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  Table of Contents    
ORIGINAL ARTICLE  
Year : 2015  |  Volume : 58  |  Issue : 2  |  Page : 158-162
Expression of CDX-2 and Ki-67 in different grades of colorectal adenocarcinomas


1 Department of Pathology, Nil Ratan Sircar Medical College, Kolkata, West Bengal, India
2 Department of Pathology, Institute of Post-Graduate Medical Education and Research (IPGMER), Kolkata, West Bengal, India
3 Department of General Surgery, Institute of Post-Graduate Medical Education and Research (IPGMER), Kolkata, West Bengal, India

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Date of Web Publication17-Apr-2015
 

   Abstract 

Background: CDX2 is a caudal homeobox gene essential for intestinal differentiation and is specifically expressed in colorectal adenocarcinomas. Its role in colorectal carcinogenesis is not fully elucidated. Aims and Objectives: To study the expression pattern of CDX2 and Ki-67 in different grades of colorectal adenocarcinomas and to observe the relationship of their staining patterns in various tumor stages and to look for correlation if any, between Ki-67 labeling index (Ki-67 LI) and CDX2 expression. Materials and Methods: A total of 74 cases were enrolled. Detailed clinical profile, peroperative findings, histological grading and staging were noted. Immunohistochemistry for CDX2 and Ki-67 was done, and Ki-67 LI was calculated. CDX2 staining was graded semi-quantitatively, and statistical analysis was done. Result: Age of presentation ranged from 20 to 75 years, and the male:female ratio was 1.83:1. There were 8, 47 and 13 cases of well, moderate and poorly differentiated adenocarcinomas, respectively. The mean Ki-67 LI of well, moderate and poorly differentiated adenocarcinomas were 14.25, 31.34 and 43.08 respectively, and their difference was statistically significant, correlation was also noted with stage. CDX2 expression appeared to be stronger in poorly differentiated cases, but there was no significant difference in its expression in the different grades and stages. There was no correlation between Ki-67 LI and CDX2 immunostaining pattern. The lymph node metastasis showed CDX2 positivity in all the cases. Conclusion: Expression of CDX2 does not significantly change with the grade of colorectal adenocarcinomas. However, it is an important diagnostic marker in metastatic colonic lesions. The Ki-67 LI, on the other hand, showed a strong correlation with histopathological grades.

Keywords: CDX-2, colorectal adenocarcinoma, grading, Ki-67, lymph nodal metastasis

How to cite this article:
Sen A, Mitra S, Das RN, Dasgupta S, Saha K, Chatterjee U, Mukherjee K, Datta C, Chattopadhyay BK. Expression of CDX-2 and Ki-67 in different grades of colorectal adenocarcinomas. Indian J Pathol Microbiol 2015;58:158-62

How to cite this URL:
Sen A, Mitra S, Das RN, Dasgupta S, Saha K, Chatterjee U, Mukherjee K, Datta C, Chattopadhyay BK. Expression of CDX-2 and Ki-67 in different grades of colorectal adenocarcinomas. Indian J Pathol Microbiol [serial online] 2015 [cited 2019 Dec 11];58:158-62. Available from: http://www.ijpmonline.org/text.asp?2015/58/2/158/155304



   Introduction Top


Adenocarcinoma of the colon is the most common malignancy of the alimentary tract and is one of the important causes of cancer-related deaths worldwide. Environmental factors like increased dietary consumption of fats and animal proteins and genetic syndromes, e.g., familial adenomatous polyposis or hereditary nonpolyposis colorectal cancer syndrome (Lynch syndrome) caused by germline mutation of DNA mismatch repair genes, particularly MSH2 and MLH1 have been implicated in its pathogenesis. [1]

Majority of colorectal carcinomas are adenocarcinomas. They are classified into three grades based on the arrangement of cells and tubular (acinar) formation.

Tumors with a higher histological grade, greater depths of invasion and evidence of lymph node involvement are associated with a worse prognosis.

CDX2 is a caudal-homeobox gene that encodes for a transcription factor that is important in the proliferation and differentiation of epithelial cells in the intestine. It is expressed by majority of colorectal carcinomas, [2] and some cases of primary mucin-producing carcinomas of ovary, bladder, lung and pancreaticobiliary adenocarcinomas. [3],[4]

Ki-67 is a nuclear nonhistone protein that is present in all phases of cell cycle, except for the G0 and early G1, making it a good marker for cycling cells. [5] Ki-67 proliferative index has a prognostic and/or predictive value in different tumor types; however, in colorectal cancer its use as a sole prognostic factor is limited. [6]

We conducted our study to classify colorectal adenocarcinomas in three histological grades by hematoxylin and eosin (H and E) stain and to examine the different patterns of expression of CDX2 and Ki-67 in these three grades of adenocarcinomas. Also, we studied the expression of CDX2 in both involved and uninvolved lymph nodes.

We studied 74 consecutive cases of colorectal carcinomas over a period of 2 years (July 2010 to June 2012). But, we considered only adenocarcinomas for further study, excluding the mucinous carcinomas and carcinoid. The cases were clinically graded as per the TNM staging. H and E stained sections of adenocarcinomas were classified histologically into three grades. In Grade I cancers, mainly simple tubular structures are seen, in which the nuclear polarity is easily discerned. Grade II cancers are composed of tubules that are simple, complex, or slightly irregular, in which the nuclear polarity is barely discernible or is lost. Grade III tumors are characterized by a predominance of solid growth pattern without glandular differentiation and lost nuclear polarity. Diagnosis of a colorectal carcinoma as a grade III tumor is done when the poorly differentiated component comprises >50% of the tumors. [7]


   Materials and Methods Top


A total of 74 cases were collected over 2 years in collaboration with department of General Surgery and it was a prospective observational study. Totally, 10 cases of breast carcinoma were used as a negative control for CDX2 immunohistochemistry, and 10 cases of normal intestinal tissue were used as a positive control for CDX2. Detailed clinical profile including dietary history, peroperative findings, histological grading and staging were noted. Immunohistochemistry for CDX2 and Ki-67 was done. Sections (4 μ) from formalin fixed paraffin embedded tissue blocks were stained by standard immunohistochemical methods using horseradish peroxidase-linked antibody. Primary anti-CDX2 (EPR2764Y) and Ki-67 antibody are rabbit monoclonal antibody supplied from CELL MARQUE and the dilution factor is 1 in 100.

Result of Ki-67, immunostaining index was interpreted as labeling index (Ki-67 LI) = Number of nuclei showing positive staining (brown color)/total number of nuclei × 100%. CDX2 staining was graded semi-quantitatively. CDX2 immunohistochemical marker in the study was scored as follows: 0 (no positivity or only very occasional cell staining); 1+ (<10% of cells stained); 2+ (10-50% of cells stained); and 3+ (>50% of cells stained). [8] The intensity of staining was also scored on a categorical scale from 0 to 3: 0 indicated absent; 1+ very weak, dubious staining; 2+ definite, mild, or moderate staining; 3+ definite, strong staining. Only tumor cells stained in the appropriate nuclear or cytoplasmic location were scored.

Statistical analysis was done using Chi-square test and Spearman's correlation coefficient. Results were tabulated, and we used statistical data analysis software version 6.0. Tulsa Oklahoma: Statsoft, Inc.; 2001 for statistical analysis.

Ethical approval was sought and obtained from institutional ethical committee.


   Results Top


Out of the 74 total cases of colorectal cancers, 68 (91.89%) cases were adenocarcinoma, 5 (6.76%) cases were mucinous carcinoma, and 1 (1.35%) case was a carcinoid tumor. Age of the patients ranged from 20 years to 75 years, (mean 45.21 years). Five cases that is, 6.76% cases were vegetarian.

Moderately differentiated adenocarcinoma [Figure 1]a was the most common histopathological type responsible for 69.1% of cases. Well differentiated and poorly differentiated [Figure 1]b and c cases were responsible for 11.8% and 19.1% respectively. Immunostain for CDX2 showed different percentage of cells showing positivity depending upon the grade of tumor [Figure 2]a-c. Statistical analysis showed there was a nonsignificant weak positive correlation between CDX2 immunostain and histopathological grade [Table 1].
Figure 1: (a) Photomicrograph of moderately differentiated adenocarcinoma of the colon (H and E, ×100) (b) Photomicrograph of well differentiated colorectal adenocarcinoma with normal colonic glands at right lower corner (H and E, ×100) (c) Photomicrograph of poorly differentiated adenocarcinoma of the rectum (H and E, ×400)


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Figure 2: (a) Photomicrograph of CDX2 immunostain in well differentiated adenocarcinoma showing 3+ grade (PAP, ×100) (b) Photomicrograph of CDX2 immunostain in moderately differentiated adenocarcinoma of sigmoid colon showing 3+ grade (PAP, ×400) (c) Photomicrograph of CDX2 immunostain in poorly differentiated adenocarcinoma of descending colon showing 3+ grade (PAP, ×100)


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Table 1: Expression of CDX-2 in different grades of colorectal adenocarcinoma


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The most common TNM stage was T 3 N 0 M X (39.7%). Two of our cases were associated with liver metastasis (T 3 N 1 M 1 and T 4 N 1 M 1 ), as proved by imaging techniques. Although well differentiated lesions were of the lower stage, and the poorer differentiated lesions had a tendency to present with higher stage, no statistical correlation was found [Table 2]. All the cases showed positivity for Ki-67 immunostain [Figure 3]a-c. Values for Ki-67 LI ranged from 9% to 51% [Table 3]. Mean values for Ki-67 LI for well, moderate and poorly differentiated lesions were 14.25% (ranges 9-31%), 31.64% (ranges 21-40%) and 43.08% (ranges 31-51%) respectively. Correlation studies between histopathological grade and Ki-67 LI showed Spearman's correlation coefficient = 0.734; P < 0.001, significant. Thus, there is a strong positive significant correlation between histopathological grade and Ki-67 LI. However, only weak positive nonsignificant correlation was found between CDX-2 grade and Ki-67 LI (Spearman's correlation coefficient = 0.051; P = 0.681). No significant correlation was detected between Ki-67 and TNM stage as well as between CDX2 immunostain and TNM stage. Correlation studies showed a strong positive significant correlation between histopathological grade and lymph node involvement (Spearman's correlation coefficient = 0.601; P < 0.001) and also between Ki-67 LI and lymph node involvement (Spearman's correlation coefficient = 0.464; P < 0.001). Totally, 25 cases (36.8%) showed lymph node involvement [Figure 4]a and all the involved lymph nodes were positive for CDX2 immunostain [Figure 4]b.
Figure 3: (a) Photomicrograph of Ki-67 immunostain in well differentiated colorectal adenocarcinoma (PAP, ×400). (b) Photomicrograph of Ki-67 immunostain in moderately differentiated adenocarcinoma of sigmoid colon (PAP, ×400). (c) Photomicrograph of Ki-67 immunostain in poorly differentiated adenocarcinoma of sigmoid colon (PAP, ×400)


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Figure 4: (a) Photomicrograph of metastasis of colorectal adenocarcinoma in lymph node (H and E, ×100) (b) Photomicrograph of CDX2 immunostain in lymph node metastasis showing strong positivity (PAP, ×100)


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Table 2: Well differentiated lesions were of the lower stage, but the poorer differentiated lesions tend to present with higher stage, although no correlation was found


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Table 3: All the cases showed positivity for Ki-67 immunostain


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   Discussion Top


Colorectal malignancies are commonly encountered in surgical practice and cause a significant mortality. In Western countries, the peak age at presentation is 65 years [9] whereas in our series the mean age of patients was 45 years. Of these, one-third were below the age of 40 years and the ratio of the patients ≤40: >40 years of age group was 1:1.72, reflecting the findings of Nayak et al. and Peedikayil et al. [10],[11]

In our study, moderately differentiated adenocarcinomas were the commonest type accounting for 69.1% of cases. Well differentiated and poorly differentiated cases formed 11.8% and 19.1% respectively. Peedikayil et al. found that most of the tumors (74%) were located distal to the splenic flexure. [11] Nayak et al. reported sigmoid colon to be the commonest site followed by cecum and rectum. [10] In our study commonest site was recto-sigmoid region (59%), followed by ascending colon (19%), cecum (12%) and descending colon (7%), while transverse colon (3%) was the rarest.

CDX2 represents a nuclear transcription factor that has found important application in diagnostic surgical pathology as specific and sensitive markers of colonic differentiation. Nuclear transcription factors have several advantages over cytoplasmic markers:

  1. Transcription factors generally yield an "all or none" signal, with most of the positive cases containing positive signal in >90% of the tumor cells.
  2. Nuclear localization of the signal is much less likely to be confused with biotin or other sources of false positive cytoplasmic signals.
  3. Lack of association between the levels of expression of nuclear transcription factors and the state of differentiation of the tumor.


In a study by Saad et al., CDX2 was found to be expressed in 29 of 30 metastatic colorectal adenocarcinomas and was negative in all mucinous and nonmucinous types of bronchioloalveolar carcinomas, thereby proving that CDX2 is a useful immunohistochemical marker for the differential diagnosis of primary versus metastatic adenocarcinomas in the lung and in the workup of patients with unknown primary. [8] Witek et al. found in their study that CDX2 was overexpressed in most colorectal tumors compared to normal mucosa. Overexpression of CDX2 mRNA was associated with increased CDX2 protein expression localized in the nuclei of tumor cells. [12] Our cases also showed similar increased expression of CDX2 compared to normal colonic mucosa. Kaimaktchiev et al. examined CDX2 expression in a series of tissue microarrays with normal and neoplastic tissues. Strong nuclear staining for CDX2 was observed in 86% of colonic adenocarcinomas. There was no significant difference in the staining of well and moderately differentiated tumor. [2] We found all the cases of adenocarcinomas to be positive for CDX2 immunostain. Mazziotta et al. showed CDX2 was strongly and diffusely expressed in 10 out of 13 colonic adenocarcinomas, ranging from well to poorly differentiated. [4] Similar to our study, they found no difference in expression of CDX2 and the microscopic grade. However, in the series by Brabletz et al., a selective down-regulation of CDX2 expression was reported in dedifferentiated tumor cells predominantly at the invasive front when compared with the central differentiated tumor areas. [13] In our study, cases bearing both poor as well as moderately differentiated areas simultaneously also showed varied expression pattern. In the study by Hinoi et al., a markedly reduced CDX2 expression was reported in 87% of minimally differentiated carcinomas and 4% of the differentiated adenocarcinomas. [14] Contrary to this series, our cases of poorly differentiated carcinomas did not show reduced CDX2 expression. Rozek et al. found reduced CDX2 expression was associated with tumor location (right sided) and poor differentiation. [15] Moskaluk et al., using tissue microarrays containing normal tissue types, showed strong, diffuse CDX2 staining only in the nuclei of small and large intestinal epithelium. Colonic adenocarcinomas showed strong staining in 90% of cases. Adenocarcinomas of the stomach, esophagus, and ovary showed significant staining in only 20-30% of cases. [16] Our study also supports similar diagnostic utility of CDX2 immunostain. In addition to the nuclear staining, some of our cases showed cytoplasmic staining also. Only one case of poorly differentiated adenocarcinoma showed 1+ positivity for CDX2 stain, while the rest were strongly positive for CDX2. Metastases in lymph nodes also showed positivity for CDX2 in all the cases. We could not detect any significant relation with histopathological grade and CDX2 expression. Werling et al. reported that high levels (>75% positive cells) of CDX2 expression were found almost exclusively in adenocarcinomas of the colorectum, and intermediate levels (26-75% positive cells) were found in adenocarcinomas arising elsewhere in the GI tract. [3] They demonstrated that primary and metastatic colorectal carcinomas showed similar scoring patterns.

Bayrak et al. established that CDX2 expression does not reliably distinguish between colorectal adenocarcinomas and adenocarcinomas arising elsewhere in the GI tract, particularly pancreatobiliary and gastric adenocarcinomas although the sensitivity of CDX2 for colorectal cancer is higher. [17] Tot found that CK7-/CK20+ expression pattern was more specific for colonic adenocarcinoma metastases than CDX2 alone, but less sensitive. [18] The CK7-/CK20+ phenotype is superior in its specificity and positive predictive value. Saad et al. also suggested that CDX2 should not be used as the sole basis for determining whether the gastrointestinal tract is the primary site of adenocarcinoma and be used as a part of a broader immunohistochemical panel. [19]

Petrisor et al. found a wide range of Ki-67 LI in colonic carcinomas ranging from 5% to 95%. They did not find any relationship between Ki-67 LI of colonic adenocarcinomas and histopathological grade. Comparison of the mean Ki-67 values with respect to the pathologic subtypes of rectal adenocarcinoma indicated the existence of significant differences. [20] In our study, all the cases of adenocarcinomas were positive for Ki-67 immunostain and Ki-67 LI ranged from 9 to 51. Mean values for Ki-67 LI for well, moderate and poorly differentiated lesions were 14%, 32% and 43% respectively, and the difference was statistically significant. There was a strong positive significant correlation between Ki-67 LI and histopathological grade. Georgescu et al. found that the Ki-67 LI increased with the histological grade of adenocarcinomas. The difference between grade 1 and grade 2 adenocarcinomas was not significant while the difference between grade 2 and 3 adenocarcinomas was significant. [21] Gurzu et al. found a significant increase of Ki67 median expression with poorer grade, age of patients and lymph node involvement. [22] Guzinska-Ustymowicz et al. reported a lack of correlation of Ki-67 expression with patient's age and tumor location and a significant association with lymph node involvement. [23] Our study also showed a significant correlation with lymph node involvement. In contrast to most of the studies and our findings, Nabi et al. 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. [24] Most of the well differentiated adenocarcinomas presented in lower TNM stage, whereas poorly differentiated lesions had a tendency to present at a higher stage. The TNM staging did not correlate with the CDX2 expression; however, we observed increased CDX2 expression in the higher histological grades.

Thus, in conclusion, CDX2 is an important diagnostic marker for both primary and metastatic colorectal adenocarcinomas although its expression does not vary significantly with the histological grade. Its expression also does not appear to correlate with the stage. From this study, it appears that CDX2 has only a limited role as a prognostic marker in colorectal carcinomas. Ki-67 LI on the other hand is helpful in differentiating between the different histological grades and is also a useful prognostic marker.


   Acknowledgment Top


I particularly thankful to our technical staffs, Janababu, Ashimda and Dayal - Also actively helped in our work. So they also owe special appreciation for their co-operation.

 
   References Top

1.
Lynch HT, Smyrk TC. Hereditary colorectal cancer. Semin Oncol 1999;26:478-84.  Back to cited text no. 1
    
2.
Kaimaktchiev V, Terracciano L, Tornillo L, Spichtin H, Stoios D, Bundi M, et al. The homeobox intestinal differentiation factor CDX2 is selectively expressed in gastrointestinal adenocarcinomas. Mod Pathol 2004;17:1392-9.  Back to cited text no. 2
    
3.
Werling RW, Yaziji H, Bacchi CE, Gown AM. CDX2, a highly sensitive and specific marker of adenocarcinomas of intestinal origin: An immunohistochemical survey of 476 primary and metastatic carcinomas. Am J Surg Pathol 2003;27:303-10.  Back to cited text no. 3
    
4.
Mazziotta RM, Borczuk AC, Powell CA, Mansukhani M. CDX2 immunostaining as a gastrointestinal marker: Expression in lung carcinomas is a potential pitfall. Appl Immunohistochem Mol Morphol 2005;13:55-60.  Back to cited text no. 4
    
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Brown DC, Gatter KC. Ki67 protein: The immaculate deception? Histopathology 2002;40:2-11.  Back to cited text no. 5
    
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Kimura T, Tanaka S, Haruma K, Sumii K, Kajiyama G, Shimamoto F, et al. Clinical significance of MUC1 and E-cadherin expression, cellular proliferation, and angiogenesis at the deepest invasive portion of colorectal cancer. Int J Oncol 2000;16:55-64.  Back to cited text no. 6
    
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Cooper HS. Intestinal neoplasms. In: Mills SE. Sternberg's Diagnostic Surgical Pathology. 5 th ed., Vol. 1. Philadelphia: Lippincott Williams & Wilkins; 2010. p. 1395-401.  Back to cited text no. 7
    
8.
Saad RS, Cho P, Silverman JF, Liu Y. Usefulness of Cdx2 in separating mucinous bronchioloalveolar adenocarcinoma of the lung from metastatic mucinous colorectal adenocarcinoma. Am J Clin Pathol 2004;122:421-7.  Back to cited text no. 8
    
9.
Jass JR. Tumors of the small and large intestines (including the anal region). In: Fletcher CD, editor. Diagnostic Histopathology of Tumours. 3 rd ed. Philadelphia: Churchill Livingston; 2007. p. 397-403.  Back to cited text no. 9
    
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Nayak SP, Sasi MP, Sreejayan MP, Mandal S. A case-control study of roles of diet in colorectal carcinoma in a South Indian Population. Asian Pac J Cancer Prev 2009;10:565-8.  Back to cited text no. 10
    
11.
Peedikayil MC, Nair P, Seena SM, Radhakrishnan L, Sadasivan S, Naryanan VA, et al. Colorectal cancer distribution in 220 Indian patients undergoing colonoscopy. Indian J Gastroenterol 2009;28:212-5.  Back to cited text no. 11
    
12.
Witek ME, Nielsen K, Walters R, Hyslop T, Palazzo J, Schulz S, et al. The putative tumor suppressor Cdx2 is overexpressed by human colorectal adenocarcinomas. Clin Cancer Res 2005;11:8549-56.  Back to cited text no. 12
    
13.
Brabletz T, Spaderna S, Kolb J, Hlubek F, Faller G, Bruns CJ, et al. Down-regulation of the homeodomain factor Cdx2 in colorectal cancer by collagen type I: An active role for the tumor environment in malignant tumor progression. Cancer Res 2004;64:6973-7.  Back to cited text no. 13
    
14.
Hinoi T, Tani M, Lucas PC, Caca K, Dunn RL, Macri E, et al. Loss of CDX2 expression and microsatellite instability are prominent features of large cell minimally differentiated carcinomas of the colon. Am J Pathol 2001;159:2239-48.  Back to cited text no. 14
    
15.
Rozek LS, Lipkin SM, Fearon ER, Hanash S, Giordano TJ, Greenson JK, et al. CDX2 polymorphisms, RNA expression, and risk of colorectal cancer. Cancer Res 2005;65:5488-92.  Back to cited text no. 15
    
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Moskaluk CA, Zhang H, Powell SM, Cerilli LA, Hampton GM, Frierson HF Jr. Cdx2 protein expression in normal and malignant human tissues: an immunohistochemical survey using tissue microarrays. Mod Pathol 2003;16:913-9.  Back to cited text no. 16
    
17.
Bayrak R, Haltas H, Yenidunya S. The value of CDX2 and cytokeratins 7 and 20 expression in differentiating colorectal adenocarcinomas from extraintestinal gastrointestinal adenocarcinomas: Cytokeratin 7-/20+ phenotype is more specific than CDX2 antibody. Diagn Pathol 2012;7:9.  Back to cited text no. 17
    
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Tot T. Identifying colorectal metastases in liver biopsies: The novel CDX2 antibody is less specific than the cytokeratin 20+/7-phenotype. Med Sci Monit 2004;10:BR139-43.  Back to cited text no. 18
    
19.
Saad RS, Ghorab Z, Khalifa MA, Xu M. CDX2 as a marker for intestinal differentiation: Its utility and limitations. World J Gastrointest Surg 2011;3:159-66.  Back to cited text no. 19
    
20.
Petrisor O, Giusca SE, Sajin M, Dobrescu G, Caruntu ID. Ki-67, p53 and bcl-2 analysis in colonic versus rectal adenocarcinoma. Rom J Morphol Embryol 2008;49:163-71.  Back to cited text no. 20
    
21.
Georgescu CV, Saftoiu A, Georgescu CC, Ciurea R, Ciurea T. Correlations of proliferation markers, p53 expression and histological findings in colorectal carcinoma. J Gastrointestin Liver Dis 2007;16:133-9.  Back to cited text no. 21
    
22.
Gurzu S, Jung J, Mezei T, Pávai Z. The correlation between the immunostains for p53 and Ki67 with bcl-2 expression and classical prognostic factors in colorectal carcinomas. Rom J Morphol Embryol 2007;48:95-9.  Back to cited text no. 22
    
23.
Guzinska-Ustymowicz K, Stepien E, Kemona A. MCM-2, Ki-67 and PCNA protein expressions in pT3G2 colorectal cancer indicated lymph node involvement. Anticancer Res 2008;28:451-7.  Back to cited text no. 23
    
24.
Nabi U, Nagi AH, Sami W. Ki-67 proliferating index and histological grade, type and stage of colorectal carcinoma. J Ayub Med Coll Abbottabad 2008;20:44-8.  Back to cited text no. 24
    

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Correspondence Address:
Dr. Ram Narayan Das
C/O, Maliandi, Murshidabad - 742 161, West Bengal
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0377-4929.155304

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