Ki-67 proliferation index but not mitotic thresholds integrates the molecular prognostic stratification of lower grade gliomas

Abstract

Despite several molecular signatures for “lower grade diffuse gliomas” (LGG) have been identified, WHO grade still remains a cornerstone of treatment guidelines. Mitotic count bears a crucial role in its definition, although limited by the poor reproducibility of standard Hematoxylin & Eosin (H&E) evaluation. Phospho-histone-H3 (PHH3) and Ki-67 have been proposed as alternative assays of cellular proliferation. Therefore in the present series of 141 LGG, the molecular characterization (namely IDH status, 1p/19q co-deletion and MGMT promoter methylation) was integrated with the tumor “proliferative trait” (conventional H&E or PHH3-guided mitotic count and Ki-67 index) in term of prognosis definition. Exclusively high PHH3 and Ki-67 values were predictor of poor prognosis (log rank test, P = 0.0281 for PHH3 and P = 0.032 for Ki-67), unlike standard mitotic count. Based on Cox proportional hazard regression analyses, among all clinical (age), pathological (PHH3 and Ki-67) and molecular variables (IDH, 1p/19q codeletion and MGMT methylation) with a prognostic relevance at univariate survival analysis, only IDH expression (P = 0.001) and Ki-67 proliferation index (P = 0.027) proved to be independent prognostic factors. In addition, stratifying by IDH expression status, high Ki-67 retained its prognostic relevance uniquely in the IDH negative patient (P = 0.029) doubling their risk of death (hazard ratio = 2.27). Overall, PHH3 immunostaining is the sole reliable method with a prognostic value to highlight mitotic figures in LGG. Ki-67 proliferation index exceeds PHH3 mitotic count as a predictor of patient's prognosis, and should be integrated with molecular markers in a comprehensive grading system for LGG.

Proliferative Index in Pediatric Pilocytic Astrocytoma by Region of Origin and Prediction of Clinical Behavior

“…Although biomarkers have demonstrated utility in the stratification of tumors by grade and in predicting the course of malignant lesions, their use in predicting the behavior of indolent tumor types has not been well assessed [13, 14, 16]. Prior studies have identified unique gene and protein expression in pathologically similar tumors located at various geographic locations [9, 11].…”

cIMPACT-NOW update 5: recommended grading criteria and terminologies for IDH-mutant astrocytomas

“…Other genetic markers of interest did not show strong evidence for the ability to stratify risk among patients with IDH-mutant astrocytomas or predict WHO grade IV behavior. Larger or additional studies may provide stronger evidence in the future [6,8,12,24,30].…”

“…In a very small biopsy, one mitosis may be sufficient, whereas in very large specimens, greater mitotic activity may be necessary [20]. These thresholds for mitotic activity have not been corroborated by several studies of IDH-mutant cohorts [12,24,33]. However, others have demonstrated that traditional grading schemes can stratify risk among patients with grade II and III IDH-mutant astrocytomas, but with ample opportunity for improvement [8,30,32].…”

“…Similarly, studies of proliferative index (e.g. based on Ki-67) have not identified criteria that unequivocally stratify risk among patients with IDH-mutant astrocytomas [12].…”

The intrinsically disorderly story of Ki-67

“…Ki-67 is now commonly used as a prognostic marker in the clinic due to its specificity for proliferating cells and ready detection in all cell cycle stages. Positive staining for Ki-67 protein [8][9][10][11][12], alongside other markers [13,14] in a patient tumour sample can be used in grading the primary tumour [15] and metastases [16]. Ki-67 staining has been reported to be of prognostic value in predicting cancer survival rates [9,17,18] and the likelihood of relapse [19].…”