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LETTER TO EDITOR
Year : 2012  |  Volume : 18  |  Issue : 4  |  Page : 224-225

Markers of cholesteatoma: Hearing is believing!


Department of Internal Medicine, Princess Durru Shehvar Children's and General Hospital,Hyderabad, India

Date of Web Publication19-Dec-2012

Correspondence Address:
Dilip Gude
Department of Internal Medicine, Princess Durru Shehvar Children's and General Hospital, Hyderabad
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0971-7749.104806

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How to cite this article:
Gude D. Markers of cholesteatoma: Hearing is believing!. Indian J Otol 2012;18:224-5

How to cite this URL:
Gude D. Markers of cholesteatoma: Hearing is believing!. Indian J Otol [serial online] 2012 [cited 2019 Nov 22];18:224-5. Available from: http://www.indianjotol.org/text.asp?2012/18/4/224/104806

Sir,

Cholesteatoma is a disorder of epithelial proliferation. The involved keratinocytes demonstrate uncoordinated hyperproliferation, migration and invasion properties. The mean epithelial proliferation marker-Ki-67 labeling index [1] and neutrophil gelatinase-associated lipocalin (NGAL) expression [2] in cholesteatoma cases is known to be higher than controls. While keratinocyte growth factor receptor (KGF-R) expression is increased in more differentiated areas of the cholesteatoma tissue and hence correlates with cytokeratins, epidermal growth factor receptor (EGF-R) is associated with proliferative and migratory portions of the lesion. [3] The degree of fibrosis is significantly higher in adult cholesteatoma than pediatric cholesteatoma, but the latter is more aggressive and invasive than the former. This is reflected in the higher proliferating cell nuclear antigen (PCNA) expression in the matrix and peri-matrix of pediatric cholesteatoma. [4] Pediatric cholesteatoma also sports higher levels of monoclonal antibody MIB 1 (which recognizes a nuclear antigen expressed by cells in the G1, S, and G2/M phases) compared to adult cholesteatoma.

The c-jun protein (a transcription factor for many genes), and the p53 protein (a negative regulator of cellular proliferation that induces DNA damage) have a major role in keratinocyte differentiation, proliferation and apoptosis in the cholesteatoma. [5] p63 (a p53 homologue and a marker expressed in replicating keratinocytes) and survivin (an inhibitor of apoptosis protein) also have increased expression in cholesteatoma. [6] MIF (macrophage migration inhibitory factor) expression in cholesteatomas is proportional to the levels of aggressiveness and correlates with recurrence. In a study, MIF correlated with retinoic acid receptor beta (RARb) expression in non-infected cholesteatomas and with MMP-3 (matrix metalloproteinase-3) and anti-apoptotic galectin-3 in infected ones. [7]

In cholesteatoma compared with the normal tissue, there is an increase of the glycoconjugate catabolism due to significantly higher concentration of N-acetyl-b-hexosaminidase, b-glucuronidase, and b-galactosidase activity. [8] Cell-mediated immunity also has a paramount role in the development of cholesteatoma and in its autodestructive properties as evidenced by increased number of CD3+ cells and CD68+ cells. [9]

Cholesteatoma epithelium sports a reduced phosphatase and tensin homolog (PTEN-gene) and an increased phosphorylated Akt (p-Akt) expression compared with retro-auricular skin. Cell survival mechanisms may play a role in the epithelial hyperplasia in cholesteatoma as reflected in the negative correlation between cholesteatoma PTEN and p-Akt. [10] Levels of tenascin and matrix metalloproteinase-9 are increased in cholesteatomas and signify bone destruction during cholesteatoma progression. Their raised levels coupled with decreased levels of apoptosis can be linked to more aggressive clinical behavior of cholesteatomas. [11] Myeloperoxidase activity significantly correlates with bone destruction in patients of chronic otitis media with cholesteatoma.

The extracellular matrix of cholesteatoma shows significantly increased transforming growth factor beta, nuclear pSmad2 and target gene extra-domain A-positive fibronectin, implying that it is a chronic wound healing process. [12] Altered intercellular communication through gap junctions may also underlie cholesteatomas. A study showed upregulated expression and a change in localization of both connexin 43 (C × 43) and C × 26 in cholesteatoma compared to normal skin. [13] b-trace protein and cochlin-tomoprotein may mark the development of perilymphatic fluid fistula.

The unraveling of pathogenesis of cholesteatoma spearheads a variety of biomarkers that help us gauge the incidence, severity and rate of complications thus enabling us to better tackle it.


  Acknowledgement Top


We thank our colleagues and staff of the department of Internal medicine for their perpetual support.

 
  References Top

1.Sharma SC, Sikka K, Thakar A, Dattagupta S. Epithelial proliferation in cholesteatoma. Otolaryngol Head Neck Surg 2012;147:P208.  Back to cited text no. 1
    
2.Woo HJ, Park JC, Bae CH, Song SY, Lee HM, Kim YD. Up-regulation of neutrophil gelatinase-associated lipocalin in cholesteatoma. Acta Otolaryngol 2009;129:624-9.  Back to cited text no. 2
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3.Raffa S, Leone L, Scrofani C, Monini S, Torrisi MR, Barbara M. Cholesteatoma-associated fibroblasts modulate epithelial growth and differentiation through KGF/FGF7 secretion. Histochem Cell Biol 2012;138:251-69.  Back to cited text no. 3
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4.Bassiouny M, Badour N, Omran A, Osama H. Histopathological and immunohistochemical characteristics of acquired cholesteatoma in children and adults. Egypt J Ear Nose Throat Allied Sci 2012;13:7-12.  Back to cited text no. 4
    
5.Shinoda H, Huang CC. Expressions of c-jun and p53 proteins in human middle ear cholesteatoma: relationship to keratinocyte proliferation, differentiation, and programmed cell death. Laryngoscope 1995;105:1232-7.  Back to cited text no. 5
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6.Park HR, Min SK, Min K, Jun SY, Seo J, Kim HJ. Increased expression of p63 and survivin in cholesteatomas. Acta Otolaryngol 2009;129:268-72.  Back to cited text no. 6
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7.Choufani G, Ghanooni R, Decaestecker C, Delbrouck K, Simon P, Schüring MP, et al. Detection of macrophage migration inhibitory factor (MIF) in human cholesteatomas and functional implications of correlations to recurrence status and to expression of matrix metalloproteinases-3/9, retinoic acid receptor-beta, and anti-apoptotic galectin-3. Laryngoscope 2001;111:1656-62.  Back to cited text no. 7
    
8.Olszewska E, Jakimowicz-Rudy J, Knas M, Chilimoniuk M, Pietruski JK, Sieskiewicz A. Cholesteatoma-associated pathogenicity: Potential role of lysosomal exoglycosidases. Otol Neurotol 2012;33:596-603.  Back to cited text no. 8
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9.Hussein MR, Sayed RH, Abu-Dief EE. Immune cell profile in invasive cholesteatomas: Preliminary findings. Exp Mol Pathol 2010;88:316-23.  Back to cited text no. 9
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10.Yune TY, Byun JY. Expression of PTEN and phosphorylated Akt in human cholesteatoma epithelium. Acta Otolaryngol 2009;129:501-6.  Back to cited text no. 10
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11.Juhász A, Sziklai I, Rákosy Z, Ecsedi S, Adány R, Balázs M. Elevated level of tenascin and matrix metalloproteinase 9 correlates with the bone destruction capacity of cholesteatomas. Otol Neurotol 2009;30:559-65.  Back to cited text no. 11
    
12.Huisman MA, de Heer E, Ten Dijke P, Grote JJ. Transforming growth factor beta and wound healing in human cholesteatoma. Laryngoscope 2008;118:94-8.  Back to cited text no. 12
    
13.Choung YH, Park K, Kang SO, Markov Raynov A, Ho Kim C, Choung PH. Expression of the gap junction proteins connexin 26 and connexin 43 in human middle ear cholesteatoma. Acta Otolaryngol 2006;126:138-43.  Back to cited text no. 13
    




 

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