Recurrence Patterns in Locally Advanced Cervical Carcinoma: Role of Nodal Status and 72-kDa Metalloproteinase Index

Abstract

Objective: The aim of the study was to analyze the relationship between lymph nodal involvement and regional and/or distant recurrences in locally advanced squamous cervical carcinomas, and also evaluate tumor 72-kDa metalloproteinase, as a biologic parameter useful for understanding the mechanisms of disease relapse and prognosis. In particular, 72-kDa metalloproteinase is an enzyme that specifically cleaves type IV collagen and seems to play a critical role in tumor invasion and metastatic dissemination. Methods: The medical records of 62 patients with FIGO (International Federation of Gynecology and Obstetrics) stage Ib and IIa squamous cervical carcinoma who underwent primary radical surgery with systematic pelvic and paraaortic lymphadenectomy and then were routinely followed were recruited from our series of 76 consecutive cases and reviewed. Fifty-four patients with complete clinicopathologic information were considered eligible for the study. All recurrences were defined as histologically and/or cytologically documented disease, following a minimum 3-month disease-free interval. Sites of recurrences were classified as distant, or regional to the pelvis. Immunostaining with 72-kDa metalloproteinase was performed on serial sections of tumors using avidin–biotin complex technique. Affinity-purified rabbit anti-72-kDa metalloproteinase antibody was used. Positive staining was expressed as a percentage of positive cells per 103counted neoplastic cells (72-kDa metalloproteinase index). Results: After a median follow-up of 38 months (range 9–71 months), 11 patients recurred with a 20% overall incidence. Seven patients (64%) recurred regionally, with side-wall infiltration in 2 cases, and 4 patients (36%) recurred distantly. By Cox hazard multivariate analysis, lymph nodal status was significantly related to disease-free survival (P= 0.01); in particular, all the patients with side-wall or distant recurrences had lymph nodal involvement. A significant relationship was also observed between tumor 72-kDa metalloproteinase immunostaining and disease-free survival (P= 0.02). The 72-kDa metalloproteinase index was significantly higher in patients who recurred than in patients with disease-free follow-up (P< 0.001); in particular, the highest values were detected in patients who recurred distantly. A relationship between 72-kDa metalloproteinase staining and nodal status was observed (P< 0.001). Conclusions: In conclusion, nodal status and the 72-kDa metalloproteinase index were two independent prognostic parameters, significantly related to recurrence risk and pattern of recurrence in locally advanced cervical carcinoma. Although they are independent prognostic parameters, a relationship between nodal involvement and 72-kDa metalloproteinase was observed. A model of tumor recurrence in which intrinsic tumor factors exert their negative influence directly or by contributing to the development of nodal metastases seems possible.