Cyclooxygenase-2 expression predicts survival in malignant pleural mesothelioma

Abstract

The expression of cyclooxygenase 2 (COX-2) protein is increased in many tumours and may be associated with a more aggressive phenotype. We aimed to assess COX-2 expression in a large series of archival mesothelioma specimens. Archival tissue was obtained from 86 malignant pleural mesothelioma samples (histological subtype: 42 epithelial, 28 biphasic and 16 sarcomatoid). Overexpression of COX-2 was detected by immunohistochemical analysis. Positive staining was located in the cytoplasm of malignant tumour cells. Overall 51/86 (59%) tumour sections demonstrated COX-2 overexpression. The frequency varied with histological subtype with 31/42 (73%) of epithelial sections, 14/28 (50%) of biphasic sections and 6/16 (37%) of sarcomatoid sections recorded as positive. Kaplan Meier survival analysis indicated that overexpression of COX-2 was significantly related to improved prognosis (P < 0.001) and was an independent prognostic factor in multivariant analysis. Overexpression of COX-2 protein may confer a survival advantage in mesothelioma patients.

Introduction

Mesothelioma is a relatively rare, aggressive disease affecting the mesothelium (lining surrounding the main internal organs), which is caused primarily by industrial exposure to asbestos fibres. It typically presents as a unilateral pleural mass with a moderate-to-large pleural effusion. Despite the rarity of this disease, it is increasing in incidence [1], [2]. Asbestos is responsible for approximately 80% of all cases of malignant pleural mesothelioma (MPM) [3]. Although MPM has a latency period of 15–40 years [4], it has very poor prognosis with a survival rate of only 10% at 3 years and the average survival time is generally accepted as 4–12 months [6]. In the UK there were 1755 recorded deaths from mesothelioma in 2002 (www.cancerresearchuk.org).

The molecular basis of the disease is unknown and treatment tends to focus on traditional methods including supportive care, surgery, radiotherapy and chemotherapy. It is unclear if any currently established form of treatment has any significant impact on the progression of mesothelioma, although modern chemotherapeutic agents such as pemetrexed are showing promising results [6]. Many clinical prognostic factors have been suggested for MPM including performance status, age and gender, but much of the data produced is conflicting [7]. The most significant clinical prognostic factor to date is histological profile, as non-epithelial types have shorter survival times [5], [8], [9], [10].

Non-steroidal anti-inflammatory drugs (NSAIDs), e.g., aspirin, is known to decrease the incidence of colorectal [11], [12], oesophageal [13] and lung [14], [15] tumours. These drugs are thought to exert their action by inhibiting cyclooxygenases, which are enzymes are involved in the production of prostaglandins from arachidonic acid [16]. At least two isoforms of cyclooxygenase (COX) exist. COX-1 is constitutively expressed in many normal tissues, whereas COX-2 is only seen at the site of inflammation. COX-2 is an initial response and is inducible by many factors including hypoxia and growth factors. COX-2 expression has been previously reported to be involved in the inhibition of apoptosis with decreased COX-2 expression increasing the levels of apoptosis [17]. COX-2 may also play a role in angiogenesis, as selective COX-2 inhibitors have been shown to be antiangiogenic [18], [19]. The abnormal overexpression of COX-2 has been reported in many tumour types [20], [21] including mesothelioma [22]. A significant association with prognosis has also been reported in mesothelioma patients [23].

In this study, COX-2 overexpression was analysed by immunohistochemistry in a large retrospective series of MPM and correlated with survival and histological subtype to clarify its role as an independent prognostic factor.