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Positive Peritoneal Cytology in Endometrial Cancer: Enhancement of Other Prognostic Indicators
Gynecologic Oncology 82, 470 – 473 (2001) doi:10.1006/gyno.2001.6301, available online at http://www.idealibrary.com on
Positive Peritoneal Cytology in Endometrial Cancer: Enhancement of Other Prognostic Indicators 1 Nobuhiro Takeshima, M.D., 2 Hidetaka Nishida, M.D., Tsutomu Tabata, M.D., Yasuo Hirai, M.D., and Katsuhiko Hasumi, M.D. Department of Gynecology, Cancer Institute Hospital, 1-37-1, Kami-Ikebukuro, Toshima-ku, Tokyo, 170-8455, Japan Received March 5, 2001; published online August 1, 2001
lished prognostic factors, such as the depth of myometrial invasion, tumor grade, and lymph node metastasis [8]. Thus, the underlying influence of such disease characteristics may be responsible for the variable evaluation of peritoneal cytology. Meanwhile, a new concept regarding the prognostic significance of positive peritoneal cytology has emerged. Several studies [9 –11] have shown that the effect of positive peritoneal cytology on survival depends on whether the disease is confined to the uterus. These studies have revealed that positive peritoneal cytology has an adverse effect only if the endometrial cancer has spread to adnexae, peritoneum, or lymph nodes, but not if the disease is otherwise confined to the uterus. The confusion regarding the prognostic significance of positive peritoneal cytology in endometrial cancer can be summarized under the following three issues: (1) whether positive washings in the absence of extrauterine spread are actually of no prognostic significance, (2) whether positive washings in the presence of extrauterine spread can determine the prognosis, and (3) whether cytology-positive patients without any other adverse factors are worth ranking as stage IIIA. The purpose of the present study was to investigate these issues based on our experience at the Cancer Institute Hospital.
Objective. The goal of this study was to investigate the prognostic significance of positive peritoneal cytology in endometrial cancer. Methods. A clinicocytopathological study was performed in 534 patients with endometrial cancer to assess the prognostic value of positive peritoneal cytology. The study population was divided into three groups: a low-risk group (disease limited to the uterus, grade 1, and depth of invasion ⬉1/2), a moderate-risk group (disease limited to the uterus, grade 2 or 3, and/or depth of invasion >1/2), and a high-risk group (extrauterine disease). In each group, disease-free survival was compared in the patients who were positive or negative for malignant cells. Results. The overall incidence of positive peritoneal cytology was 22.3% (119/534). The 5-year disease-free survival of patients positive or negative for malignant cells was 98.1% versus 100% in the low-risk group (n ⴝ 250), 77.5% versus 91.3% in the moderaterisk group (n ⴝ 211), and 42.9% versus 72.1% in the high-risk group (n ⴝ 73). A significant difference was noted in the moderate-risk (P ⴝ 0.044) and high-risk (P ⴝ 0.015) groups, but not in the low-risk group (P ⴝ 0.56). Conclusions. Positive peritoneal cytology is not a negative prognostic indicator itself, but it potentiates other prognostic indicators for endometrial cancer. Our findings also suggest that patients with positive peritoneal cytology in the absence of other adverse prognostic factors do not need upstaging. © 2001 Academic Press Key Words: peritoneal cytology; endometrial cancer; prognosis; risk factor.
MATERIALS AND METHODS
INTRODUCTION
Between 1980 and 1997, 709 patients with endometrial cancer were surgically treated at the Cancer Institute Hospital (Tokyo, Japan). Sixty-nine patients with nonendometrioid adenocarcinoma, such as clear cell adenocarcinoma, serous adenocarcinoma, and adenosquamous carcinoma, were excluded from this study. Seventy-three patients who did not undergo lymphadenectomy for various reasons and 22 patients with residual disease at surgery were also excluded, as were 5 patients in whom peritoneal cytology was judged to be suspicious and 6 patients with known previous malignancies that could have influenced the prognosis. The subjects were thus the remaining 534 patients who underwent total abdominal hysterectomy, bilateral salpingo-oophorectomy, and systemic pelvic lymphadenectomy. Among them, 181 patients also un-
Peritoneal cytology has been studied in patients with endometrial cancer, but its prognostic significance remains unsettled. Several authors [1– 4] have concluded that positive peritoneal cytology is a significant prognostic indicator, but others [5–7] did not confirm this finding. It has also been reported that positive peritoneal cytology is associated with other estab1
Partly supported by grants from the Smoking Research Foundation (Japan). 2 To whom correspondence should be addressed. Fax: ⫹81-3-5394-3889. E-mail: [email protected]. 0090-8258/01 $35.00 Copyright © 2001 by Academic Press All rights of reproduction in any form reserved.
470
471
PERITONEAL CYTOLOGY IN ENDOMETRIAL CANCER
TABLE 1 Adjuvant Therapy Relative to Cytology Status
Low-risk group Radiation Chemotherapy Moderate-risk group Radiation Chemotherapy High-risk group Radiation Chemotherapy
Positive cytology
Negative cytology
53 0 0 38 2 9 28 11 15
197 0 0 173 9 30 45 15 26
derwent paraaortic lymphadenectomy. None of the patients received any treatment before surgery. The follow-up for the surviving patients was a minimum of 3 years, with the longest being 20 years. The median follow-up was 8 years 9 months. In all patients, examination of peritoneal cytology was performed as follows. Peritoneal fluid in the pouch of Douglas was aspirated completely by syringe immediately on opening the peritoneal cavity. In patients with no ascites, 20 –30 mL of saline was instilled into the pouch. After being centrifuged, the specimens were stained with the Papanicolaou, Alcian blue, Giemsa, and periodic acid–Schiff procedures. The study population was divided into three groups: low risk, moderate risk, and high risk. The low-risk group consisted of patients whose disease was confined to the uterus, was grade 1, and invaded half or less of the thickness of the myometrium. The moderate-risk group was defined as patients whose disease was confined to the uterus, but either was grade 2 or 3 or involved more than half of the thickness of the myometrium. The high-risk group was defined as patients who had extrauterine spread, such as nodal disease, adnexal metastases, and small sites of peritoneal seeding that could be resected at surgery. The presence or absence of cervical involvement did not alter the group to which patients were assigned. No patient in the low-risk group received any adjuvant therapy. In the moderate-risk group, 5.2% of the patients received external pelvic irradiation (50 Gy) and 18.5% received platinum-based chemotherapy. In the high-risk group, 35.6% of the patients were treated with radiotherapy and 56.2% received chemotherapy (Table 1). No patient in this series had any change to the planned treatment based on the peritoneal cytology findings. In each group, the disease-free survival rate was compared in the patients who were positive and negative for malignant peritoneal cells using the Kaplan–Meier method. The log-rank method was used for statistical analysis. The incidence of clinicopathological variables and the proportion of patients who received adjuvant therapy were compared in each group between patients with and without positive cytology. The incidence of intraperitoneal recurrence was also compared be-
tween recurrent patients with and without positive cytology. The Fisher exact test was used for these analyses. RESULTS The mean age of the 543 patients was 55 years (range: 24 – 88 years). Two hundred and fifty patients were classified into the low-risk group, 211 patients into the moderate-risk group, and 73 patients into the high-risk group. Table 2 summarizes peritoneal cytology status relative to the clinocopathological findings. The overall incidence of positive peritoneal cytology was 22.3% (119/534). There was no significant difference in any variables between patients with and without positive cytology. No statistical significance in the proportion of patients who received adjuvant therapy was also observed in each group between patients with and without positive cytology. With respect to site of recurrence, the incidence of intraperitoneal recurrence was 26.1% (6/23) in recurrent patients with positive peritoneal cytology, while it was 20.7% (6/29) in those with negative cytology. No significant difference was noted. 1. Low-Risk Group Peritoneal cytology was positive in 21.2% (53/250) of the patients in this group. The 5-year disease-free survival rate was 98.1% for patients with positive peritoneal cytology and 100% for those with negative cytology, and no significant difference was noted (P ⫽ 0.56) (Fig. 1). Only 1 of 53 patients with positive cytology developed extraperitoneal recurrence. 2. Moderate-Risk Group The incidence of positive peritoneal cytology was 18% (38/211) in this group. The 5-year disease-free survival rate was 77.5% for patients with positive peritoneal cytology and 91.3% for those with negative cytology, a significant difference (P ⫽ 0.044) (Fig. 2). When an analysis of all patients with disease confined to the uterus was performed, i.e., the low-risk
TABLE 2 Peritoneal Cytology Relative to Pathological Findings
Disease limited to the uterus Grade 1 and depth ⬉ 1/2 Grade 2 or 3 Depth ⬎ 1/2 Both Extrauterine disease Nodal metastasis Adnexal metastasis Both Other extrauterine spread Total
Positive cytology
Negative cytology
53 18 10 10
197 92 45 36
16 7 3 2 119
31 10 2 2 415
472
TAKESHIMA ET AL.
FIG. 1. Disease-free survival in the low-risk group (disease limited to the uterus, grade 1, and depth of invasion ⬉ 1/2). The 5-year disease-free survival rate was 98.1% for patients with positive peritoneal cytology and 100% for those with negative cytology; the difference was not significant (P ⫽ 0.56).
group plus the moderate-risk group, there was no statistical significance in disease-free survival between patients with and without positive peritoneal cytology (P ⫽ 0.87).
FIG. 3. Disease-free survival in the high-risk group (extrauterine disease). The 5-year disease-free survival rate was 42.9% for patients with positive peritoneal cytology and 72.1% for those with negative cytology; the difference was significant (P ⫽ 0.015).
for those with negative cytology, a significant difference (P ⫽ 0.015) (Fig. 3). DISCUSSION
3. High-Risk Group The incidence of positive peritoneal cytology was 38.4% (28/73) in this group. The 5-year disease-free survival rate was 42.9% for patients with positive peritoneal cytology and 72.1%
FIG. 2. Disease-free survival in the moderate-risk group (disease limited to the uterus, grade 2 or 3, and/or depth of invasion ⬎ 1/2). The 5-year disease-free survival rate was 77.5% for patients with positive peritoneal cytology and 91.3% for those with negative cytology; the difference was significant (P ⫽ 0.044).
It has been reported that positive peritoneal cytology is associated with other established prognostic indicators for endometrial cancer [8]. So the underlying influence of these factors needs to be addressed when evaluating the relevance of peritoneal cytology, even in patients with disease limited to the uterus. In addition, systemic lymph node dissection is necessary to rule out the presence of extrauterine disease. In the current series, the analysis was adjusted for confounding variables as completely as possible. Stratification of the study population (i.e., low-risk, moderate-risk, and high-risk groups) was employed instead of multivariate analysis because it was considered that positive peritoneal cytology may have influence in only a special population of patients. Our results demonstrated that positive peritoneal cytology had no impact on survival in the low-risk group (disease limited to the uterus, grade 1, and depth of invasion ⬉1/2). An extremely low relapse rate was observed in this group regardless of the status of peritoneal cytology. Conversely, in the moderate-risk group (disease limited to the uterus, grade 2 or 3, and/or depth of invasion ⬎1/2), the influence of positive washings became obvious. The impact on disease-free survival reached statistical significance in this group, but this influence was lost in an analysis of all patients with disease limited to the uterus (i.e., the low-risk group plus the moderate-risk group). In the high-risk group (extrauterine disease), the prognostic significance of pelvic washings was even more evident. The present results may explain some of the discrepancies
PERITONEAL CYTOLOGY IN ENDOMETRIAL CANCER
between previous studies. The extremely low relapse rate despite the presence of positive pelvic washings among the low-risk patients may indicate that positive peritoneal cytology is not an adverse prognostic indicator for these patients. If positive peritoneal cytology was an independent prognostic factor, its influence should be observed even in the low-risk group. In patients who also have other established risk factors, however, the presence of positive pelvic washings seems to be an indicator of the likely clinical course. This trend may well have been present previously. Indeed, in most previous studies that supported or denied the significance of positive peritoneal cytology in patients with disease limited to the uterus, the actual survival of positive patients was usually worse than that of negative patients [3, 7, 9]. It may be that the discriminatory value of positive peritoneal cytology in the moderate-risk group was often masked by the presence of a large low-risk group. Likewise, the prognostic significance of positive cytology for the high-risk group could also have been masked. Thus, the relevance of positive peritoneal washings has varied in past reports because it has depended on the proportion of patients with other risk factors in each study population. Our current findings are partially in agreement with those of Kadar et al. [9, 10]. They reported that the effect of positive peritoneal cytology on survival depended on whether the disease was confined to the uterus, and that positive peritoneal cytology had an adverse influence only when the patient had extrauterine disease. In our study, however, positive peritoneal cytology appeared to be an adverse prognostic indicator even when the disease was confined to the uterus, if the patient had other adverse factors. It is well known that a significant proportion of recurrences in cytology-positive patients are extraperitoneal, despite the detection of positive washings [6, 9]. Positive peritoneal washings seem to be a marker of tumor behavior rather than of intraperitoneal spread. Based on these findings, we conclude that positive peritoneal cytology per se does not imply a worse
473
prognosis, but that it indicates greater tumor aggressiveness when combined with other established prognostic indicators. Our findings also suggest that patients with positive peritoneal cytology do not require upstaging in the absence of other adverse prognostic indicators. REFERENCES 1. Creasman WT, Disaia PJ, Blessing J, Wilkinson RH, Johnston W, Weed JC. Prognostic significance of peritoneal cytology in patients with endometrial cancer and preliminary data concerning therapy with intraperitoneal radiopharmaceuticals. Am J Obstet Gynecol 1981;141:921–9. 2. Mazurka JL, Krepart GV, Lotocki RJ. Prognostic significance of positive peritoneal cytology in endometrial carcinoma. Am J Obstet Gynecol 1988;158:303– 6. 3. Turner DA, Gershenson DM, Atkinson N, Sneige N, Wharton AT. The prognostic significance of peritoneal cytology for stage I endometrial cancer. Obstet Gynecol 1989;74:775– 80. 4. Kashimura M, Sugihara K, Toki N, Matsuura Y, Kawagoe T, Kamura T, et al. The significance of peritoneal cytology in uterine cervix and endometrial cancer. Gynecol Oncol 1997;67:285–90. 5. Yazigi R, Piver SM, Blumenson L. Malignant peritoneal cytology as prognostic indicator in stage I endometrial cancer. Obstet Gynecol 1983; 62:359 – 62. 6. Lurain JR, Rumsey NK, Schink JC, Wallemark CB, Chmiel JS. Prognostic significance of positive peritoneal cytology in clinical stage I adenocarcinoma of the endometrium. Obstet Gynecol 1989;74:175–9. 7. Grimshaw RN, Tupper WC, Fraser RC, Tompkins MG, Jeffrey JF. Prognostic value of peritoneal cytology in endometrial carcinoma. Gynecol Oncol 1990;36:97–100. 8. McLellan R, Dillon MB, Currie JL, Rosenshein NB. Peritoneal cytology in endometrial cancer: a review. Obstet Gynecol Surv 1989;44:711–19. 9. Kadar N, Homesley HD, Malfetano JH. Positive peritoneal cytology is an adverse factor in endometrial cancer only if there is other evidence of extrauterine disease. Gynecol Oncol 1992;46:145–9. 10. Kadar N, Homesley HD, Malfetano JH. Prognostic factors in surgical stage III and IV carcinoma of the endometrium. Obstet Gynecol 1994;84: 983– 6. 11. Ebina Y, Hareyama N, Sakuragh N, Yamamoto R, Furuya M, Sogame M, et al. Peritoneal cytology and its prognostic value in endometrial carcinoma. Int Surg 1997;82:244 – 8.
Positive Peritoneal Cytology in Endometrial Cancer: Enhancement of Other Prognostic Indicators 1 Nobuhiro Takeshima, M.D., 2 Hidetaka Nishida, M.D., Tsutomu Tabata, M.D., Yasuo Hirai, M.D., and Katsuhiko Hasumi, M.D. Department of Gynecology, Cancer Institute Hospital, 1-37-1, Kami-Ikebukuro, Toshima-ku, Tokyo, 170-8455, Japan Received March 5, 2001; published online August 1, 2001
lished prognostic factors, such as the depth of myometrial invasion, tumor grade, and lymph node metastasis [8]. Thus, the underlying influence of such disease characteristics may be responsible for the variable evaluation of peritoneal cytology. Meanwhile, a new concept regarding the prognostic significance of positive peritoneal cytology has emerged. Several studies [9 –11] have shown that the effect of positive peritoneal cytology on survival depends on whether the disease is confined to the uterus. These studies have revealed that positive peritoneal cytology has an adverse effect only if the endometrial cancer has spread to adnexae, peritoneum, or lymph nodes, but not if the disease is otherwise confined to the uterus. The confusion regarding the prognostic significance of positive peritoneal cytology in endometrial cancer can be summarized under the following three issues: (1) whether positive washings in the absence of extrauterine spread are actually of no prognostic significance, (2) whether positive washings in the presence of extrauterine spread can determine the prognosis, and (3) whether cytology-positive patients without any other adverse factors are worth ranking as stage IIIA. The purpose of the present study was to investigate these issues based on our experience at the Cancer Institute Hospital.
Objective. The goal of this study was to investigate the prognostic significance of positive peritoneal cytology in endometrial cancer. Methods. A clinicocytopathological study was performed in 534 patients with endometrial cancer to assess the prognostic value of positive peritoneal cytology. The study population was divided into three groups: a low-risk group (disease limited to the uterus, grade 1, and depth of invasion ⬉1/2), a moderate-risk group (disease limited to the uterus, grade 2 or 3, and/or depth of invasion >1/2), and a high-risk group (extrauterine disease). In each group, disease-free survival was compared in the patients who were positive or negative for malignant cells. Results. The overall incidence of positive peritoneal cytology was 22.3% (119/534). The 5-year disease-free survival of patients positive or negative for malignant cells was 98.1% versus 100% in the low-risk group (n ⴝ 250), 77.5% versus 91.3% in the moderaterisk group (n ⴝ 211), and 42.9% versus 72.1% in the high-risk group (n ⴝ 73). A significant difference was noted in the moderate-risk (P ⴝ 0.044) and high-risk (P ⴝ 0.015) groups, but not in the low-risk group (P ⴝ 0.56). Conclusions. Positive peritoneal cytology is not a negative prognostic indicator itself, but it potentiates other prognostic indicators for endometrial cancer. Our findings also suggest that patients with positive peritoneal cytology in the absence of other adverse prognostic factors do not need upstaging. © 2001 Academic Press Key Words: peritoneal cytology; endometrial cancer; prognosis; risk factor.
MATERIALS AND METHODS
INTRODUCTION
Between 1980 and 1997, 709 patients with endometrial cancer were surgically treated at the Cancer Institute Hospital (Tokyo, Japan). Sixty-nine patients with nonendometrioid adenocarcinoma, such as clear cell adenocarcinoma, serous adenocarcinoma, and adenosquamous carcinoma, were excluded from this study. Seventy-three patients who did not undergo lymphadenectomy for various reasons and 22 patients with residual disease at surgery were also excluded, as were 5 patients in whom peritoneal cytology was judged to be suspicious and 6 patients with known previous malignancies that could have influenced the prognosis. The subjects were thus the remaining 534 patients who underwent total abdominal hysterectomy, bilateral salpingo-oophorectomy, and systemic pelvic lymphadenectomy. Among them, 181 patients also un-
Peritoneal cytology has been studied in patients with endometrial cancer, but its prognostic significance remains unsettled. Several authors [1– 4] have concluded that positive peritoneal cytology is a significant prognostic indicator, but others [5–7] did not confirm this finding. It has also been reported that positive peritoneal cytology is associated with other estab1
Partly supported by grants from the Smoking Research Foundation (Japan). 2 To whom correspondence should be addressed. Fax: ⫹81-3-5394-3889. E-mail: [email protected]. 0090-8258/01 $35.00 Copyright © 2001 by Academic Press All rights of reproduction in any form reserved.
470
471
PERITONEAL CYTOLOGY IN ENDOMETRIAL CANCER
TABLE 1 Adjuvant Therapy Relative to Cytology Status
Low-risk group Radiation Chemotherapy Moderate-risk group Radiation Chemotherapy High-risk group Radiation Chemotherapy
Positive cytology
Negative cytology
53 0 0 38 2 9 28 11 15
197 0 0 173 9 30 45 15 26
derwent paraaortic lymphadenectomy. None of the patients received any treatment before surgery. The follow-up for the surviving patients was a minimum of 3 years, with the longest being 20 years. The median follow-up was 8 years 9 months. In all patients, examination of peritoneal cytology was performed as follows. Peritoneal fluid in the pouch of Douglas was aspirated completely by syringe immediately on opening the peritoneal cavity. In patients with no ascites, 20 –30 mL of saline was instilled into the pouch. After being centrifuged, the specimens were stained with the Papanicolaou, Alcian blue, Giemsa, and periodic acid–Schiff procedures. The study population was divided into three groups: low risk, moderate risk, and high risk. The low-risk group consisted of patients whose disease was confined to the uterus, was grade 1, and invaded half or less of the thickness of the myometrium. The moderate-risk group was defined as patients whose disease was confined to the uterus, but either was grade 2 or 3 or involved more than half of the thickness of the myometrium. The high-risk group was defined as patients who had extrauterine spread, such as nodal disease, adnexal metastases, and small sites of peritoneal seeding that could be resected at surgery. The presence or absence of cervical involvement did not alter the group to which patients were assigned. No patient in the low-risk group received any adjuvant therapy. In the moderate-risk group, 5.2% of the patients received external pelvic irradiation (50 Gy) and 18.5% received platinum-based chemotherapy. In the high-risk group, 35.6% of the patients were treated with radiotherapy and 56.2% received chemotherapy (Table 1). No patient in this series had any change to the planned treatment based on the peritoneal cytology findings. In each group, the disease-free survival rate was compared in the patients who were positive and negative for malignant peritoneal cells using the Kaplan–Meier method. The log-rank method was used for statistical analysis. The incidence of clinicopathological variables and the proportion of patients who received adjuvant therapy were compared in each group between patients with and without positive cytology. The incidence of intraperitoneal recurrence was also compared be-
tween recurrent patients with and without positive cytology. The Fisher exact test was used for these analyses. RESULTS The mean age of the 543 patients was 55 years (range: 24 – 88 years). Two hundred and fifty patients were classified into the low-risk group, 211 patients into the moderate-risk group, and 73 patients into the high-risk group. Table 2 summarizes peritoneal cytology status relative to the clinocopathological findings. The overall incidence of positive peritoneal cytology was 22.3% (119/534). There was no significant difference in any variables between patients with and without positive cytology. No statistical significance in the proportion of patients who received adjuvant therapy was also observed in each group between patients with and without positive cytology. With respect to site of recurrence, the incidence of intraperitoneal recurrence was 26.1% (6/23) in recurrent patients with positive peritoneal cytology, while it was 20.7% (6/29) in those with negative cytology. No significant difference was noted. 1. Low-Risk Group Peritoneal cytology was positive in 21.2% (53/250) of the patients in this group. The 5-year disease-free survival rate was 98.1% for patients with positive peritoneal cytology and 100% for those with negative cytology, and no significant difference was noted (P ⫽ 0.56) (Fig. 1). Only 1 of 53 patients with positive cytology developed extraperitoneal recurrence. 2. Moderate-Risk Group The incidence of positive peritoneal cytology was 18% (38/211) in this group. The 5-year disease-free survival rate was 77.5% for patients with positive peritoneal cytology and 91.3% for those with negative cytology, a significant difference (P ⫽ 0.044) (Fig. 2). When an analysis of all patients with disease confined to the uterus was performed, i.e., the low-risk
TABLE 2 Peritoneal Cytology Relative to Pathological Findings
Disease limited to the uterus Grade 1 and depth ⬉ 1/2 Grade 2 or 3 Depth ⬎ 1/2 Both Extrauterine disease Nodal metastasis Adnexal metastasis Both Other extrauterine spread Total
Positive cytology
Negative cytology
53 18 10 10
197 92 45 36
16 7 3 2 119
31 10 2 2 415
472
TAKESHIMA ET AL.
FIG. 1. Disease-free survival in the low-risk group (disease limited to the uterus, grade 1, and depth of invasion ⬉ 1/2). The 5-year disease-free survival rate was 98.1% for patients with positive peritoneal cytology and 100% for those with negative cytology; the difference was not significant (P ⫽ 0.56).
group plus the moderate-risk group, there was no statistical significance in disease-free survival between patients with and without positive peritoneal cytology (P ⫽ 0.87).
FIG. 3. Disease-free survival in the high-risk group (extrauterine disease). The 5-year disease-free survival rate was 42.9% for patients with positive peritoneal cytology and 72.1% for those with negative cytology; the difference was significant (P ⫽ 0.015).
for those with negative cytology, a significant difference (P ⫽ 0.015) (Fig. 3). DISCUSSION
3. High-Risk Group The incidence of positive peritoneal cytology was 38.4% (28/73) in this group. The 5-year disease-free survival rate was 42.9% for patients with positive peritoneal cytology and 72.1%
FIG. 2. Disease-free survival in the moderate-risk group (disease limited to the uterus, grade 2 or 3, and/or depth of invasion ⬎ 1/2). The 5-year disease-free survival rate was 77.5% for patients with positive peritoneal cytology and 91.3% for those with negative cytology; the difference was significant (P ⫽ 0.044).
It has been reported that positive peritoneal cytology is associated with other established prognostic indicators for endometrial cancer [8]. So the underlying influence of these factors needs to be addressed when evaluating the relevance of peritoneal cytology, even in patients with disease limited to the uterus. In addition, systemic lymph node dissection is necessary to rule out the presence of extrauterine disease. In the current series, the analysis was adjusted for confounding variables as completely as possible. Stratification of the study population (i.e., low-risk, moderate-risk, and high-risk groups) was employed instead of multivariate analysis because it was considered that positive peritoneal cytology may have influence in only a special population of patients. Our results demonstrated that positive peritoneal cytology had no impact on survival in the low-risk group (disease limited to the uterus, grade 1, and depth of invasion ⬉1/2). An extremely low relapse rate was observed in this group regardless of the status of peritoneal cytology. Conversely, in the moderate-risk group (disease limited to the uterus, grade 2 or 3, and/or depth of invasion ⬎1/2), the influence of positive washings became obvious. The impact on disease-free survival reached statistical significance in this group, but this influence was lost in an analysis of all patients with disease limited to the uterus (i.e., the low-risk group plus the moderate-risk group). In the high-risk group (extrauterine disease), the prognostic significance of pelvic washings was even more evident. The present results may explain some of the discrepancies
PERITONEAL CYTOLOGY IN ENDOMETRIAL CANCER
between previous studies. The extremely low relapse rate despite the presence of positive pelvic washings among the low-risk patients may indicate that positive peritoneal cytology is not an adverse prognostic indicator for these patients. If positive peritoneal cytology was an independent prognostic factor, its influence should be observed even in the low-risk group. In patients who also have other established risk factors, however, the presence of positive pelvic washings seems to be an indicator of the likely clinical course. This trend may well have been present previously. Indeed, in most previous studies that supported or denied the significance of positive peritoneal cytology in patients with disease limited to the uterus, the actual survival of positive patients was usually worse than that of negative patients [3, 7, 9]. It may be that the discriminatory value of positive peritoneal cytology in the moderate-risk group was often masked by the presence of a large low-risk group. Likewise, the prognostic significance of positive cytology for the high-risk group could also have been masked. Thus, the relevance of positive peritoneal washings has varied in past reports because it has depended on the proportion of patients with other risk factors in each study population. Our current findings are partially in agreement with those of Kadar et al. [9, 10]. They reported that the effect of positive peritoneal cytology on survival depended on whether the disease was confined to the uterus, and that positive peritoneal cytology had an adverse influence only when the patient had extrauterine disease. In our study, however, positive peritoneal cytology appeared to be an adverse prognostic indicator even when the disease was confined to the uterus, if the patient had other adverse factors. It is well known that a significant proportion of recurrences in cytology-positive patients are extraperitoneal, despite the detection of positive washings [6, 9]. Positive peritoneal washings seem to be a marker of tumor behavior rather than of intraperitoneal spread. Based on these findings, we conclude that positive peritoneal cytology per se does not imply a worse
473
prognosis, but that it indicates greater tumor aggressiveness when combined with other established prognostic indicators. Our findings also suggest that patients with positive peritoneal cytology do not require upstaging in the absence of other adverse prognostic indicators. REFERENCES 1. Creasman WT, Disaia PJ, Blessing J, Wilkinson RH, Johnston W, Weed JC. Prognostic significance of peritoneal cytology in patients with endometrial cancer and preliminary data concerning therapy with intraperitoneal radiopharmaceuticals. Am J Obstet Gynecol 1981;141:921–9. 2. Mazurka JL, Krepart GV, Lotocki RJ. Prognostic significance of positive peritoneal cytology in endometrial carcinoma. Am J Obstet Gynecol 1988;158:303– 6. 3. Turner DA, Gershenson DM, Atkinson N, Sneige N, Wharton AT. The prognostic significance of peritoneal cytology for stage I endometrial cancer. Obstet Gynecol 1989;74:775– 80. 4. Kashimura M, Sugihara K, Toki N, Matsuura Y, Kawagoe T, Kamura T, et al. The significance of peritoneal cytology in uterine cervix and endometrial cancer. Gynecol Oncol 1997;67:285–90. 5. Yazigi R, Piver SM, Blumenson L. Malignant peritoneal cytology as prognostic indicator in stage I endometrial cancer. Obstet Gynecol 1983; 62:359 – 62. 6. Lurain JR, Rumsey NK, Schink JC, Wallemark CB, Chmiel JS. Prognostic significance of positive peritoneal cytology in clinical stage I adenocarcinoma of the endometrium. Obstet Gynecol 1989;74:175–9. 7. Grimshaw RN, Tupper WC, Fraser RC, Tompkins MG, Jeffrey JF. Prognostic value of peritoneal cytology in endometrial carcinoma. Gynecol Oncol 1990;36:97–100. 8. McLellan R, Dillon MB, Currie JL, Rosenshein NB. Peritoneal cytology in endometrial cancer: a review. Obstet Gynecol Surv 1989;44:711–19. 9. Kadar N, Homesley HD, Malfetano JH. Positive peritoneal cytology is an adverse factor in endometrial cancer only if there is other evidence of extrauterine disease. Gynecol Oncol 1992;46:145–9. 10. Kadar N, Homesley HD, Malfetano JH. Prognostic factors in surgical stage III and IV carcinoma of the endometrium. Obstet Gynecol 1994;84: 983– 6. 11. Ebina Y, Hareyama N, Sakuragh N, Yamamoto R, Furuya M, Sogame M, et al. Peritoneal cytology and its prognostic value in endometrial carcinoma. Int Surg 1997;82:244 – 8.