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Polymeric Immunoglobulin Receptor-Negative Tumors Represent a More Aggressive Type of Adenocarcinomas of Distal Esophagus and Gastroesophageal Junction

August 30, 2008

By Gologan, Adrian Acquafondata, Marie; Dhir, Rajiv; Sepulveda, Antonia R

Context.-Polymeric immunoglobulin receptor (PIgR) expression has been found in gastric mucosa and gastric cancers, but it is not known whether PIgR expression is related to background intestinal metaplasia nor the patterns of PIgR expression in tumors arising in the distal esophagus and gastroesophageal (GE) junction. Objectives.- To identify clinicopathologic features of tumors associated with PIgR expression and to determine whether PIgR expression is associated with intestinal differentiation of tumors and intestinal metaplasia in background mucosa in 3 groups of upper gastrointestinal adenocarcinomas. These groups are (1) gastric adenocarcinomas, (2) adenocarcinomas of the distal esophagus and GE junction with background intestinal metaplasia, and (3) adenocarcinomas of the distal esophagus and GE junction without background intestinal metaplasia.

Design.-Expression of PIgR and CDX2 in nonneoplastic mucosa, intestinal metaplasia, and adenocarcinomas was examined by immunohistochemistry in 42 cases: 14 gastric and 28 from the distal esophagus and GE junction, including 13 with esophageal or GE junction intestinal metaplasia.

Results.-PIgR and CDX2 were expressed in all cases of intestinal metaplasia. PIgR expression was positive in 40% of group 3 versus 77% of group 2 and 71% of gastric adenocarcinomas (P = .06), and the expression of CDX2 was similar in all tumor groups (80%-83%). Metastaticpositive lymph nodes were more frequent in PIgR-negative tumors (94% vs 58%, P = .01).

Conclusions.-PIgR is uniformly expressed in intestinal metaplasia and in a subgroup of adenocarcinomas of the distal esophagus, GE junction, and stomach. Esophageal and GE junction adenocarcinomas that do not express PIgR show more frequent lymph node metastasis, suggesting that lack of expression of PIgR identifies a subgroup of more aggressive adenocarcinomas.

(Arch Pathol Lab Med. 2008;132:1295-1301)

Adenocarcinomas of the upper gastrointestinal (GI) tract are associated with several different underlying risk factors. Gastric carcinomas that develop in the setting of chronic Helicobacter pylori gastritis, showing extensive atrophy and intestinal metaplasia (IM) of gastric mucosa, and esophageal adenocarcinomas arising on a background of Barrett esophagus, which follows chronic gastroesophageal (GE) reflux, are two well-known pathways of cancer development.1,2 Tumors that involve the GE junction appear to include various types of neoplasms.3 Some cases are related to GE reflux, other cases may be associated with chronic H pylori carditis, and still other cases have unclear underlying mechanisms. The presence or absence of IM is a flag for cancer risk, and its presence or absence in background mucosa may be used to differentiate groups of tumors with potentially different underlying pathogenesis and molecular pathways of development and progression.

Several markers of intestinalization in the gastric and GE junction mucosa have been well characterized, such as the intestinal- type mucin MUC2,4-7 CDX2,8-14 CDX1,8,15 villin, 16-18 CD10,5,6,19 sucrase-isomaltase,17,20 human defensin, 21,22 and aminopeptidase.17 The CDX1 and CDX2 homeobox genes are expressed in the epithelia of the small and large intestines and have important roles in cell differentiation and proliferation.23 CDX2 expression has been reported in 85% to 94% of cases of gastric IM.8,10,11 CDX2 is also expressed in all cases of IM of Barrett esophagus, 12-14 representing a sensitive marker of intestinal differentiation.

The polymeric immunoglobulin receptor (PIgR) is a protein involved in the transport of immunoglobulin A (IgA) across mucosal membranes, from the basolateral aspect of epithelial cells to the luminal surface.24,25 PIgR is highly expressed in intestinal epithelial cells and is downregulated in adenocarcinomas of the colon.26 PIgR is not present in normal gastric mucosa. However, production of PIgR by gastric mucous cells is induced by H pylori infection. 27 Expression of PIgR also has been documented in IM of the gastric mucosa and stomach carcinomas, with progressive loss in advanced stages.28 The expression patterns of PIgR in adenocarcinomas of the GE junction and esophagus have not been reported. Because PIgR is associated with the intestinal epithelial cell defense functions, PIgR may be differentially expressed in upper GI tumors in a manner related to the intestinal phenotype and may correlate with the presence of IM in the background mucosa. Further, because IM has been linked to well-defined pathways of esophageal and gastric adenocarcinoma development, we hypothesized that markers of the intestinal lineage, CDX2 and PIgR, may segregate together during carcinogenesis into molecular subgroups related to a similar underlying pathogenesis.

The objectives of this study were to determine whether PIgR expression is associated with intestinal differentiation and to evaluate the clinicopathologic patterns of PIgR expression in 3 groups of upper GI adenocarcinomas, including gastric adenocarcinomas and tumors of the distal esophagus and GE junction, either associated with IM or without IM.

MATERIALS AND METHODS

Selection of Cases and Patient Demographics

A total of 42 cases of resected adenocarcinomas of the upper GI tract was selected from the files of the University of Pittsburgh Medical Center, and hematoxylin-eosin (H&E) stains, gross descriptions, and prior biopsy reports were reviewed. Based on the tumor location and presence or absence of background IM, after evaluation of the resection specimen and, when available, preceding biopsy results, the cases were separated into 3 groups that included (1) 14 primary gastric adenocarcinomas, (2) 13 adenocarcinomas of the distal esophagus and GE junction associated with background IM, and (3) 15 adenocarcinomas of the distal esophagus and GE junction not associated with background IM. The presence of IM was evaluated in the tubular esophagus, GE junction, and stomach in the resection specimens. The group of patients with gastric cancer included 3 African Americans, 1 Asian, and the remainder white, whereas all patients in groups 2 and 3 were white. There were 5, 1, and 2 women in groups 1, 2, and 3, respectively.

Histology and Immunohistochemistry

Sections of formalin-fixed, paraffin-embedded tissues were used for immunohistochemistry. Immunohistochemical staining was performed using anti-PIgR (1:4800; clone COMPO2, Lab Vision NeoMarkers, Fremont, Calif) and anti-CDX2 antibodies (1: 200; clone CDX2-88, BioGenex, San Ramon, Calif) using a standard biotin-avidin method, in a Dako Autostainer. Semiquantitative evaluation was performed as follows: 0, less than 10% positive cells; 1, 10% to 50% positive cells; and 2, more than 50% positive cells displaying cytoplasmic and membrane-associated immunoreactivity (PIgR) and nuclear staining (CDX2). Scores of 1 and 2 were interpreted as positive staining in the tumor tissues.

Statistical Analysis

Analyses were performed using Sigma Stat 3.0 (SPSS, Inc) software for Windows. Two-by-two contingency table analyses were performed using the 2-tailed Fisher exact test or chi-square, and the Student t test or Mann-Whitney rank sum test were used for noncategorical data. Survival analyses were performed with the log-rank test. Significant differences were considered for P

RESULTS

The group of cases studied included 14 primary gastric adenocarcinomas (group 1), 13 adenocarcinomas involving the distal esophagus and GE junction associated with IM (group 2), and 15 adenocarcinomas involving the distal esophagus and GE junction that were not associated with IM (group 3). The overall average age of patients in group 1, group 2, and group 3 was 69, 61, and 65 years, respectively. The gastric adenocarcinomas included 9 cases of antrum adenocarcinomas and 5 cases of gastric body adenocarcinomas. Two cases were of the diffuse type, and the others were of the intestinal type. The 2 diffuse-type adenocarcinomas in the gastric body were not associated with gastric IM and showed PIgR expression. Intestinal metaplasia in the background gastric mucosa was present in 78.6% (11/14) of cases of gastric adenocarcinomas. Helicobacter pylori organisms were not identified in any of the gastrectomy specimens. Immunohistochemical stains for PIgR in gastric, esophageal, and GE junction IM demonstrated cytoplasmic and membranous apical and lateral staining, whereas CDX2 was expressed in the nucleus (Figures 1 through 3). In adenocarcinomas, PIgR was expressed with a cytoplasmic and membranous apical and lateral pattern, with occasional accumulation within the lumen of the glands (Figures 1 through 3).

Figure 1 shows examples of esophageal IM and tumors arising on a background of IM in the distal esophagus and the GE junction. Figure 1, A (H&E), shows a representative case of esophageal IM; Figure 1, B, shows immunohistochemical staining for CDX2; and Figure 1, C, shows immunohistochemical staining for PIgR. CDX2 expression in tumors was detected in the nucleus (Figures 1 through 3). Figure 1, D (H&E), shows a representative case of poorly differentiated adenocarcinoma from the distal esophagus and GE junction; Figure 1, E, shows staining for CDX2; and Figure 1, F, shows staining for PIgR. Figure 1, G (H&E), shows a moderately differentiated adenocarcinoma from the distal esophagus and GE junction; Figure 1, H, shows staining for CDX2; and Figure 1, I, shows staining for PIgR. Figure 2 shows examples of tumors arising in the distal esophagus and GE junction without background IM. Figure 2, A (H&E), shows a representative moderately differentiated adenocarcinoma from the distal esophagus and GE junction; Figure 2, B, shows staining for CDX2; and Figure 2, C, shows staining for PIgR. Figure 2, D (H&E), shows a poorly differentiated adenocarcinoma from the distal esophagus and GE junction; Figure 2, E, shows staining for CDX2; and Figure 2, F, shows staining for PIgR.

Figure 3 shows a representative case of gastric IM and adenocarcinoma. Figure 3, A, shows gastric antral mucosa negative for IM and negative for PIgR by immunohistochemical staining. Gastric IM, positive for PIgR and CDX2, is shown in Figure 3, B and C, respectively. Figure 3, D (H&E), shows a poorly differentiated gastric adenocarcinoma; Figure 3, E, shows negative immunohistochemical staining for CDX2; and Figure 3, F and G, shows focal positive staining for PIgR. Lymph node metastases of this poorly differentiated carcinoma demonstrate negative CDX2 expression (Figure 3, H) and positive PIgR expression (Figure 3, I).

In the stomach, PIgR and CDX2 were extensively expressed in all cases of IM and only focally and weakly expressed in 42.9% and 25% of cases in nonneoplastic/ nonmetaplastic background glandular mucosa, respectively (P

PIgR and CDX2 expression in background nonneoplastic/ nonmetaplastic glandular mucosa of group 2 cases demonstrated focal positive staining for PIgR and CDX2 in 50% and in 22% of cases, respectively (Table 1), and the background nonneoplastic and nonmetaplastic glandular mucosa showed focal staining of foveolar epithelium for PIgR in 38.5% (5/13) of cases in group 3, whereas all these cases were negative for CDX2 (P

As shown in Table 1, the expression of CDX2 was similar among groups: group 1 (gastric adenocarcinomas), 83%; group 2, 80%; and group 3, 80%. PIgR expression was 77% in group 2 versus 40% in group 3 adenocarcinomas (P = .10) (Table 1). In addition, differential expression of PIgR versus CDX2 was seen in group 2 versus group 3 adenocarcinomas (P = .01, rank sum test).

There were 23 adenocarcinoma cases with IM in the background mucosa (including all group 2 and 78.6% of the gastric adenocarcinomas), whereas the remaining 19 of 42 cases studied did not have IM (these cases included group 3 and gastric adenocarcinomas without IM of the gastric mucosa). Overall, of the 23 cases with background IM, 17 expressed PIgR in the tumors, and of the 19 cases without IM, 9 expressed PIgR in the tumors (P = .10). There were 10 cases that did not have IM, and the tumor did not express PIgR; and there were 6 cases that had a PIgR-negative tumor with a positive background of IM. These data suggest that although there is overlap of PIgR expression in tumor tissue and the presence of an IM phenotype of the background mucosa, PIgR expression can be independent of the IM-carcinoma sequence.

All tumors were more frequent in men, reflecting the demographics associated with these neoplasms. There were no significant age differences between patients with tumors that expressed PIgR and those with tumors that did not (Table 2). There was no correlation of PIgR or CDX2 expression with tumor grade or tumor (T) stage (Table 3). Group 3 tumors showed lymph node metastasis at a higher rate than group 2 tumors, with lymph node metastases detected in 86.7% (13/15) and 53.9% (7/13) of cases, respectively, but the difference did not reach significance (P = .09).

Interestingly, of the 26 tumor cases positive for PIgR, including group 1 (gastric adenocarcinomas), group 2, and group 3 (Table 3), 15 (57.7%) had positive lymph nodes, whereas of the 16 cases negative for PIgR, 15 (93.7%) had positive lymph nodes, suggesting a better behavior of PIgR-positive adenocarcinomas (P = .01). This finding appears to be related to PIgR expression rather than grade or T stage of the tumors, because no statistically significant differences of grade and T stage were found in PIgRpositive versus PIgR-negative tumors (Table 3).

The pathologic stage among the 16 PIgR-negative tumors was T1 (1 case; 6%), T2 (6 cases; 37%), T3 (8 cases; 50%), and T4 (1 case; 6%). The PIgR-negative tumor with stage T1 did not have lymph node metastasis, whereas the remaining 15 cases were positive for lymph node metastatic tumor. The survival period for patients with PIgRnegative tumors in each T stage group was 25.1, 30.6, 34.4, and 24.5 months, respectively. These data suggest a high likelihood that PIgR-negative tumors with at least stage T2 will have positive lymph node metastasis. However, further studies with larger numbers of cases are warranted. The pathologic stage among the 26 PIgR- positive tumors was T1 (5 cases; 19%), T2 (5 cases; 19%), T3 (13 cases; 50%), and T4 (3 cases; 12%). The mean survival period for patients with PIgR-positive tumors in each T stage group was 45.2, 55.3, 32.2, and 23.7 months, respectively. Although the survival period for patients with PIgR-positive, stage T2 tumors was greater than that of patients with stage T4 tumors, the difference is not significant (P = .63).

Next we analyzed the data to determine whether the increased lymph node metastasis of PIgR-negative tumors was associated with a specific tumor group. This analysis was limited by the small number of cases in the subgroups. For gastric adenocarcinomas, there were 7 cases of positive lymph nodes of 10 PIgR-positive cases (70%) and 3 cases of positive lymph nodes of 4 PIgR-negative cases (75%). For group 2 tumors, there were 4 cases of positive lymph nodes of 10 PIgR-positive cases (40%) and 3 cases of positive lymph nodes of 3 PIgR-negative cases (100%). For group 3 tumors, there were 4 cases of positive lymph nodes of 6 PIgR-positive cases (67%) and 9 cases of positive lymph nodes of 9 PIgR-negative cases (100%). Combining group 2 and group 3 tumors, 50% of PIgR-positive cases had lymph node metastases, compared with 100% of PIgR-negative cases (P = .01). These data indicate that PIgR-negative tumors are most often lymph-node positive in tumors of the distal esophagus and GE junction, regardless of the presence or absence of background IM.

The overall survival rate of patients with tumors that expressed CDX2 versus tumors that did not and of patients with tumors that expressed PIgR versus tumors that did not was slightly higher, but the differences were not statistically significant (P = .43 and P = .19, respectively) (Figure 4, A and B).

COMMENT

Although the incidence of gastric cancer is decreasing, it remains the second leading cause of cancer-related deaths worldwide.29 Adenocarcinomas of the distal esophagus and GE junction have shown an increasing incidence in recent years, leading to increased interest in these tumors.30

PIgR expression has been studied in gastric cancers, but its expression in tumors of the distal esophagus and GE junction has not been reported. We studied 3 groups of upper GI adenocarcinomas: (1) gastric, (2) adenocarcinomas of the distal esophagus and GE junction with background IM, and (3) adenocarcinomas of the distal esophagus and GE junction without background IM. We found that PIgR expression was present in 71% of gastric adenocarcinomas and 77% of group 2 tumors, versus 40% of group 3 adenocarcinomas (P = .06), and the expression of CDX2 was similar in all tumor groups (80%-83%). Because we cannot exclude that some group 3 tumors developed on a background of short-segment Barrett esophagus in which the tumor overgrew the areas of IM, it is possible that some of the group 3 tumors fit into group 2 rather than group 3. Prospective studies are needed to clarify this point.

To examine the relationship between expression of PIgR in the background IM and expression in the tumor, we examined the expression of PIgR compared with that of CDX2, a well-known marker of intestinal differentiation, and found that both PIgR and CDX2 were extensively expressed in all cases of IM. However, among 19 cases without IM, 9 expressed PIgR in the tumors, and focal PIgR expression was detected in the nonmetaplastic and nonneoplastic background mucosa of some cases, suggesting that the expression of PIgR often parallels the intestinal phenotype but may develop independently. This notion is also supported by the finding that differential expression of PIgR versus expression of CDX2 was seen in group 2 versus group 3 adenocarcinomas (P = .01).

We noted a relatively high frequency of CDX2 expression in group 3 tumors, which could be explained by either intestinal differentiation of the tumor during cancer progression or by the presence of short-segment Barrett esophagus or IM at the GE junction, which was no longer detected in the specimen when the esophagectomy was performed. Both PIgR and CDX2 were expressed in the foci of IM in the esophagus and stomach, and the sensitivity of either of these markers to detect IM was 100%. Occasionally, focal PIgR and CDX2 expression was observed in gastric mucosa adjacent to areas of IM, in agreement with prior studies.12,13 It is postulated that such foci may represent epithelium in an earlier phase of intestinal phenotypic differentiation.

Importantly, of the tumor cases positive for PIgR among the 3 adenocarcinoma groups, 57.7% had lymph nodes positive for metastatic adenocarcinoma, whereas 93.7% of the cases negative for PIgR had positive lymph nodes, suggesting a more aggressive clinical behavior of PIgRnegative adenocarcinomas. This increased tendency for lymph node metastasis of PIgR-negative tumors appears to be related to PIgR and to be independent of tumor grade and stage, because PIgR expression was not associated with tumor grade or T stage in the tumors studied in our series. It is unclear from our study whether PIgR has a biologic role in tumor cells that affects tumor cell behavior or whether it is only a marker of better tumor behavior unrelated to the cellular functions of PIgR. It is tantalizing to speculate that PIgR may function to increase the local humoral immunity in the tumor and that, in cases with lower PIgR expression, changes in IgA-related immune response in the tumor environment may lead to increased metastatic potential of the tumor cells. In conclusion, expression of PIgR is focal or absent in the nonneoplastic mucosa but is uniformly expressed in IM of the stomach and esophagus. The data from our study suggest that a subgroup of the distal esophagus and GE junction adenocarcinomas that appear to develop in a mucosa without IM may express PIgR less commonly. Further prospective studies are needed to differentiate tumors that appear to arise from nonmetaplastic background from those that have overgrown foci of IM.

The finding that PIgR-negative adenocarcinomas of the distal esophagus and GE junction are associated with reduced survival and increased lymph node metastasis suggests that this subgroup of patients might benefit from different treatment approaches, such as specific adjuvant therapy. Future studies are required to address these hypotheses.

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Adrian Gologan, MD; Marie Acquafondata, BS; Rajiv Dhir, MD, PhD; Antonia R. Sepulveda, MD, PhD

Accepted for publication January 14, 2008.

From the Department of Pathology, McGill University, Sir Mortimer B. Davis-Jewish General Hospital, Montreal, Quebec (Dr Gologan); and the Department of Pathology, University of Pittsburgh, Pittsburgh, Pa (Ms Acquafondata and Drs Dhir and Sepulveda).

The authors have no relevant financial interest in the products or companies described in this article.

Reprints: Antonia R. Sepulveda, MD, PhD, Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania, 3400 Spruce St-Founders Six, Philadelphia, PA 19104 (e-mail: asepu@mail.med.upenn.edu).

Copyright College of American Pathologists Aug 2008

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