A Noninvasive Assessment of Tumor Proliferation in Lung cancer Patients using Intravoxel Incoherent Motion Magnetic Resonance Imaging

Abstract

Ki-67 is a nuclear antigen widely used in routine pathologic analyses as a tumor cell proliferation marker for lung cancer. However, Ki-67 expression analyses using immunohistochemistry (IHC) are invasive and frequently influenced by tissue sampling quality. In this study, we assessed the feasibility of noninvasive magnetic resonance imaging (MRI) in predicting the Ki-67 labeling indices (LIs). A total of 51 lung cancer patients, including 42 non-small cell lung cancer (NSCLC) cases and nine small cell lung cancer (SCLC) cases, were enrolled in this study. Quantitative MRI parameters from conventional diffusion-weighted imaging (DWI), intravoxel incoherent motion (IVIM), and diffusion kurtosis imaging (DKI) were obtained, and their correlations with tumor tissue Ki-67 expression were analyzed. We found that the true diffusion coefficient (D value) from IVIM was negatively correlated with Ki-67 expression (Spearman r =-0.76, P < 0.001). The D values in the high Ki-67 group were significantly lower than those in the low Ki-67 group (0.90 ± 0.21 × 10-3 mm 2 /s vs. 1.22 ± 0.30 × 10-3 mm 2 /s). Among three MRI techniques used, D values from IVIM showed the best performance for distinguishing the high Ki-67 group from low Ki-67 group in receiver operating characteristic (ROC) analysis with an area under the ROC curve (AUROC) of 0.85 (95% CI: 0.73-0.97, P < 0.05). Moreover, D values performed well for differentiating SCLC from NSCLC with an AUROC of 0.82 (95% CI: 0.68-0.90), Youden index of 0.72, and F1 score of 0.81. In conclusion, D values were negatively correlated with Ki-67 expression in lung cancer tissues and can be used to distinguish high from low proliferation statuses, as well as SCLC from NSCLC.

Use of diffusion-weighted magnetic resonance imaging (DW-MRI) to predict early response to anti-tumor therapy in advanced non-small cell lung cancer (NSCLC): a comparison of intravoxel incoherent motion-derived parameters and apparent diffusion coefficient

“…As shown in previous studies (7,16,17), tumor cell death by necrosis or apoptosis caused by anticancer drugs reduces cell density and increases the tumor extracellular volume in early response. Recent study showed D values from IVIM were negatively correlated with Ki-67 expression, which is likely that the highly proliferative tumors (high Ki-67 expression) had higher inner structural complexities due to increased cellularity, vascular hyperplasia, and necrosis (7), and this is the biological basis for the observed increase in ADC and D after treatment. Furthermore, because ADC is obtained from a mono-exponential model using diffusion-weighted MR imaging which is subject to errors introduced by the microcirculation of blood, D showed a higher performance at predicting response to therapy than ADC.…”

“…This means the D value decreased when tissue contained a high number of cells and ratio of nucleus to the cytoplasm, or with smaller extracellular space because of the diffusion movement of water molecule was limited (15). As shown in previous studies (7,16,17), tumor cell death by necrosis or apoptosis caused by anticancer drugs reduces cell density and increases the tumor extracellular volume in early response. Recent study showed D values from IVIM were negatively correlated with Ki-67 expression, which is likely that the highly proliferative tumors (high Ki-67 expression) had higher inner structural complexities due to increased cellularity, vascular hyperplasia, and necrosis (7), and this is the biological basis for the observed increase in ADC and D after treatment.…”

“…IVIM parameters can be used as surrogate markers to identify benign and malignant tumors (3,4), distinguish lung cancer from inflammatory lesions (5), and improve the diagnostic performance of mediastinal lymph nodes compared to using apparent diffusion coefficient (ADC) alone (6). IVIM parameters from IVIM can be used to assess tumor proliferation by analyzing the correlations between the diffusion-weighted imaging (DWI)-derived parameters and Ki-67 expression (7). The perfusion-related parameters of IVIM DWI offer an alternative to dynamic contrast-enhanced (DCE)-MRI for evaluating tumor perfusion and serve as markers of the efficacy of tumor antivascular therapies without contrast media injection.…”

Identification of key genes and biological pathways in Chinese lung cancer population using bioinformatics analysis

“…CDKN3 overexpression is prognostic of poor overall survival in lung adenocarcinoma ( Fan et al, 2015 ). Ki-67 is expressed in the active phases of the cell cycle, including G1, G2 and S, and has been used as an independent biomarker to predict prognosis in patients with lung cancer ( Zheng et al, 2021 ). The centromeric protein CEP55, encoded by the CEP55 , is widely expressed in different types of tissues, especially in proliferating tissues ( Eloubeidi et al, 2002 ).…”

Correlations between Diffusion-Weighted and Intravoxel Incoherent Motion Parameters with Ki-67 Index in Gastric Adenocarcinoma

“…The possible reason is that IVIM effectively eliminates the in uence of capillary micro perfusion on diffusion coe cient compared with single index DWI. Based on the obvious negative correlation between ADC and D value with Ki-67, the increase of Ki-67 expression may suggest a stronger tumor cell proliferation activity, tighter cell arrangement, smaller extracellular space, higher nucleocytoplasmic ratio and more organelles, which signi cantly reduces the intracellular space, shows more signi cant restriction on the free diffusion of water molecules and therefore shows lower ADC and D (21)(22)(23)(24). D * and f values mainly re ect micro perfusion of new capillaries in tumor cell space, which is related to cell density, cell necrosis and bleeding.…”