Differential protein immunoexpression profiles in appendiceal mucinous neoplasms: a special reference to classification and predictive factors

Abstract

Appendiceal mucinous neoplasms have been the focus of considerable debate in recent years. We histologically classified 70 appendiceal mucinous neoplasms into three categories: 32 mucinous adenoma, 23 mucinous neoplasm of uncertain malignant potential, and 15 mucinous adenocarcinomas. Immunohistochemistry was performed for 24 proteins in different functional categories, specifically, oncogenic proteins (bcl-2, b-catenin, CEA, C-erbB2, c-kit, Cox-2, Cyclin D1, EGFR, Ki-67, NF-jB, VEGF), tumor suppressors (E-cadherin, FHIT, hMLH1, p53, p63, smad4), cell-cycle regulators (p21, p27, p16), and mucin proteins (MUC1, MUC2, MUC5AC, MUC6). Our data showed that 9 out of the 24 proteins were more frequently altered in the mucinous adenocarcinoma group than in the mucinous adenoma group (Po0.05), including b-catenin (13% in mucinous adenoma vs 60% in mucinous adenocarcinoma), CyclinD1 (44 vs 87%), Ki-67 (high labeling index: 31 vs 67%), NF-jB (19 vs 60%), VEGF (16 vs 87%), E-cadherin (0 vs 47%), p53 (6 vs 40%), MUC2 (9 vs 67%), and MUC5AC (3 vs 40%). The distinct immunoexpression profile of mucinous neoplasm of uncertain malignant potential was placed between those of mucinous adenoma and mucinous adenocarcinoma (Po0.05). Moreover, the mucinous adenoma, mucinous neoplasm of uncertain malignant potential, and mucinous adenocarcinoma categories displayed differences in terms of the number of altered markers among the nine proteins (Po0.05; mean 1.4 vs 2.6 vs 5.5, respectively). In mucinous adenocarcinoma, the p53 status was related to disease-free survival and overall survival of patients (Po0.05, both). NF-jB status and the number of altered protein markers made statistically marginal impacts on disease-free survival; also b-catenin loss, on overall survival of patients. In conclusion, protein immunoexpression profiles may facilitate the classification of appendiceal mucinous neoplasms. In our study, the three tumor categories of mucinous adenoma, mucinous neoplasm of uncertain malignant potential, and mucinous adenocarcinoma exhibited distinct immunoexpression profiles. Five and more altered protein markers, p53 overexpression, NF-jB positivity, and b-catenin loss were predictive factors of adverse clinical outcomes in appendiceal mucinous adenocarcinomas.

Leptin, MUC2 and mTOR in Appendiceal Mucinous Neoplasms

“…Moreover, we adopted the term 'appendiceal mucinous neoplasm of uncertain malignant potential' from Carr et al [2] , and followed the criteria revisited by Pai et al [4] . We strictly defined 'appendiceal mucinous neoplasm of uncertain malignant potential' in the present study as follows: under the condition of lost muscularis mucosae or undiscerned individual layers of the appendix (accordingly, 'undetermined invasion'), appendiceal mucinous neoplasms display a bland cytoarchitecture, but the features show (1) epithelium pushing deeply into underlying tissue, (2) a cystic gland-like structure in the appendiceal wall or (3) uncertainty of complete excision, such as a positive proximal margin or extensive mucin on the appendiceal serosa [6] .…”

“…According to a recent study, leptin contributes to mucin production in colonic epithelial cells, and a leptininduced increment of mucins, such as MUC2, MUC5AC and MUC4, has been reported [11,12] . We had previously reported that MUC2 and MUC5AC were related to the malignant behaviour of appendiceal mucinous neoplasms [6] . Recently, leptin was identified as multifunctional, i.e., it not only controls food intake and energy balance [13] , but it also regulates carcinogenesis [14][15][16] and inflammatory processes [17] .…”

“…In the present study, we adopted the three-tiered categories of Carr et al [2] , i.e. mucinous adenoma, mucinous neoplasm of uncertain malignant potential and mucinous adenocarcinoma of the appendix, since this classification was supported by clinical outcome and analysis of protein alteration in our previous report [6] . Moreover, we adopted the term 'appendiceal mucinous neoplasm of uncertain malignant potential' from Carr et al [2] , and followed the criteria revisited by Pai et al [4] .…”

“…Pseudomyxoma peritonei is recognized as a neoplastic and progressive condition [3][4][5][6][7][8][9] . Appendiceal mucinous neoplasm is accepted as the primary culprit for pseudomyxoma peritonei, and the classification of appendiceal mucinous neoplasm has been additionally complicated by pseudomyxoma peritonei [3][4][5][6][7][8][9] .…”

“…Appendiceal mucinous neoplasm is accepted as the primary culprit for pseudomyxoma peritonei, and the classification of appendiceal mucinous neoplasm has been additionally complicated by pseudomyxoma peritonei [3][4][5][6][7][8][9] . Moreover, there is no standardized treatment for patients with pseudomyxoma peritonei, which often culminates in the demise of these patients, despite the many modalities of treatment, such as repeated debulking surgery, intraperitoneal chemotherapy and systemic chemotherapy [8][9][10] .…”