioid, 9 biphasic and 1 sarcomatoid.
• Exposure: Not reported. The article does not discuss asbestos or any other environmental or occupational exposure. The factors studied were three tumor cell-growth markers (MCM7, topoisomerase IIα, Ki-67) along with clinical and surgical factors.
• Main results:
  • For all 81 patients: median overall survival 40 months and median progression-free survival 16 months; 5-year overall survival 47 % and 5-year progression-free survival 21 %.
  • Topoisomerase IIα and MCM7 had intermediate combined staining scores in 94 and 87 % of cases, respectively.
  • Mean Ki-67 was 7 % and median Ki-67 was 5 %; 18 cases (22 %) had Ki-67 above 5 %.
  • There was no significant correlation between the cell-growth markers and tissue type (epithelioid vs. biphasic/sarcomatoid).
  • Ki-67 above 5 %, adjusted hazard ratios: 4.5 (95 % CI 2.1 to 9.5) for overall survival and 2.7 (95 % CI 1.3 to 5.6, p 0.007) for progression-free survival. Unadjusted hazard ratios were 4.2 (2.1 to 8.4) and 3.9 (2.1 to 7.5).
  • Patients with Ki-67 above 5 % had a median overall survival of 11 months.
  • In the adjusted analysis, the strongest predictors of overall survival were baseline serum albumin (3.5 g/dl cutoff), completeness of cytoreduction, and Ki-67 above 5 %. For progression-free survival they were ECOG performance status, baseline serum albumin, Charlson Comorbidity Index above 3, previous systemic chemotherapy, grade 3–5 complications, and Ki-67 above 5 %.
  • Topoisomerase IIα and MCM7 were not shown to be of prognostic value.
• The authors' conclusion: The authors concluded that diffuse malignant peritoneal mesothelioma has low proliferating activity, but that variation in this activity, as measured by Ki-67, independently affected patients' outcome. They stated that the data should be externally validated.
• Limitations the authors state:
  • No historical control group of untreated patients was available to confirm that patients with high Ki-67 fare no better with the combined procedure.
  • Continuous variables, including Ki-67, were split at their medians, which statisticians advise against because it can lose information.
  • The authors checked for selection bias. Compared with excluded patients, the study group had significantly lower serum albumin, higher platelet counts and higher peritoneal cancer index, although overall and progression-free survival did not differ between the two groups.
  • The authors stated that the findings need external validation.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer, Mesothelioma, Peritoneal mesothelioma.

Medical terms in this study, explained in our Lexicon: Ki-67, Peritoneal Mesothelioma, Immunohistochemistry, Cytoreductive Surgery, HIPEC, Overall Survival, Progression-Free Survival, Performance Status.

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• Significance of cell proliferation markers (Minichromosome maintenance protein 7, topoisomerase IIalpha and Ki-67) in cavital fluid cytology: can we differentiate reactive mesothelial cells from malignant cells? — F. Kimura, J. Kawamura, et al. (2010)
• Differential diagnosis of reactive mesothelial cells and malignant mesothelioma cells using the cell proliferation markers minichromosome maintenance protein 7, geminin, topoisomerase II alpha and Ki-67 — F. Kimura, I. Okayasu, et al. (2013)
• The Role of Ki-67 and Pre-cytoreduction Parameters in Selecting Diffuse Malignant Peritoneal Mesothelioma (DMPM) Patients for Cytoreductive Surgery (CRS) and Hyperthermic Intraperitoneal Chemotherapy (HIPEC) — S. Kusamura, P.A. Torres Mesa, et al. (2016)
• ERCC1, MLH1, MSH2, MSH6, and βIII-tubulin: resistance proteins associated with response and outcome to platinum-based chemotherapy in malignant pleural mesothelioma — S. Ting, F.D. Mairinger, et al. (2013)
• Malignant peritoneal mesothelioma treated by cytoreductive surgery and hyperthermic intraperitoneal chemotherapy: is GLUT1 expression a major prognostic factor? A preliminary study — J. Hommell-Fontaine, S. Isaac, et al. (2013)
• Value of mesothelial and epithelial antibodies in distinguishing diffuse peritoneal mesothelioma in females from serous papillary carcinoma of the ovary and peritoneum — R.L. Attanoos, R. Webb, et al. (2002)

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