Clinical Significance of Survivin, BAP1, and Ki-67 in Distinguishing Epithelioid

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  • Published On: 08-12-2023

Kushitani, K., Amatya, V.J., Mawas, A.S., Suzuki, R., Miyata, Y., Okada, M., Inai, K., Kishimoto, T. and Takeshima, Y., 2018. Utility of Survivin, BAP1, and Ki-67 immunohistochemistry in distinguishing epithelioid mesothelioma from reactive mesothelial hyperplasia. Oncology letters, 15(3), pp.3540-3547.

Lay summary of the above-mentioned research paper:

Epithelium mesothelioma (EM) is a mutated epithelial cell that has malignant characteristics. When the healthy epithelial cells undergo mutation and then develop cancerous cells these cells are called epithelium mesothelioma (EM). The selected research paper aims to highlight the clinical; the importance of Survivin, BRCA1-associated protein 1 (BAP1) and Ki-67 in distinguishing between the epithelium mesothelioma (EM) from reactive mesothelial hyperplasia (RMH) (Kushitani et al. 2018).

Malignant mesothelioma (MM) is a rare but highly aggressive fatal tumour. There is less clinical intervention regarding the histology of MM (Sirri et al. 2020.). This is why the diagnosis of MM is delayed which causes severe health risk to the patients suffering from MM, thereby making them vulnerable to mortality. MM generally develops from the mesothelial cells of the peritoneum, pleura, tunica vaginalis and pericardium. The development of MM is strongly associated with severe environmental and occupational asbestos exposure (Turini et al. 2019). Patients with MM or EM have a high risk of mortality. Reactive mesothelial hyperplasia (RMH) is the neoplastic condition that developed from the condition like peritonitis, pleuritis and invasion of cancerous cells. The RMH poses severe challenges in the correct diagnosis of MM in patients (Liu et al. 2018). This is because RMH mimics the characteristics of MM as it shows a similar history as MM (Cozzi et al. 2018). In this context, this study provides new insight on whether Survivin, BRCA1-associated protein 1 (BAP1) and Ki-67 can be used to distinguish EM from the EHM thereby assisting clinical staffs in diagnosing the MM in patients (Kushitani et al. 2018).


Evidence suggests that many types of immunohistochemical markers are used to distinguish the MM or EM from the other malignant cells as well as RHM (Kushitani et al. 2018). These markers are Survivin, Ki-67, BRCA1-associated protein 1 (BAP1), epithelial membrane antigen (EMA), desmin and p53. As mentioned by Butnor et al. (2017), proper histopathological differentiation between MM and RHM is crucial because it assists the oncologists to apply the specific treatment and implement an effective care plan based on the particular malignant condition. This paper has mentioned how the above-mentioned immunohistochemical markers interact with EM and RHM differently while undergoing an immunohistochemical procedure thereby distinguishing between the EM from the other malignant cells (Chen et al. 2021).

In this study researchers first collect the two types of formalin-fixed, paraffin-embedded (FFPE) specimens from patients. One specimen is collected from 79 patients who are under the histological diagnosis of EM and another specimen is collected from 80 patients who are diagnosed with RHM (Kushitani et al. 2018). These specimens are then used for the immunohistochemical procedures in which Survivin, BRCA1-associated protein 1 (BAP1) and Ki-67 markers are used to determine whether they express differently in these two malignant cell types (Kushitani et al. 2018). The nuclear straining of all these markers is checked properly to determine how they interact with the malignant cells (RM and RHM). As stated by Cozzi et al. (2018), the entire procedure needs to be carried out by clinical experts who have strong knowledge in identifying the different SD values, libelling index and the mean values of the different markers that are used to distinguish between the EM and RHM.

The result of the interaction between the markers and the specimen cells containing EM and RHM shows that the expression of Survivin and K-67 in different in EM from that in RHM (Kushitani et al. 2018). The expression of Survivin is higher in the EM as compared to RHM. The mean of the labelling indices of Survivin in EM is 9.3 with an SD (standard deviation) of 6.5. On the other hand, in RHM, Survivin shows a mean of 1.2 and SD of 12 which are lower than in the EM (Kushitani et al. 2018). On the other hand, the Survivin RHC Assay shows that 42 of 62 EM cases (67%) are positive for Survivin but none of the RHM cases is positive for Survivin. On the other hand, the immunohistochemical staining image of Ki-67 in both EM and RHM cells is significantly different. Ki-67 shows a mean of 32.4 with SD 22.1 in EM cells as compared to the mean of 3.5with SD 4.2 in the RHM cells (Kushitani et al. 2018). Additionally, 85% of the EM cases and 12% of the RHM cases show positive for Ki-67. BAP1 expression is also different in both the EM and RHM cells with higher mean and SD in EM as compared to RHM cells.

From analysing the results of the immunohistochemical study of EM and RHM cells, it is seen that Survivin, BAP1 and Ki-67 are the highly effective immunohistochemical markers showing different expression for EM and RHM cells (Kushitani et al. 2018). By interacting with EM and RHM cells, these markers show significantly different mean values, labelling index and SD for EM and RHM cells. These significant changes in the staining characteristics of these markers in EM cells and other malignant cells assist clinical assistants to distinguish EM from other malignant cells such as RHM.

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The limitation of this research paper is that it although highlights the importance of immunohistochemical markers in distinguishing EM from RHM, it fails to describe whether any risk is associated with using these markers or precaution that the clinical staffs need to considers while carrying out the immunohistochemical procedure. Despite all these limitations, this selected research paper is useful in discussing the importance of differentiation between the EM and the RHM cells in carrying out the effective clinical intervention. Additionally, the study also discusses how Survivin, BAP1 and K-67 markers work on the EM and other malignant cells thereby showing different expression in each cells type.

Reference list:

Barbarino, M., Cesari, D., Bottaro, M., Luzzi, L., Namagerdi, A., Bertolino, F.M., Bellan, C., Proietti, F., Somma, P., Micheli, M. and de Santi, M.M., 2020. PRMT5 silencing selectively affects MTAP‐deleted mesothelioma: In vitro evidence of a novel promising approach. Journal of cellular and molecular medicine, 24(10), pp.5565-5577.

Butnor, K.J., Pavlisko, E.N., Sporn, T.A. and Roggli, V.L., 2017. Malignant peritoneal mesothelioma and Crohn disease. Journal of clinical pathology, 70(3), pp.228-232.

Chen, T., Jia, Y., Li, X., Kong, F., Yin, Y. and Guo, S., 2021. ASF1B May Regulate the Tumor Microenvironment and Epithelial-mesenchymal Transition in Malignant Mesothelioma to Induce the Differentiation of Sarcomatoid Phenotype as a Prognosis Target.

Cozzi, I., Oprescu, F.A., Rullo, E. and Ascoli, V., 2018. Loss of BRCA1‐associated protein 1 (BAP 1) expression is useful in diagnostic cytopathology of malignant mesothelioma in effusions. Diagnostic cytopathology, 46(1), pp.9-14.

Kushitani, K., Amatya, V.J., Mawas, A.S., Suzuki, R., Miyata, Y., Okada, M., Inai, K., Kishimoto, T. and Takeshima, Y., 2018. Utility of Survivin, BAP1, and Ki-67 immunohistochemistry in distinguishing epithelioid mesothelioma from reactive mesothelial hyperplasia. Oncology letters, 15(3), pp.3540-3547.

Liu, J., Liao, X., Gu, Y., Fu, L., Zhao, J., Li, L., Chen, Z. and Jiang, J., 2018. Role of p16 deletion and BAP1 loss in the diagnosis of malignant mesothelioma. Journal of thoracic disease, 10(9), p.5522.

Nader, J.S., Guillon, J., Petit, C., Boissard, A., Franconi, F., Blandin, S., Lambot, S., Gregoire, M., Verriele, V., Nawrocki-Raby, B. and Birembaut, P., 2020. S100A4 is a biomarker of tumorigenesis, EMT, invasion, and colonization of host organs in experimental malignant mesothelioma. Cancers, 12(4), p.939.

Sirri, E., Kieschke, J., Vohmann, C., Katalinic, A., Nennecke, A., Ressing, M., Eberle, A., Holleczek, B., Jansen, L., Brenner, H. and GEKID Cancer Survival Working Group, 2020. Survival of malignant mesothelioma and other rare thoracic cancers in Germany and the United States: A population‐based study. International journal of cancer, 147(6), pp.1548-1558.

Turini, S., Bergandi, L., Gazzano, E., Prato, M. and Aldieri, E., 2019. Epithelial to mesenchymal transition in human mesothelial cells exposed to asbestos fibers: Role of tgf-β as mediator of malignant mesothelioma development or metastasis via emt event. International journal of molecular sciences, 20(1), p.150.

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