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Clinical Cancer Research Vol. 12, 4244-4250, July 15, 2006
© 2006 American Association for Cancer Research

Imaging, Diagnosis, Prognosis

Inverse Effects of Mucin on Survival of Matched Hereditary Nonpolyposis Colorectal Cancer and Sporadic Colorectal Cancer Patients

Jeng-Fu You1, Ling-Ling Hsieh2, Chung Rong Changchien1, Jinn-Shiun Chen1, Jim-Ray Chen3, Jy-Ming Chiang1, Chien Yuh Yeh1, Pao-Shiu Hsieh1, Chung-Wei Fan1, Chun-Ting Liu4 and Reiping Tang1

Authors' Affiliations: 1 Department of Surgery, Chang Gung Memorial Hospital, Chang Gung University College of Medicine at Linko; 2 Department of Public Health and 3 Division of Cancer Research, National Health Research Institute; and 4 Graduate Institute of Basic Medical Science, Chang Gung University, Taipei, Taiwan

Requests for reprints: Reiping Tang, Colorectal Section, Chang Gung Memorial Hospital, 199, Tung Hwa North Road, Taipei, Taiwan. Phone: 886-3-3281200 ext. 3225; Fax: 886-3-3278355; E-mail: rptang{at}adm.cgmh.org.tw.


   Abstract
Top
 Abstract
Materials and Methods
 Results
 Discussion
 References
 
Purpose: To compare survival and histologic features of hereditary nonpolyposis colorectal cancer (HNPCC; Lynch syndrome) cases to well-matched sporadic colon cancers from the same patient population.

Experimental Design: Between January 1995 and March 2002, a total of 5,138 consecutive patients underwent resection of primary colorectal adenocarcinoma in a single institution. According to the Amsterdam criteria, 56 HNPCC patients were matched to 147 sporadic colorectal cancer (SCRC) with no family history of cancer and with the same gender, tumor location, and age within 3 years. Immunohistochemical analyses were done for MUC1, MUC2, MUC3, and MUC5AC.

Results: The HNPCC group had a marginally significantly better long-term outcome than the SCRC group (P = 0.058). The trend disappeared after adjustment by tumor-node-metastasis stage in a Cox model (P = 0.774). We noted a difference of >50% in the 5-year cancer-specific survival rates of HNPCC- and SCRC-mucinous groups (92% versus 31%, P = 0.0003). Interaction between mucin and HNPCC and its effects on survival were further confirmed by comparing the Cox models with and without interaction terms (hazard ratio, 0.1; P = 0.034 with adjusting stage). Patients with tumors showing dual expression of mucin and MUC1, which appeared in 11% of those with HNPCC and 50% of those with SCRC, had a lower 5-year cancer-specific survival rate than patients without (30% versus 60%; P = 0.004 by log-rank test; P = 0.039 with adjustment for tumor-node-metastasis stage).

Conclusions: These results suggest that mucin has an inverse effect on survival in patients with HNPCC and SCRC, which might be partly explained by a lower prevalence of MUC1 expression in the mucinous HNPCC group than in the SCRC groups.

Hereditary nonpolyposis colorectal cancer (HNPCC; Lynch syndrome) is the most common form of hereditary colorectal cancer. HNPCC patients have been reported to have a better survival than those with sporadic colorectal cancer (SCRC). Molecular genetics studies have revealed a great deal about the underlying mechanisms and pathways involved in HNPCC. However, the reasons for the survival advantage remain less clear. Lynch et al. hypothesized that the genotype in hereditary cancer determines both susceptibility and natural history (including increased survival; ref. 1). The predominance of diploidy (2, 3) or microsatellite instability (4) in HNPCCs has also been suggested as a possible explanation of prolonged survival. Several other hypotheses, including those involving MLH1-associated mutation (5), mutation triggering host immune system defenses (6), and infiltration of intratumor cell-infiltrating lymphocytes (7), have been proposed as well. Not all reports agree about the favorable prognosis for HNPCC, however (8). Several biases, including selection bias and lead time bias due to improved diagnosis or preventive screening, have hampered efforts to confirm the hypothesis (8). The constant and striking features of HNPCC (9–11), including the tendency toward proximal disease, the early age of onset, and the mucinous phenotype, may also cause biases in analyzing survival differences between HNPCC and SCRC. Moreover, the low incidence of HNPCC among colorectal cancers, leading to disproportionate numbers of cases when comparing groups, may cause further bias. By analyzing and comparing the prognostic factors for patients with HNPCC and SCRC under sex-, age-, and tumor location–matched conditions in a single institution within the same period of time, we hoped to address the following issues: (a) Do HNPCC patients have a better outcome than SCRC under matched conditions? And (b) do the distinct histologic features of HNPCC play a role in the prognosis of HNPCC relative to that of SCRC?


   Materials and Methods
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 Abstract
 Materials and Methods
Results
 Discussion
 References
 
Patients. Detailed information about patient- and tumor-related variables was retrieved from the Colorectal Section Tumor Registry in Chang-Gung Memorial Hospital. The variables included age, sex, tumor location, tumor morphology, mucinous content, histologic grading, and tumor-node-metastasis (TNM) stage. Tumor location was designated as proximal colon for colorectal cancers situated at the cecum, ascending colon, hepatic flexure, and transverse colon; distal colon for those located at the splenic flexure, descending colon, and sigmoid colon; and rectum for those for which the lower edge was within 15 cm of the anal verge. Tumor morphology was classified as either polypoid or nonpolypoid appearance. We used the definition of mucinous carcinomas established by the WHO; that is, carcinomas in which the mucinous component represents >50% of the tumor (12). HNPCC was diagnosed by family history according to criteria defined by the International Collaborative Group on Hereditary Nonpolyposis Colorectal Cancer (13, 14).

A total of 5,138 consecutive patients underwent resection of primary colorectal adenocarcinoma between January 1995 and March 2002. One hundred ten of these were excluded from further analysis because of a lack of information about family history. Of the remaining 5,028 patients; 38 (0.8%) had familial adenomatous polyposis; 56 (1.1%) had HNPCC; 1,750 (34.8%) had familial cancer but did not meet the criteria of HNPCC; and 3,184 (63.3%) had SCRC with no family history of cancer. The mean age for the 56 HNPCC patients was 49.4 years (SD, 13.5; range, 26-88).

Matched HNPCCs and SCRCs. Of the 65 separate colorectal cancers identified in the 56 HNPCC patients, seven cases had double cancers, and one had a triple cancer. Thirty-six (55%) tumors were located at the proximal colon: 17 (26%) at the distal colon and 12 (19%) at the rectum. Of the 3,271 colorectal cancers identified in the 3,184 sporadic patients, 615 (19%) tumors were located at the proximal colon; 993 (30%) tumors were located at the distal colon; and 1,663 (51%) tumors were located at the rectum. For further comparison of the tumors in HNPCCs and SCRCs, 161 sporadic cases were individually matched to the 65 HNPCCs by sex, age of onset (age within 3 years), and tumor location (proximal colon, distal colon, and rectum) in a 3:1 fashion (2:1 if fewer than three sporadic cases could be matched, which was the case especially in the younger patients). For survival analysis, we chose the more advanced of the patients with double or triple cancers and their related matched cases. A total of 203 cases, including 56 patients with HNPCCs and 147 patients with SCRCs, were included for further survival analysis.

Follow-up. For HNPCC patients, the follow-up procedures and adjuvant treatment protocol were the same as for SCRC patients. All patients were subjected to a follow-up program that included outpatient visits every 3 to 6 months for physical examination and carcinoembryonic antigen tests, as well as chest X-ray, abdominal sonography or abdominal computer-assisted tomography scan, and colonoscopy every 1 to 3 years after operation. Recurrent disease was confirmed by histology of biopsy or reoperation and/or by imaging studies. The index date for survival calculation was defined as the date of operation for colorectal cancer. Only death from colorectal cancer was treated as an event (cancer-specific survival). Death from causes other than colorectal cancer was treated as censored. The median follow-up periods for those alive were 72.5 months (range, 25.8-111.9 months).

Immunohistochemical staining of MUC1, MUC2, MUC4, and MUC5AC. Paraffin sections of tumor tissue were subjected to MUC1, MUC2, MUC4, and MUC5AC immunohistochemistry. For each of these tumors, 5-µm sections from representative blocks of the tumors were deparaffinized in xylene and absolute alcohol, retrieved with heat, and treated with 3% hydrogen peroxide to remove endogenous peroxidase activity. Immunohistochemical staining was processed using specific mouse monoclonal antibodies (1:100) for MUC1, MUC2, MUC4, and MUC5AC and DAKO LSAB®2 System with DAKO 3,3'-diaminobenzidine chromogen solution (DAKO, Glostrup, Denmark). The primary antibodies for MUC1, MUC2, MUC4, and MUC5AC were Ma695 (Novocastra, Newcastle upon Tyne, United Kingdom), Ccp58 (Novocastra), 1G8 (Zymed, South San Francisco, CA), and CLH2 (Novocastra), respectively. The slides were then counterstained with hematoxylin, overslipped with Permount, and examined for the extent and intensity of cytoplasmic staining in tumor areas and for background staining in stroma. At least eight high-power fields at x40 magnification were scored for the extent of cytoplasmic staining (0: 0-10%; 1: 11-25%; 2: 26-50%; 3: 51-75%; 4: 76-100%) and intensity of staining (0: no stain; 1: weak staining; 2: intermediate staining; 3: strong staining) by an investigator who did not know the clinical status of the patients. We defined staining score as score of extent of cytoplasmic staining multiplied by intensity grade. Staining was designated as negative if staining score was 0 or 1; intermediate if the score was 2, 3, or 4; and high if the score was 6, 8, 9, or 12.

Statistics. All analyses were done using the Statistical Package for the Social Sciences, release 11.0 (SPSS, Inc. Chicago, IL). Differences of clinicopathologic features between the HNPCC and SCRC groups were assessed with the X2 method and Fisher's exact test, whichever is appropriate. Cancer-specific survival was calculated using univariate analysis by the Kaplan-Meier method. Differences were tested using the log-rank test. To control for confounding factors, the Cox proportional-hazard model was fitted with computing hazard ratios and P. Interactions between main effects were tested by adding interaction terms into the model. Survival plots were constructed using Kaplan-Meier method. All tests were two sided. Statistical significance was set at P < 0.05.


   Results
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 Abstract
 Materials and Methods
 Results
Discussion
 References
 
Table 1 shows the differences in clinicopathologic features for the HNPCC and SCRC groups. The frequency of earlier-stage disease (TNM I/II) in the HNPCC group was greater than in SCRC (60.7% versus 39.5%, P = 0.008). The frequency of mucinous tumor was also higher in the HNPCC group (23.2% versus 15.0%). This difference did not reach statistical significance, however (P = 0.237). Other clinicopathologic features were similar between the two groups. There were three postoperative deaths. The remaining 200 patients (55 HNPCCs and 145 SCRCs) were followed up for at least 3 years or until death. During the follow-up period, there were 60 deaths from cancer, including 11 HNPCC and 49 SCRC patients.


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  		Table 1. Clinicopathologic features of population, HNPCC, and matched SCRC patients

 
Survival analyses for HNPCC and SCRC patients. Figure 1A discloses that HNPCC patients are less likely than SCRCs to die from cancer (P = 0.058). After adjusting for TNM stage, this favorable trend disappears (P = 0.774). The data suggest no appreciable difference between the two matched groups. Table 2 shows the results of the univariate analysis of clinicopathologic variables and the 5-year survival rate stratified by HNPCC and SCRC. These variables can be assigned to one of three prognostic classes. The first prognostic class encompasses those variables significant in predicting outcome in both of the groups. Patients with tumors of late TNM stage and with nonpolypoid tumors exhibited worse survival than those without. The second class includes only those variables significant in predicting outcome of SCRC. Histologic grade and mucin production were highly significant in predicting SCRC outcome. On the other hand, neither of these had a significant effect on survival for the HNPCC patients. The final class involves three variables (age, sex, and tumor location), none of which were not significantly associated with survival in patients with HNPCC or SCRC.


Figure 1
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  		Fig. 1. A, proportion of cancer-specific survival figure for matched patients with HNPCC (black line, n = 55) compared with sporadic colorectal cancer (red line, n = 145). B, proportion of cancer-specific survival figure according to combined mucin production and HNPCC (mucinous SCRC, broken red line, n = 22; nonmucinous SCRC, solid red line, n = 123; mucinous HNPCC, broken black line, n = 13; nonmucinous HNPCC, solid black line, n = 42).

 

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  		Table 2. Univariate survival analysis stratified by HNPCC and SCRC groups

 
Inverse effect of mucin production on survival between HNPCC and SCRC. The second class of variables significant in predicting outcome of SCRC (instead of HNPCC) suggests a possible interaction between types of colorectal cancer and mucin or histologic grade. To further explore this possibility, Cox regression models of the main effects only and of the main effects, including an interaction term, were compared; these are listed in Table 3 . Both main effects were significant in the main-effects-only model. However, in the including-interaction-term model, interaction as well as mucin was significantly and independently related to survival. The X2 changed from 8.7 in the main-effect-only model to 18.9 in the interaction model. Such results confirm an interaction between mucin production and type of colorectal cancer on the survival of colorectal cancer patients. In a Cox model adjusting for TNM stage, the effect of the interaction between mucin and type of colorectal cancer on survival remained significant at Ps of 0.034. Figure 1B shows the contrasting effects of mucin on survival in the HNPCC and SCRC groups. We noted a difference of >50% in the 5-year cancer-specific survival rates of the HNPCC- and SCRC- mucinous groups (P = 0.0003). Mucinous SCRC had a worse survival rate than its nonmucinous counterpart, whereas mucinous HNPCC had a better survival rate than its nonmucinous counterpart (Fig. 1B). Unlike mucin, variable "histologic grade" did not have significant interaction with type of colorectal cancer in terms of survival (data not shown).


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  		Table 3. Test for interaction between mucin production and patients with HNPCC or SCRC

 
Immunohistochemical analyses of MUC1, MUC2, MUC4, and MUC5AC. Of a total of 167 cancers (43 HNPCCs and 124 SCRC) with tissue blocks available for immunohistochemical staining, 57 (46.0%) SCRC and 11 (26.2%) HNPCC displayed a high MUC1 staining score; 59 (47.6%) SCRC and 23 (53.3%) HNPCC displayed a high MUC2 score; 53 (42.7%) SCRC and 19 (44.2%) HNPCC displayed a high MUC4 score; and 23 (18.5%) SCRC and 11 (25.6%) HNPCC showed a high MUC5AC score. Compared with HNPCC, SCRC was significantly associated with greater frequency of high expression of MUC1 protein. When further stratified by mucin production (Table 4 ), mucinous tumors (either HNPCC or SCRC) were generally more likely to display a high staining score than nonmucinous counterparts. HNPCCs and SCRCs were similar in terms of the distributions of protein expressions of MUC2, MUC4, and MUC5AC. All the mucinous tumors (HNPCCs or SCRCs) highly expressed MUC2 proteins, whereas <50% nonmucinous counterparts did so. Compared with only about one third of nonmucinous tumors (38.2% SCRC and 37.5% HNPCC), more than two thirds of mucinous tumors (66.6% SCRC and 70.0% HNPCC) displayed a high MUC4 staining score. More strikingly, MUC1 protein was highly expressed in 50% of SCRC but only in 11% of HNPCC mucinous tumors (Fisher's exact test, P = 0.096). As shown in Fig. 2A , survival rate was associated with MUC1 expression. A higher expression score was associated with a poorer survival (Ptrend = 0.043). If further stratified by mucin production, high MUC1 expression seemed to be a marker of worse long-term survival in mucinous tumors though not in nonmucinous tumors (P = 0.004; Fig. 2B). The detrimental effect of dual expression of mucin by conventional H&E stain and MUC1 by immunostaining on the long-term outcome remained significant after stratification by TNM stages in Cox regression model (P = 0.039), suggesting that the higher frequency of MUC1 immunoreactivity in the mucinous colorectal cancers was independently related to a greater rate of cancer death in colorectal cancer patients. None of the other three MUC proteins studied was significantly associated with survival in these patients (data not shown).


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  		Table 4. Frequency of four classes of MUC protein expression (defined by immunohistochemical staining) versus mucinous tumors among HNPCC and SCRC

 

Figure 2
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  		Fig. 2. A, proportion of cancer-specific survival figure according to score of MUC1 protein expression (low score, n = 24; intermediate score, n = 73; high score, n = 66). B, proportion of cancer-specific survival figure according to combined mucin production and immunostaining of MUC1 (mucinous tumors with high MUC1 protein expression score, broken red line, n = 11; mucinous tumor without high expression, broken black line, n = 18; nonmucinous tumor with high expression, solid red line, n = 55; nonmucinous without high expression, solid black line, n = 79).

 

   Discussion
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 Abstract
 Materials and Methods
 Results
 Discussion
References
 
The present study compared survival and histologic features of HNPCC cases to well-matched sporadic colon cancers from the same patient population. We observed that HNPCC patients did not have a better long-term outcome than their age, sex, and tumor location-matched sporadic cancer (SCRC) counterparts if TNM stage was taken into consideration. The other surprising finding was that mucin exhibits a contrasting effect with respect to survival of HNPCC and SCRC patients. HNPCC tumors with mucin production (>50% mucin) had a better outcome than their nonmucinous counterparts, whereas SCRC tumors with mucin production had a worse outcome than their nonmucinous counterparts. Such findings concerning interactions between mucin and type of colorectal cancers might have important clinical and genetic implications.

Our data also showed that HNPCC patients had lower-stage disease than sporadic cancer patients at diagnosis. These findings were consistent with those of Watson et al. (15), who retrospectively analyzed and compared 274 HNPCCs from two separate registries with 820 unselected sporadic colorectal cancers from a single registry. This and other studies have shown that HNPCC was still associated with a better survival under the same stage (15, 16). However, data from studies (including our current study) comparing groups of patients treated in a single institution told a different story. Bertario et al. examined 2,340 colorectal cancer patients (including 144 HNPCC, 161 FAP, and 2,035 sporadic cancer patients) and did not find a significant survival advantage for HNPCC patients with respect to the sporadic group after adjusting for age, gender, stage, and tumor location (8). Although lead time and length biases may explain the improved survival for HNPCC patients, we believe that selection bias may also play a role. One of the possible reasons for the conflicting results may be that most studies have tried to compare two groups with disproportionate sample sizes and/or in different settings.

Several studies have reported that mucinous colorectal cancers have a worse prognosis than nonmucinous tumors (17–22). Symonds et al. (17) found that mucinous colorectal cancers had a poorer 5-year survival than nonmucinous tumors under stage-matched conditions. Colorectal carcinomas of high mucin content are more likely to recur locally and/or spread via lymph node or peritoneum (18, 19, 21). Green et al. (20) reported that mucinous carcinomas occurred at an advanced stage more frequently than nonmucinous carcinomas and had a markedly worse 5-year survival. By comparing two matched groups (mucinous versus nonmucinous colorectal cancer patients), Consorti et al. (22) confirmed the hypothesis that mucinous type is a distinct biological entity due to the existence of prognostic, clinical, and epidemiologic differences between mucinous and nonmucinous colorectal cancers. Our present data on the survival of matched SCRCs are consistent with the notion that SCRCs with mucin production have a worse survival than those without (Fig. 1B). Interestingly, mucin did not play a similarly detrimental role in HNPCCs. Mucin seemed to have a protective effect in terms of survival among HNPCC patients (Fig. 1B). If this is the case, then at least mucins produced by HNPCCs may be different from those produced by sporadic cancers, implying there are "good" and "bad" mucins produced by tumors.

Mucins, the major secreted glycoproteins of the gastrointestinal tract, play a role in normal physiologic processes and in the neoplastic progression and metastasis of colon cancer cells. These glycoproteins have a high molecular weight with a high content of clustered oligosaccharides O-glycosidically linked to tandem repeat peptides rich in threonine, serine, and proline (see review in ref. 23). There are two structurally and functionally distinct classes of mucins: secreted gel-forming mucins (such as MUC2 and MUC5AC) and transmembrane mucins (such as MUC1 and MUC4). Expression of MUC1, as detected immunologically, is increased in colon cancers, corresponding to a worse prognosis (24, 25). In 1994, Irimura's group found that MUC1 mucin levels correlated to the progression of colorectal cancer. In agreement with these previous observations, our data showed that a greater MUC1 expression score tended to be associated with a worse prognosis (Fig. 2A). We further stratified these patients by mucin production and found that the detrimental effect of MUC1 immunoreactivity on survival was observed only among mucinous colorectal cancers, not among nonmucinous tumors. It is possible that MUC1 mucin may play a crucial role in an aggressive behavior of a mucinous colorectal cancer; for example, the mucin with high expression of MUC1 is a bad mucin. The present immunohistochemical results of MUC2 are consistent with earlier studies that found that MUC2 expression is up-regulated in mucinous colon cancers but down-regulated in nonmucinous colon cancers (26–29). MUC2 protein expression was not significantly associated with survival in colorectal cancer patients.

In summary, the present data show an inverse effect of mucin on the survival of HNPCC and SCRC patients. These two types of tumors have different distributions of MUC1 immunoreactivity, which in turn is associated with outcome of patients with mucinous colorectal cancers. Further clinical, molecular biological and/or genetic investigations with a larger sample size are needed to confirm these findings.


   Footnotes
 
Grant support: The National Science Council, ROC grant NSC 92-2314-B-182A-156 and the National Health Research Institute, Department of Health, Executive Yuan, ROC grants DOH85-HR-516, DOH86-HR-516, and DOH87-HR-516.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 1/27/06; revised 4/11/06; accepted 4/20/06.


   References
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 References
 

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