Primary Motility  Disorders of the  Esophagus
 The Esophageal
 Esophagogastric  Junction

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Volume: The Esophagogastric Junction
Chapter: Esophageal columnar metaplasia (Barrett s esophagus)

Do studies of PCNA and Ki67 immunolocalization in Barrett's mucosa offer any information about the neoplastic progression?

A.N. Kingsnorth (Liverpool)

A possible explanation for the increased cancer risk in intestinal type (specialized type) Barrett's mucosa relates to increased cell proliferation. The intestinal histological type may be associated with a high rate of celltunalar similar to that of the small intestine [1] which is inappropriate for the esophagus. Following a genetic mutation, an increased rate of cellular proliferation makes it more likely that a mutagenic stimulus will lead to genomic instability and also lead to rapid expansion of mutated clones and the appearance of malignancies [2].

Certain tightly regulated and expressed proteins regulate the different phases of the cell cycle, thereby controlling the cell's responsiveness to stimulation or inhibition of cellular profileration [3, 4]. A number of the genes encoding these cellcycle proteins are now recognized. Proliferating cell nuclear antigen (PCNA) is a 36-kilodalton nuclear protein that accumulates progressively through G1-M of the cell cycle and disappears at the end of mitosis [5]. PCNA regulates DNA polymerase delta and, as such, is a key factor in regulation of the cellcycle. A mouse monoclonal antibody PC10 directed against PCNA is used semi-quantitatively to detect the presence and intensity of nuclear staining. Ki67 is a murine monoclonal antibody that detects a nuclear antigen expressed in all phases of the cell cycle except G0 and, as such, is a sensitive marker for cellular proliferation [6]. The availability of Ki67 has enabled a semi-quantitative analysis of cellcycle kinetics indicating an expansion of the proliferative compartment on the mucosal surface. Thus PCNA is an auxiliary protein to DNA polymerase delta and is an absolute requirement for cellular proliferation, whilst Ki67 is a more general marker of aberrant cellular proliferation.

PCNA immunolocalization has indicated that intensity of staining increases from the crypt towards the luminal cells where labelling is uncommon [7, 8]. Increased PCNA labelling is seen in intestinal type epithelium where labelling is observed more intensely in the neck and the luminal surface of the glands. This expansion of the proliferative compartment in intestinal type Barrett's metaplasia might explain the association of this type of mucosa with malignant progression. Biopsies from patient's with high grade dysplasia and adenocarcinoma have a more intense PCNA labelling index than benign metaplasia of any type.

With Ki67 labelling, Barrett's metaplasia, and negative-for-dysplasia shows the mean Ki67 positive fraction of cells to be twice that in control mucosa [9]. However more advanced stages of neoplastic progression do not show additional increases in the percentage of cells in the G1 interval of the cell cycle. Polkowski et al. however showed that with increasing grades of dysplasia there was an accompanying increase in Ki67 labelling index and an upward shift of the proliferative compartment [10].


In conclusion PCNA and Ki67 can be used to detect cell cycle abnormalities and alterations in proliferation but they are not indicative of neoplastic progression.


1. Goodlad RA. Gastrointestinal epithelial proliferation. Dig Dis 1989;7:167-177.

2. Rabinovitch PS, Reid BJ, Haggitt RC, Norwood TH, Rubin CE. Progression to cancer in Barrett's esophagus is associated with genomic instability. Lab Invest 1988;60:65-71.

3. Kaczmarek I. Protooncogene expression during the cell cycle. Lab Invest 1986;54:365-376.

4. Dunphy WG, Newport JW. Unravelling of mitotic control mechanisms. Cell 1988;55:925-928.

5. Bravo R, Frank R, Blundell PA, MacDonald-Bravo H. Cyclin PCNA is the auxiliary protein of DNA polymerase-delta. Nature 1987;326:515-517.

6. Gerdes J, Lemke H, Baisch H, Waeker HH, Schwab V, Stein H. Cell cycle analysis of a cell proliferation associated human nuclear antigen defined by the monoclonal antibody Ki67. J Immunol 1984;133:1710-1715.

7. Gray MR, Hall PA, Nash J, Ansari B, Lane DP, Kingsnorth AN. Epithelial proliferation in Barrett's esophagus by proliferating cell nuclear antigen immunolocalization. Gastroenterology 1992;103:1769-1776.

8. Jankowski J, McMenamin R, Yu C, Hopwood D, Wormsley KG. Proliferating cell nuclear antigen in oesophageal diseases: correlation with transforming growth factor alpha expression. Gut 1992;33:587-591.

9. Reid BJ, Sanchez CA, Blount PL, Levine DS. Barrett's esophagus: cell cycle abnormalities in advancing stages of neoplastic progression Gastroenterology 1993;105:119-129.

10. Polkowski W, van Lanschot JJB, ten Kate FJW, Baak JPA, Tytgat GNJ, Obertop H, Voorn WJ, Offershaus GJA. The value of p53 and Ki67 as markers of tumour progression in the Barrett's dysplasiacarcinoma sequence. Surg Oncol 1995;4:163-711.

Publication date: May 1998 OESO©2015