Cyclooxygenase-2 expression predicts recurrence of cervical dysplasia following loop electrosurgical excision procedure

Abstract

Objective. To evaluate the expression of Cox-2 protein by immunohistochemistry in cervical dysplasias, and to determine any relationship to clinical factors such as degree or recurrence of dysplasia. Methods. Immunohistochemical expression of p27 and Cox-2 was initially examined in 62 cervical LEEP specimens, which spanned the histologic spectrum from benign to severe dysplasia. Histology and cytology from colposcopic follow-up exams were reviewed for 1 year after LEEP procedure. Primary outcome variable was recurrent dysplasia, either cytologic or histologic. Statistical analysis utilizing chi-square test for trend and Fisher's Exact tests were performed to determine relative risk of recurrent dysplasia. Results. A total of 62 LEEP specimens were examined by immunohistochemistry (IHC). This included 18 mild, 19 moderate, and 25 severely dysplastic LEEP specimens. The percentage of tumor cells in each specimen that stained for p27 protein or Cox-2 enzyme was documented. A specimen was considered positive for p27 or Cox-2 if 50% or more of the cells in a specimen were stained: 94% of mild, 89% of moderate, and 44% of severe dysplasias stained positive for p27; 50% of mild, 42% of moderate, and 68% of severe dysplasia specimens stained positive for Cox-2. The average intensity of Cox-2 staining increased with severity of dysplasia—1.6 for mild, 1.8 for moderate, and 2.1 for severe dysplasia. There was a significant increase in both Cox-2 and p27 staining when severely dysplastic specimens were compared to mild and moderate dysplasia ( P < 0.001). Of the 35 specimens that stained positive for Cox-2 protein, 59% of these specimens had positive Cox-2 staining that extended to the margins of the LEEP resection specimen. The average length of Cox-2 protein staining beyond the histologic dysplasia was 1.64 mm. Positive margin status for Cox-2 was a significant independent risk factor for persistent and recurrent dysplasia, RR 1.68 95% CI (1.07 < RR < 2.65), P < 0.027. Conclusion. Cox-2 and p27 protein expression could be involved in squamous cervical cancer carcinogenesis. Cox-2 staining is often found outside the dysplastic lesion and this factor is associated with an increased risk of persistent and recurrent dysplasia following LEEP procedure. Should the histologic margin of LEEP resection approach 2.0 mm, follow-up algorithms for these patients should include intensive surveillance to ensure adequate treatment of disease.