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ORIGINAL ARTICLE  
Year : 2011  |  Volume : 54  |  Issue : 3  |  Page : 526-531
Increased expression of COX-2 in recurrent basal cell carcinoma of the skin: A pilot study


Department of Pathology, Süleyman Demirel University Faculty of Medicine, Isparta, Turkey

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Date of Web Publication20-Sep-2011
 

   Abstract 

Introduction: Basal cell carcinoma (BCC) is the most frequent malignant skin tumor. BCC rarely metastasizes, but it is often locally aggressive. Cyclooxygenase-2 (COX-2) is critical for tumor formation, angiogenesis and metastasis. Matrix metalloproteinases (MMPs) are the members of the family of zinc (Zn)- and calcium-dependent endopeptidases that degrade the extracellular matrix. Materials and Methods: In our study, we used immunohistochemical methods for the evaluation of COX-2, MMP-2 and MMP-9 expression in tissue samples of 30 primary and 10 recurrent skin BCC cases. Results: Immunohistochemical COX-2 expression was significantly higher in the infiltrating pattern of BCC compared with the nodular (P = 0.005) and superficial (P = 0.041) subtypes in the primary BCC group. There was not a significant difference between nodular and superficial BCCs for COX-2 expression. In addition, COX-2 expression was significantly higher in the recurrent BCC group than in the primary BCC group (P = 0.030). There was no statistically significant difference between the histological subtypes of primary BCCs and between primary and recurrent BCCs for MMP-2 and MMP-9 expressions. Conclusions: Our data confirm previous findings that COX-2 and MMP-9 expressions are increased in BCC. Our results revealed an elevated COX-2 expression in recurrent BCCs. We suggest that COX-2 inhibition might have beneficial effects in BCCs, especially for the tumors with a higher level of COX-2 expression or aggressive phenotype.

Keywords: Basal cell carcinoma, COX-2, MMP-2, MMP-9, recurrence

How to cite this article:
Karahan N, Baspinar S, Bozkurt KK, Caloglu E, Ciris IM, Kapucuoglu N. Increased expression of COX-2 in recurrent basal cell carcinoma of the skin: A pilot study. Indian J Pathol Microbiol 2011;54:526-31

How to cite this URL:
Karahan N, Baspinar S, Bozkurt KK, Caloglu E, Ciris IM, Kapucuoglu N. Increased expression of COX-2 in recurrent basal cell carcinoma of the skin: A pilot study. Indian J Pathol Microbiol [serial online] 2011 [cited 2020 Nov 30];54:526-31. Available from: https://www.ijpmonline.org/text.asp?2011/54/3/526/85086



   Introduction Top


Basal cell carcinoma (BCC) is the most common skin neoplasm in humans, and is usually characterized by local aggressiveness with a slight metastatic potential. The development of recurrence in BCC patients is related to several factors. In addition to the sufficiency of surgical resection of primary tumor, biological behavior of the tumor and immune status of the patient are the factors that are related to the incidence of recurrence. [1]

Matrix metalloproteinases (MMPs) are the members of the family of zinc (Zn)- and calcium-dependent endopeptidases that degrade the extracellular matrix. The MMP family currently consists of 25 enzymes, which are classified into eight distinct groups according to their structures. Five of them are secreted types and three of them are membrane-type MMPs. [2] MMPs are produced by various cell types in response to inflammation or tumor progression. Among the variety of proteinases potentially implicated in tumor progression, the MMPs have attracted considerable interest because of their ability to degrade all the essential protein constituents of connective tissues. This process is mediated by proteolytic enzymes that degrade the extracellular matrix and basement membranes, which is thought to be the facilitator of tumor invasion and metastasis. [3],[4],[5] MMP-2 is constitutively produced by numerous cell types, whereas MMP-9 is produced by inflammatory cells such as macrophages, neutrophils and epithelial cells of the respiratory tract. MMPs that are produced by inflammatory cells appear to be responsible for microvascular permeability leading to edema and cell transmigration. [4]

Recently, the attention of the investigators has been focused on cyclooxygenase type 2 (COX-2), which is a rate-limiting enzyme in the biosynthesis of prostaglandins from arachidonic acid. [6] COX-2 is an inducible immediate-early gene that is up-regulated by various stimuli, including mitogens, cytokines, growth factors and tumor promoters. [7] It has been shown that COX-2 plays important roles in the tumorigenesis of different types of tumors. Recent studies have reported the association between COX-2 and promotion of invasion, [8] suppression of apoptosis [9] and tumor angiogenesis. [10],[11] COX-2 expression was found to be associated with various tumors such as advanced ovarian serous carcinomas, [12] breast cancers, [13] gastric cancers, [14] renal cell carcinomas [15] and head and neck squamous cells carcinomas. [16] All these previous studies suggest that the cellular up-regulation of COX-2 may be a critical event in epithelial carcinogenesis. In the present study, we aimed to investigate the expression patterns of COX-2, MMP-9 and MMP-2 in primary and recurrent BCCs and the possible role of these markers in BCC recurrence.


   Materials and Methods Top


Patient Population

Thirty primary (10 superficial, 10 nodular, 10 infiltrating pattern) and 10 recurrent BCC specimens were retrieved retrospectively from the archival material of the Department of Pathology in Suleyman Demirel University Faculty of Medicine. Specimens were excisional skin biopsies from facial or nonfacial localizations. Histological subtypes of the 30 primary BCCs are defined according to the following criteria. Superficial BCC is identified by the presence of nests of peripherally palisaded, atypical basaloid cells protruding from and connected to the basal layer of the epidermis. Nodular BCC is defined as rounded masses of atypical, peripheral palisaded basaloid cells with well-circumscribed outer margins, which are seen as a nodular, polypoid or rounded tumor silhouette at scanning magnification. Infiltrating pattern BCC is defined as tumors showing elongated strands and cords of basaloid cells exhibiting "spiky" projections that impart an irregular, stellate silhouette to the tumor. All the recurrent BCC cases demonstrated as infiltrating pattern BCCs. All primary surgical resections of recurrent BCC cases were performed with completely protected and histologically negative surgical margins. All the patients were offered to use sunscreen after the surgery to prevent UV exposure. All the tumors that recurred at the primary operation site did so in the first year of follow-up.

Immunohistochemistry

Immunohistochemical analysis for MMP-2, MMP-9 and COX-2 was performed on formalin-fixed, paraffin-embedded archival tissue using the streptavidin-biotin-peroxidase technique. For all cases, 4 mm histologic section was deparaffinized in xylene and dehydrated in a descending dilution of ethanol. For the antigen retrieval, slides were treated by microwave heating in citrate buffer (pH 6.0) for 10 min. Endogenous peroxidase activity was blocked by 20 min of incubation with 0.3% hydrogen peroxidase. Slides were tested with MMP-2 antibody (1:100, Rabbit polyclonal, Lab Vision, Fremont, CA, USA), MMP-9 antibody (1:100, Rabbit polyclonal, Lab Vision, Fremont, CA, USA) and COX-2 antibody (1:100 epitope-specific rabbit antibody, Lab Vision, Fremont, CA, USA). Sections were tested using a streptavidin-biotin-peroxidase kit (Ultra Vision Large Volume Detection System Anti-polyvalent, HRP, Lab Vision, USA) and, after incubation, the reaction product was detected using diaminobenzidine (DAB). Finally, the sections were counterstained with Mayer's hematoxylin and mounted with mounting medium. The positive control for MMP-2 and MMP-9 was placental tissue. Tissue of colon cancer from humans served as the positive control in COX-2 immunostaining.

Evaluation of Slides

Three independent observers, blinded for clinical data, analyzed the staining for MMP-2, MMP-9 and COX-2. All the slides that contained tumor were re-evaluated and the slide containing the highest percentage of neoplastic cells was chosen for immunohistochemistry. The intensity of staining was evaluated at 100x magnification, considering the most intense stained area. The scoring of the immunohistochemical COX-2, MMP-2 and MMP-9 expressions was performed according to a criteria based on the intensity of cytoplasmic staining for each marker (6) . COX-2 [Figure 1], MMP-2 and MMP-9 expressions were scored as absent (score:0), weak (score: 1+) and strong (score:2+). In the case of disagreement between the observers, slides were re-evaluated using a trinocular microscope and an agreement was achieved.
Figure 1: Representative immunohistochemical staining for the evaluation of cyclooxygenase-2 expression. (a) Negativity (score:0), (b) weak positivity (score:1+), (c) strong positivity (score: 2+) (×100)

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Statistical Analysis

For statistical evaluation, the SPSS software version 13 was used. The Fisher's exact test, chi-square test and Spearman correlation test were used to analyze the association of COX-2, MMP-2 and MMP-9 expressions with clinicopathological features and the correlation of these markers with each other. One-way ANOVA and Post Hoc Tukey tests were used to compare the expressions of these markers between primary BCC subtypes and t-test was used to compare the expressions between primary and recurrent BCC groups. A P-value of <0.05 was considered as statistically significant.


   Results Top


Our study group comprised of 27 (67.5%) males and 13 (32.5%) females. The mean age was 63.82 (range: 31-92) years. The distribution of tumors according to the histological subtype in the primary BCC group was superficial BCC in 10 (33.3%) cases, nodular BCC in 10 (33.3%) cases and infiltrating pattern BCC in 10 (33.3%) cases. Histological subtype was infiltrating pattern in all 10 (100%) recurrent BCC cases. The distribution of tumors according to the anatomic localization was as follows: facial in 31 (77.5%) cases and nonfacial in nine (22.5%) cases. Solar degeneration and ulcer were present in 15 (37.5%) and 18 (45%) cases, respectively. The clinicopathological characteristics of the 40 BCC cases are presented in [Table 1].
Table 1: Clinicopathological characteristics of 40 BCC cases

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COX-2 expression was absent in nine (30%) cases, while 16 (53.3%) cases showed weak staining and five (16.7%) cases showed strong staining in the primary BCC group. All the recurrent BCCs showed COX-2 expresion, with six (60%) cases showing weak and four (40%) cases showing strong immunreactivity [Figure 2]. Immunohistochemical MMP-2 expression was observed in two cases as weak staining [Figure 3] in both the primary (6.7%) and the recurrent (20%) BCC groups. MMP-9 expression was absent, weak and strong in one (3.3%), 14 (46.7%) and 15 (50%) cases, respectively, in the primary BCC group. In the recurrent BCC group, MMP-9 expression was weak and strong [Figure 4] in three (30%) and seven (70%) cases, respectively.
Figure 2: Immunohistochemical strong (score: 2+) cyclooxygenase-2 expression in a recurrent basal cell carcinoma (x200)

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Figure 3: Immunohistochemical weak (score: 1+) matrix metalloproteinase-2 positivity in a primary basal cell carcinoma (x200)

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Figure 4: Immunohistochemical strong (score: 2+) positivity for matrix metalloproteinase-9 in a recurrent basal cell carcinoma (x200)

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Immunohistochemical COX-2 expression was significantly higher in the infiltrating pattern BCC compared with the nodular (one-way ANOVA, Post Hoc Test P0 = 0.005) and superficial (one-way ANOVA, Post Hoc Test P = 0.041) BCCs in the primary BCC group. There was no significant difference between nodular and superficial BCCs in the primary BCC group for COX-2 expression [Table 2]. COX-2 expression was significantly higher in the recurrent BCC group than in the primary BCC group (t-test, P = 0.030). There was no statistically significant differences between histological subtypes of primary BCCs and between primary and recurrent BCCs for MMP-2 and MMP-9 expressions. There was no statistically significant relationship between COX-2, MMP-2, MMP-9 and clinicopathologic features such as localization of tumor, age and ulceration in overlying skin.
Table 2: Immunohistochemical expression of COX-2, MMP-2 and MMP-9 in primary BCC subtypes

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In addition, there was a statistically significant positive correlation between COX-2 and MMP-9 positivity (Spearman correlation test, r = 0.467, P = 0.002). There was no significant correlation between MMP-2 and MMP-9 expressions. Immunohistochemical expression of COX-2, MMP-2 and MMP-9 in the primary and recurrent BCC groups is summarized in [Table 3].
Table 3: Immunohistochemical expression of COX-2, MMP-2 and MMP-9 in primary and recurrent BCCs

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   Discussion Top


BCC of the skin is a slow-growing tumor but, if not treated properly, the invasion of subcutaneous adipose tissue, muscle, cartilage and even bones may occur. [16] During the process of infiltration, neoplastic cells have to pass through various barriers such as the extacellular matrix, interstitial tissue and basement membrane. [17] COX-2 is expressed in various tumor types, and levels of expression have been shown to correlate with invasiveness and prognosis in some tumor entities, suggesting an important role for COX-2 in tumor development and progression. [7],[12],[14] There are evidences in the literature suggesting that COX-2-expressing cancer cells may obtain a survival advantage, resulting in facilitation of tumor development and progression. [18] COX-2 is present in normal skin, benign epidermal proliferation and malignant skin neoplasms. Exposure to sun light is the essential causal factor of BCC. UVB irradiation has effects on human keratinocytes, such as increased production of prostaglandin E (PGE 2) and increased expression of COX- 2. [19] Chronic inflammatory cells upregulate the mediators in the process of inflammatory response. COX-2 is one of these mediators that leads to the production of inflammatory cytokines and prostaglandins. COX-2 may also suppress cell-mediated immune response and promote angiogenesis. [20]

Several other published reports showed BCC to be COX-2-positive in a low percentage of tested biopsies and COX-2 expression level to be correlated with angiogenesis in BCC specimens. [21],[22] There are also studies that have investigated the relationship of COX-2 expression with p53 expression. [23],[24] Kim et al. [23] reported that COX-2 expression was not correlated with p53 expression, while Chen et al. [24] found a positive correlation between the two markers. Tjiu et al. [25] found that higher levels of COX-2 expression were not only associated with neovascularization but also correlated with tumor invasion depth in human BCC specimens. In addition, in a more recent study, Tjiu et al. [26] hypothesized that tumor-associated macrophages might activate COX-2 in BCC cells and subsequently increase their invasion and angiogenesis.

Previous studies showed that inhibition of prostaglandin E2 production by COX-2 inhibitors and nonsteroidal antiinflammatory drugs partly prevents UV light-induced skin carcinogenesis. [27],[28] In addition, Vogel et al. [29] indicated that COX-2 expression modulates the risk of BCC. The role of both COX-1 and COX-2 in the pathogenesis of BCC has been recently described by Tang et al. [30] using a mouse model as well as performing a 3-year clinical trial. The findings of Tang et al. have provided significant translational relevance of COX signaling for BCC treatment. [31],[32]

In our study, we found that COX-2 expression was significantly higher in infiltrating pattern BCC compared with nodular and superficial BCCs in the primary BCC group. Also, COX-2 expression was significantly higher in the recurrent BCC group than in the primary BCC group. In addition, there was a significant positive correlation between COX-2 and MMP-9 expressions in our study. Our results suggested that COX-2 expression can be associated with local aggressiveness and recurrence in BCCs.

Many studies on the mechanism of tumor infiltration have been focused on the interaction between tumor cells and extracellular matrix. In particular, MMP, which has the function of decomposing extracellular matrix and destroying the basement membrane of blood vessels, is believed to play an important role in the process of infiltration and metastasis. The dissolution of basement mebrane caused by MMP in tumors is an important process in the movement of tumor cells. [33]

Yucel et al. [34] demonstrated that human BCCs elaborate large amounts of collagenolitic (primarily MMP-1) and gelatinolytic (MMP-2 and MMP-9) enzymes. O'Grady et al. [35] suggested that MMP-2, MMP-9, (Tissue inhibitor of metalloproteinases) TIMP-1 and TIMP-2 may affect the pathogenesis of nonmelanoma skin cancers in different ways. Their results strongly indicate that MMP-2 and MMP-9 expression levels are not only associated with the development of these tumors but also play an important role in the process of invasion and local aggressiveness. [34],[35] In our study, MMP-2 expression was found in 6.6% of the primary BCC cases, whereas 20% of the recurrrent BCC cases showed positivity for MMP-2. MMP-9 expression was found in 96.6% and 100% of the primary and recurrent BCC groups, respectively. Although there was an increase in expression of these markers in the recurrent BCC group, in comparison with the primary BCC group, we did not detect any statistically significant differences between the histological subtypes of primary BCCs and between primary and recurrent BCCs for MMP-2 and MMP-9 expressions.

In conlusion, our data confirm previous findings that COX-2 and MMP-9 expressions are increased in BCCs. Furthermore, COX-2 expression was significantly higher in recurrent BCCs and primary infiltrating pattern BCCs, suggesting that it has a relationship with the aggressive phenotype in BCCs. The most important prognostic parameter is tumor-free surgical margins in BCCs. According to our results, we suggest that COX-2 inhibition might have beneficial effects in the prevention of local recurrence, especially for BCCs with a higher level of COX-2 expression or aggressive phenotype. Future prospective studies with larger series are needed to evaluate whether these differences could have an implication in the prevention and treatment of BCCs.

 
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Correspondence Address:
Kemal Kursat Bozkurt
Süleyman Demirel Universitesi, Tip Fakültesi, Arastirma ve Uygulama Hastanesi, Patoloji Anabilim Dali, Isparta
Turkey
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0377-4929.85086

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