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Year : 2018  |  Volume : 61  |  Issue : 2  |  Page : 170-175
Evaluation of p53 protein expression in Barrett esophagus

1 Department of Pathology, Kasturba Medical College, Mangalore, Manipal Academy of Higher Education, Manipal, Karnataka, India
2 Department of Gastroenterology, Kasturba Medical College, Mangalore, Manipal Academy of Higher Education, Manipal, Karnataka, India

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Date of Web Publication20-Apr-2018


Background: Loss of heterozygosity of p53 along with aneuploidy is deemed to be the early molecular steps in Barrett metaplasia-dysplasia-adenocarcinoma sequence. Objective biomarkers need to be used along with microscopy for risk stratification to predict the progression of Barrett esophagus (BE) to carcinoma. Aim: This study aims to study p53 protein expression in dysplasia and correlate the same with morphology in BE. Materials and Methods: A time-bound study was conducted from January 2011 to June 2015. All esophageal biopsies showing histological evidence of columnar epithelium with the presence of goblet cells were included. The cases which showed dysplasia were graded on hematoxylin and eosin stain. Evaluation of p53 immunohistochemistry staining was done on all the cases of BE. Dysplasia was correlated with the expression of p53 using Chi-square value (χ2) and Fischer's exact test wherever appropriate. P < 0.05 was considered to be statistically significant. Results: Of 829 esophageal biopsies received, 119 were endoscopically suspected to be BE, of which 85 cases were confirmed on microscopy. In our study, there were 75 cases negative for dysplasia (88.2%), 8 with low-grade dysplasia (LGD) (9.4%), and two with high-grade dysplasia (HGD) (2.4%). Three cases of BE had associated adenocarcinoma. Immunostaining with p53 done on all the 85 cases showed positive staining in all cases with LGD, one with HGD and two with adenocarcinoma. In the present study, immunostaining with p53 showed 90% sensitivity, 89.3% specificity, positive predictive value of 52.9%, and negative predictive value of 98.5%. Conclusion: The technical simplicity, easy availability, and comparatively lower cost enhance the role of p53 as a biomarker in risk stratification for patients with BE.

Keywords: Barrett esophagus, dysplasia, esophageal adenocarcinoma, p53

How to cite this article:
Krothapalli M, Kini JR, Kini H, Sahu KK, Shenoy S, Krishna SG, Tantry B V. Evaluation of p53 protein expression in Barrett esophagus. Indian J Pathol Microbiol 2018;61:170-5

How to cite this URL:
Krothapalli M, Kini JR, Kini H, Sahu KK, Shenoy S, Krishna SG, Tantry B V. Evaluation of p53 protein expression in Barrett esophagus. Indian J Pathol Microbiol [serial online] 2018 [cited 2021 Mar 6];61:170-5. Available from: https://www.ijpmonline.org/text.asp?2018/61/2/170/230548

   Introduction Top

Barrett esophagus (BE) refers to a metaplastic process induced by acid-peptic reflux which erodes the esophageal squamous mucosa.[1],[2] It is diagnosed on endoscopy by the presence of columnar-lined epithelium (CLE) and on biopsy by intestinal metaplasia.[3] BE is by far the strongest predisposing factor for the development of adenocarcinoma, a malignancy showing a progressively increasing incidence over the last 40 years.[4] Despite the advances in multimodality treatment, esophageal adenocarcinoma (EAC) is associated with poor prognosis and a 5-year survival of < 20%. BE develops in about 5%–10% of individuals with gastroesophageal reflux disease (GERD). About 0.5%–1% of BE patients progress to EAC and only 5%–10% of EAC cases have a prior diagnosis of BE.[2] However, the chances of EAC among BE cases are estimated to be 30–125-fold greater than that of the general population.[4] The annual risk of EAC is about 0.25% for patients having BE without dysplasia and 6% for those with high-grade dysplasia (HGD).[5] BE is found in 1.6% of the general population and in 10% of those patients with symptomatic GERD.[6] The prevalence of BE in Asia excluding Japan ranges from 0.06% to 6.2%. In Japan, the prevalence of biopsy-confirmed BE is reportedly 19.9% and as high as 43% in those series without biopsy.[7] Till date, the studies from India have reported a prevalence rate of BE ranging from 2.6% to 23%.[8],[9]

Dysplasia occurs in a backdrop of metaplasia. Dysplasia is currently the preeminent risk indicator of progression to cancer. Multiple molecular alterations have been implicated in the microscopic spectrum that progress from Barrett metaplasia-dysplasia-adenocarcinoma (MDA). Aberrant expression of oncogenes, tumor suppressor genes, and related proteins is noted in the carcinogenesis of EAC. These changes hinder the exquisite control of cell cycle, proliferation, and apoptosis. Although the chain of molecular events is not strictly defined, promoter gene hypermethylation, loss of heterozygosity (LOH), or mutations of p16 are the earliest changes in malignant progression of BE.[10],[11] LOH of p53 along with aneuploidy is deemed to be the early molecular step in Barrett's MDA sequence.[10] Upregulation of iNOS, cyclooxygenase 2, telomerase, matrix metalloproteinases along with downregulation of E-cadherin and matrix metalloproteinases inhibitors have a key role in the pathogenesis of EAC.[12] Use of objective biomarkers with microscopy is required for risk stratification to predict the progression to cancer.[13] p53 is a tumor suppressor gene located on the short arm of chromosome 17. It normally encodes wild-type 53 protein, which controls cell growth. There is a lack of large-scale prospective studies with both p53 genetic and immunohistochemistry (IHC) workup, especially from Indian subcontinent to assess the role of p53 in cancer progression.

The aim was to study the histomorphology of BE in correlation with endoscopic findings and to evaluate p53 protein expression in relation to dysplasia.

   Materials and Methods Top

A descriptive study with both retrospective and prospective components was conducted for a period of four and half years, i.e., from January 2011 to June 2015. Data were collected retrospectively from January 2011 to November 2013 and thereafter prospectively. Relevant clinical history and endoscopy findings were collected from the medical records of all the patients whose esophageal biopsies were received in the Department of Pathology of our institute. Follow-up biopsies and records were collected and analyzed. Clearance from Institutional Ethics Committee of the university was obtained. Multiple endoscopic esophageal biopsies were taken as per standard protocol from all the four quadrants over a circumferential line. Biopsies showing histological findings of metaplastic columnar lining epithelium with goblet cell and known cases of BE presenting with adenocarcinoma were included. Biopsies with insufficient histological material, purely adenocarcinoma cases without Barrett's changes, biopsies with only squamous epithelium and squamous cell carcinoma were excluded from the study.

The mucosal biopsies were processed as per the standard protocol in our laboratory and 3-μ thick serial sections were cut from the 10% buffered formalin-fixed, paraffin-embedded (FFPE) tissue blocks. The routine sections stained with H and E of all the cases were reviewed and the histopathological findings were recorded. Periodic acid–Schiff and Alcian blue (pH 2.5) special stains were done on all cases of BE.

Grading of dysplasia in BE was done following the classification given by inflammatory bowel disease study group: negative for dysplasia, indefinite for dysplasia, positive for dysplasia –LGD, HGD, and carcinoma.[14]

All cases of histologically confirmed BE were subjected to immunohistochemical staining for detection of p53 protein expression using immunoperoxidase polymer method. IHC was performed on FFPE tissue. Anti–p53 protein (D07), ready-to-use mouse monoclonal primary antibody kit (BioGenex) was used as per the manufacturer's instructions. Polymer-labeled 2-step method using super-sensitive polymer-HRP (horseradish peroxidase) IHC detection system was employed. The level of protein accumulation in the nucleus was scored as: 0 (no detectable immunostain), 1 (few nuclei up to five nuclei), 2 (up to 10% nuclei), 3 (10%–50% nuclei), and 4 (>50% nuclei).[15],[16]

The data were analyzed by proportions and tables. Various morphological features were analyzed for their frequency. Dysplasia was correlated with the expression of p53 using Chi-square value (χ2) and Fischer's exact test wherever appropriate. P < 0.05 was considered to be statistically significant. All tabulations or statistical analyses were done using IBM SPSS (Statistical Product for Services Solutions) 13 data software.

   Results Top

Of 829 esophageal biopsies received, 119 were endoscopically suspected to be BE; 85 cases were confirmed on microscopy. Hence, the prevalence of BE in referral endoscopy cases in the present study was calculated to be 10.25%. The age range in our study was 19–87 years. Overall, the mean age of presentation of BE cases was 55.38 ± 14.679 years (median 56 years). In men, it was 53.95 ± 15.38 years, and in women, it was 58.4 ± 13.87 years. Majority of the cases (51.8%) were seen in the age range of 51–70 years. In the present study, BE was more common in men, 60 out of 85 cases, i.e., 70.6%. Thereby male to female ratio was 2.4:1. Frequencies of presenting symptoms are shown in [Figure 1].
Figure 1: Frequency of presenting symptoms

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On endoscopy, based on the extent of CLE seen at the lower end of esophagus, short-segment BE (SSBE) was documented in 49.4% and long segment BE (LSBE) in 37.65% of cases. Therefore, ratio of SSBE to LSBE was 1.3:1. Of the 85 cases, in 11 cases, endoscopic extent was not available. Other associated lesions along with CLE were noted at the lower end of esophagus [Figure 2].
Figure 2: Associated lesions on endoscopy at the lower end of the esophagus

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The microscopic findings are shown in [Table 1] [Figure 3] and [Figure 4]. IHC staining with p53 was done on all 85 cases of confirmed BE. The quantitative grading was done and given a score from 0 to 4 as shown in [Table 2]. In the present study, it was noted that all eight cases of LGD have positive p53 staining, indicating p53 protein accumulation occurs with dysplastic changes. Both the cases of HGD in our study were associated with adjacent adenocarcinoma, of which one case of well-differentiated adenocarcinoma showed p53-positive staining while the other one along with adjacent moderately differentiated adenocarcinoma was negative for p53 staining. The third patient who had moderately differentiated adenocarcinoma with adjacent low-grade dysplasia (LGD) Barrett mucosa showed p53 staining of score 1 in both the dysplastic and neoplastic epithelium.
Table 1: Microscopic features

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Figure 3: (a) Endoscopic salmon pink appearance of Barrett esophagus. (b) Low-power view showing columnar mucosa with goblet cells (H and E, ×100). (c) High-power view of the same (H and E, ×400). (d) Goblet cells stained by Alcian Blue at pH 2.5 (×100). (e) Periodic acid–Schiff stain demonstrating intestinal metaplasia in Barrett esophagus (×100)

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Figure 4: (a) Barrett esophagus with low-grade dysplasia showing hyperchromatic, enlarged, pleomorphic nuclei and mild loss of polarity (H and E, ×400). (b) Barrett esophagus with low-grade dysplasia showing p53 nuclear positivity (×400, p53 immunostain). (c) Mucosa showing distorted, irregular malignant glands with back-to-back arrangement (H and E, ×100). (d) Adenocarcinoma showing p53 nuclear positivity (×400, p53 immunostain)

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Table 2: Immunohistochemistry p53 scoring on Barrett esophagus cases

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A Chi-square test of independence was performed to examine the relation between dysplasia in BE and p53 staining. The relationship between these variables was highly significant; χ2 (df: 6; n = 85) =63.72; P < 0.01. A Chi-square test of independence was performed to correlate between regenerative atypia in BE and p53 staining. The relationship between these variables was significant; χ2 (df: 3; n = 85) =14.78; P < 0.05. Since the number of adenocarcinoma associated with BE was <10, Fisher's exact test has been applied for obtaining P value.

Usefulness of p53 expression in the identification of dysplasia was calculated. p53 showed 90% sensitivity and 89.3% specificity. The positive predictive value was 52.9% and negative predictive value was 98.5% and P < 0.05.

   Discussion Top

In a time-bound study conducted in a tertiary health-care system, we evaluated patients of suspected BE, where endoscopy with biopsy was done to investigate varied presenting complaints of GERD. Although there are studies showing increased incidence of BE, the percentage of individuals with BE progressing to dysplasia and EAC are small.[13]

In the present hospital-based study, the prevalence of BE is 10.25% comparable with other studies. Previous studies from India have reported a prevalence rate between 2.6% and 23.64%.[6] Higher prevalence is noted in the nonpopulation-based studies due to the fact that in tertiary health-care center, samples were taken from patients with complaints of GERD rather than random samples in population-based studies.[4]

In this study, mean age of presentation of BE cases was 55.38 years. Majority of the cases (51.8%) were seen in the age range of 51–70 years. This is similar to age range reported in other studies; BE therefore is common in older individuals (age group of 50–60 years).[4],[8],[17],[18],[19] Men were twice more often affected than women, consistent with several studies.[4],[6],[20],[21],[22]

In our study, majority of patients presented with GERD symptoms such as dyspepsia in 36.5% (n = 31) and heartburn in 24.7% (n = 21). Rex et al. in their study on 961 patients found that LSBE was uncommon in patients without heartburn.[17] In a study done by Rajendra et al., of 123 cases of BE, reflux symptoms were present in 54 cases (43.9%).[18] In a study done on 1000 samples from general population by Ronkainen et al., 16 cases were diagnosed as BE, and of these, 40% cases had reflux symptoms.[19] Out of nine cases of BE in a study done by Wani et al., six cases had regurgitation symptoms (66.7%).[6] Hence, the symptoms of GERD are the most common presenting complaint in patients with BE.

Our study has shown highly significant correlation of p53 staining with dysplasia (P < 0.01). This is comparable to studies that have shown significant correlation with degree of dysplasia in BE.[23],[24],[25] In contrast, there are a few studies that have variable findings in the p53 expression in BE.[12],[21]

In the current study, one case out of 68 BE cases, diagnosed as negative for dysplasia, stained positive for p53, comparable to a study done by Jones et al. wherein 7/73 of negative for dysplasia cases showed positive p53 staining.[26] This however differed from the studies of Hardwick et al. (0/20), Giménez et al. (0/25), and Younes et al. (0/53) in which p53 expression was negative in all cases of negative for dysplasia.[22],[24],[27] They concluded that negative p53 staining does not promise a stable evolution.[19],[24] Jones et al. opined that positive p53 in negative for dysplasia cases indicate early mutations that occur in the neoplastic progression of BE.[26] In our study, all the eight cases of LGD showed positive p53 staining while other authors have reported a range varying from 9% to 66%.[24],[26],[27] The reasons put forward for variability in these studies could be because of different antibody sensitivity and even the methods used to score p53 staining. Giménez et al. considered p53 was positive if only minimum of 5% nuclei showed p53 staining.[24] van Dekken et al. in their study graded negative if <1% of nuclei are stained.[28] Dvorak et al. in their study considered intensity of nuclear staining by p53 and graded as 0 where there was no staining, 1 plus for mild staining, 2 plus for medium staining, and 3 plus for intense staining.[29] It was concluded that positive score given by considering minimal nuclear staining without objective minimum threshold appears inadequate and also can prone to different interpretations.[22]

Immunostaining with p53 was seen in one of the two HGD and two of the three EAC cases. In a study conducted by Hardwick et al., among 30 cases of adenocarcinoma studied, only 16 cases (53%) and 10 cases of adjacent HGD showed p53 staining.[22] Thus, they concluded that p53 dysfunction may be responsible for progression of disease from dysplasia to EAC. Seven out of eight cases of EAC showed p53 immunoreactivity in a study done by Younes et al.[27] Lower expression of p53 in EAC cases (70%) as compared to HGD cases which showed 100% p53 expression was attributed to increased turnover time of the protein thereby leading to reduction in half-life of oncoprotein and thus making its detection by IHC difficult. Other reasons put forth for not detecting p53 by IHC included supplementary mutations or coupling with different protein leading to confrontational change in p53 or lack of sufficient amount of p53 oncoprotein production in later stages of EAC.[26] It has been documented that p53 gene mutation need not always be associated with p53 positivity on IHC.[30],[31] The occurrence of p53 protein staining ranges from 34% to 87%. Majority of adenocarcinomas did not show p53 on IHC even though gene mutations were present.[31] Hence, p53 IHC in combination with different detection techniques such as fluorescent in situ hybridization (FISH) and polymerase chain reaction (PCR) is recommended.[24] These could not be performed for validation of our results due to financial constraints.

Overall sensitivity of p53 in detecting dysplasia in BE in our study was 90% implying a good detection rate. Hence, it can be used as an adjunct to histological grading and serves as a supportive tool in the diagnosis of dysplasia. In the present study, the specificity of p53 on IHC was 89.3% indicating that though p53 positivity is seen, it does not always imply the presence of dysplasia. Hence, such biopsies should be carefully reanalyzed for features of dysplasia. The presence of background inflammation should be given due attention as it favors regenerative atypia rather than dysplasia. IHC for p53 cannot be used alone for grading or detecting dysplasia as seen in our case, wherein one case with dysplasia was negative for p53. This case would need p53 protein evaluation by additional techniques such as FISH or PCR or p53 gene mutation analysis for further evaluation and confirmation. In the present study, seven cases out of 85 cases had shown positive p53 staining though they had no definite dysplastic changes noted on microscopy. These seven cases showed regenerative atypia on microscopy hence were not categorized into dysplasia group. Long-term follow-up of these cases was not possible to determine whether this regenerative atypia had subsided after treatment for GERD or if they had progressed to dysplasia. As a result, there was decreased specificity of p53 in detecting dysplasia in our study. Contrary to the present finding, in a study reviewed by Bansal et al. on 630 patients, 49% of patients with p53 positivity progressed from LGD to EAC thus inferred that p53 has more specificity than sensitivity.[32] Sensitivity and specificity of p53 immunostaining was found to be 100% and 53.5% in a study done by Giménez et al.[24]

   Conclusion Top

The technical simplicity, easy availability, and comparatively lower cost enhance the role of p53 as a biomarker in risk stratification for patients with BE. There is a lack of large-scale prospective studies assessing the role of p53 in cancer progression in BE patients, especially from the Indian subcontinent. In our study, we reviewed the efficacy of p53 as an adjunct to histopathological examination of H and E stained sections in detecting dysplasia. However, we were constrained by the lack of follow-up and the sample size in evaluating p53 to differentiate regenerative atypia from LGD. Further studies with a larger sample size are suggested to overcome the limitations of this study.

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   References Top

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Correspondence Address:
Jyoti Ramnath Kini
Department of Pathology, Kasturba Medical College, Mangalore - 575 001, Karnataka
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/IJPM.IJPM_369_16

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  [Figure 1], [Figure 2], [Figure 3], [Figure 4]

  [Table 1], [Table 2]


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