Cutoff of 25% for Ki67 expression is a good classification tool for prognosis in colorectal cancer in the AJCC‑8 stratification
- Authors:
- Published online on: February 21, 2020 https://doi.org/10.3892/or.2020.7511
- Pages: 1187-1198
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Copyright: © Tong et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
Abstract
Introduction
The incidence and mortality rates of colorectal cancer (CRC) vary around the world (1,2). Early stage CRC commonly shows limited clinical signs, and patients are often diagnosed at the metastatic stage, rendering therapy difficult (3). Therefore, early diagnosis and treatment of CRC remains challenging for patients and surgeons. In 2016, CRC ranked fourth and second among the most frequently diagnosed and the deadliest malignancies, respectively, in the USA (4–7). According to the American Cancer Society, there were approximately 13,450 newly diagnosed cancer patients in the US in 2016, 30% of whom presented with CRC (8). In 2015, 376,000 new CRC cases were diagnosed in China, with 191,000 succumbing to the malignancy (9). National polyp screening programs constitute an early diagnosis tool, which can markedly improve CRC prognosis (10–14). Early diagnosis and treatment of CRC is becoming increasingly important to surgeons. Surgery remains the principal therapeutic option for loco-regional CRC. At present, robotic and laparoscopic surgeries are performed for CRC, with improve patient outcome in comparison with traditional surgical techniques (15–17). However, patient prognosis is not significantly enhanced. In order to improve the prognosis of CRC patients, surgeons and pathologists have made unremitting efforts to examine the prognostic values of various tumor markers. The American Joint Committee on Cancer (AJCC) tumor-node-metastasis (TNM) staging system provides a universal modality and guides clinical treatment (18–21). Based on the original version, AJCC-8 (American Joint Committee on Cancer 8 edition) provides improved guidance for the individualized treatment of CRC patients and more effective treatment of patients with IVC peritoneal metastases.
Tumor invasion and metastasis of CRC result from well-coordinated events involving many intracellular and extracellular factors (22–24). While many factors affect prognosis in CRC (25,26), Ki67 is broadly employed in pathological analyses to evaluate cell proliferation in various malignancies (27–30). Although Ki67 is expressed in benign tumors, its levels are very low; however, it is found at high levels in multiple malignant lesions, and tightly associated with distant metastasis, resulting in poor patient prognosis. The prognostic value of Ki67 has been assessed in various types of cancers, particularly brain, neuroendocrine, and lymphoid tissue malignancies, and its levels are commonly utilized to grade tumors (31). Nevertheless, its prognostic and predictive roles remain debatable mostly as standard quantification techniques for Ki67 are in existence (32). Ki67 expression is usually examined as a percentage, which is closely related to the pathologist's clinical experience.
Hashimoto et al assessed the rate and clinical significance of fascin expression in association with CRC progression and cancer cell proliferation based on Ki67 (33). Most often, Ki67 is assessed visually by pathologists although no consensus is available concerning the specific regions to score (34). Meanwhile, whether automated techniques could yield suitable accuracy and prognostic power for Ki67 is not known. Indeed, head-to-head comparisons between scores from automated and pathologist-based techniques in terms of prognostic value have been rarely reported, and discrepant findings in breast cancer have been obtained (35–37). Previous reports (38,39) discussed the role of Ki67 expression in lung and breast cancers, examining ways to define the cutoff of Ki67 expression. Similar questions remain for CRC. How to grade Ki67 expression remains therefore an open question. A 20% cutoff has been reported (38). Nonetheless, a previous meta-analysis assessing various cut-off levels of Ki67 in regards to prognosis suggested a visual cut-off >25% to provide a higher discriminatory power in mortality risk compared with the remaining cut-off points evaluated (39). Signal intensity scores were 0 (negative), 1 (weak), 2 (moderate) and 3 (strong); positivity extent was scored as 0 (<5%), 1 (5–25%), 2 (>25–50%, 3 (<50–75%) and 4 (>75%). Both sub-scores were multiplied to yield the final score, which was considered to be positive if >5 (40). Can a suitable cutoff increase the prognostic value of Ki67 expression in colorectal cancer? This is the starting point of the present research; as not many studies have been reported. Some scholars hold opposite views on the relationship between Ki67 expression and prognosis in CRC, suggesting that high Ki67 expression instead reflects better prognosis (41). Other studies have reported that mean Ki67 expression is higher in p53-positive cases, and Ki67 and p53 are not correlated to clinical and pathological parameters (42). Whether Ki67 expression is related to clinicopathological indicators and prognosis remains controversial. Meanwhile, the cutoffs vary, and the outcomes are rather controversial among previous studies. Therefore, we analyzed the associations of Ki67 expression with clinicopathological parameters and the prognosis of CRC patients in this study.
Here we divided cases into four grades based on 25% intervals of Ki67 immunohistochemical signals. Associations of Ki67 expression levels with clinicopathological factors and CRC prognosis were analyzed. Prognosis in CRC was also analyzed based on Ki67 expression according to 5-year disease-free survival (DFS) and overall survival (OS) in and out of the AJCC-8 stratification.
Patients and methods
Patients
In total, 2,080 CRC cases were enrolled at Huzhou Central Hospital between January 2006 and December 2012. A total of 400 cases did not undergo surgery, 400 succumbed to non-CRC causes, and 190 were lost to follow-up and thus were excluded from the present study. Therefore, 1,090 cases (stage 0 to stage IV) were involved in the final analysis. Inclusion criteria were CRC diagnosis by colonoscopy, computed tomography and pathology; no pre-surgical adjuvant therapy, radical surgery and normal lymph nodes harvested; other organ metastases found before or during surgery, and combined resection to achieve R0 resection; complete postoperative clinical and pathological data; postoperative routine immunohistochemical and pathological analyses; post-surgical chemotherapy based on the National Comprehensive Cancer Network (NCCN) guidelines; adenocarcinoma by pathological diagnosis; complete follow-up data, including recurrence and metastasis at follow-up. Exclusion criteria included severe heart, brain, liver or lung disease which may influence tolerance to surgery; non-CRC parameters causing death, interstitial or neuronal tumor, lymphoma, melanoma and other non-adenocarcinomas concomitant with CRC (Fig. 1).
Follow-up
Routine follow-up was carried out in the outpatient clinic two weeks post-operation, at 3- and 6-month intervals for the first and second years, respectively, and yearly for the remaining 3 years. Phone calls and mail were also used for follow-up. During the follow-up period, the patient statuses included i) death, censored and ii) death and recurrence and censored.
Ethics statement
The current trial followed the 2008 Declaration of Helsinki, and had approval from the Ethics Committee of Huzhou Central Hospital (Huzhou, Zhejiang, China). All patients provided signed informed consent for the use of their tissue samples for Ki67 immunohistochemistry immunoassay and medical records for research.
Detection of tissue Ki67
Immunohistochemistry was performed by the Envision two-step method [cat. no. ZM-0166 (Beijing Zhongshang Jinqiao Co.); K5007 (Dako)]. The primary antibody was raised against Ki67 (cat. no. ZM-0166, 1:200 dilution) and K5007 (Dako; no dilution) was used as the secondary antibody. The steps included: i) Dewaxing with hot water; ii) antigen repair under high pressure citric with acid at pH 6.0; iii) hydrogen peroxide blocking of endogenous peroxidase; iv) primary antibody incubation at 37°C for 30 min; v) secondary antibody incubation at 37°C for 15 min; vi) DAB staining at 22°C for 5 min; vii) dehydration and mounting. We compared conventional hematoxylin and eosin (H&E) staining with Ki67 DBA immunostaining and defined + as >0 and ≤25%; ++ as >25 and ≤50%; +++ as >50 and ≤75%; and ++++ as >75% (Fig. 2).
Surgical methods
According to lesion location and the principle of malignant tumor resection, the following resection methods were used: Right hemicolectomy (RHC); left hemicolectomy specimen (LHC), with the excised portion including the left colon and the descending colon; Hartmann (HO), with 5 cm tissue distal to the tumor removed and the distal colorectal segment closed, the proximal end removed (10 cm), and the proximal end taken for fistula; anterior rectal resection specimen (AR), with the extent of resection involving the sigmoid colon and part of the rectum; anterior rectal perineal resection specimen (APR), with the scope of resection involving the sigmoid colon, whole rectum and anal canal and perineum.
Statistical analysis
SPSS 21.0 (IBM Corp.) was employed for data analysis. Clinicopathological measurement data among groups with different Ki67 expression patterns were assessed by one-way analysis of variance (ANOVA); count data were analyzed by Crosstabs and the Pearson's χ2 test. Bivariate correlation analysis was performed to assess clinical and pathological indicators with significant significance in Ki67 expression. Five-year DFS and OS were analyzed by the Kaplan-Meier method and the Breslow test. Survival rates were equally assessed by multivariable Cox's regression according to various clinical, pathological, and biochemical parameters, which were analyzed in our previous studies (21,26). Patient statuses were divided into two: i) Only death was considered an event, and other parameters were censored for OS analysis; ii) death and recurrence were considered events, and other parameters were censored for DFS analysis. Weighted analysis and the non-parametric Chi-square test were applied to compare DFS and OS under different Ki67 levels.
Results
General data
A total of 1,090 patients of the 2,080 enrolled CRC cases were evaluated (52.4%), including 550 men (50.5%) and 540 women (49.5%). According to Ki67 expression (+, ++, +++ and ++++), the entire patient population consisted of 61 (11.1%), 141 (25.6%), 202 (36.7%) and 146 (26.5%) male patients, and 70 (13%), 144 (26.7%), 195 (36.1%) and 131 (24.3%) females, respectively. The mean age was 62.26 years (range, 17–89).
Clinicopathological properties of the various groups based on Ki67 expression
According to Ki67 expression (from low to high), sex, age, American Society of Anesthesiologists (ASA) stage, location, surgical method, operation time, invasive depth, tumor differentiation, tumor size, AJCC-8 stage, the number of lymph nodes harvested, the number of positive lymph nodes, complications, and chemotherapy status were assessed. By single factor ANONA and F test, there were no significant differences in age, operation time and the number of lymph nodes harvested. However, there were significant differences noted in regards to tumor size and the number of positive lymph nodes. Regarding measurement variations, from Ki67+ to Ki67++++, mean and standard deviations were as follows: Age, 61.64±15.80, 62.79±14.33, 62.21±14.28 and 62.07±14.31 (P=0.880); operation time (min), 153.6±34.8, 151.2±38.6, 155.0±33.2 and 154.1±33.2 (P=0.568); number of lymph nodes harvested, 14.04±1.9, 14.17±1.8, 14.25±1.8 and 14.19±1.9 (P=0.727); tumor size (cm), 3.58±1.1, 3.38±1.2, 3.74±0.9 and 3.79±0.9 (P<0.001); number of positive lymph nodes, 0.25±0.9, 0.61±1.4, 2.45±2.2 and 2.86±2.5 (P<0.001). From Ki67(+) to Ki67(++++) significant differences were found in count variables such as invasive depth, tumor differentiation, AJCC-8 stage and chemotherapy status (P<0.001; P<0.001; P=0.003 and P=0.005, respectively). However, no statistical differences were found in sex, ASA stage, location, surgical method, and complications (P=0.684, P=0.860, P=0.439, P=0.768 and P=0.587, respectively). Details are shown in Table I.
 | Table I.Association of the clinicopathological features and Ki67 expression in all involved CRC cases. |
Associations of Ki67 with clinicopathological features showing significant differences
We further analyzed the associations of clinicopathological indices which showed significant differences based on Ki67 expression. Spearman rho coefficients of invasive depth, tumor differentiation, tumor size, AJCC-8 stage, the number of positive lymph nodes and chemotherapy status were 0.170 (95% CI 0.113–0.225, P<0.001), 0.456 (95% CI 0.411–0.500, P<0.001), 0.122 (95% CI −0.063–0.181, P<0.001), 0.195 (95% CI 0.138–0.254, P<0.001), 0.514 (95% CI 0.468–0.558) and −0.201 (95% CI −0.253–0.148, P<0.001), respectively, as summarized in Table II.
Five-year DFS and OS by Ki67 expression in AJCC-8 stratification
The Kaplan-Meier method and Breslow test were applied to assess DFS and OS based on Ki67 expression in the AJCC-8 stratification. There were significant differences in DFS among the various Ki67 expression groups from AJCC-8=I to AJCC-8=III (all P<0.001), but no statistical significance at AJCC-8=IV (P=0.334; Fig. 3A-D). There were significant differences in OS among the different Ki67 expression groups from AJCC-8=I to AJCC-8=III (all P<0.001), but no statistical significance at AJCC-8=IV (P=0.334; Fig. 4A-D). DFS and OS survival rates were assessed based on Ki67 expression and AJCC-8 stratification. Table III documents the DFS and OS survival rates at different Ki67 levels in the AJCC-8 stratification. There were no patients with Ki67+++ or Ki67++++ at stage 0, not only in DFS but also in OS. Table IV shows a comparison of DFS and OS at different Ki67 expression levels. There were no significant differences among all columns (χ2=0.202, P=0.653; χ2=0.098, P=0.755; χ2=0.136, P=0.713 and χ2=0.211 P=0.646 respectively). DFS and OS showed statistical differences only between Ki67 expression groups (Breslow=164.66, P<0.001; Brelow=166.79, P<0.001), indicating elevated Ki67 expression was associated with poorer prognosis. Details are shown in Table IV and Fig. 5A and B. Crosstabs analysis showed that there were no significant differences between DFS and OS at different Ki67 expression levels (χ2=0.041, P=0.098; Fig. 5C).
Multivariable analysis of CRC prognostic factors
To identify independent predictive factors of CRC prognosis, Cox proportional hazard model analysis was performed. Sex, invasive depth, lymph node metastasis, tumor differentiation, AJCC-8 stage, chemotherapy status and Ki67 were included in the model. Regarding sex and chemotherapy status, hazard ratios (HRs) (95% CIs) for Female/Male and No/Yes were 0.976 (0.796–1.198) and 0.986 (0.522–1.862), respectively, which were not significant (P=0.819 and P=0.964, respectively). HRs (95% CIs) for invasive depth at T2/Tis and T1, T3/Tis and T1, T4/Tis and T1 were 1.5336 (0.855–2.748), 1.845 (1.034–3.290) and 1.331 (0.746–2.376), respectively, showing statistically significant differences (P=0.03). HRs (95% CIs) for lymph node metastasis at N1/N0 and N2/N0 were 0.909 (0.616–1.342) and 1.690 (1.168–2.446) (P<0.001). Regarding differentiation (moderate/well, poor or no/well), AJCC-8 stage (I/0, II/0, III/0 and IV/0), Ki67 expression (++/+, +++/+ and ++++/+) HRs (95% CIs) were, respectively, 1.677 (1.036–2.715), 6.443 (3.883–10.756) and 134.375 (0–1.173E+29); 2,015.297 (0–1.736E+30), 1,098.443 (0–9.461E+30) and 30582.466 (0–2.637E+31); and 2.59 (1.327–50055), 4.732 (2.275–9.843) and 6.762 (3.226–14.174), showing significant differences (all P<0.001; Table V).
Discussion
In the present study, we initially considered whether to include stage 0. Some Ki67 data were not available in this period, which inevitably resulted in that survival classified by Ki67 was not calculated. According to AJCC-8 (American Joint Committee on Cancer 5th edition) and later versions, colorectal cancer CRC) stage 0 refers to TisN0M0. This refers to carcinoma in situ, which is localized within the epithelium or infiltrates the lamina propria. Although it is not invasive cancer, it is invasive. We believe that stage 0 tumors are within the mucosa, but not invasive malignant tumors because invasive malignancies usually refer to advanced cancer. Therefore, we included stage 0 in this study. With the increasing attention paid to early CRC detection, this study found that stages 0-II only accounted for 34.12% of all cases, and most cases were stage III in the same period, accounting for 60%. Therefore, the diagnosis and treatment of CRC still requires further investigation to improve prognosis. As published in previous reports (10–14), national polyp screening programs could improve CRC prognosis drastically. Research and application of many tumor markers improve the early detection rate of tumors as well as patient prognosis (43–45). Ki67 expression is a tumor marker that has been used for a long time in clinical practice, but its classification criteria and relationship with prognosis remain controversial (39,46,47). What role does Ki67 expression play in the prognosis of colorectal cancer? Melling et al (41) considered that high Ki67 has a good prognostic value for CRC, contrasting with Luo et al (40). Their results showed that high Ki67 expression is associated with low tumor stage and nodal status, but not with tumor grade, histological tumor type or tumor localization, representing an independent predictor of favorable survival; these findings strongly argue for a clinical utility of Ki67 immunostaining as an independent prognostic biomarker in CRC. This study showed that high Ki67 expression was associated not only with tumor stage (AJCC-8), tumor size and nodal status, but also with tumor differentiation, tumor invasive depth, and chemotherapy status, which were not discussed in Meling et al (41). We used 25% as a cutoff for Ki67 expression and different study methods such as in and out AJCC-8 stratification, which may explain the discrepancy. The above findings indicate that it is ideal to use 25% as a cutoff for Ki67 expression.
The nuclear protein Ki67 was first described in Hodgkin lymphoma-derived cells (48). It is expressed throughout cell division, but is highly suppressed in resting cells (G0 phase) (49,50). Ki67 staining is broadly utilized clinically as an index of cell proliferation, although its functions and dynamics are poorly understood. Miller et al (51) tracked Ki67 amounts in single cells without external stimuli, and demonstrated that it accumulates only in the S, G2, and M phases, with continuous degradation in G1 and G0. Ki67 expression is commonly utilized in oncology as a proliferation indicator. Here we explored the association of Ki67 expression with CRC.
Forones et al (42) hypothesized that Ki67 and P53 are not correlated with clinical and pathologic parameters. This study showed differences in tumor invasive depth based on the Ki67 amounts, and elevated Ki67 expression was associated with increased invasive depth. This may be because tumor invasion and metastasis result from highly coordinated events involving many intracellular and extracellular factors (18,19). Another reason may be that higher Ki67 amounts are associated with poorer tumor differentiation and high AJCC grade, as well as elevated positive lymph node rate, corroborating this study.
We assessed the associations of clinicopathological features with Ki67 expression, and the results showed strong correlations, which require confirmation by molecular and genetic studies. We also showed that the surgical method was not related to Ki67 expression, demonstrating that cancer location in CRC is not associated with Ki67 expression. In this study, all tumor cases were adenocarcinomas. The associations of other types of cancer, such as melanoma, carcinoid, malignant stoma tumor and neurofibroma, with Ki67 expression, were not covered in this work. This is a flaw in the present study. We expect relevant studies to be performed.
One of the highlights of this work is that DFS and OS were analyzed based on Ki67 expression in and out of the AJCC-8 stratification. Higher Ki67 expression levels reflected poorer DFS and OS out of the AJCC-8 stratification with statistical significance.
Feng et al (52) reported that elevated Ki67 expression is associated with poorer prognosis in breast cancer. Shin et al (53) pointed out that high Ki67 reflects poor prognosis in CRC. This suggests that the gene encoding Ki67 has a similar function in tumors. However, it is puzzling that analysis based on the AJCC-8 stratification revealed comparable DFS and OS for different Ki67 levels in stage IV cases. In general, Ki-67 is closely related to RNA transcription, and shows high expression levels during cell division and proliferation, reflecting the activity of cell division and increasing the risk of tumor invasion and metastasis, which worsen patient prognosis (54). We believe that patients with stage IV disease have poorer prognosis, and adverse factors other than Ki67 expression may play additional roles, such as surgery, chemotherapy, patient physical status, and genetic factors (55–60). In the present study, cases with stage IV disease were limited in number, which could have caused a bias. We look forward to undergoing future research to assess patients with stage IV CRC and Ki67 expression. Finally, the present study demonstrated that Ki67 expression is an independent risk factor for poor prognosis in CRC by multivariate analysis and Cox regression.
Mucinous vs. non-mucinous lesions have different molecular mechanisms (61,62), but this issue was not investigated in this study. We used the Broder classification of clinicopathological features to analyze Ki67 expression. Some limitations may exist, including no analysis of the marker P53.
In conclusion, a cutoff of 25% is a good classification tool. In such classification, high Ki67 amounts are closely associated with poor prognosis in CRC and independently predict prognosis in the AJCC-8 stratification.
Acknowledgements
We are grateful to Professors Liqing Li, Qiang Yan and Zhihong Ma for critically revising this manuscript, as well as to Professor Jingliang Ping and Wei Xu for carrying out the pathological analyses. Trial registration: Chinese Clinical Trial Registry ChiCTR20190404 Registered 4 April 2019 Retrospectively registered http://:www.chictrorgcnindexaspx.
Funding
No current external funding sources sponsored this study, which was funded by Project 2018C37090 to GT.
Availability of data and materials
The corresponding author will provide all data upon reasonable request.
Authors' contributions
GT, GZ, JL and ZZ conceived and designed the study. GT and YC performed the procedures of data collection and statistical analysis and wrote the initial manuscript. PN and XX were involved in the conception of the study and edited the manuscript. All authors read and approved the final manuscript.
Ethics approval and consent to participate
The current trial followed the 2008 Declaration of Helsinki, and had approval from the Ethics Committee of Huzhou Central Hospital (Huzhou, Zhejiang, China). All patients provided signed informed consent for the use of their tissue samples for Ki67 immunohistochemistry immunoassay and medical records for research.
Patient consent for publication
Not applicable.
Competing interests
All authors declare no competing interests regarding the present study.
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