Departments of 1 Surgery, 2 Biostatistics, 3 Radiation Therapy and 4 Medical Oncology, 5 Pathology, Institut Gustave Roussy, Villejuif, France
Received 6 February 2003; revised 9 May 2003; accepted 17 June 2003
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Abstract |
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Our aim was to study the prognostic value of the presence of lymphovascular space invasion (LVSI) in patients with stage IB and II cervical carcinoma treated by initial surgery.
Patients and methods:
A retrospective analysis was performed on 193 patients who underwent, between 1985 and 1998, an initial radical hysterectomy with pelvic (± para-aortic) lymphadenectomy using midline laparotomy for stage IB (180 patients) or II (13 patients) cervical carcinoma. Postoperative therapy was delivered according to prognostic factors.
Results:
The rate of LVSI correlated significantly with tumor stage, nodal status and the location of positive nodes. Using univariate analysis, tumor size (<4 or 4 cm), LVS status and nodal status were prognostic factors. At multivariate analysis, two prognostic factors were identified: LVS status and nodal status. In a subgroup of 89 patients with a small tumor (
2 cm) and absence of nodal or isthmic involvement, the overall survival was significantly correlated with the presence of LVSI.
Conclusions:
LVSI is a frequent occurrence in patients with early stage cervical cancer. It represents an unfavorable prognostic factor in univariate and multivariate analyses. Such results suggest that improvement is needed in the treatment of patients with a small tumor and LVS invasion.
Key words: cervical cancer, multivariate analysis, nodal involvement, vascular space invasion
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Introduction |
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In order to evaluate the prognostic impact and therapeutic implications of the LVS status, we decided to conduct a retrospective analysis of a large number of patients treated in our institution by initial radical surgery since 1985 for stage IB and II cervical carcinoma.
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Patients and methods |
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Postoperative pelvic irradiation (4045 Gy), followed by vaginal brachytherapy (1520 Gy according to the ICRU recommendations) [9], was delivered to patients with a bulky tumor (extension to the uterus and/or involvement of parametria) and/or to patients with histologically proven pelvic node involvement and/or to patients with LVSI in parametria or numerous LVSI in the paracervix or paravagina. Since 1996, external radiation therapy has been delivered with concomitant platinum-based chemotherapy (40 mg/m2/weekly) to patients with nodal or parametrial involvement. Pelvic irradiation (4045 Gy) and cisplatin-containing chemotherapy (100 mg/m2/4 weeks) were given to patients with metastatic common iliac and/or para-aortic nodes. Postoperative para-aortic irradiation was not performed after complete para-aortic lymphadenectomy.
Statistical analysis
The 2 test was used to compare percentages and P <0.05 was considered statistically significant. Survival curves were calculated using the KaplanMeier method. Groups were compared in a univariate analysis using the log-rank test and a multivariate analysis was conducted using Coxs model.
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Results |
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In the univariate analysis, tumor size >4 cm, LVSI and nodal involvement decreased survival rate significantly (Table 3). The 5-year overall survival was 97% in patients without LVSI compared with 78% for patients with LVSI (P <0.0001) (Figure 2). Disease-free survival at 5 years was 96% in patients without LVSI compared with 74% for patients with LVSI (P <0.0001) (Figure 3). In the subgroup of 145 patients without nodal involvement, overall survival was significantly correlated to LVS status (Figure 4). When we studied the prognostic influence of LVS status in the subgroup of 89 patients with, a priori, a good prognosis (tumor size 2 cm, free margins with an absence of extension to the uterine isthmus and absence of nodal involvement), the 5-year overall survival was 100% in 55 patients without LVSI compared with 92% in 34 patients with LVSI (P <0.05) (Figure 5). In the multivariate analysis, only two factors were prognostic: LVS status [relative risk (RR) of death 5.7] and nodal involvement (RR of death 4.9 for pelvic positive nodes and 17.1 for para-aortic positive nodes) (Table 4).
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Discussion |
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The present series confirms that the presence of LVSI is an independent prognostic factor in cervical cancer. A Gynecologic Oncology Group (GOG) study, conducted 15 years ago on the prognostic factors for stage IB cervical carcinoma treated by primary radical hysterectomy, concluded that clinical size, depth of tumor invasion and capillary lymphatic space status were independent prognostic factors [1]. The GOG then developed a scoring system including these prognostic factors in order to evaluate the risk of recurrent disease and to define a population who needed adjuvant therapy (particularly in patients with negative nodes) [1]. In the recent review by Creasman involving 18 publications (4000 patients with stage IB or II carcinoma) with multivariate analysis, only three papers found similar results [6]. The therapeutic implications of these results are important. In teams where patients are treated exclusively by radiation therapy for early stage cervical tumor, the presence of LVSI diagnosed during histological examination of (cone) biopsies does not change the modalities of radiation therapy (in the absence of nodal spread). However, for teams where patients are treated by exclusive surgery or radio-surgical combination, our results are important. Since the prognosis of patients with LVSI is worse than the prognosis of patients without LVSI, this treatment should be optimized, and exclusive surgery is not sufficient.
Which treatment optimization, chemotherapy or radiation therapy, should be selected? A recent randomized GOG trial by Sedlis et al. demonstrated that adjuvant external pelvic radiation therapy following radical hysterectomy reduces the number of recurrences, with an acceptable morbidity, in patients with stage IB cervical carcinoma (and negative lymph nodes) associated with stromal invasion of the cervix >1/3 and/or LVSI and/or bulky tumor [13]. Should external radiation be performed in all patients with LVSI? Probably not. External radiation (with concomitant chemotherapy) should be performed in patients with negative nodes but LVSI in the parametria. However, external radiation used as adjuvant therapy following radical hysterectomy increases the rate of complications, particularly for chronic enteritis [14, 15]. Such management (initial radical surgery followed by external radiation therapy) should be avoided in patients with LVS located only in the cervix. In the study by Sedlis et al. brachytherapy was not used. For 30 years such treatment was routinely used in our institution for early stages of cervical carcinoma (combined with radical surgery) and nearly 1000 of these procedures were performed. We observed good survival results using this combination (94% 5-year survival) [8, 10]. The advantage of brachytherapy is that it optimizes local control. No randomized study has demonstrated the superiority of combined brachytherapy plus radical surgery compared with exclusive radical surgery in patients with stage IB1 cervical cancer and negative nodes. However, the good survival results of this radio-surgical combination observed in several retrospective analyses confirm the potential advantage of treatments combining surgery and brachytherapy [10, 14, 16]. In the present series two out of five patients treated by surgery alone with LVSI recurred compared with one out of 26 patients who were treated by radical surgery plus brachytherapy.
Other histological factors are important to evaluate the prognosis of patients with LVS invasion (number and topography of LVSI, type of LVSI: lymphatic or blood vessel invasion) [17, 18]. Such a histological differentiation is difficult and reproducibility in the interpretation of these factors between several pathologists is not yet demonstrated. In order to improve the rate of LVSI detection, should systematic immunostaining be used or is H&E staining sufficient? A recent paper by Obermair et al. demonstrates that the addition of immunostaining analysis for factor VIII-related antigen in order to detect LVSI provides additional information on the outcome of stage IB cervical cancer with negative nodes [19]. However, the cost-effectiveness of this routine procedure compared with H&E staining was not evaluated. Further studies are needed in order to evaluate such results. In the present series, the diagnosis of LVSI was performed by an experienced pathologist using (only) H&E-stained specimens. We observed that none of the patients with small tumors, negative nodes and no LVSI died from recurrent disease. Our criteria to evaluate LVS status using H&E staining are good. The pathologists experience is the key point in evaluating this status.
In conclusion, the presence of LVSI is a frequent occurrence in patients with early stage cervical cancer. This is an unfavorable prognostic factor in univariate and multivariate analyses in this series. Such results could suggest that improvement in treatment is needed for patients with small tumors and LVSI. However, further studies are needed in order to evaluate optimal modalities for treatment of patients with early stage tumor associated with LVSI.
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Footnotes |
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References |
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