Differential mucin phenotypes and their significance in a variation of colorectal carcinoma

Abstract

Aim: To investigate mucin expression profiles in colorectal carcinoma (CRC) histological subtypes with regard to clinicopathologic variables and prognosis.

Methods: Mucin (MUC)2 and MUC5AC expressions were assessed by immunohistochemistry for a total of 250 CRC cases that underwent surgical resection. CRCs included 63 well-to-moderately differentiated adenocarcinomas (WMDAs), 91 poorly differentiated adenocarcinomas (PDAs), 81 mucinous adenocarcinoma (MUAs), and 15 signet-ring cell carcinomas (SRCCs). MUC2 and MUC5AC were scored as positive when ≥ 25% and ≥ 1% of cancer cells were stained positive, respectively. The human mutL homolog 1 and human mutS homolog 2 expressions were assessed by immunohistochemistry in PDAs to investigate mismatch-repair (MMR) status. Tumors that did not express either of these two were considered MMR-deficient. Results were analyzed for associations with clinicopathologic variables and the prognosis in individual histological CRC subtypes.

Results: MUC2-positive and MUC5AC-positive WMDA percentages were 49.2% and 30.2%, respectively. In contrast, MUC2-positive and MUC5AC-positive PDA percentages were 9.5% and 51.6%, respectively. MUC2 levels tended to decrease and MUC5AC levels tended to increase from WMDA to PDA. In 21 tumors comprising both adenoma and adenocarcinoma components in a single tumor (4 WMDAs, 7 PDAs, and 10 MUAs), MUC2 was significantly downregulated in PDA and MUC5AC was downregulated in PDA and MUA in the adenoma-carcinoma sequence. These results suggested that MUC2 levels might be associated with malignant potential and that MUC5AC expression was an early event in tumorigenesis. Despite worse prognoses than WMDA, high MUC2 expression levels were maintained in MUA (95.1%) and SRCC (71.5%), which suggested a pathogenesis for these subtypes distinct from that of WMDA. No significant associations were found between MUC2 expression and any clinicopathologic variables in any histological subtype. MUC5AC expression in PDA was closely associated with right-sided location (P = 0.017), absence of nodal metastasis (P = 0.010), low tumor node metastasis stage (P = 0.010), and MMR deficiency (P = 0.003). MUC2 expression in WMDA was a marginal prognostic factor for recurrence/metastasis-free survival (RFS) by univariate Cox analysis (P = 0.077) but not by multivariate Cox analysis (P = 0.161). MUC5AC expression in PDA was a significant prognostic factor for RFS by univariate Cox analysis (P = 0.007) but not by multivariate Cox analysis (P = 0.104). Kaplan-Meier curves and log-rank tests revealed that MUC2 expression was marginally associated with a better WMDA prognosis [P = 0.064 for RFS and P = 0.172 for overall survival (OS)] but not for PDA. In contrast, MUC5AC expression was significantly and marginally associated with a better PDA prognosis in terms of RFS and OS, respectively (P = 0.004 for RFS and P = 0.100 for OS), but not for WMDA and MUA.

Conclusion: Mucin core protein expression profiles and clinical significance differ according to histological CRC subtypes. This may reflect different pathogeneses for these tumors.

Keywords: Adenoma-carcinoma sequence; Colorectal carcinoma; Microsatellite instability; Mismatch repair; Mucin 2; Mucin 5AC; Pathogenesis; Poorly differentiated adenocarcinoma; Prognosis.

Figure 1

Expression of mucin 2 and mucin 5AC in colorectal carcinomas. A: Mucin (MUC)2 expression in normal colonic mucosa; B: MUC2 expression in cancer: level 0; C: MUC2 expression in cancer: level 4; D: MUC5AC expression in normal colonic mucosa; E: MUC5AC expression in cancer: level 1; F: MUC5AC expression in cancer: level 4 (immunohistochemical staining, × 10).

Figure 2

Colorectal carcinoma overall survival curves generated by the Kaplan-Meier method. WMDA: Well-to-moderately differentiated adeno-carcinoma; PDA: Poorly differentiated adenocarcinoma; MUA: Mucinous adenocarcinoma; SRCC: Signet-ring cell carcinoma.

Figure 3

Expression profiles of mucin 2 and mucin 5AC in each colorectal carcinoma histological subtype. Each closed circle indicates one tumor. MUC: Mucin; WMDA: Well-to-moderately differentiated adenocarcinoma; PDA: Poorly differentiated adenocarcinoma; MUA: Mucinous adenocarcinoma; SRCC: Signet-ring cell carcinoma.

Figure 4

Survival curves. A-D: Well-to-moderately differentiated adenocarcinoma (WMDA); E-H: Poorly differentiated adenocarcinoma (PDA); I and J: Mucinous adenocarcinoma (MUA). A: Recurrence/metastasis-free; B: Overall survival curves with or without mucin (MUC) 2 expression of WMDA; C: Recurrence/metastasis-free; D: Overall survival curves with or without MUC5AC expression; E: Recurrence/metastasis-free; F: Overall survival curves with or without MUC2 expression; G: Recurrence/metastasis-free; H: Overall survival curves with or without MUC5AC expression; I: Recurrence/metastasis-free; J: Overall survival curves with or without MUC5AC expression. Curves were generated using the Kaplan-Meier method and compared by log-rank tests. P values were derived from comparing mucin-negative and -positive tumors.