Pathobiological Implications of Mucin (MUC) Expression in the Outcome of Small Bowel Cancer

<div><p>Mucins have been associated with survival in various cancer patients, but there have been no studies of mucins in small bowel carcinoma (SBC). In this study, we investigated the relationships between mucin expression and clinicopathologic factors in 60 SBC cases, in which expression profiles of MUC1, MUC2, MUC3, MUC4, MUC5AC, MUC6 and MUC16 in cancer and normal tissues were examined by immunohistochemistry. MUC1, MUC5AC and MUC16 expression was increased in SBC lesions compared to the normal epithelium, and expression of these mucins was related to clinicopathologic factors, as follows: MUC1 [tumor location (p = 0.019), depth (p = 0.017) and curability (p = 0.007)], MUC5AC [tumor location (p = 0.063) and lymph node metastasis (p = 0.059)], and MUC16 [venous invasion (p = 0.016) and curability (p = 0.016)]. Analysis of 58 cases with survival data revealed five factors associated with a poor prognosis: poorly-differentiated or neuroendocrine histological type (p<0.001), lymph node metastasis (p<0.001), lymphatic invasion (p = 0.026), venous invasion (p<0.001) and curative resection (p<0.001), in addition to expression of MUC1 (p = 0.042), MUC5AC (p = 0.007) and MUC16 (p<0.001). In subsequent multivariate analysis with curability as the covariate, lymph node metastasis, venous invasion, and MUC5AC and/or MUC16 expression were significantly related to the prognosis. Multivariate analysis in curative cases (n = 45) showed that SBC with MUC5AC and/or MUC16 expression had a significantly independent high hazard risk after adjusting for the effects of venous invasion (hazard ratio: 5.6, 95% confidence interval: 1.8–17). In conclusion, the study shows that a MUC5AC-positive and/or MUC16-positive status is useful as a predictor of a poor outcome in patients with SBC.</p></div

The cumulative survival rates of patients with SBC.

<p>The expression of MUC1 (A), MUC5AC (B) and MUC16 (C) were poorer than those of patients without expression of MUC1 (p = 0.042), MUC5AC (p = 0.007) and MUC16 (p<0.001), respectively. Survival data were calculated using the Kaplan-Meier method.</p

The expression rate of mucins in tissue.

<p>MUC1, MUC5AC and MUC16 showed increased expression; MUC4 and MUC6 showed equal expression; and MUC2 and MUC3 showed decreased expression in SBC compared to normal epithelium.</p

Analysis of the expression of mucins by immunohistochemistry.

<p>In mucins with increased expression in SBC, MUC1 showed apical and cytoplasmic expression in cancer cells, but not in the normal epithelium (A and B); MUC5AC showed cytoplasmic expression in cancer cells, but not in the normal epithelium (C and D); and MUC16 showed apical expression in cancer cells, but not in the normal epithelium (E and F). In mucins with equal expression in SBC, MUC4 showed cytoplasmic expression in normal epithelium and cancer cells (G and H); and MUC6 showed cytoplasmic expression in normal epithelium (insets) and cancer cells (I and J). In mucins with decreased expression in SBCs, MUC2 showed cytoplasmic expression in normal epithelium, but not in cancer cells (K and L); and MUC3 showed apical expression in normal epithelium, but not in cancer cells (M and N).</p

Survival analysis for curative cases (n = 45) using a Cox proportional hazard model*.

*1<p>The status of venous invasion was included as a covariate in models 1.</p>*2<p>The status of lymph node metastasis was included as a covariate in models 2.</p><p>NA: not available, D/T: Deaths/Total, P-y: Person-year, HR: Hazard ratio, 95% CI: 95% confidence interval, ref.: reference.</p

Survival in Patients with Appendiceal Carcinoma by the Log-Rank Test (n = 108).

a<p>pap, papillary adenocarcinoma; well, well differentiated adenocarcinoma; mod, moderately differentiated adenocarcinoma; por, poorly differentiated adenocarcinoma; sig, signet-ring cell carcinoma; muc, mucinous carcinoma.</p>b<p>m, mucosa; sm, submucosa; mp, muscularis propria; ss, subserosa, se, serosa; si, invasion to other organ.</p>c<p>27 cases without lymph node dissection were excluded.</p>d<p>3 cases with unknown details regarding curative or non-curative resection were excluded.</p><p>Survival in Patients with Appendiceal Carcinoma by the Log-Rank Test (n = 108).</p

In appendiceal carcinoma cells (A, D, G, J, M, P and S), MUC1 showed membrane expression (B and C); MUC2 showed supranuclear expression (E and F); MUC4 (H and I), MUC5AC (K and L) and MUC6 (N and O) showed cytoplasmic expression; MUC16 showed membrane expression (Q and R); and MUC17 (T and U) showed supranuclear expression. HE, hematoxylin and eosin stain; IHC, immunohistochemical stain.

<p>In appendiceal carcinoma cells (A, D, G, J, M, P and S), MUC1 showed membrane expression (B and C); MUC2 showed supranuclear expression (E and F); MUC4 (H and I), MUC5AC (K and L) and MUC6 (N and O) showed cytoplasmic expression; MUC16 showed membrane expression (Q and R); and MUC17 (T and U) showed supranuclear expression. HE, hematoxylin and eosin stain; IHC, immunohistochemical stain.</p

Correlation between mucin expression and the cumulative survival rate.

<p>In the study of the correlation between mucin expression and the cumulative survival rate in patients with appendiceal carcinoma using the Kaplan-Meier method, the survival rate of patients with a positive expression of MUC3 were poorer than those of patients with negative expression of MUC3 (p = 0.004).</p

Multivariate Analysis of Prognostic Factors.

<p>Multivariate Analysis of Prognostic Factors.</p