Mucin Expression in Bile Ducts Neoplasms - Systematic Review and Metaanalysis

  

    
Mucin gene 
    
OR of mucin expression 
    
P 
  
  

    
MUC1 
    
8.5
    
0.004
  
  

    
MUC2 
    
2.5
    
0.045
  
  

    
MUC3 
    
0.2
    
NS
  
  

    
MUC4 
    
42.4
    
<0.0001
  
  

    
MUC5AC 
    
37.1
    
<0.0001
  
  

    
MUC5B 
    
0.2
    
NS
  
  

    
MUC6 
    
2.1
    
NS
  
  

    
Tn antigen 
    
12.6
    
0.001
  
  

    
STn antigen 
    
8.3
    
0.052
  
  

    
T antigen 
    
1.3
    
NS
  
  

    
Total mucin 
    
6.8
    
<0.0001
  
  

    
OR = odds ratio 
      
 
  

Table 1:  Summary of mucin expression in bile ducts lesions.

Studies Description

Sasaki et al found a decrease in MUC1 and MUC2 expression in CC [4-6].

Higashi et al described 3 different patterns of CC [7]. MUC1 expression was associated with poor outcome, while expression of MUC2 was a favorable prognostic indicator. Amaya et al found that biliary papillomatosis could undergo overt malignant transformation along with altered phenotypic expression of MUC1, MUC2 and tumor antigens Tn and Sialyl Tn (STn) [3]. Expression of MUC2 and STn, decreased and increased respectively, in CC. Matsumura et al found a positive correlation between MUC1 expression and bad prognosis in mass forming intrahepatic CC, especially when the cytoplasm of the cancer cells was stained positive [8]. Ishikawa et al described an increased expression of MUC2 in normal bile ducts of patients with biliary stones, similar to that found in intraductal papillary neoplasm and mucinous Cholangiocarcinoma [9]. Goto et al could not demonstrate a difference in MUC6 expression between CC and normal bile ducts [2]. Hong et al studied 193 patients with CC, and found that MUC2 expression was a good prognostic factor [10]. The opposite was demonstrated for MUC4 and MUC1 [11]. Zen et al found increased expression of MUC1 in ductal CC, but not in colloid carcinoma, in patients with hepatolithiasis [12]. Higashi et al found that MUC16 expression is a prognostic factor of poor survival in CC [13]. MUC1 expression was found in 100% of 21 cases of CC by Xu et al, and was associated with cell adhesion and invasive ability [14]. Sasaki et al looked at mucin expression using in situ hybridization [15]. The intramural and extramural peri biliary glands in hepatolithiasis expressed MUC3 and MUC6 apomucins and focally expressed MUC2 and MUC5 apomucins. These mucins could be involved in hepatolithiasis. They also found expression of MUC1 in the late cystogenetic process of the liver [16]. Yeh et al found a better survival for CC patients without expression of MUC4 [17]. Yamashita et al found that expression of Tn and sialyl Tn antigens of mucin are indicators of malignancy in the intrahepatic bile ducts [18]. Shibahara et al found MUC1 expression in the invasive growth of CC with disappearing of MUC2 [19]. The same group demonstrated that expression of MUC4 in intrahepatic Cholangiocarcinoma-mass forming type is an independent factor for poor prognosis and is a useful marker to predict outcome [20]. Aishima et al divided 100 cases of CC according to mucin expression into null type, gastric foveolar type, pyloric gland type and gastric combined type [21]. Gastric foveolar type was associated with aggressive tumour behaviour. Lee and Liu demonstrated that neoplastic transformation of the biliary epithelium is accompanied by increased expression of MUC4 and MUC5AC [22]. Mall et al found a positive correlation between MUC1 and metastasis in CC, and a negative correlation with MUC3 [23]. MUC5AC expression was found to be an independent predictor of poor prognosis in patients who underwent hepatectomy for mass forming CC [24]. Hughes et al found a similar mucin expression pattern in bile duct adenoma to the expression of mucins in the stomach [25]. Onoe et al found that papillary Cholangiocarcinoma that produced mucin (MUC1, MUC2, MUC5AC, and MUC6) was similar in prognosis and morphology to non-mucin producing papillary Cholangiocarcinoma [26]. Aquaporin-1is responsible for water transport across bile duct epithelium [27]. Its expression was found to inversely correlate with that of mucus core protein MUC5AC in CC, and their distribution tended to be complementary. Sasaki et al found that over expression of enhancer of MUC1 may be related to malignant behaviour in intraductal papillary neoplasm of the bile duct [28]. Lok et al found MUC5AC in 12% of CC patients [29]. Tamada et al found that MUC1core peptide was the most useful prognosis indicator among the various glycoforms of MUC1 mucins [30]. In contrast, the expression of MUC2 was inversely related with the tumor progression factors and poor outcome.

Discussion

MUC1, MUC2, MUC4, MUC5AC and Tn antigen were up regulated and had significantly higher expression in IPNB and CC than in normal bile ducts epithelium in our metaanalysis. Thus, these mucins may play a role in the transformation from normal epithelium to IPNB and CC; serve as markers for early detection and therapeutic targets. This is also an important argument for hepatolithiasis and IPNB being pre malignant states and precursors of CC and mucinous bile ducts carcinoma.

Up regulation of MUC1 was associated with poor prognosis, while expression of MUC2 and MUC3 was a favorable prognostic indicator [7,8,10,11,14,19,23,28,30]. MUC4 and MUC5AC were also bad prognostic factors when expressed in CC [11,17,22,31]. MUC4, an intra membrane ligand for the tyrosine kinase receptor ErbB2, is related with regulation of p27 [20]. The patients with CC positive for MUC4 showed a short survival period compared to non-expressing patients.

Increased expression of MUC5AC in the serum in CC patients was also found to be significantly higher than in benign bile ducts pathologies [32,33]. Serum MUC5AC was associated with advanced CC. The determination of serum MUC5AC may be predictive of poor prognosis and may be useful in selecting treatment options.

The weakness of our systematic review and metaanalysis is in the lack of homogeneity between studies neither in regard to bile ducts lesions definition nor in using the same methods for evaluation of mucin expression. Cholangiocarcinoma comprises a heterogeneous group of cancers with different types of biliary tract differentiation, and arises from the intra- or extra hepatic biliary tract. On the basis of its origin, CC was recently classified as intrahepatic, peri hilar, or distal CC [31]. This classification had no expression in our review. In addition, the prevalence of CC is very different in the east and west. An example is the very high prevalence of 80 per 100,000 population in Northeast Thailand, and much lower rates in Canada of only 0.3 per 100,000 [31]. In conclusion, a new era of investigations is now open in the field of CC. According to the new classification and accumulated data on different CC type’s behaviour, mucin genes may serve as important clues for prognosis and prediction of treatment success.

References

1. Nakanuma Y, Zen Y, Harada K, Ikeda H, Sato Y, Uehara T, et al. Tumorigenesis and phenotypic characteristics of mucin-producing bile ducts tumors: an immunehistochemical approach. J hepatobiliary Pancreat Sci. 2010; 17: 211-222.
2. Goto M, Shibahara H, Tamada S, Hamada T, Oda K, Nagino M, et al. Aberrant expression of pyloric gland-type mucin in mucin-producing bile duct carcinoma: a clear difference between the core peptide and the carbohydrate moiety. Pathol Int. 2005; 55: 464-470.
3. Amaya S, Sasaki M, Watanabe Y, Tsui WM, Tsuneyama K, Harada K, et al. Expression of MUC1 and MUC2 and carbohydrate antigen Tn change during malignant transformation of biliary papillomatosis. Histopathology. 2001; 38: 550-560.
4. Sasaki M, Nakanuma Y, Kim YS. Characterization of apomucin expression in intrahepatic cholangiocarcinomas and their precursor lesions: an immunohistochemical study. Hepatology. 1996; 24: 1074-1078.
5. Sasaki M, Nakanuma Y, Terada T, Kim YS. Biliary epithelial expression of MUC1, MUC2, MUC3, and MUC5/6 apomucins during intrahepatic bile duct Development and maturation, an Immunohistochemical study. Am J Pathol. 1995; 147: 574-579.
6. Nakanuma Y, Sasaki M, Sato Y, Ren X, Ikeda H, Harada K. Multistep carcinogenesis of perihilar cholangiocarcinoma arising in the intrahepatic large bile ducts. World J Hepatol. 2009; 1: 35-42.
7. Higashi M, Yonezawa S, Ho JJ, Tanaka S, Irimura T, Kim YS, et al. Expression of MUC1 and MUC2 mucin antigens in intrahepatic bile duct tumors: its relationship with a new morphological classification of cholangiocarcinoma. Hepatology. 1999; 30: 1347-1355.
8. Matsumura N, Yamamoto M, Aruga A, Takasaki K, Nakano M. Correlation between expression of MUC1 core protein and outcome after surgery in mass-forming intrahepatic cholangiocarcinoma. Cancer. 2002; 94: 1770-1776.
9. Ishikawa A, Sasaki M, Ohira S, Ohta T, Oda K, Nimura Y, et al. Aberrant expression of CDX2 is closely related to the intestinal metaplasia and MUC2 expression in intraductal papillary neoplasm of the liver in hepatolithiasis. Lab Invest. 2004; 84: 629-638.
10. Hong SMD, Cho H, Moskaluk CA, Frierson HF, Yu E, Ro JY. CDX2 and MUC2 protein expression in extrahepatic bile duct carcinoma. Am J Clin Pathol. 2005; 124: 361-370.
11. Tamada S, Shibahara H, Higash Mi, Goto M, Batra SK, Imai K, et al. MUC4 is a novel prognostic factor of extrahepatic bile duct carcinoma. Clin Cancer Res. 2006; 12: 4257-4264.
12. Zen Y, Sasaki M, Fujii T, Chen TC, Chen MF, Yeh TS, et al. Different expression patterns of mucin core proteins and cytokeratins during intrahepatic cholangiocarcinogenesis from biliary intraepithelial neoplasia and intraductal papillary neoplasm of the bile duct- an immunohistochemical study of 110 cases of hepatolithiasis. J Hepatol. 2006; 44: 350-358.
13. Higashi M, Yamada N, Yokoyama S, Kitamoto S, Tabata K, Koriyama C, et al. Pathobiological implications of MUC16/CA125 expression in intrahepatic cholangiocarcinoma- mass forming type. Pathobiology. 2012; 79: 101-106.
14. Xu HL, Inagaki Y, Seyama Y, Kokudo N, Nakata M, Wang FS, et al. Expression of KL-6 mucin, a human MUC1 mucin, in intrahepatic cholangiocarcinoma and its potential involvement in tumor cell adhesion and invasion. Life Sciences. 2009; 85: 395-400.
15. Sasaki M, Namanuma Y, Kim YS. Expression of apomucins in the intrahepatic biliary tree in hepatolithiasis differs from that in normal liver and extrahepatic biliary obstruction. Hepatology. 1998; 27: 46-53.
16. Sasaki M, Nakanuma Y. Abnormal expression of MUC1 apomucin and mature MUC1mucin in biliary epithelial cells in various cystic liver diseases. Hepatology. 1996; 24: 539-543.
17. Yeh CN, Pang ST, Wu RC, Chen TW, Jan YY, Chen MF. Prognostic value of MUC4 for mass-forming intrahepatic cholangiocarcinoma after hepatectomy. Oncol Rep. 2009; 21: 49-56.
18. Yamashita K, Yonezawa S, Tanaka S, Shirahama H, Sakoda K, Imai K, et al. Immunohistochemical study of mucin carbohydrates and core proteins in hepatolithiasis and cholangiocarcinoma. Int J Cancer. 1993; 55: 82-91. 4Shirahama H,
19. Shibahara H, Tamada S, Goto M, Oda K, Nagino M, Nagasaka T, et al. Pathologic features of mucin-producing bile duct tumors: two histopathologic categories as counterparts of pancreatic intraductal papillary-mucinous neoplasms. Am J Surg Pathol. 2004; 28: 327-338.
20. Shibahara H, Tamada S, Higashi M, Goto M, Batra SK, Holligsworth MA, et al. MUC4 is a novel prognostic factor of intrahepatic cholangiocarcinoma-mass forming type. Hepatology. 2004; 39: 220-229.
21. Aishima S, Kuroda Y, Nishihara Y, Taguchi K, Taketomi A, Maehara Y, et al. Gastric mucin phenotype defines tumour progression and prognosis of intrahepatic cholangiocarcinoma: gastric foveolar type is associated with aggressive tumour behavior. Histopathology. 2006; 49: 35-44.
22. Lee KT, Liu TS. Altered mucin gene expression in stone-containing intrahepatic bile ducts and cholangiocarcinomas. Dig Dis Sci. 2001; 46: 2166-2172.
23. Mall AS, Tyler MG, Ho SB, Krige JE, Kahn D, Spearman W, et al. The expression of MUC mucin in cholangiocarcinoma. Res Pract. 2010; 206: 805-809.
24. Abe T, Amano H, Shimamoto F, Hattori M, Kuroda S, Kobayashi T, et al. Prognostic evaluation of mucin-5AC expression in intrahepatic cholangiocarcinoma, mass-forming type, following hepatectomy. EJSO. 2015; 41: 1515-1521.
25. Hughes NR, Goodman ZD, Bhathal PS. An Immunohistochemical profile of the so-called bile duct adenoma clues to pathogenesis. Am J Surg Pathol. 2010; 34: 1312-1318.
26. Onoe S, Shimoyama Y, Ebata T, Yokoyama Y, Igami T, Sugawara G, et al. Clinicopathological significance of mucin production in patients with papillary cholangiocarcinoma. World J Surg. 2015; 39: 1177-1184.
27. Aishima S, Kuroda Y, Nishihara Y, Taguchi K, Iguchi T, Taketomi A, et al. Down-regulation of aquaporin-1 in intrahepatic cholangiocarcinoma is related to tumor progression and mucin expression. Hum Pathol. 2007; 38: 1819-1825.
28. Sasaki M, Matsubara T, Yoneda N, Nomoto K, Tsuneyama K, Sato Y, et al. Overexpression of enhancer of zeste homolog 2 and MUC1 may be related to malignant behaviour in intraductal papillary neoplasm of the bile duct. Histopathology. 2013; 62: 446-457.
29. Lok T, Chen L, Lin F, Wang HL. Immunohistochemical distinction between intrahepatic cholangiocarcinoma and pancreatic ductal adenocarcinoma. Hum Pathol. 2014; 45: 394-400.
30. Tamada S, Goto M, Nomoto M, Nagata K, Shimizu T, Tanaka S, et al. Expression of MUC1 and MUC2 mucins in extra hepatic bile duct carcinomas: Its relationship with tumor progression and prognosis. Pathol Intern. 2002; 52: 713-723.
31. Bridgewater J, Galle PR, Khan SA, Llovet JM, Park JW, Patel T, et al. Guidelines for the diagnosis and management of intrahepatic cholangiocarcinoma. J Hepatol. 2014; 60: 1268-1289.
32. Boonla C, Wongkham S, Sheehan JK, Wongkham C, Bhudhisawasdi V, Tepsiri N, et al. Prognostic value of serum MUC5AC mucin in patients with cholangiocarcinoma. Cancer. 2003; 98: 1438-1443.
33. Danese E, Ruzzenente O, Ruzzenente A, Iacono C, Bertuzzo F, Gelati M, et al. Assessment of bile and serum mucin 5AC in cholangiocarcinoma: Diagnostic performance and biologic significance. Surgery. 2014; 156: 1218-1224.