GYNECOLOGIC
ONCOLOGY
46,
143-144 (1992)
EDITORIAL The Significance of Positive Peritoneal Cytology in Endometrial Cancer Conflicting results from at least a dozen studies within the past 12 years have made the importance of malignant peritoneal cytology in endometrial cancer a controversial issue. Several reports in the literature have noted increased recurrence rates and decreased survival in patients with malignant peritoneal cytology and on this basis have recommended treatment for positive cytology [l-5]. Other reports, including those by our group at Northwestern, have failed to corroborate these results [6-121. The report by Kadar, Homesley, and Malfetano in this issue provides additional insight into understanding the impact of positive peritoneal cytology in endometrial cancer. In 1981, Creasman et al. [l] reported positive peritoneal cytology in 26 (16%) of 167 patients with clinical stage I adenocarcinoma of the endometrium. Recurrent cancer developed in 10 (38%) of these 26 patients, compared with 14 (10%) of 141 patients with negative cytology. Positive peritoneal cytology was found to be associated with deep myometrial invasion, cervical involvement, adnexal spread, and lymph node metastasis as well as a propensity for intra-abdominal disease recurrence. Several subsequent reports supported the observation that positive peritoneal cytology was associated with an increased risk for cancer recurrence [2-41. Most of these reports included patients with other evidence of extrauterine disease spread without appropriate multivariate analysis or patients who were incompletely staged. The recent Gynecologic Oncology Group study reported by Morrow et al. [5], however, critically analyzed 1180 clinical stage I and II endometrial cancer patients in whom appropriate surgical-pathologic staging was obtained. Considering only the 697 patients with peritoneal cytology information and adequate follow-up, 25 (29%) of 86 patients with positive cytology developed recurrence compared with 64 (10.5%) of 611 patients with negative cytology. They noted that 17 of the 25 recurrences in the positive cytology group were distant rather than regional (abdominal/pelvic). In contrast to these reports, at least six published studies have found no significant relationship between malig-
nant peritoneal cytology and an increased incidence of disease recurrence in early endometrial cancer [6-111. Yazigi et al. [6] found that recurrence rates and survival were comparable with respect to peritoneal cytology status in 93 patients with clinical stage I disease. There was 1 recurrence (10%) among 10 patients with positive cytology, compared with 6 recurrences (7%) among 83 patients with negative cytology. Actuarial survival rates at 10 years were 87.5 and 92.5% for patients with positive and negative cytology, respectively. Likewise, Kennedy et al. [7] failed to identify positive pelvic washings as an important factor in the clinical management of 163 patients with stage I and II endometrial cancer. Both Konski et al. [9] and Grimshaw et al. [lo] found no significant differences in recurrence rates or survival in surgicalpathologic stage I patients with or without positive peritoneal cytology. Our group at Northwestern prospectively evaluated peritoneal cytology in patients with clinical stage I endometrial cancer who underwent primary surgical therapy [ll]. No treatment was directed specifically for positive cytology. Positive cytology was not significantly associated with disease recurrence (P = 0.33). Recurrence developed in 5 (17%) of 30 patients with positive cytology and in 11 (9%) of 127 patients with negative cytology. Of the 5 patients with positive peritoneal cytology who had disease recurrence, only 1 recurrence arose within the peritoneal cavity. Patients with malignant washings often did have other poor prognostic factors. Thirty-seven percent had deep myometrial invasion, 37% had grade 3 tumors, and 17% had positive lymph nodes. None of the patients with positive cytology but without other poor prognostic factors developed disease recurrence. In a more recent study, we confirmed by multivariate analysis that positive peritoneal cytology was not an independent prognostic factor for endometrial cancer recurrence [12]. Only 6 (22%) of the 27 patients with positive cytology as their only evidence of extrauterine disease spread suffered recurrence despite no therapy directed toward this finding. Kadar et al. found positive peritoneal cytology in 12.6% of 269 surgically staged patients with clinical stage I and
143 CWO-8258/92$4.00 Copyright 0 1992 by Academic Press, Inc. All rights of reproduction in any form reserved.
144
EDITORIAL
II endometrial carcinoma. Only 1 of the 34 patients received treatment directed specifically against the positive cytology. They noted more grade 3 tumors (41% versus 19%), vascular invasion (18% versus 6%), adnexal spread (18% versus 4%), lymph node metastasis (29% versus 8%), and peritoneal spread (18% versus 2%), as well as an overall higher recurrence rate (47% versus ll%), in patients with positive peritoneal cytology. Positive peritoneal cytology did not, however, significantly influence survival if disease was otherwise confined to the uterus, exceeding 90% at 5 years. The source and clinical significance of malignant peritoneal cytology in patients with early endometrial adenocarcinoma has, therefore, not yet been completely defined. It has been postulated that the presence of malignant cells within the peritoneal cavity of patients with endometrial cancer in the absence of extrauterine disease may be the result of transtubal transport, multifocal disease arising from peritoneal mesothelium, or direct extension of tumor through the myometrium or via serosal lymphatics into the peritoneal cavity in patients with deep myometrial invasion. Each of these proposed mechanisms of spread may have far different prognostic and therapeutic implications. Kadar and colleagues found that positive peritoneal cytology had an adverse effect on survival only if the endometrial cancer had spread to the adnexa, peritoneum, or lymph nodes, but not if disease was otherwise confined to the uterus. This finding suggests that not all cells found within the peritoneal cavity are capable of independent growth and metastasis, but that positive peritoneal cytology associated with other demonstrable disease outside the uterus is a marker for an aggressive type of metastasizing tumor and bodes a worse prognosis. From the foregoing discussion, the following conclusions regarding positive peritoneal cytology in endometrial cancer may be reached: (1) Positive peritoneal cytology is associated with other known poor prognostic factors such as grade 3 histology, deep myometrial invasion, and other evidence of extrauterine disease spread. (2) Positive peritoneal cytology without other evidence of disease spread outside of the uterus and/or in the absence of other poor prognostic factors probably has no significant effect on recurrence and survival. (3) Positive peritoneal cytology when associated with other poor prognostic factors and/or extrauterine disease increases the likelihood for distant as well as intra-abdominal disease recurrence and has a significant adverse effect on survival. (4) Use of several different therapeutic modalities has not resulted in any proven benefit to patients with endometrial cancer and positive peritoneal cytology. Most
reports, including that of Kadar et al. show no benefit to treating positive cytology in the absence of other evidence of extrauterine disease. On the other hand, patients with extrauterine disease and positive cytology have a very poor prognosis with a propensity for distant spread and should receive systemic therapy. REFERENCES 1.
Creasman,W. T., DiSaia, P. J., Blessing, J., Wilkinson, R. H.,
Jr., Johnston, W., and Weed, J. C., Jr. Prognostic significance of peritoneal cytology in patients with endometrial cancer and preliminary data concerning therapy with intraperitoneal radiopharmaceuticals, Am. J. Obstet. Gynecol. 141, 921-927 (1981). 2. Mazurka, J. L., Krepart, G. V., and Lotocki, R. J. Prognostic significance of positive peritoneal cytology in endometrial carcinoma, Am. J. Obstet. Gynecol. 158, 303-306 (1988). 3. Harouny, V. R., Sutton, G. P., Clark, S. A., Geisler, H. E., Stehman, F. B., and Ehrlich, C. E. The importance of peritoneal cytology in endometrial carcinoma, Obstet. Gynecol. 72, 394-398 (1988). 4. Turner, D. A., Gershenson, D. M., Atkinson, N., Sneige, N., and Wharton, A. T. The prognostic significance of peritoneal cytology for stage I endometrial cancer, Obstet. Gynecol. 74,775780 (1989). 5. Morrow, C. P., Bundy, B. N., Kurman, R. J., Creasman, W. T., Heller, P., Homesley, H. D., and Graham, J. E. Relationship between surgical-pathological risk factors and outcome in clinical stage I and II carcinoma of the endometrium: A Gynecologic Oncology Group study, Gynecol. Oncol. 40, 55-60 (1991). 6. Yazigi, R., Piver, M. S., and Blumenson, L. Malignant peritoneal cytology as prognostic indicator in stage I endometrial cancer, Obstet. Gynecul. 62, 359-362 (1983). 7. Kennedy, A. W., Peterson, G. L., Becker, S. N., Nunez, C., and Webster, K. D. Experience with pelvic washings in stage I and II endometrial carcinoma, Gynecol. Oncol. 28, 50-60 (1987). 8. Imachi, J., Tsukamoto, N., Matsuyama, T., and Nakano, H. Peritoneal cytology in patients with endometrial carcinoma, Gynecol. Oncol. 30, 76-86 (1988). 9. Konski, A., Poulter, C., Keys, H., Rubin, P., Beecham, J., and Doane, K. Absence of prognostic significance, peritoneal dissemination and treatment advantage in endometrial cancer patients with positive peritoneal cytology, Int. J. Radiut. Oncol. Bid. Phys. 4, 49-55 (1988). 10. Grimshaw, R. N., Tupper, W. C., Fraser, R. C., Tompkins, M. G., and Jeffrey, J. F. Prognostic value of peritoneal cytology in endometrial cancer, Gynecol. Oncol. 36, 97-100 (1990). 11. Lurain, J. R., Rumsey, N. K., Schink, J. C., Wallemark, C. B., and Chmiel, J. S. Prognostic significance of positive peritoneal cytology in clinical stage I adenocarcinoma of the endometrium, Obstet. Gynecol. 74, 175-179 (1989). 12. Lurain, J. R., Rice, B. L., Rademaker, A. W., Poggensee, L. E., Schink, J. C., and Miller, D. S. Prognostic factors associated with recurrence in clinical stage I adenocarcinoma of the endometrium, Obstet. Gynecol. 78, 63-69 (1991).
John R. Lurain, Department of Obstetrics and Gynecology Northwestern University Medical School Chicago, Illinois 60611
M.D.
ONCOLOGY
46,
143-144 (1992)
EDITORIAL The Significance of Positive Peritoneal Cytology in Endometrial Cancer Conflicting results from at least a dozen studies within the past 12 years have made the importance of malignant peritoneal cytology in endometrial cancer a controversial issue. Several reports in the literature have noted increased recurrence rates and decreased survival in patients with malignant peritoneal cytology and on this basis have recommended treatment for positive cytology [l-5]. Other reports, including those by our group at Northwestern, have failed to corroborate these results [6-121. The report by Kadar, Homesley, and Malfetano in this issue provides additional insight into understanding the impact of positive peritoneal cytology in endometrial cancer. In 1981, Creasman et al. [l] reported positive peritoneal cytology in 26 (16%) of 167 patients with clinical stage I adenocarcinoma of the endometrium. Recurrent cancer developed in 10 (38%) of these 26 patients, compared with 14 (10%) of 141 patients with negative cytology. Positive peritoneal cytology was found to be associated with deep myometrial invasion, cervical involvement, adnexal spread, and lymph node metastasis as well as a propensity for intra-abdominal disease recurrence. Several subsequent reports supported the observation that positive peritoneal cytology was associated with an increased risk for cancer recurrence [2-41. Most of these reports included patients with other evidence of extrauterine disease spread without appropriate multivariate analysis or patients who were incompletely staged. The recent Gynecologic Oncology Group study reported by Morrow et al. [5], however, critically analyzed 1180 clinical stage I and II endometrial cancer patients in whom appropriate surgical-pathologic staging was obtained. Considering only the 697 patients with peritoneal cytology information and adequate follow-up, 25 (29%) of 86 patients with positive cytology developed recurrence compared with 64 (10.5%) of 611 patients with negative cytology. They noted that 17 of the 25 recurrences in the positive cytology group were distant rather than regional (abdominal/pelvic). In contrast to these reports, at least six published studies have found no significant relationship between malig-
nant peritoneal cytology and an increased incidence of disease recurrence in early endometrial cancer [6-111. Yazigi et al. [6] found that recurrence rates and survival were comparable with respect to peritoneal cytology status in 93 patients with clinical stage I disease. There was 1 recurrence (10%) among 10 patients with positive cytology, compared with 6 recurrences (7%) among 83 patients with negative cytology. Actuarial survival rates at 10 years were 87.5 and 92.5% for patients with positive and negative cytology, respectively. Likewise, Kennedy et al. [7] failed to identify positive pelvic washings as an important factor in the clinical management of 163 patients with stage I and II endometrial cancer. Both Konski et al. [9] and Grimshaw et al. [lo] found no significant differences in recurrence rates or survival in surgicalpathologic stage I patients with or without positive peritoneal cytology. Our group at Northwestern prospectively evaluated peritoneal cytology in patients with clinical stage I endometrial cancer who underwent primary surgical therapy [ll]. No treatment was directed specifically for positive cytology. Positive cytology was not significantly associated with disease recurrence (P = 0.33). Recurrence developed in 5 (17%) of 30 patients with positive cytology and in 11 (9%) of 127 patients with negative cytology. Of the 5 patients with positive peritoneal cytology who had disease recurrence, only 1 recurrence arose within the peritoneal cavity. Patients with malignant washings often did have other poor prognostic factors. Thirty-seven percent had deep myometrial invasion, 37% had grade 3 tumors, and 17% had positive lymph nodes. None of the patients with positive cytology but without other poor prognostic factors developed disease recurrence. In a more recent study, we confirmed by multivariate analysis that positive peritoneal cytology was not an independent prognostic factor for endometrial cancer recurrence [12]. Only 6 (22%) of the 27 patients with positive cytology as their only evidence of extrauterine disease spread suffered recurrence despite no therapy directed toward this finding. Kadar et al. found positive peritoneal cytology in 12.6% of 269 surgically staged patients with clinical stage I and
143 CWO-8258/92$4.00 Copyright 0 1992 by Academic Press, Inc. All rights of reproduction in any form reserved.
144
EDITORIAL
II endometrial carcinoma. Only 1 of the 34 patients received treatment directed specifically against the positive cytology. They noted more grade 3 tumors (41% versus 19%), vascular invasion (18% versus 6%), adnexal spread (18% versus 4%), lymph node metastasis (29% versus 8%), and peritoneal spread (18% versus 2%), as well as an overall higher recurrence rate (47% versus ll%), in patients with positive peritoneal cytology. Positive peritoneal cytology did not, however, significantly influence survival if disease was otherwise confined to the uterus, exceeding 90% at 5 years. The source and clinical significance of malignant peritoneal cytology in patients with early endometrial adenocarcinoma has, therefore, not yet been completely defined. It has been postulated that the presence of malignant cells within the peritoneal cavity of patients with endometrial cancer in the absence of extrauterine disease may be the result of transtubal transport, multifocal disease arising from peritoneal mesothelium, or direct extension of tumor through the myometrium or via serosal lymphatics into the peritoneal cavity in patients with deep myometrial invasion. Each of these proposed mechanisms of spread may have far different prognostic and therapeutic implications. Kadar and colleagues found that positive peritoneal cytology had an adverse effect on survival only if the endometrial cancer had spread to the adnexa, peritoneum, or lymph nodes, but not if disease was otherwise confined to the uterus. This finding suggests that not all cells found within the peritoneal cavity are capable of independent growth and metastasis, but that positive peritoneal cytology associated with other demonstrable disease outside the uterus is a marker for an aggressive type of metastasizing tumor and bodes a worse prognosis. From the foregoing discussion, the following conclusions regarding positive peritoneal cytology in endometrial cancer may be reached: (1) Positive peritoneal cytology is associated with other known poor prognostic factors such as grade 3 histology, deep myometrial invasion, and other evidence of extrauterine disease spread. (2) Positive peritoneal cytology without other evidence of disease spread outside of the uterus and/or in the absence of other poor prognostic factors probably has no significant effect on recurrence and survival. (3) Positive peritoneal cytology when associated with other poor prognostic factors and/or extrauterine disease increases the likelihood for distant as well as intra-abdominal disease recurrence and has a significant adverse effect on survival. (4) Use of several different therapeutic modalities has not resulted in any proven benefit to patients with endometrial cancer and positive peritoneal cytology. Most
reports, including that of Kadar et al. show no benefit to treating positive cytology in the absence of other evidence of extrauterine disease. On the other hand, patients with extrauterine disease and positive cytology have a very poor prognosis with a propensity for distant spread and should receive systemic therapy. REFERENCES 1.
Creasman,W. T., DiSaia, P. J., Blessing, J., Wilkinson, R. H.,
Jr., Johnston, W., and Weed, J. C., Jr. Prognostic significance of peritoneal cytology in patients with endometrial cancer and preliminary data concerning therapy with intraperitoneal radiopharmaceuticals, Am. J. Obstet. Gynecol. 141, 921-927 (1981). 2. Mazurka, J. L., Krepart, G. V., and Lotocki, R. J. Prognostic significance of positive peritoneal cytology in endometrial carcinoma, Am. J. Obstet. Gynecol. 158, 303-306 (1988). 3. Harouny, V. R., Sutton, G. P., Clark, S. A., Geisler, H. E., Stehman, F. B., and Ehrlich, C. E. The importance of peritoneal cytology in endometrial carcinoma, Obstet. Gynecol. 72, 394-398 (1988). 4. Turner, D. A., Gershenson, D. M., Atkinson, N., Sneige, N., and Wharton, A. T. The prognostic significance of peritoneal cytology for stage I endometrial cancer, Obstet. Gynecol. 74,775780 (1989). 5. Morrow, C. P., Bundy, B. N., Kurman, R. J., Creasman, W. T., Heller, P., Homesley, H. D., and Graham, J. E. Relationship between surgical-pathological risk factors and outcome in clinical stage I and II carcinoma of the endometrium: A Gynecologic Oncology Group study, Gynecol. Oncol. 40, 55-60 (1991). 6. Yazigi, R., Piver, M. S., and Blumenson, L. Malignant peritoneal cytology as prognostic indicator in stage I endometrial cancer, Obstet. Gynecul. 62, 359-362 (1983). 7. Kennedy, A. W., Peterson, G. L., Becker, S. N., Nunez, C., and Webster, K. D. Experience with pelvic washings in stage I and II endometrial carcinoma, Gynecol. Oncol. 28, 50-60 (1987). 8. Imachi, J., Tsukamoto, N., Matsuyama, T., and Nakano, H. Peritoneal cytology in patients with endometrial carcinoma, Gynecol. Oncol. 30, 76-86 (1988). 9. Konski, A., Poulter, C., Keys, H., Rubin, P., Beecham, J., and Doane, K. Absence of prognostic significance, peritoneal dissemination and treatment advantage in endometrial cancer patients with positive peritoneal cytology, Int. J. Radiut. Oncol. Bid. Phys. 4, 49-55 (1988). 10. Grimshaw, R. N., Tupper, W. C., Fraser, R. C., Tompkins, M. G., and Jeffrey, J. F. Prognostic value of peritoneal cytology in endometrial cancer, Gynecol. Oncol. 36, 97-100 (1990). 11. Lurain, J. R., Rumsey, N. K., Schink, J. C., Wallemark, C. B., and Chmiel, J. S. Prognostic significance of positive peritoneal cytology in clinical stage I adenocarcinoma of the endometrium, Obstet. Gynecol. 74, 175-179 (1989). 12. Lurain, J. R., Rice, B. L., Rademaker, A. W., Poggensee, L. E., Schink, J. C., and Miller, D. S. Prognostic factors associated with recurrence in clinical stage I adenocarcinoma of the endometrium, Obstet. Gynecol. 78, 63-69 (1991).
John R. Lurain, Department of Obstetrics and Gynecology Northwestern University Medical School Chicago, Illinois 60611
M.D.
