Seminars in Surgical Oncology 6:339-342 (1990)
Recent Advances in Endometrial Cancer WILLIAM T. CREASMAN, MD, AND GARY L. EDDY, MD From the Department of Obstetrics and Gynecology, Medical University of South Carolina, Charleston
There are well-defined prognostic factors that identify patients with clinical stage I (confined to the uterus) endometrial adenocarcinoma and patients at high risk vs. low risk for recurrent disease and allow for treatment tailored to those specific prognostic indicators. This had led the International Federation of Gynecologists and Obstetricians (FIGO) in 1988 to revise the FIGO staging from a clinical to a surgical/histopathological evaluation. The use of these prognostic factors should lead to improved initial surgery and adjuvant therapy for patients considered at high risk for recurrence. KEYWORDS:lymph nodes, staging, peritoneal cytology
INTRODUCTION In the United States today, cancer of the uterine corpus is the most common female pelvic malignancy. The American Cancer Society estimates that approximately 34,000 women will develop uterine cancer this year. This malignancy is almost twice as common as is carcinoma of the ovary and almost three times more common than cervical cancer. Over the last 2 decades there has been a rather marked increase in the incidence of endometrial cancer in the industrial world. In the United States, however, the incidence apparently peaked in the early 1980s. At that time approximately 39,000 new cases were identified, and this has slowly decreased to the current level. Although several factors have been suggested as the reason for the initial increase and then a decrease in the figures, estrogen replacement therapy has been one explanation that has received considerable attention. In the 1970s, the relationship between estrogen and endometrial cancer was described by many investigators. This caused a rather sharp decrease in the prescriptions for estrogen. However, we now appreciate that estrogen plus progesterone actually protects against endometrial cancer, and we have seen a marked increase in estrogen replacement therapy (ERT) in the recent past. Certainly the multiple beneficial effects of ERT, such as prevention of osteoporosis and cardiovascular disease, outweigh any potential detriment in regard to endometrial cancer. Other countries such as Norway and Czechoslovakia have also experienced an increase in the
0 1990 Wiley-Liss, Inc.
incidence of endometrial cancer, yet estrogen was either not available or rarely prescribed in those countries. Since FIGO first suggested a staging classification for endometrial cancer, it has always been a clinically staged entity. The grade of differentiation was used in the subclassification, particularly of stage I. This entity was really the only histopathological criteria used in staging. Clinical staging did include some laboratory parameters such as a chest X-ray. At one time there was even a subgroup classified as “inoperable. Since this disease entity appeared in the older age range, many patients were in fact inoperable. Most of these patients were treated with radiation therapy, and, since hysterectomy was considered an integral part of the therapy for endometrial cancer, these patients were withdrawn from overall statistical considerations in order not to prejudice the results. Since 1971, FIGO staging suggested that stage I should be further delineated using two parameters: one, the depth of the uterine cavity as noted with sounding and, two, the differentiation of the tumor. Therefore, six substages were then identified in stage I. This staging was the one we ‘‘lived with” for essentially the whole of the 1970s and 1980s. The two criteria for inclusion in the substaging within stage I were identified as prognostic factors in this disease entity. In fact, when one evaluates the data in the last Annual Report (1988) published by ”
Address reprint requests to William T. Creasman, MD, Department of Obstetrics and Gynecology, Medical University of South Carolina, 171 Ashley Ave., Charleston, SC 29425.
340
Creasman and Eddy
FIGO (results of treatment around the world), it can be noted that survival does relate to these six substages. Among almost 8,000 patients reported, those individuals with a stage IA G1 cancer had a 78.7% absolute survival compared with 52.7% for a stage IB G3. Those patients with stage IB G3 actually showed worse survival than did patients with stage I1 disease (56%) [ 11.
PROGNOSTIC FACTORS During the last 2 decades there has been a considerable amount of data collected in regard to identification and delineation of prognostic factors in endometrial cancer. These have been identified mainly through two large studies that have been performed by the Gynecologic Oncology Group (GOG) that are being reported. A brief review of suggested prognostic factors follows.
Differentiation Histological differentiation of endometrial cancer has long been recognized as one of the most sensitive indicators of prognosis. As previously noted, this was incorporated in the 1971 staging by FIGO. As the tumor loses its differentiation, the chance for survival decreases. In the GOG pilot study of 222 surgically evaluated clinically stage 1 endometrial cancers, the recurrence rate was only 4% in grade I lesions compared with 15% and 41% in grade I1 and 111, respectively [2]. The data from the last FIGO (1988) Annual Reports show that patients with stage I GI lesions have an 81.6% 5 year survival, grade 11 78.9%, and grade 111 66.3%. The differentiation of the tumor also correlates with other factors of prognosis, such as the depth of myometrial invasion, although some exceptions do exist.
Uterine Size Most studies that have evaluated this factor agree that patients with larger uterine cavities have a poor survival rate; however, some investigators have suggested that this might not be the case. It is appreciated that all enlarged uteri are not the results of increasing amounts of cancer. Other conditions such as fibromyomata and adenomyosis may contribute to uterine enlargement. Javert and Douglas [3], in evaluating hysterectomy specimen of 100 patients with endometrial cancer, noted that about one-half were enlarged, but in only eight was the cancer the cause.
Pathology Adenocarcinoma has been recognized for decades, and variants have been described in the literature for almost a half century. In the 194Os, mixed adenocarcinoma and squamous carcinomas of the uterus were being described. Subsequently, adenoacanthomas were identi-
fied, and these were all recognized entities today. It has been suggested that patients with adenoacanthoma are usually associated with well-differentiated cancers and have characteristics similar to those patients with pure adenocarcinomas. The significance of adenosquamous carcinoma appears still to be the topic for discussion [4]. Some authors have suggested that adenosquamous carcinomas have increased in incidence and appear to be associated with a less differentiated glandular adenocarcinoma. As a result, they usually carry a poorer prognosis than pure adenocarcinomas. Several authors, however, have suggested that the degree of differentiation of adenocarcinoma is the important criteria in adenosquamous carcinoma and not the fact of squamous carcinoma per se being present. More recently, two additional histological variants of adenocarcinoma have been discussed more frequently. Clear cell carcinomas are recognized histologically by their large epithelial cells, which may be admixed with typical nonclear cell carcinomas. Investigators have suggested a worse prognosis for clear cell carcinoma than for pure adenocarcinomas. Because of the small number of these lesions, the exact implication of this finding has not yet been resolved. On the other hand, papillary adenocarcinoma of the endometrium has been known for many years but has only recently received increased attention [ 5 ] . Survival does not appear to be as good as with pure adenocarcinoma but is better than with mixed adenosquamous and clear cell. It has been suggested that there may be two clinical pathological types of papillary adenocarcinoma. The so-called papillary serous carcinomas appear to be present in older patients, have deep myometrial invasion, and have a tendency for extrauterine spread. The mortality therefore is poorer than with patients with pure adenocarcinoma. On the other hand, patients with well-differentiated papillary adenocarcinoma were similar in regard to characteristics and survival in comparison with adenocarcinoma of the endometrium.
Myometrium It is appreciated that the degree of myometrial invasion is an indicator of tumor virulence and volume. As a generalization, the depth of myometrial invasion does correlate with the degree of differentiation; i.e., the depth of penetration increases with the degree of differentiation. It is appreciated that patients with wendifferentiated cancers can have deep myometrial invasion and that those with poorly differentiated cancers can have superficial involvement only. Irrespective of the grade of the tumor, the depth of invasion does appear to be an independent prognostic factor. DiSaia et al. [2], reviewing the survival data of the initial GOG study,
Endometrial Cancer
found that, in patients with stage I endometrial carcinoma of the endometrium, there is only an 8% recurrence rate if endometrium only was involved, but this increased to 46% when deep muscle was invaded.
Peritoneal Cytology It has been suggested that cytological evaluation of the peritoneal fluids or washings is an important prognostic factor in several pelvic malignancies. Over almost 2 decades, several reports have appeared in the literature, and, although it has not been unanimous, the vast majority of studies do suggest that the presence of malignant cells in the peritoneal cytology is a poor prognostic factor. In a preliminary study of 167 patients with clinical stage I carcinoma of the endometrium treated primarily with surgery, it was noted that 26 (15%) had malignant cells present in the peritoneal cytology [6]. Recurrence developed in 10 of these 26 patients (34%) compared with 14 of 141 (10%) patients with negative peritoneal cytology. Thirteen of these twenty-six patients had disease outside of the uterus at the time of surgery, and seven (54%) have died from their disease. Malignant cells were found in the peritoneal cytology of 13 patients but without any disease outside the uterus, and six (46%) have died with disseminated intraabdominal carcinomatosis. In the latter GOG study of 621 patients, 76 (12%) had malignant cells identified by cytological examination of the peritoneal washings. In a multivariant analysis, it was found that malignant cells in peritoneal cytology was an independent important prognostic factor [7]. It has been suggested that intraperitoneal P-32 as treatment for these patients may be efficacious. Lymph Node Metastases For many years, the significance of lymph node metastases was not appreciated, or evaluated, in corpus cancer. When the literature is reviewed, a significant number of women even with stage I endometrial cancers will have pelvic node metastases. In the early 1970s, review of the recent literature noted, in a collective series of 369 patients with clinical stage I carcinoma, that 39 had metastases to the pelvic lymph nodes. In 1976, an initial report from the pilot COG study evaluated 140 patients. Sixteen of these patients had positive lymph nodes [8]. In the final evaluation of 222 patients in the pilot GOG study, as well as the subsequent group protocol of 621 patients, it was noted that 81 of 843 (9.6%) had lymph node metastases. As expected, those patients without lymph node metastases had a very good survival in comparison with those with lymph node metastases (10% and 56%, respectively). Although it has been suggested that paraaortic lymph nodes could be involved in endometrial cancer, until recently there has been very little, if any, data except from
341
autopsy studies. The COG study reported by Boronow et al. in 1985 [9], noted that 16 of 156 stage I patients in whom paraaortic nodes wre removed had metastases. In a subsequent GOG study of 621 patients, 34 had metastases to the paraaortic area. In that study of 621 patients with stage I disease, l l % had metastases to either the pelvic or the paraaortic nodes or both. Other prognostic factors have been suggested by some authors as important. These include spread to the adnexa, uterine tumor size and location, hormone receptors, and the presence or lack of capillary-like space involvement with malignant cells present within the uterus.
CORRELATION OF PROGNOSTIC FACTORS Multiple prognostic factors are important in endometrial cancer. Although several of these have been known for many years and even decades, it was not until the final report of the initial GOG study as well as the preliminary data from the subsequent study that all suggested prognostic factors were evaluated in the same database. In the second GOG study, 621 patients with stage I carcinoma of the endometrium were treated primarily with TAH, BSO, peritoneal cytology, and pelvic and paraaortic selectice lymphadenectomy [7]. The size of the uterus, histology, grade, depth of myometrial invasion, adnexal involvement, peritoneal cytology, and extrauterine disease (intraabdominal) were correlated with both pelvic and paraaortic lymph node metastases. The size of the uterus, grade of tumor, and depth of muscle invasion all correlated with nodal metastases. There were 35 (5%) patients who had adnexal metastases not known before exploratory laparotomy . The likelihood of having disease in the adnexa increased with depth of invasion and when the lower uterine segment and endocervix was involved. The chance of lymph node metastases was greater when disease was present in the lower uterine segment or endocervix compared with those individuals who had disease limited to the fundus. When the six substages of clinical stage I was evaluated, lymph node metastases increased with the grade of the tumor and uterine size. The correlation of prognostic factors and survival has been fully evaluated in the GOG pilot study of 222 patients. When the sites for recurrence were evaluated in this database, only two ( 1 %) of patients had an isolated vault recurrence; one patient had been treated with surgery only, and another had received surgery plus preoperative radium [2]. The data from this study as well as other data in the recent literature suggest that we do very well in regard to local control (i.e., vaginal) in stage I carcinoma of the endometrium irrespective of therapy. It would appear that the vaginal vault is not at high risk of recurrence; therefore, the role of preoperative or postoperative bradytherapy must be questioned. Only five pa-
342
Creasman and Eddy
tients had recurrence identified in the pelvis only. Of the ously indicated, this can be predicted to a certain degree recurrences, 79% were at distant sites outside the treat- and therapy then prescribed accordingly. As a result of these studies, FIGO in 1988 decided that ment field. It is obvious that, if disease is limited to the uterus, the patients do much better; only 7% with uterine endometrial cancer should be a surgically staged cancer. disease developed recurrence compared with 43% with This certainly follows the trend of other gynecological cancers as well as malignancies elsewhere in the body. extrauterine disease present at the time of surgery. It appears from these data that patients with clinical The new staging classification for endometrial cancer is stage I disease could be identified with prognostic factors currently being utilized [lo]. It is hoped that with knowlas being at high risk or low risk for recurrence. These edge of the true extent of the malignant process better studies would therefore suggest that this disease entity therapy can be applied in a more prudent fashion. Using should be staged surgically and not based on clinical this information, true individualization of patient care is information only. Knowing the grade of the tumor, the possible and this is appropriate. chance of deep myometrial invasion, lymph node meREFERENCES tastasis, and recurrence can be projected, and to a certain 1. Pettersson F. (ed): “Annual Report on the Results of Treatment in degree this dictates initial surgical management. In paGynecological Cancer. Stockholm: International Federation of tients with grade l stage I disease, the surgery can be Gynecology and Obstetrics, 1988, 81. 2. DiSaia PJ, Creasman WT, Boronow RC, et al.: Risk factors in limited to peritoneal cytology, total abdominal hysterecrecurrent patterns in stage I endometrial carcinoma. Am J Obstet tomy, and bilateral salpingooophorectomy . Only a small Gynecol 15 1: 1009-1015, 1985. number of grade I patients will have deep myometrial 3 . Javert C, Douglas R: Treatment of endometrial carcinoma. Am J invasion, and those patients can be evaluated intraoperRoentgen01 75:58&587, 1956. 4. Christopherson WM, Connelly PJ, Alberhasky RC: Carcinoma of atively. If deep invasion is present, then selective lymphthe endometrium. Cancer 51:1705-1709, 1983. adenectomy would be advocated by some investigators. 5 . Chnstopherson WN, Alberhasky RC, Connely PJ: Carcinoma of In grade 2 and grade 3 disease, patients are considered to the endometrium. 11. Papillary adenocarcinoma: A clinicopathological study of 46 patients. Am J Clin Pathol 77534540, be at higher risk for lymph node metastases, and it is 1982. suggested that a pelvic and paraaortic selective lymph6. Creasman WT, DiSaia PJ, Blessing J, et al.: Prognostic signifiadenectomy be added to the surgical procedure described cance of peritoneal cytology in patients with endometrial cancer and preliminary data concerning therapy with intraperitoneal rafor grade 1. Postoperative adjunctive therapy if needed diophmaceuticals. Am J Obstet Gynecol 141:921-929, 1981. can then be planned, depending mainly on whether there 7. Creasrnan WT, Morrow CP, Bundy L, et al.: Surgical pathologis intrauterine or extrauterine disease. ical spread patterns of endometrial cancer. Cancer 60:2035-2041, ”
NEW STAGING FOR CORPUS CANCER Probably the most significant recent advance in our knowledge of corpus cancer has been the identification of the true surgical pathological spread pattern of endometrial cancer based on prognostic factors. As previ-
1987. 8. Creasman WT, DiSaia PJ, Boronow RC, et al.: Adenocarcinoma of the endometrium: Its metastatic lymph node potential: A preliminary report. Gynecol Oncol4:239-243, 1976. 9. Boronow RC, Morrow CP, Creasman WT, et al.: Surgical staging in endometrial cancer: Clinical pathological findings of a prospective study. Obstet Gynecol63:825-832, 1985. 10. FIGO Stages, 1988 Revision. Gynecol Oncol35:125-126, 1989.
Recent Advances in Endometrial Cancer WILLIAM T. CREASMAN, MD, AND GARY L. EDDY, MD From the Department of Obstetrics and Gynecology, Medical University of South Carolina, Charleston
There are well-defined prognostic factors that identify patients with clinical stage I (confined to the uterus) endometrial adenocarcinoma and patients at high risk vs. low risk for recurrent disease and allow for treatment tailored to those specific prognostic indicators. This had led the International Federation of Gynecologists and Obstetricians (FIGO) in 1988 to revise the FIGO staging from a clinical to a surgical/histopathological evaluation. The use of these prognostic factors should lead to improved initial surgery and adjuvant therapy for patients considered at high risk for recurrence. KEYWORDS:lymph nodes, staging, peritoneal cytology
INTRODUCTION In the United States today, cancer of the uterine corpus is the most common female pelvic malignancy. The American Cancer Society estimates that approximately 34,000 women will develop uterine cancer this year. This malignancy is almost twice as common as is carcinoma of the ovary and almost three times more common than cervical cancer. Over the last 2 decades there has been a rather marked increase in the incidence of endometrial cancer in the industrial world. In the United States, however, the incidence apparently peaked in the early 1980s. At that time approximately 39,000 new cases were identified, and this has slowly decreased to the current level. Although several factors have been suggested as the reason for the initial increase and then a decrease in the figures, estrogen replacement therapy has been one explanation that has received considerable attention. In the 1970s, the relationship between estrogen and endometrial cancer was described by many investigators. This caused a rather sharp decrease in the prescriptions for estrogen. However, we now appreciate that estrogen plus progesterone actually protects against endometrial cancer, and we have seen a marked increase in estrogen replacement therapy (ERT) in the recent past. Certainly the multiple beneficial effects of ERT, such as prevention of osteoporosis and cardiovascular disease, outweigh any potential detriment in regard to endometrial cancer. Other countries such as Norway and Czechoslovakia have also experienced an increase in the
0 1990 Wiley-Liss, Inc.
incidence of endometrial cancer, yet estrogen was either not available or rarely prescribed in those countries. Since FIGO first suggested a staging classification for endometrial cancer, it has always been a clinically staged entity. The grade of differentiation was used in the subclassification, particularly of stage I. This entity was really the only histopathological criteria used in staging. Clinical staging did include some laboratory parameters such as a chest X-ray. At one time there was even a subgroup classified as “inoperable. Since this disease entity appeared in the older age range, many patients were in fact inoperable. Most of these patients were treated with radiation therapy, and, since hysterectomy was considered an integral part of the therapy for endometrial cancer, these patients were withdrawn from overall statistical considerations in order not to prejudice the results. Since 1971, FIGO staging suggested that stage I should be further delineated using two parameters: one, the depth of the uterine cavity as noted with sounding and, two, the differentiation of the tumor. Therefore, six substages were then identified in stage I. This staging was the one we ‘‘lived with” for essentially the whole of the 1970s and 1980s. The two criteria for inclusion in the substaging within stage I were identified as prognostic factors in this disease entity. In fact, when one evaluates the data in the last Annual Report (1988) published by ”
Address reprint requests to William T. Creasman, MD, Department of Obstetrics and Gynecology, Medical University of South Carolina, 171 Ashley Ave., Charleston, SC 29425.
340
Creasman and Eddy
FIGO (results of treatment around the world), it can be noted that survival does relate to these six substages. Among almost 8,000 patients reported, those individuals with a stage IA G1 cancer had a 78.7% absolute survival compared with 52.7% for a stage IB G3. Those patients with stage IB G3 actually showed worse survival than did patients with stage I1 disease (56%) [ 11.
PROGNOSTIC FACTORS During the last 2 decades there has been a considerable amount of data collected in regard to identification and delineation of prognostic factors in endometrial cancer. These have been identified mainly through two large studies that have been performed by the Gynecologic Oncology Group (GOG) that are being reported. A brief review of suggested prognostic factors follows.
Differentiation Histological differentiation of endometrial cancer has long been recognized as one of the most sensitive indicators of prognosis. As previously noted, this was incorporated in the 1971 staging by FIGO. As the tumor loses its differentiation, the chance for survival decreases. In the GOG pilot study of 222 surgically evaluated clinically stage 1 endometrial cancers, the recurrence rate was only 4% in grade I lesions compared with 15% and 41% in grade I1 and 111, respectively [2]. The data from the last FIGO (1988) Annual Reports show that patients with stage I GI lesions have an 81.6% 5 year survival, grade 11 78.9%, and grade 111 66.3%. The differentiation of the tumor also correlates with other factors of prognosis, such as the depth of myometrial invasion, although some exceptions do exist.
Uterine Size Most studies that have evaluated this factor agree that patients with larger uterine cavities have a poor survival rate; however, some investigators have suggested that this might not be the case. It is appreciated that all enlarged uteri are not the results of increasing amounts of cancer. Other conditions such as fibromyomata and adenomyosis may contribute to uterine enlargement. Javert and Douglas [3], in evaluating hysterectomy specimen of 100 patients with endometrial cancer, noted that about one-half were enlarged, but in only eight was the cancer the cause.
Pathology Adenocarcinoma has been recognized for decades, and variants have been described in the literature for almost a half century. In the 194Os, mixed adenocarcinoma and squamous carcinomas of the uterus were being described. Subsequently, adenoacanthomas were identi-
fied, and these were all recognized entities today. It has been suggested that patients with adenoacanthoma are usually associated with well-differentiated cancers and have characteristics similar to those patients with pure adenocarcinomas. The significance of adenosquamous carcinoma appears still to be the topic for discussion [4]. Some authors have suggested that adenosquamous carcinomas have increased in incidence and appear to be associated with a less differentiated glandular adenocarcinoma. As a result, they usually carry a poorer prognosis than pure adenocarcinomas. Several authors, however, have suggested that the degree of differentiation of adenocarcinoma is the important criteria in adenosquamous carcinoma and not the fact of squamous carcinoma per se being present. More recently, two additional histological variants of adenocarcinoma have been discussed more frequently. Clear cell carcinomas are recognized histologically by their large epithelial cells, which may be admixed with typical nonclear cell carcinomas. Investigators have suggested a worse prognosis for clear cell carcinoma than for pure adenocarcinomas. Because of the small number of these lesions, the exact implication of this finding has not yet been resolved. On the other hand, papillary adenocarcinoma of the endometrium has been known for many years but has only recently received increased attention [ 5 ] . Survival does not appear to be as good as with pure adenocarcinoma but is better than with mixed adenosquamous and clear cell. It has been suggested that there may be two clinical pathological types of papillary adenocarcinoma. The so-called papillary serous carcinomas appear to be present in older patients, have deep myometrial invasion, and have a tendency for extrauterine spread. The mortality therefore is poorer than with patients with pure adenocarcinoma. On the other hand, patients with well-differentiated papillary adenocarcinoma were similar in regard to characteristics and survival in comparison with adenocarcinoma of the endometrium.
Myometrium It is appreciated that the degree of myometrial invasion is an indicator of tumor virulence and volume. As a generalization, the depth of myometrial invasion does correlate with the degree of differentiation; i.e., the depth of penetration increases with the degree of differentiation. It is appreciated that patients with wendifferentiated cancers can have deep myometrial invasion and that those with poorly differentiated cancers can have superficial involvement only. Irrespective of the grade of the tumor, the depth of invasion does appear to be an independent prognostic factor. DiSaia et al. [2], reviewing the survival data of the initial GOG study,
Endometrial Cancer
found that, in patients with stage I endometrial carcinoma of the endometrium, there is only an 8% recurrence rate if endometrium only was involved, but this increased to 46% when deep muscle was invaded.
Peritoneal Cytology It has been suggested that cytological evaluation of the peritoneal fluids or washings is an important prognostic factor in several pelvic malignancies. Over almost 2 decades, several reports have appeared in the literature, and, although it has not been unanimous, the vast majority of studies do suggest that the presence of malignant cells in the peritoneal cytology is a poor prognostic factor. In a preliminary study of 167 patients with clinical stage I carcinoma of the endometrium treated primarily with surgery, it was noted that 26 (15%) had malignant cells present in the peritoneal cytology [6]. Recurrence developed in 10 of these 26 patients (34%) compared with 14 of 141 (10%) patients with negative peritoneal cytology. Thirteen of these twenty-six patients had disease outside of the uterus at the time of surgery, and seven (54%) have died from their disease. Malignant cells were found in the peritoneal cytology of 13 patients but without any disease outside the uterus, and six (46%) have died with disseminated intraabdominal carcinomatosis. In the latter GOG study of 621 patients, 76 (12%) had malignant cells identified by cytological examination of the peritoneal washings. In a multivariant analysis, it was found that malignant cells in peritoneal cytology was an independent important prognostic factor [7]. It has been suggested that intraperitoneal P-32 as treatment for these patients may be efficacious. Lymph Node Metastases For many years, the significance of lymph node metastases was not appreciated, or evaluated, in corpus cancer. When the literature is reviewed, a significant number of women even with stage I endometrial cancers will have pelvic node metastases. In the early 1970s, review of the recent literature noted, in a collective series of 369 patients with clinical stage I carcinoma, that 39 had metastases to the pelvic lymph nodes. In 1976, an initial report from the pilot COG study evaluated 140 patients. Sixteen of these patients had positive lymph nodes [8]. In the final evaluation of 222 patients in the pilot GOG study, as well as the subsequent group protocol of 621 patients, it was noted that 81 of 843 (9.6%) had lymph node metastases. As expected, those patients without lymph node metastases had a very good survival in comparison with those with lymph node metastases (10% and 56%, respectively). Although it has been suggested that paraaortic lymph nodes could be involved in endometrial cancer, until recently there has been very little, if any, data except from
341
autopsy studies. The COG study reported by Boronow et al. in 1985 [9], noted that 16 of 156 stage I patients in whom paraaortic nodes wre removed had metastases. In a subsequent GOG study of 621 patients, 34 had metastases to the paraaortic area. In that study of 621 patients with stage I disease, l l % had metastases to either the pelvic or the paraaortic nodes or both. Other prognostic factors have been suggested by some authors as important. These include spread to the adnexa, uterine tumor size and location, hormone receptors, and the presence or lack of capillary-like space involvement with malignant cells present within the uterus.
CORRELATION OF PROGNOSTIC FACTORS Multiple prognostic factors are important in endometrial cancer. Although several of these have been known for many years and even decades, it was not until the final report of the initial GOG study as well as the preliminary data from the subsequent study that all suggested prognostic factors were evaluated in the same database. In the second GOG study, 621 patients with stage I carcinoma of the endometrium were treated primarily with TAH, BSO, peritoneal cytology, and pelvic and paraaortic selectice lymphadenectomy [7]. The size of the uterus, histology, grade, depth of myometrial invasion, adnexal involvement, peritoneal cytology, and extrauterine disease (intraabdominal) were correlated with both pelvic and paraaortic lymph node metastases. The size of the uterus, grade of tumor, and depth of muscle invasion all correlated with nodal metastases. There were 35 (5%) patients who had adnexal metastases not known before exploratory laparotomy . The likelihood of having disease in the adnexa increased with depth of invasion and when the lower uterine segment and endocervix was involved. The chance of lymph node metastases was greater when disease was present in the lower uterine segment or endocervix compared with those individuals who had disease limited to the fundus. When the six substages of clinical stage I was evaluated, lymph node metastases increased with the grade of the tumor and uterine size. The correlation of prognostic factors and survival has been fully evaluated in the GOG pilot study of 222 patients. When the sites for recurrence were evaluated in this database, only two ( 1 %) of patients had an isolated vault recurrence; one patient had been treated with surgery only, and another had received surgery plus preoperative radium [2]. The data from this study as well as other data in the recent literature suggest that we do very well in regard to local control (i.e., vaginal) in stage I carcinoma of the endometrium irrespective of therapy. It would appear that the vaginal vault is not at high risk of recurrence; therefore, the role of preoperative or postoperative bradytherapy must be questioned. Only five pa-
342
Creasman and Eddy
tients had recurrence identified in the pelvis only. Of the ously indicated, this can be predicted to a certain degree recurrences, 79% were at distant sites outside the treat- and therapy then prescribed accordingly. As a result of these studies, FIGO in 1988 decided that ment field. It is obvious that, if disease is limited to the uterus, the patients do much better; only 7% with uterine endometrial cancer should be a surgically staged cancer. disease developed recurrence compared with 43% with This certainly follows the trend of other gynecological cancers as well as malignancies elsewhere in the body. extrauterine disease present at the time of surgery. It appears from these data that patients with clinical The new staging classification for endometrial cancer is stage I disease could be identified with prognostic factors currently being utilized [lo]. It is hoped that with knowlas being at high risk or low risk for recurrence. These edge of the true extent of the malignant process better studies would therefore suggest that this disease entity therapy can be applied in a more prudent fashion. Using should be staged surgically and not based on clinical this information, true individualization of patient care is information only. Knowing the grade of the tumor, the possible and this is appropriate. chance of deep myometrial invasion, lymph node meREFERENCES tastasis, and recurrence can be projected, and to a certain 1. Pettersson F. (ed): “Annual Report on the Results of Treatment in degree this dictates initial surgical management. In paGynecological Cancer. Stockholm: International Federation of tients with grade l stage I disease, the surgery can be Gynecology and Obstetrics, 1988, 81. 2. DiSaia PJ, Creasman WT, Boronow RC, et al.: Risk factors in limited to peritoneal cytology, total abdominal hysterecrecurrent patterns in stage I endometrial carcinoma. Am J Obstet tomy, and bilateral salpingooophorectomy . Only a small Gynecol 15 1: 1009-1015, 1985. number of grade I patients will have deep myometrial 3 . Javert C, Douglas R: Treatment of endometrial carcinoma. Am J invasion, and those patients can be evaluated intraoperRoentgen01 75:58&587, 1956. 4. Christopherson WM, Connelly PJ, Alberhasky RC: Carcinoma of atively. If deep invasion is present, then selective lymphthe endometrium. Cancer 51:1705-1709, 1983. adenectomy would be advocated by some investigators. 5 . Chnstopherson WN, Alberhasky RC, Connely PJ: Carcinoma of In grade 2 and grade 3 disease, patients are considered to the endometrium. 11. Papillary adenocarcinoma: A clinicopathological study of 46 patients. Am J Clin Pathol 77534540, be at higher risk for lymph node metastases, and it is 1982. suggested that a pelvic and paraaortic selective lymph6. Creasman WT, DiSaia PJ, Blessing J, et al.: Prognostic signifiadenectomy be added to the surgical procedure described cance of peritoneal cytology in patients with endometrial cancer and preliminary data concerning therapy with intraperitoneal rafor grade 1. Postoperative adjunctive therapy if needed diophmaceuticals. Am J Obstet Gynecol 141:921-929, 1981. can then be planned, depending mainly on whether there 7. Creasrnan WT, Morrow CP, Bundy L, et al.: Surgical pathologis intrauterine or extrauterine disease. ical spread patterns of endometrial cancer. Cancer 60:2035-2041, ”
NEW STAGING FOR CORPUS CANCER Probably the most significant recent advance in our knowledge of corpus cancer has been the identification of the true surgical pathological spread pattern of endometrial cancer based on prognostic factors. As previ-
1987. 8. Creasman WT, DiSaia PJ, Boronow RC, et al.: Adenocarcinoma of the endometrium: Its metastatic lymph node potential: A preliminary report. Gynecol Oncol4:239-243, 1976. 9. Boronow RC, Morrow CP, Creasman WT, et al.: Surgical staging in endometrial cancer: Clinical pathological findings of a prospective study. Obstet Gynecol63:825-832, 1985. 10. FIGO Stages, 1988 Revision. Gynecol Oncol35:125-126, 1989.
