© 2005 Foundation for Promotion of Cancer Research
Clinical Characteristics of Prognostic Factors in Poorly Differentiated (G3) Endometrioid Adenocarcinoma in Japan
Department of Obstetrics and Gynecology, Keio University School of Medicine, Tokyo, Japan
For reprints and all correspondence: Yoshiko Kuwabara and Nobuyuki Susumu, Department of Obstetrics and Gynecology, Keio University School of Medicine, Shinanomachi 35, Shinjuku-ku, Tokyo 160-8582, Japan. E-mail: di045021{at}sc.itc.keio.ac.jp
Received August 9, 2004; accepted October 15, 2004
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Abstract |
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 TOP Abstract INTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONReferences |
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Background: It has been reported that prognosis is less favorable in poorly (G3) differentiated endometrioid adenocarcinoma than in well (G1) or moderately (G2) differentiated endometrioid adenocarcinoma. The goal of this study is therefore to analyze the prognosis of G3 endometrioid adenocarcinoma and various factors that may predict a favorable prognosis.
Method: This study included 699 Japanese cases of endometrioid adenocarcinoma at the International Federation of Gynaecology and Obstetrics (FIGO) surgical stages I–IV (including 74 G3 cases). We investigated the G1–G3 survival rates of endometrioid adenocarcinoma cases and the G2 and G3 disease-free periods. We also examined the clinicopathological characteristics of G3 endometrioid adenocarcinoma.
Result: The prognosis was poor in stages III and IV in G3 and in G2 cases, but recurrence was observed more frequently in G3 cases than in G2 cases. Adnexal metastasis and high pre-surgery CA602 values showed significantly low P-values for survival.
Conclusions: We suggest that the risk of late recurrence is higher in G3 than in G2 cases. The absence of adnexal metastasis and low pre-surgery CA19-9 values may suggest a relatively favorable prognosis in G3 endometrioid adenocarcinoma.
Key Words: poorly differentiated type • G3 • endometrioid adenocarcinoma
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INTRODUCTION |
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TOPAbstractINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONReferences |
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Endometrial carcinoma has a high morbidity in the advanced countries of Western Europe and the USA and also in Japan, where its morbidity has increased in recent years. In 1970, endometrial carcinoma constituted
3% of total uterine cancers in Japan, but the ratio increased to 40% in 1998. Therefore, it has become increasingly important to understand the oncogenic mechanisms and prognostic factors in endometrial cancer. It was previously reported that grade of differentiation is one of the critical prognostic factors in endometrial carcinoma (1–4). Creasman et al. (5) reported that the 5-year survival rate was 92.0% for G1 endometrial carcinoma cases and 86.9% and 74.0%, respectively, for G2 and G3 cases. This suggested a significantly poorer prognosis for carcinomas of lower differentiation grades. Delaloye et al. (6) investigated the rates of local recurrence, metastasis, disease-free survival and overall survival according to differentiation grade for stage I endometrial adenocarcinoma cases, and showed that the lower the grade was, the higher the metastasis rate was and the lower the disease-free survival rate and overall survival rate were.
It has been suggested that there are two types of endometrial cancer based on oncogenic pathology. One type develops in women with signs of high-estrogen conditions such as obesity, hyperlipidemia, anovular bleeding, infertility, delayed menopause and proliferation of the ovarian stroma or endometrium. Another type develops in women without these signs. Many cases of the former type have the G1 or G2 differentiation grade with shallow muscle invasion, a high sensitivity to hormone therapy and a relatively favorable prognosis (7–9). The latter group, in many cases, has the G3 differentiation grade, with deep muscle invasion, high probability of lymph node metastasis, and shows a poor sensitivity to hormone therapy and a poor prognosis (8). Therefore, it is important to examine clinical characteristics of G3 endometrial carcinoma cases separately from highly differentiated cases.
Endometrioid adenocarcinoma constitutes 70% of endometrial carcinomas (5), and those with other tissue types such as clear cell adenocarcinoma and serous adenocarcinoma show a significantly poorer prognosis compared with endometrioid adenocarcinoma (5,10–14). Therefore, in this study, we limited the subjects to endometrioid adenocarcinoma patients. Specifically, we compared the prognosis of G3 endometrioid adenocarcinoma with G2 and examined the prognostic factors of G3.
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SUBJECTS AND METHODS |
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Of the 890 endometrial carcinoma cases treated at the Keio University Hospital from 1975 to 2002, this study included 699 patients with endometrioid adenocarcinoma (including adenoacanthoma and adenosquamous cell carcinoma) for whom surgery had been performed. The breakdown was as follows: 405 G1 cases, 220 G2 cases and 74 G3 cases. The age at the start of treatment was 22–86 years (mean 54.8 years). The follow-up period was 1–302 months (mean 93.6 months). Patient backgrounds are summarized in Table 1. We had obtained informed consent to analyze prognostic factors from G3 endometrioid adenocarcinoma patients.
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The standard surgical method in endometrial cancer in our department is modified radical hysterectomy for clinical stage I cases, radical hysterectomy for stage II cases, modified radical hysterectomy for stage III cases and total hysterectomy for stage IV cases. Pelvic lymphadenectomy is performed in all stages (I–IV). In modified radical hysterectomy, we dissect the anterior layer of the vesicouterine ligament, remove the ureter to the lateral side, dissect part of the posterior layer of vesicouterine ligament and part of the cardinal ligament and then deliver the uterus with about 1 cm of vaginal wall. Para-aortic lymphadenectomy is performed for: (i) patients with invasion to more than half of the myometrium; (ii) those with metastasis to the pelvic lymph nodes or the adnexas (diagnosed by the intraoperative frozen section); and (iii) those with G3 endometrioid adenocarcinoma (or specific pathological types such as serous adenocarcinoma and clear cell adenocarcinoma). Adjuvant therapy after surgery is selected according to the protocol (the first to the fifth editions) of the Japan Gynecological Oncology Group (JGOG).
The G1–G3 survival rates of endometrioid adenocarcinoma cases and the G2–G3 disease-free periods (defined as the period from surgery to recurrence) were investigated. The survival rates and disease-free survival rates were calculated by the Kaplan–Meier method and statistical tests were performed with the log-rank method.
Univariate analysis was performed with the 5-year survival rate and disease-free survival rate of 74 cases of G3 endometrioid adenocarcinoma, to examine the relationships between clinicopathological factors and prognosis. The following 12 factors were examined: vessel permeation, muscle invasion (>1/3 versus 
1/3), cervical involvement, lymph node metastasis, ascites cell analysis, parametrium invasion, adnexal metastasis, CA125 pre-surgery values (>35 U/ml versus 35 U/ml), CA602 pre-surgery values (>63 U/ml versus 63 U/ml), CA19-9 pre-surgery values (>37 U/ml versus 37 U/ml), the age at the start of the first treatment (age >60 versus age 60), and a family history of cancer or multiple cancers. This analysis was performed with the chi-square test. SAS Re16.12 TS060 was used for statistical analysis.
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RESULTS |
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We first investigated the survival rates separately for each differentiation grade (G1–G3) of endometrioid adenocarcinoma in our hospital. The 5-year survival rates were 97.0% for G1, 86.0% for G2 and 78.6% for G3, clearly showing the poorest prognosis in G3 cases. The 10-year survival rate was 95.1% for G1, 82.2% for G2 and 78.6% for G3. In G1 and G3, the survival rate decreased for 5 years and stabilized in the following 5 years whereas the survival rate appeared to decrease steadily for 10 years in G2 cases (Fig. 1).
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When the survival rate was compared separately in each surgical stage of G2 and G3 cases, the 5-year survival rate was 93.9% for stage I, 86.9% for stage II, 71.9% for stage III and 0% for stage IV G2 cases, and 93.2% for stage I, 100% for stage II, 68.9% for stage III and 34.3% for stage IV G3 cases. This clearly shows a poor prognosis in stages III and IV, even in G2 cases (Fig. 2).
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When the G2–G3 disease-free periods were compared, there were recurrences in many cases within 5 years after surgery and some late recurrences after more than 10 years in G3 cases. In G2 cases, recurrences were observed steadily until 8 years after surgery, but not after 8 years (Fig. 3).
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In the univariate analysis of the 5-year survival rate of 74 cases of G3 endometrioid adenocarcinoma, adnexal metastasis (P = 0.0027) and high pre-surgery CA19-9 values (P = 0.020) showed significantly low P-values for survival (Table 2). Cervical involvement (P = 0.063) and high pre-surgery CA602 values (P = 0.070) showed relatively low P-values, although they were not statistically significant. The 5-year survival rate, as analyzed separately by the presence or absence of these four factors, was 63.1% in the presence and 87.9% in the absence of cervical involvement, 61.9% in the presence or 87.9% in the absence of adnexal metastasis, 34.3% with high CA602 values and 87.5% with low CA602 values, and 50.8% with high CA19-9 values and 100% with low CA19-9 values (Fig. 4).
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DISCUSSION |
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TOPAbstractINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONReferences |
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We examined the prognosis and the prognostic factors of G3 endometrioid adenocarcinoma in this study. First, we analyzed the 10-year survival rates for all grades. The rate decreased steadily for 5 years but remained steady without further decreases in G1 and G3, suggesting that recurrence was rare during the 5–10-year period. In G2 cases, on the other hand, the survival rate decreased steadily for 10 years, but there were recurrences in many cases after 5 years. Compared with G1, both G2 and G3 showed poor prognosis, and the 10-year G2 survival rate was similar to that of G3.
Next, we analyzed the survival rate for each surgical stage of the G2 and G3 grades. Since the prognosis of G1 cases was much more favorable than that of G2 or G3 cases (as shown in Fig. 1), we limited the subjects to G2 and G3 cases. It was found that, in both G2 and G3 cases, prognosis was favorable in stages I and II, but poor in stages III and IV (Fig. 2). We could not find any critical difference between G2 and G3 from this analysis.
We subsequently examined the disease-free period for G2 and G3 cases (Fig. 3), and showed that in G2 recurrences were observed steadily for 8 years after surgery, but there was no recurrence after 8 years. In G3, recurrences were often observed within 5 years after surgery and some late recurrences were also observed after 10 years. It was thus found that in G3 cases, recurrence occurred relatively early, quickly leading to death, but that late recurrences could also occur. We suggest that the high risk of late recurrence is one of the most significant features of G3 cases. Careful follow-up observation is important over a long period after surgery in G3 endometrioid adenocarcinoma.
In clinical practice we sometimes encounter G3 patients whose prognosis is rather favorable. In order to determine what factors might predict a favorable outcome, we analyzed 12 clinicopathological prognostic factors for G3 endometrioid adenocarcinoma. Most of the factors that we examined in this analysis proved to have a significant effect on the prognosis of endometrioid adenocarcinoma (1,15–17). However, we initially conjectured that the grade of differentiation might be so critical a prognostic factor that it could be expected that none of the other clinicopathological factors would be significant in our G3 case analysis. In fact, in the univariate analysis of clinicopathological prognostic factors in G3 endometrioid adenocarcinoma cases, adnexal metastasis and high pre-surgery CA19-9 values were the only factors that showed significantly low P-values for the 5-year survival. Of the other 10 factors, cervical involvement and high pre-surgery CA602 values showed relatively low P-values. Therefore, the absence of adnexal metastasis and cervical involvement, and low pre-surgery CA19-9 and CA602 values suggest relatively favorable prognosis in G3 endometrioid adenocarcinoma cases.
We examined the prognosis and the prognostic factors of G3 endometrioid adenocarcinoma. Although the prognosis of G2 and G3 cases was significantly poorer than that of G1, we could not find any critical difference between the G2 and G3 survival rates. We suggest that the high risk of late recurrence is one of the most significant features of G3 endometrioid adenocarcinoma. The univariate analysis of prognostic factors showed that the absence of adnexal metastasis and cervical involvement, and low pre-surgery CA19-9 and CA602 values had some favorable effect on the prognosis of G3 endometrioid adenocarcinoma.
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Notes |
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The first two authors contributed equally to this report
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References |
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TOPAbstractINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONReferences |
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