OJSTOpen Journal of Stomatology2160-8709Scientific Research Publishing10.4236/ojst.2021.112008OJST-107355ArticlesMedicine&Healthcare Histopathological and Immunohistochemical Study of the Distinction between Oral Lichen Planus and Oral Lichenoid Lesions TakehiroSuzuki1MasaakiSuemitsu2MitsukoNakayama3ChiekoTaguchi4MasayukiUkigaya2ChioriNakamura1YoshikazuNakayama1HiroshiYamamoto5KayoKuyama2*Department of Pathology, Nihon University School of Dentistry at Matsudo, Chiba, JapanNihon University Graduate School Dentistry at Matsudo, Oral Pathology, Chiba, JapanDepartment of Community Oral Health, Nihon University School of Dentistry at Matsudo, Chiba, JapanDepartment of Pathological Diagnosis, Nihon University Hospital at Matsudo, Chiba, JapanDepartment of Oral Surgery, Nihon University School of Dentistry at Matsudo, Chiba, Japan0302202111029110628, December 202022, February 2021 25, February 2021© Copyright 2014 by authors and Scientific Research Publishing Inc. 2014This work is licensed under the Creative Commons Attribution International License (CC BY). http://creativecommons.org/licenses/by/4.0/

Background: Oral potentially malignant disorders, which include oral lichen planus (OLP), are clinical presentations that carry a risk of development to cancer in the oral cavity. Oral lichenoid lesions (OLLs) are also termed interface/lichenoid mucositis. Malignant transformation of them remains controversial, but distinct clinical and histological criteria for how to differentiate OLP from OLLs have not been developed. Objectives: The purpose of this study was to elucidate findings that can allow histopathological differentiation of OLP and OLLs using histomorphological and immunohistochemical analyses. Materials and Methods: Analyses were performed in 10 cases diagnosed with OLP and 9 cases diagnosed with OLLs. Cytokeratin 19 (CK19), Ki-67 and CD3 were used as primary antibodies to detect basal cells, proliferative activity and T-cell distribution, respectively , and Perlecan and COX-2 to evaluate epithelial intracellular arrangements and interstitial distributions of proteoglycans and enzymes. Results: For CK19, positive cells were significantly found in OLLs at both the prominent area and site adjacent to the lesion comparison with those of OLP’s. The number of COX-2 positive cells was significantly higher in spinous and basal layers in OLLs of the prominent area. Additionally, OLLs showed mild to moderate expression for perlecan in the basal to spinous layers and in subepithelial tissue. Conclusion: Almost no basal cells were noted in the prominent area in OLP. COX-2 and perlecan were found in the basal to spinous layers in OLLs. Although there are restrictions, these suggested the possibility of helping to distinguish between OLP and OLLs.

Oral Lichen Planus (OLP) Oral Lichenoid Lesions (OLLs) Immunohistochemical Staining CK19 COX-21. Introduction

Oral lichen planus (OLP) is a chronic inflammatory disease involving abnormal keratinization of the oral mucosa [1] [2]. Several clinical types of OLP have been described. The most common is the reticular form, involving the buccal mucosa with symmetrical lesions, characterized by numerous interlacing white keratotic lines or striae (so-called Wickham’s striae) and few symptoms [1]. In addition, OLP has histopathologically demonstrated hyperkeratosis or parakeratosis, a saw-tooth profile of the rete ridges, liquefaction degeneration of the basal cell layer, and compact and band-like lymphocytic (predominantly T-cell) infiltration of the epitheliomesenchymal junction [3]. As mentioned above, although OLP is diagnosed by combining gross and histopathological findings, concordance rates are low compared to other oral mucosal diseases [4]. Our previous study proposed oblique running of papillary loops to white striae as a histopathological finding allowing definitive diagnosis of OLP, because this finding is observed regardless of the stage [4]. In addition, the basal cell layer is lost due to liquefaction degeneration and lymphocytes were reportedly in contact with the spinous layer [4]. Various histopathological reports have provided descriptions of the basal cell layer in OLP, but no consensus has yet been reached [5] [6] [7].

On the other hand, clinically and histopathologically similar cases have been distinguished as oral lichenoid lesions (OLLs) in the oral mucosa. Differentiation between OLP and OLLs is extremely difficult unless the cause of the pathological condition can be identified [8]. OLLs appear clinically similar to OLP, and also present with liquefaction degeneration of the basal cell layer and an appearance of civatte bodies histopathologically [9].

In 2017, precancer lesions and precancer conditions were combined to create the new concept of oral potentially malignant disorders (OPMDs), which included OLP [10]. OPMDs are clinical presentations that carry a risk of development to cancer in the oral cavity [10]. OLLs are also termed interface mucositis or lichenoid mucositis [11]. Malignant transformation of these lesions remains controversial, but distinct clinical and histological criteria for how to differentiate OLP from OLLs have not been developed [11].

The purpose of this study was thus to elucidate those findings that can allow histopathological differentiation of OLP and OLLs using histomorphological and immunohistochemical analyses.

2. Materials and Methods2.1. Subjects

Histopathological, and immunohistochemical evaluations were performed in 10 cases (5 males, 5 females) diagnosed with OLP and 9 cases (4 males, 5 females) diagnosed with OLLs. Subjects were selected from the pathology files of the Department of Oral Pathology in Nihon University School of Dentistry at Matsudo from 2000 to 2019. Mean age was 50.3 ± 11.4 years in OLP and 63.8 ± 14.0 years in OLLs. Subject characteristics in this study are summarized in Table 1. Cases diagnosed as OLP or OLLs by 3 dentists (including an oral surgeon) were based on gross findings of surface shape, background, and intraoral pictures of the lesion described in the electronic medical records. The conditions for the case selection of the present study are shown. At first, complete macroscopic view records were available for all patients, along with dental history of the lesion and a biopsy specimen comprising an area with epithelium and submucosal tissue. As for OLP, the cases were of unknown cause [9]. Meanwhile OLLs were considered as cases with a cause, such as, drugs, dental restorative materials, GVHD and other associated factors [9]. Patients with a history of exposure to dental materials, drugs [12], any treatment for lichen planus or drugs associated with lichenoid reaction before biopsy, any malignant or viral involvement in the mouth and pregnant women were excluded from the study sample.

Macroscopic findings were reconfirmed and classified by oral surgeons for 19 patients with well-defined looping and intersecting white lines/striae/patches with or without erosions and ulcerations [13] [14] [15] in the present study. For both lesions, clinical inspection classifications for the most prominent site were made independently by 2 oral surgeons and 3 oral pathologists based on the 6 types described by Andreasen [16] and the 2 types defined by Brant [17]. In cases of disagreement, classifications were discussed in a joint session until a consensus was reached. Biopsy specimens were obtained for all 19 patients by oral surgeons, sampling an area at the boundary of the most prominent lesion and an adjacent area of normal mucosa.

2.2. Histological Preparation

Histological specimens of OLP were stained using hematoxylin and eosin and selected by the following definitive histopathological criteria according to the American Academy of Oral and Maxillofacial Pathology: 1) presence of a well-defined band-like zone of cellular infiltration consisting mainly of lymphocytes in the superficial part of the connective tissue; and 2) signs of “liquefaction degeneration” in the basal layer; and 3) absence of epithelial dysplasia [18]. Conversely, specimens of OLLs stained by HE were selected by the criteria described in previous reports [9] [18]: 1) presence of associated factors; 2) diffuse and deeper distribution of lymphocytes; 3) no degeneration of basement membrane; and 4) no vascularity in basal cells. Patients with lesions that did not reflect the above strict histological criteria were not included in the study. Cases

 ReferencesPetruzzi, M., De Benedittis, M., Grassi, R., Cassano, N., Vena, G. and Serpico, R. (2002) Oral Lichen Planus: A Preliminary Clinical Study on Treatment with Tazarotene. Oral Diseases, 8, 291-295. https://doi.org/10.1034/j.1601-0825.2002.02833.xPindborg, J.J., Reichart, P.A., Smith, C.V. and van der Waa, I. (1997) Histological Typing of Cancer and Precancer of the Oral Mucosa. 2nd Edition, Springer, Berlin, Heidelberg, 30. https://doi.org/10.1007/978-3-642-60592-5Cawson, R.A. and Odell, E.W. (1998) Diseases of the Oral Mucosa: Non-Infective Stomatitis. In: Cawson, R.A. and Odell, E.W., Eds., Cawson’s Essentials of Oral Pathology and Oral Medicine, 6th Edition, Churchill Livingstone, London, 187-191.Hasegawa, K., Sakamaki, H., Higuchi, M., Suemitsu, M., Chieko, T., Ito, K. and Kayo, K. (2018) Histomorphometric Evaluation of Intraepithelial Papillary Capillaries in Oral Lichen Planus: A Histopathological Study. Journal of Dermatology Research and Therapy, 4, 58. https://doi.org/10.23937/2469-5750/1510058Bombeccari, G. P., Giannì, A. B. and Spadari, F. (2017) Immunoexpression of Cytokeratin-19 in the Oral Lichen Planus and Related Oral Squamous Cell Carcinoma. Annali Di Stomatologia, 8, 104-109.Liu, Y., Liu, G., Liu, Q., Tan, J., Hu, X., Wang, J. and Wang, X. (2017) The Cellular Character of Liquefaction Degeneration in Oral Lichen Planus and the Role of Interferon Gamma. Journal of Oral Pathology and Medicine, 46, 1015-1022. https://doi.org/10.1111/jop.12595Mattila, R., Alanen, K. and Syrjänen, S. (2007) Immunohistochemical Study on Topoisomerase IIα, Ki-67 and Cytokeratin-19 in Oral Lichen Planus Lesions. Archives of Dermatological Research, 298, 381-388. https://doi.org/10.1007/s00403-006-0711-zEisenberg, E. and Krutchkoff, D.J. (1992) Lichenoid Lesions of Oral Mucosa. Oral Surgery, Oral Medicine, Oral Pathology, 73, 699-704. https://doi.org/10.1016/0030-4220(92)90013-GKamath, V., Setlur, K. and Yerlagudda, K. (2015) Oral Lichenoid Lesions—A Review and Update. Indian Journal of Dermatology, 60, 102. https://doi.org/10.4103/0019-5154.147830Reibel, J., Tilakaratne, W., Gale, N., Westra, W., Hille, J., Williams, M. and Zain, R. (2017) Oral Potentially Malignant Disorders and Oral Epithelial Dysplasia. In: El-Naggar, A.K., Chan, J.K.C., Grandis, J.R., Takata, T. and Slootweg, P.J., Eds., WHO Classification of Head and Neck Tumours, 4th Edition, International Agency for Research on Cancer (IARC), Lyon, 112-115.El-Naggar, A.K. and Reichart, P. (2015) Proliferative Verrucous Leukoplakia and Precancerous Conditions. In: Barnes, L., Eveson, J.W., Reichart, P. and Sidransky, D., Eds., World Health Organization Classification of Tumours, Pathology & Genetics Head and Neck Tumours, International Agency for Research on Cancer (IARC), Lyon, 180-181.Thornhill, M.H., Sankar, V., Xu, X.J., Barrett, A.W., High, A.S., Odell, E.W. and Farthing, P.M. (2006) The Role of Histopathological Characteristics in Distinguishing Amalgam-Associated Oral Lichenoid Reactions and Oral Lichen Planus. Journal of Oral Pathology and Medicine, 35, 233-240. https://doi.org/10.1111/j.1600-0714.2006.00406.xAlrashdan, M.S, Cirillo, N. and Mccullough, M. (2016) Oral Lichen Planus: A Literature Review and Update. Archives of Dermatological Research, 308, 539-551. https://doi.org/10.1007/s00403-016-1667-2Al-Hashimi, I., Schifter, M., Lockhart, P.B., Wray, D., Brennan, M., Migliorati, C.A. and van der Waal, I. (2007) Oral Lichen Planus and Oral Lichenoid Lesions: Diagnostic and Therapeutic Considerations. Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology and Endodontology, 103, S25.e1-S25.e12. https://doi.org/10.1016/j.tripleo.2006.11.001Schmidt-Westhausen, A.M. (2020) Oral Lichen Planus and Lichenoid Lesions: What’s New? Quintessence International, 51, 156-161. https://doi.org/10.3290/j.qi.a43868Andreasen, J.O. (1968) Oral Lichen Planus. 1. A Clinical Evaluation of 115 Cases. Oral Surgery, Oral Medicine, Oral Pathology, 25, 31-42. https://doi.org/10.1016/0030-4220(68)90194-1Brant, J.M.C., Vasconcelos, A.C. and Rodrigues, L.V. (2008) Role of Apoptosis in Erosive and Reticular Oral Lichen Planus Exhibiting Variable Epithelial Thickness. Brazilian Dental Journal, 19, 179-185. http://dx.doi.org/10.1590/S0103-64402008000300001Van der Meij, E.H., Mast, H. and van der Waal, I. (2007) The Possible Premalignant Character of Oral Lichen Planus and Oral Lichenoid Lesions: A Prospective Five-Year Follow-up Study of 192 Patients. Oral Oncology, 43, 742-748.https://doi.org/10.1016/j.oraloncology.2006.09.006Yamazaki, M., Cheng, J., Hao, N., Takagi, R., Jimi, S., Itabe, H. and Saku, T. (2004) Basement Membrane-Type Heparan Sulfate Proteoglycan (Perlecan) and Low-Density Lipoprotein (LDL) Are Co-Localized in Granulation Tissues: A Possible Pathogenesis of Cholesterol Granulomas in Jaw Cysts. Journal of Oral Pathology and Medicine, 33, 177-184. https://doi.org/10.1111/j.0904-2512.2004.00087.xIkarashi, T., Ida-Yonemochi, H., Ohshiro, K., Cheng, J. and Saku, T. (2004) Intraepithelial Expression of Perlecan, a Basement Membrane-Type Heparan Sulfate Proteoglycan Reflects Dysplastic Changes of the Oral Mucosal Epithelium. Journal of Oral Pathology and Medicine, 33, 87-95. https://doi.org/10.1111/j.1600-0714.2004.00026.xMasai, K., Nakagawa, K., Yoshida, A., Sakurai, H., Watanabe, S., Asamura, H. and Tsuta, K. (2014) Cytokeratin 19 Expression in Primary Thoracic Tumors and Lymph Node Metastases. Lung Cancer, 86, 318-323. https://doi.org/10.1016/j.lungcan.2014.09.018Piattelli, A., Carinci, F., Iezzi, G., Perrotti, V., Goteri, G., Fioroni, M. and Rubini, C. (2007) Oral Lichen Planus Treated with 13-cis-Retinoic Acid (Isotretinoin): Effects on the Apoptotic Process. Clinical Oral Investigations, 11, 283-288. https://doi.org/10.1007/s00784-007-0117-0Hirota, M., Ito, T., Okudela, K., Kawabe, R., Yazawa, T., Hayashi, H. and Kitamura, H. (2002) Cell Proliferation Activity and the Expression of Cell Cycle Regulatory Proteins in Oral Lichen Planus. Journal of Oral Pathology & Medicine, 31, 204-212. https://doi.org/10.1034/j.1600-0714.2002.310403.xKaratsaidis, A., Schreurs, O., Helgeland, K., Axéll, T. and Schenck, K. (2003) Erythematous and Reticular Forms of Oral Lichen Planus and Oral Lichenoid Reactions Differ in Pathological Features Related to Disease Activity. Journal of Oral Pathology and Medicine, 32, 275-281. https://doi.org/10.1034/j.1600-0714.2003.00134.xZhao, Z.Z., Savage, N.W., Sugerman, P.B. and Walsh, L.J. (2002) Mast Cell/T Cell Interactions in Oral Lichen Planus. Journal of Oral Pathology and Medicine, 31, 189-195. https://doi.org/10.1034/j.1600-0714.2002.310401.xDutz, J.P. (2009) T-Cell-Mediated Injury to Keratinocytes: Insights from Animal Models of the Lichenoid Tissue Reaction. Journal of Investigative Dermatology, 129, 309-314. https://doi.org/10.1038/jid.2008.242Pigatti, F.M., Taveira, L.A. de A. and Soares, C.T. (2015) Immunohistochemical Expression of Bcl-2 and Ki-67 in Oral Lichen Planus and Leukoplakia with Different Degrees of Dysplasia. International Journal of Dermatology, 54, 150-155. https://doi.org/10.1111/ijd.12279Acay, R.R., Felizzola, C.R., Soares de Araújo, N. and Machado de Sousa, S.O. (2006) Evaluation of Proliferative Potential in Oral Lichen Planus and Oral Lichenoid Lesions Using Immunohistochemical Expression of p53 and Ki67. Oral Oncology, 42, 475-480. https://doi.org/10.1016/j.oraloncology.2005.09.012Walton, L.J., Macey, M.G., Thornhill, M.H. and Farthing, P.M. (1998) Intraepithelial Subpopulations of T Lymphocytes and Langerhans Cells in Oral Lichen Planus. Journal of Oral Pathology & Medicine, 27, 116-123. https://doi.org/10.1111/j.1600-0714.1998.tb01926.xMurata, M., Hara, K. and Saku, T. (1997) Dynamic Distribution of Basic Fibroblast Growth Factor during Epulis Formation: An Immunohistochemical Study in an Enhanced Healing Process of the Gingiva. Journal of Oral Pathology and Medicine, 26, 224-232. https://doi.org/10.1111/j.1600-0714.1997.tb01228.xSobolewski, C., Cerella, C., Dicato, M., Ghibelli, L. and Diederich, M. (2010) The Role of Cyclooxygenase-2 in Cell Proliferation and Cell Death in Human Malignancies. International Journal of Cell Biology, 2010, Article ID: 215158. https://doi.org/10.1155/2010/215158Arreaza, A.J., Rivera, H. and Correnti, M. (2014) Expression of COX-2 and BCL-2 in Oral Lichen Planus Lesions and Lichenoid Reactions. Ecancermedicalscience, 8, Article no. 411. https://doi.org/10.3332/ecancer.2014.411Sarode, G.S., Sarode, S.C., Patil, A., Anand, R., Patil, S.G., Rao, R.S. and Augustine, D. (2015) Inflammation and Oral Cancer: An Update Review on Targeted Therapies. The Journal of Contemporary Dental Practice, 16, 595-602. https://doi.org/10.5005/jp-journals-10024-1727Sarode, S.C., Sarode, G.S. and Patil, A. (2014) Therapeutic Aspects of the Inflammation Mediated Oral Carcinogenesis. Oral Oncology, 50, e13-e14. https://doi.org/10.1016/j.oraloncology.2013.12.026Shibata, M., Kodani, I., Osaki, M., Araki, K., Adachi, H., Ryoke, K. and Ito, H. (2005) Cyclo-Oxygenase-1 and -2 Expression in Human Oral Mucosa, Dysplasias and Squamous Cell Carcinomas and Their Pathological Significance. Oral Oncology, 41, 304-312. https://doi.org/10.1016/j.oraloncology.2004.09.009Sanketh, D.S., Kumari, K., Rao, R.S., Haragannavar, V.C., Sarode, S.C., Sarode, G.S. and Patil, S. (2019) Expression of Ki-67, p53, α-SMA and COX-2 in Lichen Planus and Related Lesions: A Pilot Study. Journal of Oral Biology and Craniofacial Research, 9, 230-235. https://doi.org/10.1016/j.jobcr.2018.02.003Chankong, T., Chotjumlong, P., Sastraruji, T., Pongsiriwet, S., Iamaroon, A. and Krisanaprakornkit, S. (2016) Increased Cyclooxygenase 2 Expression in Association with Oral Lichen Planus Severity. Journal of Dental Sciences, 11, 238-244. https://doi.org/10.1016/j.jds.2015.12.002Cortés-Ramírez, D.A., Rodrguez-Tojo, M.J., Gainza-Cirauqui, M.L., Martnez-Conde, R. and Aguirre-Urizar, J.M. (2010) Overexpression of Cyclooxygenase-2 as a Biomarker in Different Subtypes of the Oral Lichenoid Disease. Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology and Endodontology, 110, 738-743. https://doi.org/10.1016/j.tripleo.2010.08.005Lynch P.M. ,et al. (2001)COX-2 Inhibition in Clinical Cancer Prevention Oncology 15, 21-26.Arber N. ,et al. (2008)Cyclooxygenase-2 Inhibitors in Colorectal Cancer Prevention: Point Cancer Epidemiology Biomarkers and Prevention 17, 1852-1857.Arun, B. and Goss, P. (2004) The Role of COX-2 Inhibition in Breast Cancer Treatment and Prevention. Seminars in Oncology, 31, 22-29. https://doi.org/10.1053/j.seminoncol.2004.03.042Patil, S., Rao, R.S., Sanketh, D.S. and Warnakulasuriya, S. (2015) Lichenoid Dysplasia Revisited—Evidence from a Review of Indian Archives. Journal of Oral Pathology & Medicine, 44, 507-514. https://doi.org/10.1111/jop.12258Fitzpatrick, S.G., Honda, K.S., Sattar, A. and Hirsch, S.A. (2014) Histologic Lichenoid Features in Oral Dysplasia and Squamous Cell Carcinoma. Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology, 117, 511-520. https://doi.org/10.1016/j.oooo.2013.12.413