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 Table of Contents  
ORIGINAL ARTICLE
Year : 2018  |  Volume : 15  |  Issue : 2  |  Page : 99-104

An analysis of Bcl-2 and Bax markers expression in polymorphous low-grade adenocarcinoma and epithelial–myoepithelial carcinoma of salivary gland


1 Department of Oral Pathology, Faculty of Dentistry, Al-Azhar University, Cairo, Egypt
2 Department of Oral Biology, Faculty of Dentistry, Al-Azhar University, Cairo, Egypt
3 Department of Oral Medicine, Faculty of Dentistry, Taif University, Taif, Saudi Arabia

Date of Submission20-Dec-2017
Date of Acceptance30-Apr-2018
Date of Web Publication25-Jun-2018

Correspondence Address:
Mohamed A Mohamed
Department of Oral Pathology, Faculty of Dentistry, Al.Azhar University, Cairo
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/tdj.tdj_57_17

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  Abstract 

Aim
To study the evaluation of the expression of Bcl-2 and Bax markers in polymorphous low-grade adenocarcinoma (PLGA) and epithelial–myoepithelial carcinoma.
Materials and Methods
Hematoxylin and eosin and streptavidin–biotin immunoperoxidase staining techniques was used to detect the expression of Bcl-2 and Bax protein in five cases of PLGA and five cases of epithelial–myoepithelial carcinoma. Evaluation of immunostaining was done by image analysis computer system.
Results
Showed that there was a statistically significant difference (P < 0.001) in means of Bcl-2 and Bax expression between PLGA and epithelial–myoepithelial carcinoma.
Conclusion
The expression of Bcl-2 and Bax could be used as an effective biomarker to predict aggressive biologic behavior of PLGA and epithelial–myoepithelial carcinoma.

Keywords: Bax, Bcl-2, epithelia-myoepithelial carcinoma, polymorphous low-grade adenocarcinoma, salivary gland


How to cite this article:
Mohamed MA, Kamal KA, Nasr GA, AlQarni AA. An analysis of Bcl-2 and Bax markers expression in polymorphous low-grade adenocarcinoma and epithelial–myoepithelial carcinoma of salivary gland. Tanta Dent J 2018;15:99-104

How to cite this URL:
Mohamed MA, Kamal KA, Nasr GA, AlQarni AA. An analysis of Bcl-2 and Bax markers expression in polymorphous low-grade adenocarcinoma and epithelial–myoepithelial carcinoma of salivary gland. Tanta Dent J [serial online] 2018 [cited 2018 Jul 18];15:99-104. Available from: http://www.tmj.eg.net/text.asp?2018/15/2/99/235137


  Introduction Top


Salivary gland tumors comprise 1–4% of all human neoplasms [1]. Salivary gland tumors comprise a significant proportion of oral tumors and are the next common neoplasm of the mouth aftersquamous cell carcinoma. These neoplasms have widely variable histopathologic and biologic characteristics, which makes it difficult todetermine the pathogenesis and selection of therapeutic modalities [2]. Polymorphous low-grade adenocarcinoma (PLGA) is a tumor that almost exclusively affects minor salivary glands andcomprises the third most common malignant salivary glandtumor in the oral cavity [3]. PLGA, now shortened to polymorphous adenocarcinoma is without a doubt the most contentious entity for this iteration of the WHO classification for salivary gland tumors [4]. While described earlier, the term PLGA was first used in 1984 by Evans and Batsakis [5].

Although PLGAs have many distinctive features, including optically clear chromatin and atargetoid pattern of perineural invasion, the architectural heterogeneity that their name reflects can create a diagnostic dilemma for pathologists. Since the 1990s, many studies have attempted to develop a useful marker for PLGA or to differentiate it from other histologically similar tumors. PLGA can demonstrate multiple patterns of growth including solid, trabecular, glandular, cribriform, fascicular, cord-like, and papillary configurations [6],[7]. As such, they exhibit considerable morphologic overlap with other salivary neoplasms, especially pleomorphicadenoma/canalicular adenoma and adenoid cysticcarcinoma. In practice, it is sometimes difficult to distinguish PLGA from these tumors, especially in small biopsy specimens [8]. Because of the considerable difference in prognosis, treatment, and follow-up for these three neoplasms, there is aclinical imperative to accurately distinguish PLGAs from these two mimickers. However, while many immunohistochemical stains (e.g. c-kit, Ki-67, glial fibrillary acidic protein, CD43, S100, bcl-2, etc.) have been used to aid in this differential diagnosis, none of them distinguishes these tumors in a consistently reliable manner [9],[10],[11],[12]. The percentage of PLGAs among malignant minor salivary gland tumors varied among the studies, ranging from 0 to 46.8%. PLGA rates have varied over the period studied and have most recently increased. The PLGA percentages also varied significantly by continent, with frequencies ranging from 3.9 in Asia to 20.0% in Oceania [13]. Epithelial–myoepithelial carcinoma (EMC) is a rare salivary gland tumor that was initially reported by Donath et al. [14]. Histologically, EMC is characterized by biphasic tubular structures comprising inner duct-lining epithelial cells and outer clear myoepithelial cells, and it exhibits a high degree of cellular differentiationand low-grade aggressiveness. EMC is therefore considered a clinically low-grade carcinomashowing favorable prognosis, with 5-year overall survival rates of more than 80% [15],[16].

Several histological variants overlapping with other salivary type tumors such as oncocytic and apocrine EMC have been recognized [17],[18]. Moreover, an increasing number of reports have described hybrid carcinoma combining EMC and dedifferentiated EMC [19],[20],[21]. In clinical practice, the histopathological diagnosis of salivary gland tumors is made carefully through the assessmentof the growth pattern of the tumor borders, histological architecture, cellular structure and differentiation, and components of the tumor stroma, along with the clinical information. Although hematoxylin-eosin (H and E) staining is still the gold standard method used for diagnosing the salivary gland tumor, immunohistochemistry (IHC) canenhance the accuracy of such analysis, while its role maybe limited. IHC can be a helpful tool when in cases to investigate the patients that cannot be assessed by histological examination, such as the cell nature and differentiation status, cell proliferation, and tumor protein expression [1].

Apoptosis (programmed cell death) is a specific form of cell death that constitutes an important mechanism of maintaining homeostasis. Apoptosis occurs physiologically as well as in the course of many diseases. Alterations of apoptosis are always coupled with pathological conditions and/or oncogenesis. The B-cell lymphoma (Bcl-2) family comprises different regulators involved in apoptosis. Bcl-2 is an important proto-oncogene located at chromosome 18q21 [22]. It was the first gene implicated in the regulation of apoptosis. Its protein is able to stop programmed cell death (apoptosis) facilitating cell survival independent of promoting cell division [23]. Bcl-2 is thought to be involved in resistance to conventional cancer treatment and its increased expression has been implicated in a number of cancers [24]. Apparently, many cancers depend on the antiapoptotic activity of Bcl-2 for tumor initiation and maintenance [25]. Bax (Bcl-2-associated protein X) is the most characteristic death-promoting member of the Bcl-2 family. The translocation of Bax protein from the cytosol to the mitochondria triggers the activation of the caspases cascade, leading to death [26].

Antiapoptotic marker like Bcl-2 may potentially be able to predict the tumor behavior [27]. Bcl-2 contributes to malignant cell expansion primarily by prolonging cell survival rather than by increasing the rate of cellular proliferation, and accumulation of cells with an aberrant Bcl-2 expression could be an important step in carcinogenesis [28],[29]. Its overexpression has been reported in most human low-grade tumors and this inhibition of apoptosis has been regarded as being one of the most common pathways of tumourigenesis [30]. The Bcl-2 gene family seems to act as a regulator of the apoptotic pathway. The two most important apoptosis regulating proteins of this family are most likely Bcl-2 and Bax. Loss of function mutations have been identified in the Bax gene of human tumors. The expression ofmutated Bax protein may fail to release cytochrome c and increase the Bax–Bcl-2 ratio resulting in the escape from programmed cell death [24],[31],[32]. In this regard, the present study was carried out to investigate PLGA and EMC, The assessment was based on IHC examination utilizing antibodies against Bcl-2 and Bax proteins and differentiate the proliferative activity of PLGA and EMC.


  Materials and Methods Top


Ten formalin-fixed paraffin embedded blocks were used, five of them were previously diagnosed as PLGA and five EMC were collected from the archives of Pathology Department, the National Cancer Institute (Cairo University), Oral and Dental Pathology Department, Faculty of Dental Medicine – Boys, Al-Azhar University, Cairo, Egypt. All the sections were being stained with H and E and streptavidin–biotin immunoperoxidase staining techniques was used to detect the expression of Bcl-2 and Bax protein. The immunostaining procedure was performed according to the manufacturer instructions. A section was considered either positive or negative according to the presence or absence of brown staining in cytoplasm of tumor cells; regarding Bcl-2 and Bax (Thermo Fisher Scientific, Waltham, Massachusetts, USA). Theimmunostained sections were examined using light microscope to assess the prevalence of positive cases and the localization of immmunostaining within the tissues. In addition, image analysis computer system was used to assess area percentage of positive cells of the immunostaining. This was done in the Oral and Dental Pathology Department, Faculty of Dental Medicine – Boys, Al-Azhar University, Cairo. Area percentage of positive staining for Bcl-2 and Bax stains of tumor was measured in an area with reference to a standard measuring frame of area per five fields using a magnification (×200) by light microscopy. These areas were counted and the positive index was calculated by image analyzer computer system to assess area percentage of positive cells, the image analysis was performed using a computer system (Software Leica Quin 500; Leica, Wetzlar, Germany) consisting of color video camera, color monitor, personal computer (IBM, Armonk, New York, USA) connected to the microscope. The image analyzer was first calibrated automatically to convert the measurement units (pixels) produced by the image analyzer program into actual micrometer units. Statistical presentation and analysis of the present study was conducted, using the mean, SD, unpaired student t-test by SPSS V20 (IBM SPSS Statistics, London, UK). Significant levels: nonsignificant >0.05, significant <0.05, high significant <0.001.


  Result Top


Histopathological and immunohistochemical results

Polymorphous low-grade adenocarcinoma

H and E stain for the five cases of PLGA tissue sections showed cuboidal to columnar cells that have uniform ovoid to spindle nuclei which arranged in papillary, solid, and cribriform patterns. The tumor nests are separated by fibrovascular stroma [Figure 1]. The IHC staining using Bax showed moderate positive expression (mean area %: 33.11, [Figure 2]) while Bcl-2 exhibited weak positive expression (mean area %: 12.63) which present throughout neoplastic epithelial cells [Figure 3].
Figure 1: Hematoxylin and eosin stain of polymorphous low-grade adenocarcinoma tissue sections showed cuboidal to columnar cells that have uniform ovoid to spindle nuclei which arranged in papillary, solid, and cribriform patterns (arrow) (×100).

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Figure 2: Immunohistochemistry expression of Bax for polymorphous low-grade adenocarcinoma showing positive cytoplasmic expression throughout neoplastic epithelial cells (arrows) (×400).

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Figure 3: Immunohistochemistry expression of Bcl-2 for polymorphous low-grade adenocarcinoma showing positive cytoplasmic expression throughout neoplastic epithelial cells (arrows) (×400).

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Epithelial–myoepithelial carcinoma

H and E stain for the five cases of EMC tissue sections showed islands of well circumscribed neoplastic cells arranged in lobular pattern. Each lobule comprised of inner ductal cells with eosinophilic cytoplasm and outer layers of myoepithelial cells. These cells were further enveloped on outside by a well-defined basement membrane. There was variable degree of intervening stroma [Figure 4]. The IHC staining using Bax showed weak positive expression (mean area %: 10.12 and [Figure 5]) while Bcl-2 expression exhibited moderate positive expression (mean area % 33.32) which present throughout neoplastic epithelial cells [Figure 6].
Figure 4: Hematoxylin and eosin stain of epithelial–myoepithelial carcinoma tissue sections showed islands of well circumscribed neoplastic cells arranged in lobular pattern. Each lobule comprised of inner ductal cells with eosinophilic cytoplasm and outer layers of myoepithelial cells (arrow) (×100).

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Figure 5: Immunohistochemistry expression of Bax for epithelial–myoepithelial carcinoma showing positive cytoplasmic expression throughout neoplastic epithelial cells (arrows) (×400).

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Figure 6: Immunohistochemistry expression of Bcl-2 for epithelial-myoepithelial carcinoma showing positive cytoplasmic expression throughout neoplastic epithelial cells (arrows) (×400).

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Statistical analysis results

Statistical analysis results of Bcl-2 and Bax expression were obtained by comparing the area % between PLGA and EMC. Statistical analysis results were revealed that, in regard to expression of Bax, PLGA had recorded the highest mean area (mean area %: 33.11), while EMC had recorded the lowest mean area (mean area %: 10.12) and the comparison revealed that there was high significant difference between these lesion where P value was less than 0.001 [Table 1] and [Chart 1]. In regard to expression of Bcl-2, EMC had recorded the highest mean area (mean area %: 33.32), while PLGA had recorded the lowest mean area (mean area %: 12.63) and the comparison revealed that there was high significant difference between these lesion where P value was less than 0.001 [Table 1] and [Chart 2].
Table 1: Mean, SD, P values and results of comparison between expression of Bax and Bcl-2 in PLGA and EMC

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  Discussion Top


Tumor initiation, progression, and invasion involve cellular proliferation, apoptosis as well as cell adhesion and communication that ensure cell survival, renewal, and co-ordination. Salivary gland neoplasms show a varied behavior [30]. Salivary gland tumors are a relatively rare and morphologically diverse group of lesions. Although most clinicians and pathologists will have encountered the more common benign neoplasms, few have the experience of all types of salivary cancers, which are best managed in specialist centers [33]. PLGA is one such tumor, misunderstood, under diagnosed, controversial in nomenclature, and unpredictable in behavior [6]. EMC is a rare tumor accounting for slightly less than 1% of salivary gland neoplasms [34]. Although EMC is considered as a low-grade malignant salivary gland tumor [35], follow-up information from previous studies indicated that EMC has frequent recurrences and it has a tendency to metastasize [36]. To the best of our knowledge no studies were reported in the English language literature on the combined analysis of Bcl-2 and Bax in comprises between PLGA and EMC of salivary glands. The few number of cases in the present study was due to rarity of EMC, this problem was also encountered by other investigators [37],[38],[39],[40].

In the present study, EMC showed statistically significant highest mean Bcl-2 area % (33.32) than PLGA (12.63) where P value was less than 0.001. This result confirms that PLGAs have a slower proliferation rate compared with that of EMC and cell proliferation is related to tumor aggressiveness and prognosis. These findings may be supported by those of Meer et al. [41], who reported that Bcl-2 in PLGA, the overall staining intensity appeared weaker than that of acinic cell carcinoma, with membrane staining and a cytoplasmic blush typically seen. Also Kaur et al. [42] described IHC localization of Bcl-2 in malignant tumors varied from weak to intense with PLGAs overall weaker expression of Bcl-2 when compared with malignant salivary gland tumors. PLGA showed generalized weak expression, which may be associated with the low-grade malignant potential of this neoplasm. The high expression of Bcl-2 proteinamong EMC cases of the present study was also reported by Taher et al. [37], who showed that high Bcl-2 expression was evident in three (75%) out of the four Bcl-2 positive cases. The remaining EMC case (25%) showed mild Bcl-2 expression. Yanez et al. [43] they reported the expression of Bcl-2 protein in all the studied benign and malignant salivary gland tumors except in one mucoepidermoid carcinoma case. Furthermore, nearly similar percentage of Bcl-2 expression to that of the present study was reported in the study of Fujita et al. [44] and in the study of Yin et al. [45].

In the present study we reported the expression of Bax in PLGA had recorded the highest mean area % (33.11), while EMC had recorded the lowest mean area % (10.12) and the comparison revealed that there was high significant difference between these lesion where P value was less than 0.001, these results supported by Qutaiba et al. [46] who reported that the high proliferative rate could explain the natural course of these tumors and the decreased expression of Bax in salivary gland tumors indicate that loss of Bax expression might give the tumor cells a double growth advantage because uncontrolled proliferation is combined with reduce cell death rate. The interaction may trigger a multistep process which is able to promote and may play a role in salivary gland tumourigenesis, possibly by inhibiting the apoptosis mediated by Bax. The expression of this study was observed in PLGAs and EMC irrespective of histological subtypes or morphological growth pattern and suggests that loss of Bax expression may play a role in the development of epithelial salivary gland tumors.


  Conclusion Top


The expression of Bcl-2 and Bax could be used as an effective biomarker to predict aggressive biologic behavior of PLGAs and EMC. Studies of a larger sample with a wide variety of malignant salivary gland tumors comprising of all subtypes or variants of tumors are required to understand the significance of Bcl-2 and Bax expression in the prognosis.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
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