Does size matter? Tumor size and morphology as predictors of nodal status and recurrence in endometrial cancer
Introduction
Endometrial cancer is the most common gynecologic malignancy in the United States. In 2004, an estimated 40,320 new cases of endometrial cancer were identified, which led to 7090 deaths. Currently, endometrial cancer is the eighth leading cause of cancer deaths in women in the United States (3%) [1]. In 1988 the International Federation of Gynecology and Obstetrics (FIGO) introduced surgical staging as the standard for endometrial cancer with total abdominal hysterectomy, bilateral salpingo-oophorectomy, and pelvic and paraaortic lymph node biopsies [2]. Since its inception, controversy has existed with respect to efficacy, need, and extent of surgical staging. The decision is often based primarily on intra-operative assessment of uterine findings and pre-operative tumor grade [3].
Historical data abstracted from Gynecologic Oncology Group (GOG) #33, a study analyzing endometrial cancer surgical pathologic features and patterns of spread, identified increasing age, moderate to poorly differentiated tumor grade, presence of lymphovascular invasion, and outer-third myometrial invasion to be associated with increased risk of extrauterine disease and recurrence. In GOG #99, a randomized study evaluating post-operative radiation therapy within an intermediate risk group, several risk factors conferred an increased risk of recurrence. A high intermediate risk group was defined as either at least 70 years of age with only one of the risk factors (grades 2–3, lymphovascular invasion, outer third invasion), 50 years of age with two risk factors, or any age with all three risk factors. Adjunctive radiation therapy decreased the risk of recurrence in this high intermediate risk group of women [4]. In women with higher risk grade 3 or papillary serous or clear-cell histology, there remains less controversy with respect to need for surgical staging and adjuvant therapy. For example in uterine papillary serous carcinoma (UPSC), Kato demonstrated a survival advantage in early surgical staged tumors reinforcing the need for thorough staging at the time of laparotomy [5]. Surgical findings additionally can be utilized to tailor adjuvant radiation treatments in these high-risk histologies as outlined by Grice [6].
Tumor size has been postulated to be an indicator of prognosis in endometrial cancer as early as 1960 by Gusberg, who demonstrated a worse prognosis when the uterus sounded to greater than 10 cm [7]. This fairly imprecise estimate was redefined by Schink who evaluated tumor size by the average tumor diameter, determined by averaging the two largest two dimensions of the tumor [8]. Using these measurements, tumor size was independently associated with risk of lymph node metastasis (4% for tumors less than 2 cm or 15% for tumors greater than 2 cm) and was a significant prognostic factor for survival (98% vs. 84%) [8]. Lurain found that tumor size was associated with disease recurrence in univariate analysis: 7% for tumors less than 2 cm and 17.3% for tumors greater than 2 cm; however, in multivariate analysis tumor size was not an independent variable [9]. Similarly, Mariani found no nodal metastases in patients with a primary tumor diameter less than or equal to 2 cm compared to 7% in those with tumors greater than 2 cm. This study demonstrated a significant difference in recurrence based on tumor size; however, in multivariate analysis, size was not an independently significant predictor [10].
These studies have been limited by lack of complete surgical staging in many patients. In addition, there was heterogeneity with respect to post-operative management. Because tumor size is easily measured intra-operatively, clinicians continue to use tumor size in deciding whether to proceed with complete surgical staging. Hence, the purpose of this study was to determine whether tumor size or morphology is predictive of extrauterine disease and/or recurrence risk in endometrial cancer and therefore should guide decisions about the necessity of complete surgical staging and adjuvant therapy.
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Materials and methods
This study was undertaken after approval by the Institutional Review Board of the Human Subjects Division at the University of Washington. International Classification of Diseases codes were used to create a list of patients treated surgically at the University of Washington Medical Center for endometrial cancer from 1 January 1990 to 1 January 2000. Four hundred and thirty-nine patients were identified. Fifty-three patients were excluded for incomplete medical records. Three hundred and
Results
Mean age for our study population was 60 years (range 23–95 years). Racial population was similar to that of the University of Washington hospital population, 322 were Caucasian (93.6%), 3 were African-American (0.9%), 3 were Hispanic (0.9%), 9 were Asian or Pacific Islander (2.6%), and 7 Native American (2.0%). The mean BMI was 34.8 kg/m2 (range 15–98 kg/m2). Comorbid conditions in the population were as follows: 154 with hypertension (44.6%), 77 with diabetes (22.3%), 38 with coronary artery
Discussion
In our study, which is the largest such analysis of tumor size with respect to nodal metastases, we demonstrated that there was still a sizeable risk of nodal metastases in those patients with tumors smaller than 2 cm, 6.3% (Table 7). In our series, 85.5% of patients underwent surgical staging, and the majority of our patients had lymphadenectomy as opposed to lymph node sampling which may be the reason for the higher incidence of nodal metastases observed. As tumor size increases, there is an
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