MUC4 and ErbB2 Expression in Squamous Cell Carcinoma of the Upper Aerodigestive Tract: Correlation With Clinical Outcomes

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Abstract
Objectives/Hypothesis: Expression of the membrane mucin MUC4 has been associated with a variety of malignancies, including squamous cell carcinoma of the upper aerodigestive tract. MUC4 modulates cell signaling pathways as an intramembrane ligand of ErbB2. The hypotheses of the study were that MUC4 expression would correlate with ErbB2 expression and that MUC4 expression would correlate with clinical outcomes in squamous cell carcinoma of the upper aerodigestive tract. Study Design: Retrospective chart review was combined with immunohistochemical analysis of paraffin-embedded tumor specimens from patients treated with initial definitive surgical resection at an academic tertiary care medical center. Methods: MUC4 and ErbB2 receptor expression was localized by immunohistochemical studies using archival formalin-fixed and paraffin-embedded tissue. A limited number of fresh-frozen tissues were further analyzed by Western blot. Clinical outcomes and histopathological parameters were determined by retrospective chart review and correlated with immunohistochemical findings. Results: One hundred fifty-four patients were analyzed with a median follow-up of 12 months among 54 patients who died and 49 months among 100 surviving patients. Membrane expression of MUC4 and ErbB2 was seen in 12% and 13% of tumors, respectively. MUC4 expression was not correlated with pathological grade. A significant correlation was found between MUC4 expression and ErbB2 expression. Multivariate survival analyses revealed that patients whose tumors exhibited MUC4 membrane expression had statistically significant improvement in survival and longer time to recurrence compared with patients whose tumors did not express MUC4 as defined by immunohistochemical staining patterns. No correlations between ErbB2 expression and survival or recurrence were observed. Conclusion: Patients with tumors that retain MUC4 expression exhibit improved survival and decreased recurrence in squamous cell carcinoma of the upper aerodigestive tract. Correlations between MUC4 expression patterns and ErbB2 expression are also observed, suggesting that MUC4-ErbB2 mediated cell signaling pathways may provide insights into this clinical result.

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