Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2019 Nov 14;5(11):e02753.
doi: 10.1016/j.heliyon.2019.e02753. eCollection 2019 Nov.

Assessing the prognostic significance of MUC4β in mucoepidermoid carcinoma of the salivary glands: An immunohistochemical study

Poonam R Sawant  1 , Anita Spadigam  1 , Anita Dhupar  1 , Shaheen Syed  1 , Karla Carvalho  1
Affiliations

Assessing the prognostic significance of MUC4β in mucoepidermoid carcinoma of the salivary glands: An immunohistochemical study

Poonam R Sawant et al. Heliyon. .

Abstract

Objectives: - Routine histopathological grading for salivary gland mucoepidermoid carcinoma (MEC) have failed to prognosticate these tumors, resulting in poor post-surgical outcomes. In developing countries, the lack of technologically advanced infrastructure curtails, efficient treatment modalities. This study aimed at determining if MUC4β can characterize salivary gland MEC and serve as a practical and inexpensive method to prognosticate salivary gland MEC.

Materials and methods: - Fifteen cases of archived paraffin embedded tissue blocks of mucoepidermoid carcinomas were reassessed for histopathological grading using Healey's system, modified by Batsakis and Luna and immunohistochemically evaluated for expression of MUC4β. Statistical analysis (Kappa statistics and Spearman's rho correlation coefficient) was performed to assess inter-observer reproducibility and to correlate the expression of MUC4β with the histopathological grade of the tumor.

Results: MUC4β expression is related to tumor differentiation in an inverse relationship. Two cases of high grade MEC were the exception to this rule.

Conclusion: Our study revealed that MUC4β alone cannot serve as a reliable prognostic marker due to its divergent tumor suppressor and oncogenic pathway. The role of MUC4β needs further evaluation and research so as to potentiate therapeutics depending upon its context dependent function, as a cancer marker or an oncogenic factor.

Keywords: Cancer research; Dentistry; MUC4; Mucoepidermoid carcinoma; Oncology; Prognosis; Salivary gland cancer.

PubMed Disclaimer

Figures

Fig. 1
Fig. 1
Graphical representation of negative correlation between, grade of MECs and extent of MUC4β positive neoplastic cells.
Fig. 2
Fig. 2
Photomicrographs of MUC4β immunohistochemistry in different grades of MECs: (A) and (B) (100X magnification) - Positive control – Colon mucosa and excretory duct of normal salivary gland tissue respectively. (C) (100X magnification) and (D) (400X magnification) - Low grade (Grade 1) MEC, showing strong (Score 3) membranous and cytoplasmic staining of neoplastic cells. (E) (100X magnification) and (F) (400X magnification) – Intermediate grade (Grade II) MEC, showing moderate (Score 2) membranous and cytoplasmic staining of neoplastic cells. (G) and (H) (400X magnification) – High grade (Grade III) MEC, showing weak (Score 1) or negative (Score 0) staining for MUC4β in neoplastic cells, respectively.
Fig. 3
Fig. 3
Photomicrographs from the two cases of Grade III MEC that revealed high expression of MUC4β. (A) (100X magnification) and (B) (400X magnification), are the haematoxylin and eosin stained sections of CASE 1, showing histomorphology of tumor cells and perineural, perivascular invasion, respectively. (C) (400X magnification), CASE 1, immunohistochemistry revealed high expression (Score 3) of MUC4β in neoplastic cells. (D) (100X magnification) and (E) (400X magnification), are the haematoxylin and eosin stained sections of CASE 2, showing histomorphology of tumor cells and intravascular spread, respectively. (F) (400X magnification), CASE 2, immunohistochemistry revealed moderate (Score 2) to high expression (Score 3) of MUC4β in neoplastic cells.
Fig. 4
Fig. 4
Pathways for MUC4β mediated ErbB2 phosphorylation: Phosphorylation and activation of ERbB2 can be mediated by three pathways, subsequent to formation of either MUC4β-ERbB2 complex, ERbB2-ERbB3-Neu complex or MUC4β -ERbB2-ERbB3-Neu complex. The latter being characterized by high degree of phosphorylation (indicated by the plus sign) resulting in down-regulation of p27kip (cyclin-dependent kinase inhibitor) and activation of the Mitogen-activated protein kinase and phosphoinositide 3-kinase pathway, thus inhibiting cell differentiation and apoptosis and promoting cell proliferation associated with tumor progression.
Fig. 5
Fig. 5
Prognosticators of Mucoepidermoid carcinomas (MECs): MECs can broadly be classified based on the presence or absence of CRTC1-MAML2/CRTC3-MAML2 translocation. MECs positive for CRTC1-MAML2 translocation and associated with deletion and hypermethylation of cyclin-dependent kinase Inhibitor 2A (CDKN2A), show poor prognosis. CDKN2A gene codes for p16INK4a and p14arf, tumor suppressor proteins that act by regulating the cell cycle by inhibiting CDK4 and CDK6; and by preventing degradation of p53 (Kozloski et al., 2010; Weber et al., 2002). Irrespective of MEC being fusion positive or not, high expression of ErbB2 and/or evidence of p53 mutations indicate poor prognosis. Independent of the histopathological grade of MEC, aberrant co-expression of ErbB2 and MUC4β, potentiates phosphorylation of ErbB2 causing activation of downstream signaling pathways responsible for tumor progression and poor prognosis. (MAPK-Mitogen-activated protein kinase; PI3K-phosphoinositide 3-kinase; CDK- cyclin-dependent kinase; (CREB)-regulated transcriptional coactivator 1 (CRTC1) and mastermind-like 2 (MAML2).
See this image and copyright information in PMC

Similar articles

See all similar articles

References

    1. Alos L., Lujan B., Castillo M., Nadal A., Carreras M., Caballero M., de, Bolos C., Cardesa A. Expression of membrane-bound mucins (MUC1 and MUC4) and secreted mucins (MUC2, MUC5AC, MUC5B, MUC6 and MUC7) in mucoepidermoid carcinomas of salivary glands. Am. J. Surg. Pathol. 2005;29:806–813. - PubMed
    1. Alroy I., Yarden Y. The ErbB signaling network in embryogenesis and oncogenesis: signal diversification through combinatorial ligand-receptor interactions. FEBS let. 1997;410:83–86. PMID: 9247128. - PubMed
    1. Ansari M.H. Salivary gland tumors in an Iranian population: a retrospective study of 130 cases. J. Oral Maxillofac. Surg. 2007;65:2187–2194. - PubMed
    1. Anzick S.L., Chen W.D., Park Y., Meltzer P., Bell D., El-Naggar A.K., Kaye F.J. Unfavorable prognosis of CRTC1-MAML2 positive mucoepidermoid tumors with CDKN2A deletions. Genes Chromosomes Cancer. 2010;49:59–69. - PMC - PubMed
    1. Aro K., Rosa L.E., Bello I.O., Soini Y., Mäkitie A.A., Salo T., Leivo I. Expression pattern of claudins 1 and 3-an auxiliary tool in predicting behavior of mucoepidermoid carcinoma of salivary gland origin. Virchows Arch. 2011;458:341–348. - PubMed

LinkOut - more resources