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Cyclin-dependent kinase inhibitor p21 and proliferative marker ki67 in colonic carcinoma

1 Department of Pathology, PGIMS, Rohtak, Haryana, India
2 Department of Pathology, MMIMSR, Mullana, Ambala, Haryana, India

Date of Submission29-Apr-2021
Date of Acceptance23-Jul-2021
Date of Web Publication22-Jun-2022

Correspondence Address:
Neha Singh,
Assistant Professor, Department of Pathology, MMIMSR, Mullana, Ambala, Haryana, (Former Senior Resident, Department of Pathology, PGIMS, Rohtak), H. NO. 24, MC Colony, Rohtak Road, Bhiwani, Haryana
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jcrt.jcrt_712_21

 > Abstract 

Objective: Tumor grade employed for colorectal cancer has long been based on the degree of differentiation, which is difficult to judge objectively. The aim of this study was to assess the immunohistochemical expression of p21 and ki67 and their correlation with the histological grading of colorectal carcinoma.
Materials and Methods: A total of 45 biopsy specimens of colorectal cancer were pathologically reviewed and correlation of grade and differentiation of tumor was performed with immunostaining.
Results: Ki 67 and p21 markers showed inverse relationship. An inverse relationship of p21 was found with tumor grade, differentiation, Dukes staging and lymph node status, whereas no correlation could be found between these parameters and ki67 expression.
Conclusion: We found that p21 can be used to assess the grading and metastatic potential of colorectal carcinoma whereas increased Ki67 expression can help us in the diagnosis of malignancy.

Keywords: Colorectal carcinoma, immunohistochemistry expression, Ki67, molecular genetics, p21, tumor grade

How to cite this URL:
Kumar S, Singh N, Kataria SP, Kandoi S, Verma M, Sen R. Cyclin-dependent kinase inhibitor p21 and proliferative marker ki67 in colonic carcinoma. J Can Res Ther [Epub ahead of print] [cited 2022 Jul 2]. Available from: https://www.cancerjournal.net/preprintarticle.asp?id=347948

 > Introduction Top

Colorectal cancer (CRC) is currently one of the major contributors to cancer-related deaths worldwide.[1] Environmental factors such as increased dietary consumption of fats, animal proteins, and genetic syndromes, e.g., familial adenomatous polyposis or hereditary nonpolyposis CRC syndrome (Lynch syndrome) caused by germline mutation of DNA mismatch repair genes, particularly MSH2 and MLH1 have been implicated in its pathogenesis. In recent years, more and more people have been afflicted with CRC and they tend to be younger with improvements in living standards, changes in dietary habits and components, and increased aging populations. Uncontrolled proliferation of tumor cells and disordered apoptosis play important roles in the occurrence and development of malignant tumor.[2] Factors such as tumor size, histological type, subtype, presence of signet ring morphology, the degree of differentiation, presence of lymphovascular invasion, and lymph node involvement are well-known factors that influence the outcome. Incidence rates vary approximately 20-fold around the world, with the highest rates seen in the developed world and one of the lowest in India.[3]

Ki67 is a nuclear protein that is detected by MIB-1 monoclonal antibody. Its expression is inversely proportional to the survival of patients.[4],[5] Prognostic value of Ki67 had been investigated in many studies with its potential as reliable marker for poor survival in breasts, soft tissue, lungs, prostate, cervix, and central nervous system malignancies.[6],[7] However, the prognostic value of Ki67 in patient with CRC is still a controversy.[8] In cancerous tissues, expression of ki67 is more in highly proliferative cells. These fast proliferative cells are more susceptible to adjuvant radiotherapy.[9]

p21 is a tumor suppressor protein, a universal cell cycle inhibitor which is involved in the regulation of G0/G1 phase arrest and cell proliferation.[10] It is activated by wild-type p53 and is also known as WAF1 (wild-type p53 activated factor). p21 is expressed at higher levels in normal tissue than in cancerous tissue.[11]

Pathologic tumor stage is the most important predictor of tumor behavior and outcome for patients with colon cancer.[12] This study was planned to assess the immunohistochemical expression of p21 and ki67 and their correlation with the histological grading of colorectal carcinoma.

 > Materials and Methods Top

The present study was conducted in the Department of Pathology at a tertiary care institute. The study group comprised of forty-five biopsy specimens of CRC. The tumor tissue was fixed in 10% buffered formaldehyde, dehydrated, and embedded in paraffin wax. Hematoxylin and eosin-stained sections of 4–5 μm were examined. All the forty-five consecutive carcinomas were graded according to the World Health Organization criteria for the classification of CRC.

The Ki-67 and p21 immunoquantitation were performed using light microscopy at X400 magnification. The immunohistochemical results were interpreted according to the intensity of immune reactive products seen in nuclei of the tumor cells. The percentage of tumor cells with nuclear staining was determined by counting at least 1000 tumor cells in ten selected fields that displayed highest immune reactivity. Scoring was done according to the percentage of positive tumor cells as under:

For p21: <5% negative; 5%–25% weak positive; >25% strong positive.

For Ki67: <20% non expressors, >20% expressor.

These quantitative features using the proliferative marker Ki67 and cyclin-dependent kinase inhibitor p21 were correlated in different grades of tumors. For quantitative analysis, Student's unpaired “t”-test has been used for comparing two groups while ANOVA test was used to compare three groups.

 > Results Top

A total of 45 cases comprising of 21 excision biopsy specimens and 24 trucut biopsies were included in this study. All cases of colorectal carcinoma were diagnosed following established histopathological criteria reported in the standard literatures. Out of 45 cases studied, 40 cases were of adenocarcinoma (88.88%), 3 cases were of mucinous adenocarcinoma (6.67%) [Figure 1], and 1 case each was of intra-mucosal carcinoma and atypical carcinoid (2.22%) [Figure 2].
Figure 1: Mucinous adenocarcinoma with mucin lakes (H and E ×100)

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Figure 2: Carcinoid tumor (H and E ×40)

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On IHC, 93% (42/45) of cases were expressor of Ki67 (>20% immunostaining) whereas only 6.7% (3/45) cases were nonexpressor (<20% immunostaining). A total of 66.6% cases (30/45) showed positive p21 expression whereas 33.3% cases (15/45) showed negative expression (<5% immunostaining). Out of the positive 30 cases, 25 cases revealed weak positive expression (5% to 25% immunostained cells) whereas 5 cases showed strong positive expression (>25% immunostained cells). Thus, maximum cases were in category of weak positive expression (55.5%) whereas least cases were in category of strong positive expression (11.1%).

Mean expression of p21 in low-grade tumors was 15.833 ± 11.363 whereas in high-grade tumors, it was 6.67 ± 5.895. The P value was calculated by both qualitative and quantitative methods and came out to be 0.0498 and 0.0246 which was statistically significant [Table 1].
Table 1: Expression of p21 according to grade of tumor

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Mean expression of p21 in well-differentiated, moderately differentiated, and poorly differentiated cases of colorectal carcinoma was 22.5 ± 13.288, 13.52 ± 10.188, and 5.8 ± 4.025, respectively. P value was calculated by both qualitative and quantitative methods and was found to be 0.0343 and 0.0221 which was statistically significant [Table 2].
Table 2: p21 expression according to differentiation of tumors

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Twenty-one cases of excision biopsy specimens were classified according to Modified Dukes staging and according to the positivity or negativity of lymph node metastasis. Mean p21 expressions for Stage A, B, C1, and C2 were 25 ± 0, 15.6 ± 9.766, 6.285 ± 5.678, and 2.667 ± 0.577, respectively. P value was calculated by both qualitative and quantitative methods and was 0.01559 and 0.0255 which was statistically significant. No case is presented in Stage D [Table 3].
Table 3: Expression of p21 according to modified Dukes staging

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Mean p21 expression for lymph node-negative and lymph node-positive group was 16.45 ± 9.69 and 5.2 ± 4.96. P value was calculated by both qualitative and quantitative methods and was found to be 0.0168 and 0.0038, respectively, which was statistically significant [Table 4].
Table 4: Expression of p21 according to lymph node status

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The P value of Ki67 expression and grade of tumor was calculated by both qualitative and quantitative methods and was 0.8812 and 0.6255, respectively, which was statistically not significant [Table 5]. The P value of Ki67 expression and differentiation of adenocarcinoma was assessed by using both qualitative and quantitative methods and was 0.458 and 0.2246 respectively which was statistically not significant [Table 6]. The relationship of Dukes staging with Ki67 and lymph node status with Ki67 could not be studied as all the 21 excision biopsy specimens were expressor (>20% Ki67 expression).
Table 5: Ki67 expression according to grade of tumor

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Table 6: Expression of ki67 according to differentiation of adenocarcinoma

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Spearman rank correlation test was used to study the correlation between Ki67 and p21. The “r” value calculated was 0.2487 (showing inverse relation). However, “P” value was 0.0995 which is statistically not significant. Thus, it can be said that an inverse correlation exists between Ki67 and p21 but it is statistically not significant.

 > Discussion Top

Colorectal carcinoma is one of the most common types of cancer in western countries and is consistently ranked among top causes of cancer-related deaths.[13] Assessment of tumor stage and other stage-independent morphologic features influences the treatment strategies for a patient. The Ki67 and cyclin-dependent kinase inhibitor p21 are important immunohistochemical proliferative markers which aid in deciding the course of disease.

The mean age of presentation of colorectal carcinoma in our study was 52.3 ± 12.2 years which is in concordance with the studies done by Tong et al.,[14] Amin et al.[3] with mean age of presentation being 62.2, 54.8 ± 14.5, and 63.5 years, respectively. The disease was found to be more prevalent in male gender irrespective of the age groups and tumor subtype. The male-to-female ratio was 1.6:1 which correlated with the studies done by Tong et al.[14] (1.01:1), Ohuchi et al.[11] (1.5:1), and Shepherd et al.[15] (1.2:1). Yoshida et al.,[16] Ohuchi et al.,[11] and Tong et al.[14] studied distribution of carcinoma in different colorectal regions and concluded that the majority of the cases were present in recto-sigmoid region as 59%, 53.4%, and 54.2% cases, respectively. This is also in concordance with our present study.

The majority of the cases of adenocarcinoma NOS (Not otherwise specified) in the present study were of moderately differentiated type (67.5%). The well-differentiated and poorly differentiated tumors constituted only 20% and 12.5% of the cases, respectively. This is similarly corroborated in studies done by Ueno et al.,[17] Nabi et al.,[18] and Yoshida et al.[16] who all claimed that moderately differentiated type is the most common type at the time of presentation amongst adenocarcinoma NOS constituting 51%, 58%, and 60% of cases in their respective studies.

All cases showed positive expression of Ki67 in study done by Sen et al.[19] whereas only 79.30% cases were positive for Ki67 in study done by Heidari et al.[20] In our study, 93.3% cases showed positive expression (>20% expression). In our study, 66% of the tumors had positive p21 expression (>5% cells expressing p21). The studies done by Pasz-Walczak et al.,[21] Zirbes et al.,[22] Bukholm and Nesland,[23] Jahantigh et al.[24] concluded positive p21 expression in 39%, 67%, 16.1%, and 47.1% of the tumors, respectively.

In our study, expression of p21 decreased as grade and differentiation of tumor increased [Figure 3]a, [Figure 3]b and [Figure 4]a, [Figure 4]b and [Figure 5]a, [Figure 5]b. A statistically significant inverse correlation of grade of tumor with p21 expression (P = 0.0246) and differentiation of tumor with p21 expression (P = 0.0221) was found which is consistent with the study done by Pasz-Walczak et al.[21] whereas no significant correlation could be proved in the study done by Jahantigh et al.[24] This difference in results might be explained by the work of Pasz-Walczak et al.[21] who stated that in colon cancer, abnormality of p21 genes is not found but instead, the attenuation of expression of p21 is reported to be correlating with the grade of malignancy. Study done by Hou et al.[25] showed transcriptional regulation of p21 facilitates the proliferation of CRC in vitro and in vivo through kinesin family member (KIF) 4A which is one of the KIFs.
Figure 3: Adenocarcinoma NOS, well-differentiated (a, H and E), positive p21 expression (b), and high Ki67 expression (c) (×40)

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Figure 4: Adenocarcinoma NOS, moderately differentiated (a, H and E), negative p21 expression (b) high Ki67 expression (c) and (×40)

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Figure 5: Adenocarcinoma NOS, poorly differentiated (a, H and E), negative p21expression (b) high Ki67 expression (c) (×40)

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When Dukes staging and lymph node status were correlated with p21 expression in the tumor cells, we found a significant inverse correlation between p21 expression and modified Dukes staging (P = 0.0255) and with lymph node status (P = 0.0038). We observed that expression of p21 decreases with increasing stage and positive lymph node status. The association was found to be statistically not significant in studies done by Jahantigh et al.,[24] Emmanouil et al.[26] whereas it was significant in study done by Ohuchi et al.,[11] Bukholm and Nesland.[23]

In our study, no correlation was found between Ki67 expression and grade and differentiation of tumor [Figure 3]c, [Figure 4]c and [Figure 5]c whereas this correlation was statistically significant in the study done by Heidari et al.,[20] Sen et al.[18] and Ahmed et al.[27] Study done by Luo et al.[5] demonstrated that high Ki-67 expression significantly predicts poor overall survival and disease-free survival. High Ki-67 expression may serve as a valuable predictive biomarker for poor prognosis in CRC patients. This difference in the results can be attributed to geographical variation, sample size, immunohistochemical techniques and antibody used, scoring system applied, statistical methods used, and interobserver variability.

Our study also revealed that an inverse correlation exists between p21 and Ki67 expression which was statistically not significant (P = 0.0995). No such correlation was found in any other studies. Petrisor et al.[28] found a wide range of Ki-67 expression in colonic carcinomas ranging from 5% to 95%. They did not find any relationship between Ki-67 expression in colonic adenocarcinomas and histopathological grade.

In another study, Georgescu et al.[29] found that the Ki-67 expression increased with the histological grade of adenocarcinomas. The difference between Grade 1 and Grade 2 adenocarcinomas was not significant while the difference between Grades 2 and 3 adenocarcinomas was significant. Gurzu et al.[30] in their study found a significant increase of Ki67 median expression with poorer grade, age of patients, and lymph node involvement. Contrary to this, Guzinska-Ustymowicz et al.[31] reported a lack of correlation of Ki-67 expression with patient's age and tumor location and a significant association with lymph node involvement. Nabi et al.[18] showed significant decrease in Ki-67 values between Grade 1 and Grade 3 lesions as well as between Grade 2 and Grade 3 lesions but no significance between Grade 1 and Grade 2 adenocarcinomas.

Role of Ki67expression in the prognosis of CRC was observed by various authors. Melling et al.[9] considered that high Ki67 has a good prognostic value for CRC, contrasting with Luo et al.[5] 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. Their 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.

Induction of p21 is linked to poor prognosis which is supported by the analysis of tumor cell proliferation which was observed by Rau et al.[32] As expected, the patients with higher p21 expression are mainly the same as those with a reduced Ki-67 expression. Thus, induction of p21 was linked to a decrease in proliferative activity. This, in turn, shows that the increase in p21 is functionally relevant and is a further argument for the functional integrity of the p21 detected posttherapy. Similar to p21, the reduction of Ki-67 expression after therapy was associated with a worse survival.

A notable limitation of the present study is the small number of samples due to a single institutional study design. Further studies involving a larger number of samples considering geographical, racial, and genetic differences are therefore required.

 > Conclusion Top

The focus of this study was to support the clinical relevance of p21 and Ki67 in the prognostic stratification of CRC patients and to help guide their proper management. The patients with a decrease in the p21 expression may have better disease-free survival.

The emergence of novel IHC markers such as p21 and Ki67 has improved the prediction of clinical behavior of colorectal tumors which has contributed significantly to rapidly developing newer treatment strategies. This IHC expression needs to be incorporated into the information gleaned by the traditional, still valuable, histological analysis. Furthermore, our findings provide immunohistochemical evidence that the p21 can be used to assess the grading and metastatic potential of CRC whereas increased Ki67 expression can help us in predicting the mitotic count. Further studies in this area shall continue to refine the prognostic information and help govern new therapeutic interventions.

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Conflicts of interest

There are no conflicts of interest.

 > References Top

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[PUBMED]  [Full text]  
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