Gynecologic Oncology 92 (2004) 833 – 838 www.elsevier.com/locate/ygyno
Endometrial carcinoma: paraaortic dissemination
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Andrea Mariani, a Gary L. Keeney, b Giacomo Aletti, c Maurice J. Webb, a Michael G. Haddock, d and Karl C. Podratz a,* a
Section of Gynecologic Surgery, Mayo Clinic, Rochester, MN 55905, USA Division of Anatomic Pathology, Mayo Clinic, Rochester, MN 55905, USA c Department of Mathematics, University of Milano, Milan, Italy d Division of Radiation Oncology, Mayo Clinic, Rochester, MN 55905, USA
b
Received 11 June 2003
Abstract Objective. The objective of our study was to identify pathologic factors predictive of tumor dissemination to paraaortic lymph nodes (LNs) in endometrial carcinoma. The identification of the risk factors may potentially facilitate selection of patients for radical surgery or radiotherapy directed to the paraaortic area (PAA). Methods. The study population was a cohort from 612 consecutive patients with endometrial cancer surgically managed at our institution over a 10-year period. Tumor dissemination to the PAA was identified by selecting those patients who had either paraaortic LNs positive for disease at the time of primary surgery or those who subsequently experienced paraaortic failure or both (n = 41; the ‘‘PA mets’’ subgroup). Therefore, patients for whom no information was available about the status of paraaortic LNs but who had received adjuvant irradiation to the PAA and those for whom information was not available about sites of recurrent disease were excluded from the analysis, leaving 566 patients to compose the study population. Results. On the basis of univariate analysis, numerous pathologic variables were significantly ( P V 0.01) associated with PA mets. However, logistic regression analysis identified only two independent factors predictive of PA mets: positive pelvic LNs ( P < 0.001, OR = 5.00) and lymphovascular invasion (LVI) ( P = 0.01, OR = 1.99). Notably, only 2% of patients with negative pelvic LNs had PA mets compared with 47% of those with positive pelvic LNs ( P < 0.001). When both pelvic LNs and LVI were negative, only 0.8% of the patients had PA mets compared with 31% of patients for whom at least one of the two variables was positive ( P < 0.001). Conclusion. Positive pelvic LNs and LVI identify a subgroup of high-risk patients (approximately one sixth of the overall population) who potentially may benefit from formal lymphadenectomy or adjuvant therapy or both directed to the PAA. Furthermore, with 47% of patients with positive pelvic LNs having PA mets, unstaged patients at risk for pelvic LN involvement should be considered candidates for both pelvic and paraaortic external beam radiotherapy or surgical restaging. D 2004 Elsevier Inc. All rights reserved. Keywords: Adjuvant therapy; Endometrial cancer; Extended-field radiotherapy; Lymphovascular invasion; Myometrial invasion; Paraaortic lymphadenectomy; Paraaortic failure; Positive lymph nodes
Introduction In the United States, endometrial adenocarcinoma is the most common malignancy of the female genital tract. It has been estimated that during calendar year 2003, 40,100 new cases and 6800 deaths will be attributed to this disease [1]. $ Presented as a poster at the 33rd Annual Meeting of the Society of Gynecologic Oncologists, Miami Beach, FL, March 16 to 20, 2002. There is no conflict of interest with this manuscript. * Corresponding author. Section of Gynecologic Surgery, Mayo Clinic, 200 First Street SW, Rochester, MN 55905. E-mail address:
[email protected] (K.C. Podratz).
0090-8258/$ - see front matter D 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.ygyno.2003.11.032
In 1988, the staging system of endometrial cancer was changed from clinical to surgical [2]. This decision implied that both pelvic and paraaortic lymph nodes (LNs) should be assessed in all patients with endometrial cancer [3]. However, we recently identified a subgroup of patients with lowrisk endometrial cancer, in which both pelvic and paraaortic lymphadenectomies may be safely avoided [4]. Furthermore, we observed that paraaortic lymphadenectomy may have a therapeutic value in a selected group of patients with positive LNs [5]. Therefore, the identification of patients at high risk for paraaortic LN invasion or paraaortic relapse would significantly increase the diagnostic and therapeutic
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indexes for paraaortic lymphadenectomy. Furthermore, the identification of risk factors for metastases to the paraaortic LNs would allow initiation of potentially curative adjuvant therapy to the paraaortic area (PAA) [6,7]. The objective of our study was to identify pathologic factors predictive of tumor dissemination to the paraaortic LNs in patients who have endometrial carcinoma. The identification of the above risk factors may potentially facilitate the selection of patients for radical surgery or radiotherapy (or both) directed to the PAA.
Materials and methods From 1984 to 1993, 815 patients with endometrial cancer were managed surgically at Mayo Clinic (Rochester, MN). We retrieved their records from the database and selected 612 patients with epithelial endometrial cancer who satisfied the following inclusion criteria: (1) treatment included hysterectomy and removal of existing adnexal structures and (2) no other malignancy was diagnosed within 5 years before or after the diagnosis of endometrial cancer (except for carcinoma in situ or skin cancer other than melanoma). Of the 612 study patients, information for most of the prognostic variables was not available for two, who therefore were not included in the study. Moreover, we reasoned that tumor dissemination to the PAA may be identified selecting those patients who had either paraaortic LNs positive for disease at the time of primary surgery or those who subsequently experienced paraaortic relapse or both (n = 41; the ‘‘PA mets’’). To eliminate a possible bias, we excluded from analysis 34 patients for whom no information was available about the status of paraaortic LNs but who received adjuvant irradiation to the PAA (also, no information was available about the site of recurrence in 1 of these patients). Furthermore, we excluded 10 patients for whom no information was available about the site or sites of recurrent disease. Therefore, the present analysis was conducted on a group of 566 patients. Staging was defined according to the International Federation of Obstetricians and Gynecologists (FIGO) surgical staging system [2]. For patients who received treatment before 1988, stage was determined retrospectively from surgical and pathologic assessment. Histologic classification was performed according to the World Health Organization classification [8]. Architectural grading was based on the degree of glandular differentiation in accordance with the FIGO guidelines [2]. Lymphovascular invasion (LVI) was considered to be present when tumor cells were within or attached to the wall of a capillary-like space. Hyperplasia associated with the tumor was diagnosed when an area of hyperplasia was found in the same sample adjacent to the tumor. Primary tumor diameter was measured macroscopically by the pathologist on fresh tissue. The method for measuring the tumor has been described elsewhere [4].
All hematoxylin- and eosin-stained sections of the tumor were reviewed retrospectively by one of us (G.L.K.) to confirm the original diagnosis of adenocarcinoma and to determine FIGO grade, histologic subtype, presence of tumor-associated hyperplasia, and LVI. All surgical procedures were the responsibility of a gynecologic oncologist. We defined ‘‘lymph node dissection’’ as the removal of at least one pelvic or paraaortic (or both) LN. LN dissection was usually performed in patients considered by the surgeon, from an intraoperative analysis of histologic grade of the tumor and depth of myometrial invasion determined from frozen section tissue review, to be at risk for LN metastasis. Paraaortic LN dissection usually was performed if intraoperative risk factors (such as deep myometrial invasion or presence of extrauterine disease) were identified by the pathologist. We considered LNs as ‘‘grossly positive’’ when they were described as ‘‘palpable’’ or ‘‘suspicious’’ in the surgical report. Postoperative adjuvant radiotherapy consisted of external pelvic, paraaortic, or abdominal irradiation or vaginal brachytherapy or some combination of these. Irradiation of the PAA was defined as extended-field radiotherapy. Occasionally, oral megestrol acetate was prescribed or adjuvant chemotherapy was administered. When follow-up information about survival and recurrence was not sufficiently detailed in the clinical records, information was obtained from death certificates and letters or telephone calls to patients and family physicians. We defined paraaortic relapse as tumor relapse in the PAA as the primary site of failure (eventually associated with other sites of relapse). For statistical purposes, endometrioid, endometrioid with squamous differentiation, and adenosquamous tumors were considered together. Grades 1 and 2 lesions were combined and compared with grade 3 lesions. The choice of 2 cm as a determinant for the analysis of primary tumor diameter was based on our previous experience [4]. Statistical analysis was performed with the Fisher exact test, v2 analysis, and logistic regression analysis. Differences were considered statistically significant at P < 0.05. SAS System 6.10 statistical software was used for the analysis.
Results The mean age (Fstandard deviation [SD]) of the 566 study patients was 64.7 F 10.6 years (range, 22 –90 years), and the mean body mass index (FSD) was 30.8 F 8.4 kg/m2 (range, 16.0– 65.5 kg/m2). Preoperative therapy was administered to 11 patients (2%): 8 received external radiotherapy and 3 chemotherapy. Pelvic LN dissection was performed in 337 patients (60%) and paraaortic dissection in 93 (16%) (overall, 342 patients had pelvic or paraaortic [or both] LN dissection). The number and percentage of patients undergoing pelvic or paraaortic lymphadenectomy (or both), stratified by grade, are summarized in Table 1. The mean number of LNs
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Table 1 Number and percentages of patients undergoing pelvic (PLN) and paraaortic lymphadenectomy (PALN) stratified by grade
Table 3 Identification of independent risk factors for either positive paraaortic lymph nodes or paraaortic failure or both according to regression analysis
PLN
PALN
+ + +
+
Grade 1 – 2 (n = 458), no. of patients (%)
Grade 3 (n = 108), no. of patients (%)
Independent risk factor
Odds ratio
P value
95% CI
Positive pelvic node(s) Lymphovascular invasion
5.00 1.99
2 cm, tumor invasion of the entire uterine cavity, positive peritoneal cytology, positive pelvic LNs, histologic grade 3, nonendometrioid histologic subtype, and LVI. Age, body mass index, and hyperplasia associated with the tumor were not significant ( P > 0.05) predictors of PA mets on univariate analysis. However, logistic regression analysis, using the stepwise forward inclusion variable selection method, identified only two independent factors predictive of PA mets: positive pelvic LNs and LVI (Table 3). Notably, 2% of patients with negative pelvic LNs had PA mets compared with 47% of those with positive pelvic LNs. Moreover, 2% of patients without LVI had PA mets, compared with 33% with LVI ( P < 0.001) (Tables 4 and 5). Patients with positive pelvic LNs or LVI (or both) represented 17% (n = 98; 15 had LVI without assessment of pelvic LNs) of the overall population of 566 patients with endometrial Table 4 Presence of either positive paraaortic lymph nodes or paraaortic relapse or both (PA mets) according to lymphovascular invasion (LVI) and pelvic lymph node status Characteristic
Pelvic lymph nodes Negative Positive Missing LVI Yes No Missing a
Patients
% PA mets
No.
%a
288 49 229
85 15
2 47
83 461 22
15 85
33 2
P value
