Malignant Pleural Mesothelioma—Does Ki67 Make the Grade?

Abstract

https://doi.org/10.1016/j.jtocrr.2021.100170 In this issue, Belderbos et al. investigate various histopathologic features of malignant pleural mesothelioma (MPM) that could help to predict the risk of recurrence and guide the appropriateness of various therapeutic strategies. They studied growth pattern (epithelioid, sarcomatoid, transitional, and mixed), degree of nuclear atypia (three-tier scale), degree of necrosis (< or >50%), mitotic count ( 4 or >4 per 10 high-power fields), proportion of cells expressing Ki67 (Ki67 labeling index, 10% or >10%), and the presence or absence of BAP-1 and MTAP expression. They concluded that Ki67 was the strongest prognostic factor for overall survival and progression-free survival. On the basis of their results, they suggest that patients with a Ki67 greater than 10% would be unlikely to benefit from surgery. Although this is a small retrospective study (27 patients), and all patients were somewhat unusually treated with extended pleurectomy/decortication, raising possibility of selection bias, the findings support those from multiple previous studies which also found that Ki67 had prognostic significance in MPM. This raises the question as whether Ki67 labeling index now be reported as part of the histopathology data set and used as the sole factor to assign a tumor grade? Ki67 has many attractions as a prognostic marker. It is an antigen that is robustly expressed in all phases of actively cycling cells, and it makes biological sense for there to be an association of a high proportion of cycling tumor cells and outcome. Dysregulated cell cycle control is a hallmark of oncogenesis, and many pathogenic variants occur in genes involved either directly or indirectly in cell cycle progression, for example, receptor tyrosine kinases, MAPK pathway, p16/CDKN2A, cyclin D1, and RB1. There are many tumors for which measures of cell proliferation have been found to be prognostic and are incorporated into grading. Nevertheless, this is not universal, as architectural growth pattern or nuclear features, or both, and not cell proliferative markers are used to grade some common tumors, including those carcinomas from lung, colorectum, kidney, uterus, ovary, and prostate. Mitotic activity and not Ki67 labeling is the most frequently used proliferative marker. Mitotic figures are typically counted manually in H&E sections, either within a given number of high-power fields, or, in recognition that this varies between microscope objectives, within a defined area. There are strong supportive data from multiple large studies for the prognostic value of mitotic counts in breast carcinoma and melanoma. Scoring criteria have been progressively refined to provide relatively clear instructions to pathologists regarding common issues that include tumor heterogeneity and sample size adequacy. Other tumors for which mitotic figures are routinely counted include sarcomas and gastrointestinal stromal tumors. Although counting mitotic figures is reasonably reproducible and quick, it can be susceptible to significant errors. Mitotic figures can sometimes be surprisingly difficult to recognize or may be mistakenly scored in nontumor cells. Apoptotic bodies and infiltrating lymphocytes can be mistaken for mitotic figures, and variations in section thickness will modify the count. Immunohistochemistry for antigens expressed in mitosis (e.g., phosphoserine 10 on histone H3) can help with some of these issues but not with other problems including the loss of mitotic figures owing to delayed fixation, particularly for large specimens, as unfixed cells can progress through mitosis into G1 phase. The Ki67 labeling index is less affected by delayed fixation and has more recently been incorporated into prognostic data for some tumors, including neuroendocrine