The assessment of Ki-67 for prognosis of gastroenteropancreatic neuroendocrine neoplasm patients: a systematic review and meta-analysis
Highlight box
Key findings
• The Ki-67 index is important for predicting the prognosis of GEP-NENs patients, and the prognosis of patients tends to decrease as the index increases.
What is known and what is new?
• Ki-67 index is associated with prognosis in GEP-NENs patients.
• Increasing the cut-off value of Ki-67 index for G1 grade from ≤2% to 3% did not significantly decrease the 5-year survival rate.
What is the implication, and what should change now?
• A large homogeneous population-based cohort study is needed to validate the findings of this study. Meanwhile, some studies have shown that GEP-NENs with Ki-67 >55% are more likely to develop peritoneal and lymph node metastases, and patients above and below the 55% cut-off value have different responses to chemotherapy, so it is worthy to investigate whether there is any difference in prognosis between patients with Ki-67 20–55% and Ki-67 >55%.
Introduction
Neuroendocrine neoplasms (NENs) are rare tumors that originate from peptidergic neurons or neuroendocrine cells that are clustered in various endocrine glands (pituitary, parathyroid, pancreatic islets, adrenal medulla, and other glands) or scattered in the skin, gastrointestinal tract, bronchial and pulmonary airway mucosa. Therefore, theoretically, neuroendocrine neoplasms can occur in all organs and tissues of the body (except fingernails, toenails and hair) (1). Among which, gastroenteropancreatic neuroendocrine neoplasm (GEP-NEN) is the most common group, accounting for about 2/3 of all NENs (2). Several studies have shown that the prognosis of patients with GEP-NENs is related to factors such as the pathological grade, tumor diameter, pathological classification, site of onset and so on (2,3). In 2010, the World Health Organization (WHO) classified gastroenteropancreatic neuroendocrine neoplasms into well differentiated neuroendocrine tumors (NETs), poorly differentiated neuroendocrine carcinoma (NEC), and mixed adenoneuroendocrine carcinoma (MANEC), based on tumor cell composition (4). In addition, NET can be classified into NET G1 (Ki-67 ≤2%) and NET G2 (2%< Ki-67 <20%) based on the Ki-67 index (5). Ki-67 index, a nuclear protein encoded by MKI67, belongs to a cell proliferation antigen and is commonly used clinically to assess the activity of cell proliferation (6). Several previous studies proved that Ki-67 index was related to tumor prognosis, but some other studies still reported that the Ki-67 index has no predictive value for tumor prognosis. Böger et al. found that Ki-67 could respond to tumor tissue heterogeneity in gastric cancer, but was not associated with patient prognosis by studying Ki-67 expression in whole tissue sections (WTS) and tissue microarrays (TMAs) of gastric cancer patients (7). There is still a lack of studies on Ki-67 index as a prognostic predictor for GEP-NENs. In 2019, WHO updated the grading criteria for GEP-NENs and remodified the Ki-67 index cut-off for NET G1 from the original ≤2% to <3%. But whether the revision of this cut-off value affects the predictive value of Ki-67 for the prognosis of GEP-NENs patients remains unclear (8). In this study, we evaluated the predictive value of the Ki-67 index based on the WHO 2010 grading criteria for the prognosis of patients with GEP-NENs by meta-analysis, and compared the impact of the change in the NET G1 cut-off value in WHO 2019 with the WHO 2010 grading criteria to provide references for clinical diagnosis and treatment. We present this article in accordance with the MOOSE reporting checklist (available at https://tcr.amegroups.com/article/view/10.21037/tcr-23-248/rc).
Methods
Literature search
Literatures were searched using Ki-67, Ki67, gastro-entero-pancreatic neuroendocrine neoplasms, GEP-NEN, prognosis, assessment, survival, NET, NEC, G-NET, G-NEC, P-NET, P-NEC, Si-NET, colon NET, colon NEC, colorectal neuroendocrine tumors as the subject, keyword, and free word in PubMed, Embase, Web of Science, and ClinicalTrials.gov. The literature search was conducted in May 2022.
Study selection
The retrieved literature was initially screened by two independent investigators by viewing the literature abstracts. If the literature met the inclusion criteria, the full-text content and its citations were evaluated in detail, and the useful data were extracted. If two investigators hold different opinions, the disagreement is resolved through negotiation with a third investigator reassesses. The extracted content included the study name, author, year of publication, study type, population size, general information about the study population, tumor site, tumor grade, Ki-67 index, 5-year survival rate, and other indicators.
Inclusion/exclusion criteria
Inclusion criteria
(I) Patients pathologically diagnosed with GEP-NENs; (II) data included Ki-67 index; (III) outcome index included 5-year survival rate in the cohort study.
Exclusion criteria
(I) Patients pathologically diagnosed with combined subtypes of GEP-NENs (other pathological types of tumors combined with GEP-NENs); (II) patients with severe diabetic complications, hypoxic diseases, cardiovascular diseases or other serious systemic diseases; (III) studies lacking complete raw data such as Ki-67 index and 5-year survival rate; (IV) studies lacking corresponding accurate data on the axes through Kaplan-Meier survival curve response grading and 5-year survival rate; (V) studies published before 2000; (VI) studies not published in English.
Quality assessment
The quality of the included studies was assessed using the Newcastle-Ottawa quality assessment scale. A total score equal to or higher than six indicated high quality. Assessment and review were completed by two independent authors.
Statistical analysis
Indicators such as study name, authors, year of publication, study type, population size, general information of the population, tumor site, Ki-67 index, and 5-year survival rate were extracted and statistically analyzed using Review Manager 5.4. For studies in which the 5-year survival rate P for some of the outcome indicators and the total number of corresponding observers N, there existed N*P or N*(1-P) ≤5, the logarithmic method was used to calculate the combined 5-year survival rate for each group, and 0.5 was entered in the unit cell at N-n for the case which the number of events in the group was equal to the total number; 0.5 was entered in the cell for the case which the number of events was 0 to ensure non-zero variance occurrence, and the meta-analysis using a random effects model was performed to calculate the combined 5-year survival rate and draw conclusions (9).
Results
A total of 303 articles were initially screened for this study, and 15 studies were included after screening by exclusion criteria finally (10-24) (Figure 1). The internal validity of the included literature was assessed in Table 1. A total of 4,651 patients were included, among them, clear date of Ki-67 index and corresponding prognostic index of 5-year survival rate were collected in 3,640 patients. All Ki-67 indexes were documented by pathological specimen re-staining microscopy or database to ensure the accuracy of the source.
Table 1
| Features | Quality control of articles in research |
|---|---|
| Samples of patients | Some patients in each study had missing Ki-67 indexes but the number missing and the number with indexes were clearly marked, information on all patients with Ki-67 indexes was obtained by immunohistochemistry or documented in databases, and detailed demographic characteristics were described in each study |
| Follow-up of cases | The number of patients lost during the five-year follow-up was not specified in the trial |
| Conclusion | The five-year survival rate of the conclusion was not biased |
| Prognostic variables | The Ki-67 index is clearly defined in the WHO guidelines, and each article indicates how the Ki-67 index was obtained |
| Analysis | All articles were unadjusted for prognostic factors |
| Treatment after inclusion in the cohort | The extent to which treatment of neuroendocrine neoplasms affects prognosis is unclear, and only some articles describe treatment after diagnosis |
WHO, World Health Organization.
According to WHO 2010 classification standard, Ki-67 index <2%, ≤2%, 0–2%, <3% were all classified as ≤2% in GEP-NEN G1, and Ki-67 index was unified as 2–20% in GEP-NEN G2, and the index were combined if there was a subdivision in the experiment; Ki-67 index was unified as >20% in GEP-NEN G3.
Data analysis was performed using Review Manager 5.4, and the random-effect model was selected to generate forest plots for each level (Figures 2-6). The calculation of ratio type information was taken, with the outcome indicator being OR, and 95% CI confidence intervals. The line after each trial in the forest plot represents the 5-year survival rate and its 95% CI for patients in the Ki-67 grade the figure belongs to. Total (95% CI) represents the combined effect value of the 5-year survival rate for that grade obtained by meta-analysis. The area of each red square in Figures 2-6 represents the weight of this trial. The black diamond represents the combined OR and 95% CI. The area of each black diamond represents the total sample size after the combination. Overall 5-year survival rates were obtained by conversion of the outcome indicator (9).
Ki-67 correlation analysis with 5-year survival rate (according to WHO 2010)
A total of 14 studies were included (10-23), of which 7 from clinicopathological immunohistochemical staining counts to obtain Ki-67 indexes and 7 based on database registration data were included. The detailed raw data of the studies is shown in Table 2. A total of 4,568 patients with GEP-NEN were included, of which 3,557 had information on grading according to WHO 2010 classification, 1,628 were included in GEP-NEN G1 (Ki-67 ≤2%), and the cumulative 5-year survival rate for GEP-NEN G1 was 86%. For GEP-NEN G2 (Ki-67 2–20%), 1,429 patients were included, with a cumulative 5-year survival rate of 65%. Five hundred patients were included in GEP-NEN G3 (Ki-67 >20%), with a cumulative 5-year survival rate of 25% (excluding 2 studies lacking 5-year survival). Forest plots and detailed results were shown in Figures 2-4, Table 3, and an analysis of heterogeneity within the group of included articles was shown in Table 4.
Table 2
| Author | Pathology type | Data source | Ki-67 original grading (%) | 5-year survival rate (%) | No. of patients |
|---|---|---|---|---|---|
| Watzka et al. (10) | nf-pNENs | Surgical and biopsy specimens | <2 | 96.9 | 34 |
| 2–5 | 90.0 | 45 | |||
| >5–20 | 93.3 | 30 | |||
| Nuñez-Valdovinos et al. (11) | GEP-NENs | Spanish Cancer Registry | <2 | 86.4 | 689 |
| 3–5 | 80.7 | 347 | |||
| 6–10 | 72.0 | 190 | |||
| 11–20 | 52.2 | 143 | |||
| 21–50 | 35.3 | 132 | |||
| >50 | 21.9 | 178 | |||
| Sohn et al. (12) | Rectal NETs | Medical Center Registration Database | ≤2 | 100.0 | 47 |
| >3, ≤20 | 50.0 | 8 | |||
| >20 | 38.1 | 7 | |||
| Pape et al. (13) | Foregut NETs | Surgical and biopsy specimens | ≤2 | 95.7 | 44 |
| 3–20 | 73.4 | 85 | |||
| >20 | 27.7 | 29 | |||
| Gonulal et al. (14) | GI-NETs | Surgical and biopsy specimens | ≤2 | 35.7 | 7 |
| 3–20 | 65.6 | 10 | |||
| >20 | 53.3 | 5 | |||
| Scarpa et al. (15) | pNETs | Surgical and biopsy specimens | 0–2 | 90.0 | 130 |
| >2–20 | 63.0 | 85 | |||
| >20 | 12.0 | 22 | |||
| Komaç et al. (16) | GEP-NENs | Surgical and biopsy specimens | ≤2 | 86.0 | 43 |
| 3–20 | 50.0 | 30 | |||
| >20 | 25.0 | 20 | |||
| Norlén et al. (17) | Small intestinal NETs | Medical Center Registration Database | ≤2 | 82.0 | 203 |
| 3–20 | 54.0 | 89 | |||
| ≥20 | 51.0 | 7 | |||
| Benetatos et al. (18) | pNETs | Medical Center Registration Database | ≤2 | 82.0 | 46 |
| 3–20 | 81.0 | 41 | |||
| >20 | 25.0 | 4 | |||
| Garcia-Carbonero et al. (19) | GEP-NENs | National Cancer Registry | <2 | 83.3 | 126 |
| 3–20 | 77.1 | 109 | |||
| >20 | 43.5 | 53 | |||
| Arnold et al. (20) | GEP-NETs | Surgical and biopsy specimens | <2 | 77.8 | 9 |
| 2–10 | 0 | 5 | |||
| 10–20 | 0 | 2 | |||
| >20 | 0 | 3 | |||
| Martin-Perez et al. (21) | pNENs | Spanish National Cancer Registry | <2 | 80.4 | 71 |
| 3–20 | 68.7 | 93 | |||
| >20 | 17.4 | 20 | |||
| Boyar Cetinkaya et al. (22) | pNETs | Medical Center Registration Database | <2 | 75.2 | 34 |
| 3–20 | 55.8 | 45 | |||
| Fujimori et al. (23) | pNENs | Surgical and biopsy specimens | <3 | 97.1 | 145 |
| 3–5 | 76.9 | 35 | |||
| 5.1–10 | 69.8 | 22 | |||
| 10.1–20 | 40.8 | 15 | |||
| >20 | 11.5 | 20 |
nf-pNENs, non-functioning pancreatic neuroendocrine neoplasms; GEP-NENs, gastroenteropancreatic neuroendocrine neoplasms; GEP-NETs, gastroenteropancreatic neuroendocrine tumors; NETs, neuroendocrine tumors; GI-NETs, gastrointestinal neuroendocrine tumors; pNETs, pancreatic neuroendocrine tumors; pNENs, pancreatic neuroendocrine neoplasms.
Table 3
| WHO 2010 classification criteria | 5-year survival rate | 95% CI | No. of patients |
|---|---|---|---|
| G1 | 0.86 | 0.81–0.89 | 1,628 |
| G2 | 0.65 | 0.57–0.72 | 1,429 |
| G3 | 0.25 | 0.19–0.33 | 500 |
WHO, World Health Organization; 95% CI, 95% confidence interval.
Table 4
| Grading (%) | I2 (%) |
|---|---|
| ≤2% (combined) | 73 |
| 2–20% | 86 |
| >20% | 73 |
| ≤2% | 66 |
| <3% | 0 |
Subgroup analysis of Ki-67 cut-off values in GEP-NEN G1 patients
A total of 15 studies were included (10-24), and 1669 patients with detailed Ki-67 index and prognostic information were included in the analysis, with 1483 patients with Ki-67 ≤2% and 186 patients with Ki-67 <3%. The detailed raw data of the 15 studies is shown in Table 5 and Table 6. There was no experimental crossover in the two subgroups. For the 13 studies with Ki-67 ≤2% (10-22) the combined estimates were calculated and forest plots were drawn using Review Manager 5.4 software, and the results obtained were converted to give a combined 5-year survival rate of 84%. The two studies with Ki-67 <3% (23,24) had a combined estimated 5-year survival rate of 97% (Figures 5,6, Table 7). The heterogeneity of the included articles in this section is shown in Table 4.
Table 5
| Author | Ki-67 labelling index (%) | 5-year survival (%) | No. of patients |
|---|---|---|---|
| Watzka et al. (10) | <2 | 96.9 | 34 |
| Nuñez-Valdovinos et al. (11) | <2 | 86.4 | 689 |
| Sohn et al. (12) | ≤2 | 100.0 | 47 |
| Pape et al. (13) | ≤2 | 95.7 | 44 |
| Gonulal et al. (14) | ≤2 | 35.7 | 7 |
| Scarpa et al. (15) | 0–2 | 90.0 | 130 |
| Komaç et al. (16) | ≤2 | 86.0 | 43 |
| Norlén et al. (17) | ≤2 | 82.0 | 203 |
| Benetatos et al. (18) | ≤2 | 82.0 | 46 |
| Garcia-Carbonero et al. (19) | <2 | 83.3 | 126 |
| Arnold et al. (20) | <2 | 77.8 | 9 |
| Martin-Perez et al. (21) | <2 | 80.4 | 71 |
| Boyar Cetinkaya et al. (22) | <2 | 75.2 | 34 |
Table 7
| G1 standard before and after update | 5-year survival rate (%) | 95% CI | No. of patients |
|---|---|---|---|
| G1 (≤2%) | 84 | 0.79–0.88 | 1,483 |
| G1 (<3%) | 97 | 0.93–0.99 | 186 |
95% CI, 95% confidence interval.
Discussion
Data from the SEER database showed that the OS of NEN improved significantly over the last decades, reflecting the importance of early diagnosis and treatment (25). For pNEN, studies were showing that surgical resection is currently the main treatment, but the authors found that preoperative assessment of tumor size alone was not a reliable predictor of malignancy (26). Therefore, it is essential to explore the prognostic makers of GEP-NEN.
In the previous grading criteria for GEP-NENs (2010 and 2019 grading criteria), WHO used Ki-67 index combined with morphological index to achieve stratification of GEP-NENs, showed the importance of Ki-67 for the diagnosis of GEP-NENs (5,8,27). Several studies have shown that Ki-67 is correlated with the prognosis of patients with neuroendocrine tumors, but this association may have some differences in terms of different locations and types of tumors (28-30). This study supported the predictive value of Ki-67 on the prognosis of patients with GEP-NENs through literature search and meta-analysis, and confirmed that the higher the Ki-67 index, the worse the prognosis of patients, providing a clinical reference for the preliminary classification of patients with GEP-NENs according to Ki-67 index (7). In this study, we found that the overall 5-year survival rate of patients showed a decreasing trend as the Ki-67 index increased, and the prognosis of patients decreased significantly when Ki-67 >20%, which was consistent with previous studies (10), indicating that the higher the Ki-67 index, the higher the malignancy of the tumor, the higher the risk of recurrence and metastasis in patients and a relatively poorer prognosis.
Most of the studies we included only provided the number of patients with different tumor grades and the corresponding prognostic indicators without detailed follow-up data, so the number of 5-year survivors could only be approximated by using the product of the number of patients and the 5-year survival rate in the corresponding grade (9). In some of the studies we included, the grading system were not complete according to WHO 2010 grading system, but had detailed prognostic indicators and numbers. These studies were not included in the comprehensive estimation based on the correlation between the Ki-67 index and the 5-year survival rate, and could only be used in subgroup analysis for the estimation of cut-off values.
The most commonly used grading criteria for GEP-NENs is the WHO grading criteria based on Ki-67 index and mitotic rate, which was first proposed in 2010 (5,21). The WHO first updated the pathological grading criteria for pancreatic NETs in 2017, changing the cut-off value for G1 grade from ≤2% to <3% and proposing a relatively better prognosis for NET G3 with high proliferative activity (31). The WHO fully applied these pathological grading criteria to GEP-NENs in 2019 (8). According to the clinical method of Ki-67 detection, Ki-67 index should be a continuous variable, and a study showed that in pulmonary ACTH-secreting NETs, 1% increase in Ki-67 index increased the risk of recurrence by 1.41 (32). In ileal NETs, each unit increase in Ki-67 index increased the risk of death by 8% (33). Therefore, we believe that this change is significant and the result is based on extensive clinical experience. More evidence is needed to support the definition of the optimal cut-off value for GEP-NENs G1. In this study, we calculated the combined 5-year survival rate estimates using two different Ki-67 cut-off values as G1 grading criteria. We found that the combined 5-year survival rate estimates for the group with a Ki-67 cut-off value of <3% for G1 GEP-NEN did not significantly decrease compared with the group with a cut-off value of ≤2%, so the increase in the cut-off value did not affect the accuracy of Ki-67 for prognosis prediction. The results of the meta-analysis showed that the combined 5-year survival rates for GEP-NEN G1 (Ki-67 <3%) and GEP-NEN G1 (Ki-67 ≤2%) were 97% and 84%, respectively. This result might due to the small number of patients observed with a <3% cut-off value and does not indicate an improved prognosis for patients with an elevated Ki-67 index. Unlike the previous tertiary comparisons, this part of the comparison has an overlapping area of Ki-67 index, and also reflected that the overall definition of well differentiated and good prognosis for G1 grade was more consistent using <3% as the cut-off value, providing some evidence for the change in the WHO 2019 GEP-NEN grading criteria. Lee et al. found an increase in value-added Ki-67 index indicated that tumor cells were more proliferative, but highly proliferating tumor cells had less invasive subclones and therefore had less metastatic potential, resulting in a better prognosis for gastric cancer patients. However, based on our results, we suggested that elevating the cut-off value of Ki-67 in GEP-NEN G1 with no significant decrease in patient prognosis. That means a similar mechanism may exist for GEP-NEN, which needs to be further confirmed by subsequent studies (34).
The limitation of this study was that the included studies were retrospective, therefore, the study population, tumor staging, and grading were heterogeneous to some extent. A larger cohort study with a homogeneous population is still needed to validate the results of this study. In the comprehensive estimation of the 5-year survival rate for patients with GEP-NEN G3 (Ki-67 >20%), because of the lack of original patient pathology data, this study did not classify the cytological nature according to the latest WHO 2019 criteria. We only graded NETs according to Ki-67 labelling index, which means that this population contained both NET G3, which had relatively good differentiation and prognosis, and NEC, resulting in a lower prognosis for this group of patients. Therefore to further assess the prognosis of patients with the GEP-NENs (Ki-67 >20%) should consider the impact of the type of pathology. At the same time, the Ki-67 index is currently used as a categorical variable in most cases, but some studies have suggested that Ki-67 expression should be a continuous variable to reflect the continuous variability of the index more comprehensively, such analysis has not been performed due to the limited sample size of this study (35,36). Some studies have shown that GEP-NENs with Ki-67 ≥55% respond well to platinum chemotherapy drugs, while GEP-NENs with Ki-67 less than 55% respond poorly to platinum drugs (37,38). Moreover, some studies have shown that tumors with Ki-67 index ≥55% are more likely to involve the plasma membrane and to have lymph node metastases, Therefore, whether there is a difference in the prognosis of GEP-NENs patients with Ki-67 20–55% and those Ki-67 >55% needs to be further investigated (25,39).
Conclusions
The overall prognosis of GEP-NENs patients showed a decreasing trend with the increase of Ki-67 index, which confirmed the significance of Ki-67 index as a prognostic marker for the prognosis of GEP-NENs. Increasing the cut-off value of Ki-67 index for G1 grade from ≤2% to <3% according to WHO classification 2019 did not significantly decrease the 5-year survival rate.
Acknowledgments
We would like to thank Xu Gao, Yixin Liu, and Qiuju Ran (all are from The Second Affiliated Hospital of Xi’an Jiaotong University, No. 157 West Fifth Road, Xi’an 710004, China) for their kind help in literature search and data collection.
Funding: None.
Footnote
Reporting Checklist: The authors have completed the MOOSE reporting checklist. Available at https://tcr.amegroups.com/article/view/10.21037/tcr-23-248/rc
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