Elsevier

Gynecologic Oncology

Volume 119, Issue 2, November 2010, Pages 309-313
Gynecologic Oncology

Prognostic significance of preoperative plasma fibrinogen in endometrial cancer

https://doi.org/10.1016/j.ygyno.2010.07.014Get rights and content

Abstract

Objective

To investigate the prognostic significance of preoperative plasma fibrinogen concentration, with particular focus on tumor dissemination and nodal involvement, in a substantial cohort of patients with endometrial cancer.

Methods

The study population comprised 336 women with endometrial cancer who underwent surgical staging at two tertiary institutions, from 2000 to 2009. Pretreatment plasma samples from the study cohort were assayed for fibrinogen by the Clauss assay. Information on demographics, laboratory testing, histopathology and follow-up was gathered from databases of prospectively collected data. Factors associated with survival were identified in a Cox proportional hazards model. Univariate and multivariate analyses were used to evaluate predictors of extrauterine disease and nodal metastasis.

Results

One-hundred-thirty-seven (40.8%) patients exhibited preoperative hyperfibrinogenemia. Univariate analysis demonstrated that histological type, tumor grade, depth of myometrial invasion, surgical stage, patient age, and hyperfibrinogenemia affect disease-free (DFS) and overall survival rates significantly. When these variables were entered simultaneously into a Cox regression model, raised preoperative levels of plasma fibrinogen retained significance as poor prognosticator of DFS (HR 2.0, 95%CI 1.1–3.6) and overall survival (HR 2.7, 95%CI 1.3–5.5). Preoperative hyperfibrinogenemia was an independent determinant of extrauterine disease (OR 2.7, 95%CI 1.3–5.6). In the subcohort of women with endometrioid histology, increased fibrinogen concentration at presentation was predictive of pelvic nodal involvement (OR 3.6, 95%CI 1.1–11.7).

Conclusion

Plasma fibrinogen level may be of value in the prediction of outcome, improve the stratification of endometrial cancer patient, at diagnosis, based on their risk of recurrence, and possibly alter their treatment accordingly.

Introduction

The host response to cancer is not a unique phenomenon, as it shares the same molecular and signaling pathways as those involved in physiological and pathological processes such as inflammation and tissue injury repair. By the mid-1980s histological analysis revealed a similarity between the tumor microenvironment and that of a healing wound, prompting Harvard pathologist Dvorak to conceptualize cancer as a wound that does not heal [1]. Much like in a healing wound, the deposition of fibrinogen, along with other adhesive glycoproteins, into a provisional matrix was found to serve as a scaffold to support binding of growth factors and to promote the cellular responses of adhesions, proliferation, and migration during angiogenesis and tumor cell growth [2], [3].

Fibrinogen is fundamentally important in hemostasis in that it functions as a bridging molecule, non-covalently linking adjacent platelets, and as the primary building block for the formation of fibrin matrices in the final stages of blood clotting. In recent years, an expanding body of work is reshaping our understanding of the impressive number of functional properties of fibrinogen, that are seemingly different from those necessary to merely controlling blood loss and were previously unrecognized. This feature of fibrinogen as a component of extra-cellular matrix that influences a multitude of cellular processes became further important in the light of the many studies showing considerable amounts of fibrinogen within the stroma of different solid tumors both in humans and experimental animals [4], [5], [6]. Detailed research on tumor cell-associated procoagulants and fibrinolytic factors provided insight into the role of fibrinogen as key determinant of tumor progression and metastatic potential [7], [8]. Several clinical studies have shown that the expression of procoagulants by tumor cells correlates with advanced disease and poor outcome for multiple cancer types [9], [10], [11], [12], [13], [14]. Moreover, the preoperative levels of plasma fibrinogen have been used as marker for risk stratification in tumor patients, independent of known clinico-pathological risk factors.

In the setting of gynecologic malignancies, higher fibrinogen concentrations before surgical staging have been shown to be associated with poor survival following a potentially curative resection for cervical [15] and ovarian cancer [16], [17]. The hypothesis that preoperative fibrinogen may be of value for survival prediction in endometrial cancer patients has been just recently tested for the first time [18]. Predicting recurrence and survival following surgical treatment of endometrial cancer is conventionally based on standard pathologic criteria such as tumor grade, histotype, depth of myometrial invasion, and lymphatic space invasion. Unfortunately, the detection of risk factors for extrauterine spread is only made in retrospect, given the inaccuracies of preoperative and intraoperative pathological analysis. A tool for prospectively identifying those patients likely to have extrauterine metastatic disease, particularly occult nodal spreads, could improve the stratification of patients based on their risk and it might be used to alter treatment accordingly.

The current study was designed to investigate the prognostic significance of preoperative plasma fibrinogen concentration, with particular focus on tumor dissemination and nodal involvement, in a substantial cohort of patients with endometrial cancer.

Section snippets

Materials and methods

The study group comprised consecutive clinical stage I endometrial cancer patients who underwent surgical staging at the Gynecologic Oncology Services of the University of Insubria and the University of Verona over the period from January 2000 to November 2009. Patients with a history of synchronous or metachronous cancer, chronic inflammatory diseases or acute inflammatory conditions, chronic liver diseases, recent deep venous thrombosis, and those taking anticoagulant medications were

Results

During the study period there were 382 women surgically treated for endometrial cancer at the University of Insubria and the University of Verona. After excluding patients found to have preexisting or coexisting cancer at another site (n = 13) or chronic inflammatory conditions (n = 6), those with missing information on preoperative fibrinogen level (n = 10), and those on anticoagulants (n = 7), 336 patients were included in this study.

Clinical and pathologic characteristics of the study population are

Discussion

The results of the present study suggest that preoperative fibrinogen concentration predicts metastatic disease spread and patient's prognosis in endometrial cancer independent of tumor-based factors. It is increasingly recognized that coagulation parameters, particularly fibrinogen levels, have prognostic significance in several tumors, including cervical, ovarian, lung, pancreas, esophagus, and colon cancer [9], [10], [11], [12], [13], [14], [15], [16], [17]. The primary source of raised

Conflict of interest statement

The authors have no conflict of interest to disclose.

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