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Annals of Surgical Oncology 9:887-893 (2002)
© 2002 Society of Surgical Oncology

ORIGINAL ARTICLES

Correlation of MUC5AC Immunoreactivity With Histopathological Subtypes and Prognosis of Gastric Carcinoma

Stephan E. Baldus, MD, Stefan P. Mönig, MD, Verena Arkenau, Franz-Georg Hanisch, PhD, Paul M. Schneider, MD, Juergen Thiele, MD, Arnulf H. Hölscher, MD and Hans P. Dienes, MD

From the Institute of Pathology (SEB, VA, JT, HPD), Department of Visceral and Vascular Surgery (SPM, PMS, AHH), and Center of Biochemistry (SEB, VA, JT, HPD, SPM, PMS, AHH), Medical Faculty, University of Cologne, Cologne, Germany.

Correspondence: Address correspondence and reprint requests to: S. E. Baldus, MD, Institute of Pathology, Joseph-Stelzmann-Str. 9, University of Cologne, Cologne, Germany 50931; Fax: 49-221-478-6360; E-mail: s-e.baldus{at}uni-koeln.de


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIAL AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: MUC5AC represents a mucin peptide core expressed in normal gastric epithelia. Its presence in gastric carcinomas was previously described as a characteristic of gastric differentiation.

Methods: MUC5AC reactivity was investigated by immunohistochemistry and correlated with clinicopathological variables in a large series (n = 200) of gastric carcinomas.

Results: A statistically significant association between MUC5AC positivity and parameters of cancer progression (pTNM staging and grading) could not be observed. However, MUC5AC exhibited correlations with certain subtypes of histopathological differentiation. A significant reduction of MUC5AC expression was evident in mucinous and undifferentiated carcinomas according to the World Health Organization classification, as well as in type III cancers according to the Goseki classification system. Furthermore, reduced MUC5AC reactivity (confined to up to 35% of the tumor area) was significantly correlated with an unfavorable prognosis of all patients in univariate and multivariate analysis. The same association could be observed in the subgroup of pTNM stage I patients (n = 60).

Conclusions: A significant reduction of gastric differentiation as reflected by MUC5AC immunoreactivity represents a marker of worse survival probability in gastric cancer. Finally, reduced MUC5AC positivity defines a high-risk subgroup of pTNM stage I patients.

Key Words: Mucin • MUC5AC • Monoclonal antibody • Immunohistology • Stomach • Gastric carcinoma


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIAL AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Mucins represent highly glycosylated, membrane-bound, or secreted glycoproteins, which form an important part of the gastrointestinal mucosal defense system. Several aspects of their structure and function, as well as the histological distribution in normal and neoplastic tissues, have been elucidated in the past.1,2 The tandem repeat sequences of two major secretory mucins of the stomach could be detected, which were named MUC5AC3 and MUC6.4 Furthermore, it was described5 that the MUC5 gene encodes the gastric M1 mucin, which had been earlier demonstrated in gastric columnar epithelial cells and colorectal adenocarcinomas.6 Subsequently, the existence of numerous mucin genes7 and the expression of the respective core proteins8 were investigated systematically by ribonucleic acid analysis and immunohistochemistry (including MUC1–MUC7), respectively. Interestingly, MUC5AC colocalizes with Helicobacter pylori9 and may therefore play an important role in Helicobacter adhesion and infection. The latter is mediated by blood group antigens,10 which might be MUC5AC associated.11 In intestinal metaplasia, the expression pattern of mucin peptides is also altered, leading to a reduced MUC5AC immunoreactivity, especially in type I intestinal metaplasia.12 Earlier studies revealed a decrease of MUC5AC associated with neoplastic transformation.13,14 Comparing the different histopathological subtypes of gastric carcinomas, a strong positivity of tumors belonging to the diffuse type according to the Laurén classification was reported, whereas intestinal and unclassifiable carcinomas exhibited a decrease of MUC5AC.15 MUC5AC immunoreactivity was observed in 100% of early cancers but less than 60% of advanced cancers. Additionally, a strong correlation between MUC5AC and trefoil peptide 1 (TFF1) expression in gastric foveolar epithelium and in the majority of gastric adenocarcinomas, especially of the diffuse type, could be described.16 MUC5AC was colocalized with MUC6 in nearly half of the MUC6 positive carcinomas.17 This pattern was independent of histomorphology and staging. Summarized, the previous publications suggest that MUC5AC expression represents a marker of gastric differentiation in preneoplastic and neoplastic lesions, which may be lost during the progression of disease. In the present work, 200 cases of gastric carcinomas were investigated by immunohistochemistry to elucidate the possible relationship between MUC5AC expression, histopathological differentiation, progression, and prognosis of gastric cancer.


   MATERIAL AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIAL AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patients and Tissue Material
In the present retrospective study, primary gastric carcinomas from 200 patients were included. All specimens were derived from the files of the Institute of Pathology of the University of Cologne. All patients received a potentially curative (total or subtotal) gastrectomy between 1982 and 1991. Nearly all patients received at least a systematic lymphadenectomy of compartment 1 (D1 lymphadenectomy) and lymph node station 7 (left gastric artery). An adjuvant or neoadjuvant radio- and/or chemotherapy was not performed. Patients with gastric stump cancer as well as nonprimary gastric carcinomas were excluded. Furthermore, patients with incomplete resectability (R1 and R2 resections) and those suffering from other malignant tumors were not included in our study. The follow up was performed in our outpatient clinic. Patients who died postoperatively (i.e., 4 weeks after the surgical intervention) were excluded from the study because most of these deaths were not due to the neoplastic disease but other causes (i.e., cardiovascular complications, embolism). Patients’ ages ranged from 19.6 to 88.7 years (mean, 60.8 years; SD, 13.1; median age, 61.0); 107 patients were men and 93 were women. Surviving patients were followed for at least 5 years (range, 5–14 years). At closure of the study, 63 patients (31.5%) were still alive. The median survival time of all patients was 2.2 years. Gastric carcinomas were classified according to the tumor, node, metastasis classification of the International Union Against Cancer,18 the World Health Organization classification,19 Laurén, 20 and Goseki.21 For this reason, histopathological diagnoses and slides derived from the files of the institute were re-evaluated and reclassified. Approval of the study was obtained from the Institutional Review Board.

Immunohistochemical Staining
MUC5AC was visualized immunohistochemically applying monoclonal antibody NCL-MUC-5AC (Novocastra, Newcastle, United Kingdom) after dilution 1:50 (v/v). A streptavidin-biotin procedure was performed as described previously.22 Specimens were incubated with the primary mab for 30 minutes at room temperature. Appropriate positive and negative controls (the latter replacing the primary mab with adequate mouse immunoglobulin) were included. As chromogen, 3-amino-9-ethyl-carbazol (Sigma, Munich, Germany) was applied.

Scoring and Statistical Analysis
A case was considered positive if more than 5% of the tumor area was stained, irrespective of intensity or localization. Positive cases were furthermore divided according to the percentage of immunoreactive tumor areas: 1, >5% to 35%; 2, >35% to 65 %; 3, >65%. A correlation between the degree of MUC5AC reactivity and the previously mentioned histopathological classifications was performed applying the {chi}2 test at a significance level of 5%. Survival analyses included a univariate analysis according to Kaplan and Meier,23 testing for significant differences in survival distribution with the log-rank test. Furthermore, a multivariate analysis using the Cox proportional hazards model24 was performed.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIAL AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
MUC5AC immunoreactivity was detectable in 131 (65.5%) of the gastric carcinomas under study (Fig. 1,A–D). In 63 cases (31.5%), a weak MUC5AC staining (score 1) was observed, whereas 51 cases (25.5%) exhibited a moderate staining (score 2), and 17 cases (8.5 %) exhibited a strong reactivity (score 3). The staining pattern was mostly characterized by a diffuse cytoplasmic distribution of the epitopes (Fig. 1, A and B). Normal tissues, which were present in most specimens adjacent to the tumor tissue, exhibited a constant MUC5AC expression in superficial and foveolar epithelium.



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  		FIG. 1. Strong immunoreactivity of MUC5AC as observed in intestinal, as well as diffuse-type adenocarcinomas of the stomach (A, B). MUC5AC displayed a weaker staining in diffuse carcinomas with reduced mucin production (C), whereas undifferentiated tumors remained mostly nonreactive (D). Original magnification x360.

 
Significant correlations of MUC5AC positivity and gender, as well as age of patients, could not be observed (Table 1). Furthermore, the distribution of the different MUC5AC scores was independent from pT, pN, and pTNM stages and the grade of differentiation (Table 2). On the other hand, different histopathological subtypes exhibited typical patterns of MUC5AC immunoreactivity. Both tubular/papillary as well as signet-ring cell carcinomas were positive for MUC5AC in 66.3% and 69.3% of the cases, respectively. The distribution of cases representing the different staining degrees was similar as well (Table 3). On the other hand, no mucinous adenocarcinomas were MUC5AC reactive, and only 59.0% of the undifferentiated carcinomas contained, in most cases weakly, MUC5AC epitopes. On the other hand, there were no evident associations between MUC5AC and any of the subgroups according to Laurén’s classification. Tumors belonging to the intestinal type were positive in 63.6% (Fig. 1A), diffuse-type cancers in 65.4% (Fig. 1, B and C), and unclassifiable/mixed carcinomas in 75%. Regarding the Goseki classification system, 65.6% of tubular carcinomas without (type I) and 82.6% of tubular carcinomas exhibiting intracellular mucin (type II) were MUC5AC positive. Accordingly, 67.0% of carcinomas without conspicuous tubular differentiation (type IV) were stained by mab NCL-MUC-5AC (Novocastra). Type IV cancers showed the highest percentage of cases with staining scores 2 and 3. On the other hand, only 36.8% of carcinomas lacking these features of differentiation (type III according to Goseki) showed MUC5AC reactivity (Fig. 1D and Table 3).


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  		TABLE 1. Correlations between MUC5Ac immunoreactivity and gender/age
 

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  		TABLE 2. Correlations between MUC5AC immunoreactivity and tumor staging/grading
 

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  		TABLE 3. Correlations between MUC5AC immunoreactivity and histopathological subtypes
 
Univariate survival analysis performed according to Kaplan and Meier revealed a significantly better survival probability of patients with a higher MUC5AC immunoreactivity (scores 2 and 3) compared with patients with absent or low MUC5AC positivity as reflected by scores 0 and 1 (Fig. 2A). The same observation could be made for patients belonging to the subgroup of pTNM stage I (Fig. 2B). In pTNM stage I cancers, only 13.6% of patients with high MUC5AC scores, but 42.1% of patients with low MUC5AC scores, died within the follow-up period. If other subgroups of the International Union Against Cancer system were analyzed, significant differences could not be detected. Additionally, application of the multivariate survival analysis (Cox proportional hazards model) revealed that not only pTNM staging (P < .0001) but also MUC5AC immunoreactivity and patients’ age (P < .05) represent independent prognostic variables in gastric cancer (Table 4).



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  		FIG. 2. Univariate survival analysis according to Kaplan and Meier investigating MUC5AC immunoreactivity as a prognostic factor in a series of 200 patients with gastric adenocarcinomas (A), as well as the subgroup of 60 patients with pTNM stage I cancer (B). For both series a significant difference was observed (P < .05).

 

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  		TABLE 4. Correlation between clinicopathological variables, MUC5AC immunoreactivity, and survival probability according to multivariate survival analysis (Cox proportional hazards model)
 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIAL AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Like MUC6, MUC5AC represents a secreted mucin typically expressed by normal epithelia of the stomach. According to previous reports, it is reduced or lost in a certain number of neoplastic lesions.13,14 In the present study, the association between MUC5AC immunoreactivity in gastric carcinoma and numerous clinicopathological variables was evaluated in a series of 200 patients. Furthermore, the prognostic value of MUC5AC was investigated. In a previous study involving 66 patients and MUC5AC demonstration by mab CLH2, a significantly stronger staining of early versus advanced cancers was observed.15 However, as reflected by our results, MUC5AC expression did not correlate with gender, age, staging (pT, pN, pTNM), or tumor grading. Some of these subsets were relatively small, but all observed differences were far from any significance. Therefore, we cannot confirm any relevant correlation of MUC5AC positivity with the well-established clinicopathological parameters of progression of gastric cancer.

On the other hand, differences between subtypes of the World Health Organization, as well as Goseki classification were significant (P < .05) in our series, but Laurén’s subgroups exhibited only insignificant differences. We observed MUC5AC staining of most tubular and papillary as well as signet-ring cell carcinomas, whereas mucinous tumors were completely negative, and undifferentiated cancers showed a markedly reduced reactivity. If the Goseki system was applied, all types with marked tubular differentiation or intracellular mucin (types I, II, and IV) were reactive in the majority of the cases. Similar results had been obtained by Gürbüz et al.25 Significant differences of MUC5AC reactivity between the subgroups of the Goseki classification were observed in both studies. In parallel, Laurén’s subtypes did not show any correlation. This phenomenon reflects the fact that carcinomas of the intestinal type, according to Laurén, reveal at least partial gastric differentiation,26 as demonstrated by pepsinogen II or MUC5AC reactivity. On the other hand, we could not confirm a MUC5AC staining of 100% of Goseki type IV cancers. Goseki type III carcinomas demonstrated a reduced MUC5AC positivity. Previous publications described inconsistent data. One study reported a significantly stronger staining of diffuse versus atypical gastric cancers.15 In another study, differences between the groups in a series of 96 patients were insignificant.16 According to our data, a significantly lower MUC5AC reactivity can only be observed in cancers that lack typical glandular secretion as well as intracellular mucin storage, such as mucinous or undifferentiated cancers.

However, we agree with Reis et al.15 that MUC5AC is generally reduced in carcinomas compared with normal or reactively altered tissues because only 34% of the tumors exhibited MUC5AC in more than 35% of the tumor area in our series. These data are of special interest because a coexpression of MUC5AC and TFF1 was described as a marker of so-called gastric differentiation of gastric carcinomas. A complete gastric phenotype (MUC5AC and TFF1 positivity) could be observed in 52.1% and an incomplete gastric phenotype in 29.2%, but only 18.7% belonged to the nongastric phenotype lacking TFF1, TFF2, MUC5AC, as well as MUC6.16 On the other hand, as reported earlier, MUC1 and MUC2 reactivity is significantly enhanced in carcinomas exhibiting tubular/papillary or intestinal differentiation compared with signet-ring cell or diffuse types, respectively.22

Furthermore, we investigated whether MUC5AC immunoreactivity represents a useful prognostic marker in gastric cancer. According to our data, patients with carcinomas retaining MUC5AC in more than 35% of the tumor area have a significantly better survival probability. This result is in contrast to a report of Pinto-de Sousa et al.,27 who did not observe significant differences in the overall comparison of cumulative survival according to MUC1, MUC2, MUC5AC, and MUC6 reactivity in a series of 94 patients (applying a cut-off point of 5% for the discrimination of negative vs. positive cases). However, we also demonstrated a significantly different survival probability in the subgroup of pTNM stage I patients. According to our data, a reduction of MUC5AC reactivity in early gastric cancer defines a high-risk subgroup of these patients. Multivariate survival analysis confirmed that loss of MUC5AC immunoreactivity is an independent prognostic marker for a worse survival probability of patients with gastric cancer. In summary, MUC5AC represents a marker of gastric differentiation that is obviously lost, especially in cancers exhibiting an accelerated course of disease. Interesting conclusions can be drawn comparing this pattern with other mucin peptide cores: the presence of secreted mucins, which are normally expressed in human gastric (MUC5AC) or intestinal (MUC2) tissues, is associated with a better prognosis of gastric cancer.22,28 On the other hand, the membrane-associated MUC1 mucin exhibits inverse characteristics, since its reactivity is significantly enhanced in progressive carcinomas with an unfavorable survival probability, as described earlier.22,28–30 Investigating these proteins may contribute to a more accurate identification of gastric cancer patients belonging to low-risk and high-risk subgroups.


   Acknowledgments
 
This work was supported by the Cologne Fortune Program. The authors thank Mrs. S. Landsberg for her expert technical assistance.


   Footnotes
 
MUC5AC represents a mucin peptide core normally expressed in gastric mucosa. On the other hand, a significant reduction of MUC5AC immunoreactivity correlated with an unfavorable prognosis in gastric carcinoma defines a high-risk subgroup of patients, especially with pTNM stage I cancer.

Received for publication February 21, 2002. Accepted for publication July 15, 2002.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIAL AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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