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Evaluation of epithelial-mesenchymal markers and correlation with clinical aspects in keratocyst lesions

Journal of Research in Medical and Dental Science
eISSN No. 2347-2367 pISSN No. 2347-2545

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Review Article - (2021) Volume 9, Issue 12

Evaluation of epithelial-mesenchymal markers and correlation with clinical aspects in keratocyst lesions

Joana Leticia Vendruscolo1, Mariana de Souza Lessa1, Sergio Ossamu Ioshii2, Juliana Lucena Schussel3 and Laurindo Moacir Sassi1*

*Correspondence: Laurindo Moacir Sassi, Department of Oral and Maxillofacial Surgery, Erasto Gaertner Hospital, Curitiba, Parana?, Brazil, Email:

Author info »

Abstract

Objective

Odontogenic keratocysts (OK) have a high recurrence rate and aggressive clinical behavior. The event called epithelial-mesenchymal transition (EMT) is a process in which the epithelial cell loses its epithelial characteristics and acquires properties typical of mesenchymal cells. Studies have already demonstrated that OC has expression of tumor markers, but the lack of clarification about its development mechanism and molecular composition makes the therapeutic options remain limited. The aim of this study is to evaluate the expression of EMT marker proteins in these lesions, correlating the expression of these proteins with clinical aspects of each case.

Method

Patients with OK diagnoses, treated by the Department of Oral and Maxillofacial Surgery of the Erasto Gaertner Hospital, Curitiba, Brazil in the period between 2016 and 2019 were evaluated by immunohistochemical analysis, to assess the expression of EMT markers (Vimentin, beta-catenin and E-cadherin).

Results

Eighteen patients were included, with a mean age of 43 years, and most of them were male. The mandible was more affected than the maxilla. No association between the clinical characteristics of the cysts and the immunohistochemical profile for EMT proteins was observed.

Conclusion

Even though it is a benign lesion, OK is associated with severe complications. For this reason, the study of markers that allow a better understanding of its biological behavior is important for the best management of the patient.

Keywords

Epithelial-Mesenchymal Transition, Odontogenic Cysts, Odontogenic Keratocysts, Odontogenic Tumors.

Introduction

The term "odontogenic" refers to lesions derived from elements of the epithelium, ectomesenchyme and/or mesenchyme that participated or are participating in the formation of the dental apparatus. These lesions are found exclusively in the maxillofacial region and can occur at any age.

Odontogenic keratocysts (OK) present a distinct form of development from other odontogenic cysts. According to the literature, the mandible is involved in 60-80% of OK cases, with a greater tendency to involve the posterior body and ascending ramus, affecting mainly male patients in the second, third and fourth decades of life.

Most cases are sporadic lesions, occurring singly mainly in the mandible, with a high recurrence rate and aggressive clinical behavior [1].

The etiology of OK is probably associated with the development of the dental lamina and its remnants, however, despite being intensively studied, the pathogenesis of this lesion still holds unanswered questions [2]. Due to its peculiar characteristics, this lesion has long been a matter of debate, being reclassified numerous times as cyst or tumor.

Numerous studies have already demonstrated that OK is different from lesions such as Dentigerous Cyst or Orthokeratinized Odontogenic Cyst and has a tumor markers expression that resemble those of Ameloblastoma, however, the lack of clarification about its development mechanism and molecular composition makes therapeutic options other than conventional ones remain limited [3].

The event called epithelial-mesenchymal transition (EMT) is a complex process in which the epithelial cell loses its epithelial characteristics and acquires properties typical of mesenchymal cells. In this way, the cell increases its ability to invade, migrate, and generate metastasis. The dissociation of tumor cells across tissues due to changes in cell-cell adhesion is one of the main causes of the tumor's invasive capacity, being a possible explanation for the aggressive behavior of OK.

The concept of EMT in tumor metastasis formation is based on observations that epithelial carcinoma cells that acquired mesenchymal markers such as vimentin and loss of cell-cell adhesion molecules such as E-cadherin were associated with a higher metastatic potential. Currently, the most commonly used markers for EMT verification are vimentin, fibronectin and N-cadherin (mesenchymal markers), E-cadherin (epithelial markers) and Snail and Slug (transcription factors) [4].

Evidence for the involvement of EMT in OK progression is still limited, however, dysregulation of these proteins may explain the molecular mechanism by which these lesions develop.

The aim of this paper is to survey the cases of OK diagnosed at the Department of Oral and Maxillofacial Surgery of the Erasto Gaertner Hospital (EGH) in the period between 2016 and 2019 and evaluate the expression of EMT marker proteins in these lesions, correlating the expression of these proteins with clinical aspects of the lesions and with the prognosis of each case.

Material and Method

The study was approved by the Research Ethics Committee of EGH under protocol CAE 24601119.0.0000.0098 and was conducted respecting resolution 466/12 CONEP. The cases of OK diagnosed and treated at the Department of Oral and Maxillofacial Surgery of the EGH, Curitiba, Brazil, during the years 2016 to 2019 were surveyed. The cases were surveyed through electronic medical-hospital records, from which clinical information such as gender, age, race, year of diagnosis, location and size of the lesion, type of treatment used, use of Carnoy's solution, and occurrence or not of recurrence were retrieved.

All patients who underwent surgical treatment at EGH from 2016 to 2019 were included. Syndromic patients, cases in which the data in the medical records were incomplete, or who underwent treatment outside EGH were excluded.

The histopathological slides of each case, stained in Hematoxylin and Eosin, were selected and analyzed again to confirm the diagnosis of OK. The paraffin blocks from each slide were then selected and immunohistochemical analysis was requested to evaluate the expression of EMT markers, which were the proteins Vimentin, beta-catenin and E-cadherin for each of the cases.

Clinical findings and data resulting from immunohistochemical analysis were described in a table to identify possible associations between clinical behavior and immunohistochemical profile of EMT proteins.

Results

The study included 18 patients with a mean age of 43 years, most of them male (61.11%) and all of them were Caucasian. The mandible was more affected when compared to the maxilla (72.22%) and the lesions had an average of 3 cm in their largest diameter.

Only one patient presented lesion recurrence in the mandible. The other patients did not present lesion recurrence during the period analyzed in this study and are still under follow-up. As for treatment, cystic enucleation by curettage was the surgical treatment performed in all cases, and of these, 8 cases (44.44%) was associated with transoperative Carnoy's solution application.

In the immunohistochemical analysis, positivity of the markers E-cadherin and beta-catenin was observed for all cases, both maxilla and mandible. Regarding the Vimentin protein, all cases were negative. No association between the clinical features of the cysts and the immunohistochemical profile for EMT proteins was observed (figure 1, figure 2, figure 3).

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Figure 1: Immunohistochemistry aspect showing positivity of e-cadherin.

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Figure 2: Immunohistochemistry aspect showing positivity of beta-catenin.

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Figure 3: Immunohistochemistry aspect showing negativity of vimentin

Discussion and Conclusion

Due to its peculiar characteristics and behavior, the etiopathology of OK remains a debate. In 2005, the 3rd edition of the WHO classified OC as a tumor, and it is now called Keratocystic Odontogenic Tumor and defined as a "benign intraosseous tumor of odontogenic origin with a characteristic layer of parakeratinized stratified squamous epithelium and with a potential for aggressive and infiltrative behavior". However, the latest edition of the WHO, reclassified the OK as an odontogenic cyst due to a debate regarding the neoplastic origin of this lesion. New findings regarding its etiology and molecular composition permit a better understanding of how this lesion functions and may mean advances in treatment and a better prognosis for affected patients.

Similar results to those reported in the literature were found in this study regarding the clinical characteristics of OK. According to Kshirsagar et al. (2019) the mandible is involved in 60-80% of OK cases and affects mainly male patients in the second, third and fourth decades of life [3].

In relation to signs and symptoms, most patients in our study presented signs such as increased volume in the region of the lesion (55%) accompanied or not by pain symptoms (10%), while others had their diagnosis from radiographic findings and did not present any visible changes through physical examination (40% of cases). These findings corroborate with Kshirsagar et al in 2019, who states that patients may present symptoms such as pain, edema, and rarely have paresthesia in the lower lip region. On the other hand, some patients are asymptomatic until the lesion reaches large dimensions or develops pathological fractures. In many cases the lesion is only noticed through routine radiographic examinations.

Concerning treatment, options range from more conservative procedures such as marsupialization and enucleation of the lesion with or without peripheral osteotomy to more radical therapies such as segmental resection. The location of the lesion (mandible or maxilla), the size, and evidence of cortical bone perforation must be considered for treatment choice [5]. In our study, all cases were treated with surgical enucleation. More radical techniques such as segmental resection are indicated in the treatment of lesions that involve the adjacent soft tissue and in which there is evidence of cortical bone disruption.

Conservative surgical treatment options such as enucleation and marsupialization are often associated with high recurrence rates. For this reason, the combination of these procedures with additional therapies such as cryotherapy and the use of Carnoy's Solution are described in the literature. Only one of the cases reported int his study did not receive application of Carnoy’s solution as an adjuvant therapy and was also the only case that presented recurrence of the lesion.

Previous studies have shown that EMT is associated with aggressive behavior of OKs [6]. Although no association was observed between the variables analyzed and the immunohistochemical profile of EMT, the positivity of E-cadherin protein and negativity of vimentin demonstrates that its function is preserved, as well as beta-catenin. Both proteins have cell adhesion function and they are part of the Wnt signaling pathway, with tumor suppressor function. Loss of function of E-cadherin is associated with worse prognosis and survival in different cancers, mainly associated with tumor invasion, apoptosis, cell cycle, and differentiation [14]. The identification of the EMT process as a prognostic marker for odontogenic cysts and tumors could be an important tool for defining treatment and follow-up of these patients.

Even though it is a benign lesion, OK is associated with complications and extensive defects, especially in larger lesions, with the possibility of losing large segments of bone tissue, as well as repeated recurrences. For this reason, the study of markers that allow a better understanding of its biological behavior is important for the best management of the patient.

References

Author Info

Joana Leticia Vendruscolo1, Mariana de Souza Lessa1, Sergio Ossamu Ioshii2, Juliana Lucena Schussel3 and Laurindo Moacir Sassi1*

1Department of Oral and Maxillofacial Surgery, Erasto Gaertner Hospital, Curitiba, Paraná, Brazil
2Department of Pathologic Anatomy, Erasto Gaertner Hospital, Curitiba, Paraná, Brazil
3Departament of Stomatology, Universidade Federal do Paraná, Curitiba, Paraná, India
 

Citation: Joana Leticia Vendruscolo, Mariana de Souza Lessa, Sergio Ossamu Ioshii, Juliana Lucena Schussel Evaluation of epithelial-mesenchymal markers and correlation with clinical aspects in keratocyst lesions, J Res Med Dent Sci, 2021, 9(9): 188-191

Received: 01-Dec-2021 Accepted: 15-Dec-2021 Published: 22-Dec-2021

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