|Year : 2014 | Volume
| Issue : 2 | Page : 173-177
Expression of cytokeratin 18 and 19 in oral potentially malignant disorders: A systematic review
Sam Prasad Prabakaran, Arvind Muthukrishnan
Department of Oral Medicine and Radiology, Saveetha Dental College, Chennai, Tamil Nadu, India
|Date of Submission||28-Aug-2014|
|Date of Acceptance||16-Oct-2014|
|Date of Web Publication||30-Oct-2014|
Sam Prasad Prabakaran
Department of Oral Medicine and Radiology, Saveetha Dental College, Poonamalle High Road, Chennai, Tamil Nadu
Source of Support: None, Conflict of Interest: None
| Abstract|| |
The aim of this review is to evaluate the expression of cytokeratin 18 and 19 in oral potentially malignant disorders (OPMD). Systematic review was performed using Medline and PubMed. Hand searches were taken from the back references. Articles published till 15 July 2014 were included in the search. The search yielded a total of 20 articles, out of which 16 articles were eliminated, as they did not fulfill the inclusion criteria and 4 articles were included for the final analysis. The available literature showed that cytokeratin 18 and 19 were expressed in all OPMDs. The level of expression varied among different oral, potentially malignant disorders and among different studies.
Keywords: Cytokeratins, OPMDs, oral potentially malignant disorders, oral submucous fibrosis, leukoplakia, lichen planus
|How to cite this article:|
Prabakaran SP, Muthukrishnan A. Expression of cytokeratin 18 and 19 in oral potentially malignant disorders: A systematic review
. J Indian Acad Oral Med Radiol 2014;26:173-7
|How to cite this URL:|
Prabakaran SP, Muthukrishnan A. Expression of cytokeratin 18 and 19 in oral potentially malignant disorders: A systematic review
. J Indian Acad Oral Med Radiol [serial online] 2014 [cited 2018 Oct 23];26:173-7. Available from: http://www.jiaomr.in/text.asp?2014/26/2/173/143694
| Background|| |
Cytokeratins (CKs) are a group of intermediate filament proteins dispersed in the cytoplasm of eukaryotic cells that contribute to the maintenance of the cytoskeletal framework of these cells and are specifically expressed in epithelial tissues. Cytokeratins are broadly classified on the basis of their molecular weight and isoelectric points into Type 1 - Acidic with low molecular weight CKs 9-23, and Type 2 - Basic or Neutral with high molecular weight CKs 1-8.  Each type of epithelium expresses two or more specific pairs based on their differentiation status.  Cytokeratins, which are important components of the cytoskeleton, are excellent epithelial differentiation markers, used to study neoplastic and inflammatory diseases. Alterations in CK pattern have been reported in oral potentially malignant and malignant lesions.  Cytokeratins 8, 18, and 19 are the most abundant in simple epithelial cells. Both CKs 18 and 19 have been demonstrated in oral carcinoma. 
An oral potentially malignant disorder (OPMD) is a common term suggested to replace oral pre-cancer, including both oral precancerous lesions and oral precancerous conditions. All oral lesions that carry a risk of malignant transformation are included under this term.  The OPMDs included in this review are leukoplakia, oral lichen planus, and oral submucous fibrosis.
Leukoplakia has been defined as white plaques of questionable risk, having excluded (other) known diseases or disorders that carry no increased risk for cancer.  Oral lichen planus is a chronic autoimmune disorder of unknown etiology.  The World Health Organization (WHO) recognizes seven different clinical forms of oral lichen planus: Reticular, plaque-like, papular, erosive, atrophic, bullous, and ulcerated.  Out of the seven forms, erosive is most prone to malignant transformation. Oral submucous fibrosis is a chronic insidious disease that is associated with significant functional morbidity and increased risk of malignancy. 
Oral carcinoma may be preceded by oral potentially malignant disorders. Early recognition and treatment of an OPMD can prevent possible malignant transformation. Tumor markers help us to predict the possibility of malignant transformation from OPMDs. It is important to identify markers that can help us ascertain those lesions that have a high potential for malignant transformation so that we can treat them appropriately.  Cytokeratins 18 and 19 have been demonstrated in oral carcinoma. Assessing the expression of CKs 18 and 19 in OPMDs can be an aid to predict possible malignant transformation and also help us to initiate early treatment, resulting in a better prognosis. ,,
| Materials and Methods|| |
A systematic literature search of MEDLINE and PUBMED for articles published till 15 July 2014, with language restricted to English, was done using the terms: 'Oral potentially malignant disorders', 'oral premalignant lesions', 'oral premalignant conditions', 'oral precancerous lesions', 'oral precancerous conditions', 'leukoplakia', 'erythroplakia', 'oral lichen planus', 'erosive lichen planus', 'oral submucous fibrosis', 'smoker's palate', 'stomatitis nicotina palati', 'stomatitis nicotina', 'actinic chelitis', 'plummer vinson syndrome', 'oral chronic non healing ulcer', 'cytokeratin 18', 'cytokeratin 19', 'keratin 18,' and 'keratin 19'. All abstracts were reviewed independently and if an article was considered relevant, full articles were obtained and evaluated.
The inclusion criteria for considering this review were set prior to the search. They are as follows:
Types of studies: In-vivo studies.
Experimental studies, where expression of CK 18 and/or 19 assessed in one or more OPMDs was confirmed histopathologically.
Types of studies: In-vitro studies.
Case reports, case series, review articles.
Articles in languages other than English.
Studies in which another parameter or tumor marker, apart from CK, was also assessed.
| Results|| |
Results of the search strategy
A total of four articles were identified for inclusion in this review. The search of PubMed and MeSH databases provided a total of 19 articles and a hand search gave one article through back references, out of which four met the inclusion criteria and 16 were excluded. The full texts of the included four articles were examined in detail.
Evidence level of the included studies
[Table 1] shows the level of evidence according to the Canadian task force's hierarchy of evidence.
The characteristic of the studies included are summarized in [Table 2].
Description and interpretation of the results of the studies
[Table 3] and [Table 4], and [Graph 1], [Additional file 1] [Graph 2], [Additional file 2] [Graph 3], [Additional file 3] [Graph 4] [Additional file 4]show the description and interpretation of the results of the studies evaluating the expression of CK 18 and 19 in OPMDs.
| Discussion|| |
Cytokeratin 18 (CK 18) is one of the most common characteristic members of the large intermediate filament gene family and is expressed in the simple or single-layered epithelial tissues. The keratin profile of a given epithelium is linked to several apparently diverse factors, such as, differentiation state, proliferation rate, and histogenesis. Their persistent expression in tumor cells, derived from these epithelia, has led to the widespread use of monoclonal antibodies, as aids in the detection and identification of carcinoma. 
Cytokeratin 19 (CK 19) is an intermediate filament protein, which is found in most of the simple and non-keratinizing stratified epithelia. It has been shown as a useful marker of cellular atypia, associated with malignant lesions in the oral epithelium. Its expression in the supra basal layers of the oral mucosa may also be a useful marker in the identification of oral lesions, with a potential malignant transformation. 
Thus, studies assessing the expression of CK 18 and/or 19 in one or more oral potentially malignant disorders were included in this review. Studies that assessed any other parameter along with CK were excluded. Abstracts and letters were not considered, as their data are often insufficient for analysis in a systematic review.
In this review, four experimental studies were included, in which a total of 121 samples (60 samples of oral submucous fibrosis, 10 samples of leukoplakia, and 51 samples of lichen planus) from patients with oral potentially malignant disorders were subjected to immunohistochemical examination for the expression of CK 18 and/or 19. Twenty-one samples of lichen planus were examined only for CK 19. Thirty samples of lichen planus were examined for both CK 18 and 19. One hundred samples, including 60 samples of oral submucous fibrosis, 10 samples of leukoplakia, and 30 samples of lichen planus were examined for CK 19. ,,,
The primary outcome measure in these studies was the expression of CK. In one study, by Ranganathan et al.,  in 2005, CK 18 expression was 12% in the examined 50 samples of oral submucous fibrosis, which inferred that the aberrant expression of CK18 in these tissues could be indicative of the initiation of abnormal cell differentiation. In another study by Kittipong Dhanuthai et al.  in 2007, CK 18 expression was 16.7% in the examined 30 samples of lichen planus, suggesting an increased expression in lichen planus. In the third study by Nanda et al,  in 2012, CK expression was 40% in 10 samples of leukoplakia and 30% in 10 samples of oral submucous fibrosis [Table 3].
Cytokeratin 19 expression was found in 30% of the 30 samples examined in lichen planus in the first study by Kittipong Dhanuthai et al.,  in 2007, while 19% of the samples showed CK 19 expression in the 21 samples of lichen planus examined by Claudio MC Jacques et al.,  in 2009 [Table 4].
Mattila et al. determined the expression patterns of the proliferation markers topoisomerase II alpha (topo II alpha), Ki-67, and CK 19 in atrophic oral lichen planus. Twenty-nine percent of the specimen in the study showed CK 19 positivity. 
Coltrera et al. have reported that CK19 is a specific marker of moderate-to-severe dysplasia and carcinoma-in-situ in the oral epithelium. In contrast, the normal epithelium and hyperplastic lesions reportedly express CK 19 only in the basal layer, if at all. The authors concluded that suprabasal CK 19 expression is neither a sensitive nor a specific marker of premalignancy in the oral epithelium and cannot be used to distinguish hyperplasia from dysplasia. 
According to Ram Prassad et al., CK 19 was detected in the basal cell layer of non-keratinized normal mucosa, while dysplasia (diagnosed in H and E stained sections, mild-severe) stained strongly for CK 19 in the basal and supra basal cell layers, indicating layer specificity for CK 19 expression. Furthermore, according to their study, in oral squamous cell carcinoma, the number of CK 19 labeled cells increased from well to poorly differentiated tumors. 
Boisnic et al. have reported that in the buccal mucosa, which is not keratinized, CKs 4 and 13 are expressed in a majority. In lichen planus of the buccal mucosa, the appearance of CKs 1, 2, 10, and 11 coincides with a decrease in CKs 4 and 13 and a moderate increase in CKs 6, 16, 17, and 19. In the normal gingiva, which is normally keratinized, the main CKs are 1, 2, 10, and 11. In gingival lichen planus, a slight decrease in these CKs and in CK 13 expression was noted. 
Fillies et al. have reported that the expression of CK 8/18 and CK 19 in transformed oral lesions can be regarded as an early feature in the pathogenesis of invasive oral squamous cell carcinoma. However, the aberrant expression of CK 8/18 and CK 19 in an even higher frequency in invasive carcinomas, characterizes the expression of typical glandular CKs as a general progression marker in squamous cell carcinomas. 
| Conclusion|| |
The available literature shows that CK 18 and 19 are expressed in oral potentially malignant disorders (leukoplakia, lichen planus, and oral submucous fibrosis) although the level of expression of CK 18 and 19 varies among different OPMDs and among different studies. The review emphasizes on the potential use of CK 18 and 19 as an aid to predict the possible malignant transformation of OPMD, which would help initiate early treatment with a better prognosis.
| References|| |
Nanda KD, Ranganathan K, Devi U, Joshua E. Increased expression of CK8 and CK18 in leukoplakia, oral submucous fibrosis, and oral squamous cell carcinoma: An immunohistochemistry study. Oral Surg Oral Med Oral Pathol Oral Radiol 2012;113:245-53.
Ranganathan K, Kavitha R, Sawant SS, Vaidya MM. Cytokeratin expression in oral submucous fibrosis - An immunohistochemical study. J Oral Pathol Med 2006;35:25-32.
Jacques CM, Pereira AL, Maia V, Cuzzi T, Ramos-e-Silva M. Expression of cytokeratins 10, 13, 14 and 19 in oral lichen planus. J Oral Sci 2009;51:355-65.
Dhanuthai K, Chaiyarit P, Chowsrikul W, Wongsana P, Rojanawatsirivej S. Cytokeratin 18 and 19 expression in normal mucosa, lichen planus and squamous cell carcinoma. Acta Stomatol Croat 2007;41:23-30.
Syrjänen S, Lodi G, von Bültzingslöwen I, Aliko A, Arduino P, Campisi G, et al
. Human papillomaviruses in oral carcinoma and oral potentially malignant disorders: A systematic review. Oral Dis 2011;17(Suppl 1):58-72.
Kerr AR, Warnakulasuriya S, Mighell AJ, Dietrich T, Nasser M, Rimal J, et al
. A systematic review of medical interventions for oral submucous fibrosis and future research opportunities. Oral Dis 2011;17(Suppl 1):42-57.
Barak V, Goike H, Panaretakis KW, Einarsson R. Clinical utility of cytokeratins as tumor markers. Clin Biochem 2004;37:529-40.
Heyden A, Huitfeldt HS, Koppang HS, Thrane PS, Bryne M, Brandtzaeg P. Cytokeratins as epithelial differentiation markers in premalignant and malignant oral lesions. J Oral Pathol Med 1992;21:7-11.
Vaidya MM, Sawant SS, Borges AM, Ogale SB, Bhisey AN. Cytokeratin expression in precancerous lesions of the human oral cavity. Oral Oncol 1998;34:261-4.
Schulz J, Ermich T, Kasper M, Raabe G, Schumann D. Cytokeratin pattern of clinically intact and pathologically changed oral mucosa. Int J Oral Maxillofac Surg 1992;21:35-9.
Mattila R, Alanen K, Syrjänen S. Immunohistochemical study on topoisomerase II alpha, Ki-67 and cytokeratin-19 in oral lichen planus lesions. Arch Dermatol Res 2007;298:381-8.
Coltrera MD, Zarbo RJ, Sakr WA, Gown AM. Markers for dysplasia of the upper aerodigestive tract. Suprabasal expression of PCNA, p53, and CK19 in alcohol-fixed, embedded tissue. Am J Pathol 1992;141:817-25.
Ram Prassad VV, Nirmala NR, Kotian MS. Immunohistochemical evaluation of expression of cytokeratin 19 in different histological grades of leukoplakia and oral squamous cell carcinoma. Indian J Dent Res 2005;16:6-11.
Boisnic S, Ouhayoun JP, Branchet MC, Frances C, Béranger JY, Le Charpentier Y, et al
. Alterations of cytokeratin expression in oral lichen planus. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1995;79:207-15.
Fillies T, Jogschies M, Kleinheinz J, Brandt B, Joos U, Buerger H. Cytokeratin alteration in oral leukoplakia and oral squamous cell carcinoma. Oncol Rep 2007;18:639-43.
[Table 1], [Table 2], [Table 3], [Table 4]