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Is omentectomy mandatory in the operation for ovarian cancer? Preliminary results in a rat study
European Journal of Obstetrics & Gynecology and Reproductive Biology 164 (2012) 89–92
Contents lists available at SciVerse ScienceDirect
European Journal of Obstetrics & Gynecology and Reproductive Biology journal homepage: www.elsevier.com/locate/ejogrb
Is omentectomy mandatory in the operation for ovarian cancer? Preliminary results in a rat study Yoshihito Yokoyama *, Hachidai Hirakawa, Hui Wang, Hideki Mizunuma Department of Obstetrics and Gynecology, Hirosaki University Graduate School of Medicine, 5-Zaifu-cho, Hirosaki 036-8562, Japan
A R T I C L E I N F O
A B S T R A C T
Article history: Received 29 October 2011 Received in revised form 20 February 2012 Accepted 5 May 2012
Objective: To investigate whether omentectomy is required in the operation for ovarian cancer, in particular at the early stage. Study design: F344 nude rats were divided into two groups: one in which laparotomy and omentectomy were performed (primary omentectomy group, n = 6) and one without omentectomy (n = 12). Concurrently, DISS cells derived from ovarian cancer were transplanted intraperitoneally. After three weeks, the 12 rats without omentectomy were divided into two more groups: one in which the omentum was resected together with the tumor (sham operation/omentectomy group, n = 6) and one without omentectomy (sham operation alone group, n = 6). Results: The survival of the sham operation alone group was shortest with a median of 35 days, while the median of the primary omentectomy group was 42 days. In the sham operation/omentectomy group, four rats survived beyond Day 90, which was significant compared with other two groups. The intraperitoneal findings in the primary omentectomy group revealed extensive disseminated foci on the mesentery and under the abdominal wall. The sham operation alone group was characterized by jaundice resulting from the compression of the biliary system at the liver hilum by the omental mass. Disseminated foci were not observed in the peritoneal cavity from the sham operation/omentectomy group. Conclusions: This study suggests the possibility that the omentum has a role in capturing cancer cells and suppressing further peritoneal dissemination. Therefore, although omentectomy is rewarding if disseminated foci are present in the omentum, it is suggested that the timing of omentectomy requires reconsideration in the absence of omental metastasis. ß 2012 Elsevier Ireland Ltd. All rights reserved.
Keywords: Ovarian cancer Timing of omentectomy Dissemination Survival
1. Introduction Because the diameter of a residual tumor correlates closely with the prognosis in stages III–IV advanced epithelial ovarian cancer, surgeons aim to perform a complete operation that does not leave any gross residual tumor. Omental metastasis occurs in 70–80% of advanced ovarian cancer cases and omentectomy is considered as a procedure required to achieve a complete operation in the advanced stages. However, the guideline of the International Federation of Gynecology and Obstetrics recommends omentectomy at the first operation for the purpose of reasonable staging even if clinical stage I is speculated [1], and
* Corresponding author at: Department of Obstetrics and Gynecology, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki, Aomori 036-8562, Japan. Tel.: +81 172 39 5107; fax: +81 172 37 6842. E-mail address: [email protected] (Y. Yokoyama). 0301-2115/$ – see front matter ß 2012 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ejogrb.2012.05.020
omentectomy is recognized as one of the standard procedures for ovarian cancer. The omentum is a peritoneal organ that hangs inferiorly from the greater curvature of the stomach to the front of the transverse colon. The omentum is thin and translucent in the early stage of development, but gradually becomes yellow-brown because adipose tissue, lymphocytes, and plasma cells accumulate toward the blood vessels that run in the membranous connective tissue. The omentum wraps the source of inflammation and prevents it spreading over the entire peritoneal cavity. It has been shown that resection of the omentum in rodents results in collapse of the protection against intraperitoneal inflammation [2]. Moreover, the omentum is suggested to have a protective function against fibrous peritoneal adhesions [3]. Hence, the omentum plays an important role in the immunological defence mechanism of the organism. Furthermore, the omentum contains a large number of so-called milky spots, which are rich in macrophages and lymphocytes, and it is said that omental immune cells such as macrophages and
90
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lymphocytes have a function of attacking cytotoxically and capturing tumor cells in the peritoneal cavity [4]. It is believed that the omentum may have a role of local prevention against peritoneal dissemination. Thus, omentectomy in theory possibly weakens protection against exfoliated tumor cells. Is omentectomy mandatory in the operation for ovarian cancer? This question was addressed by using a rat model of carcinomatous peritonitis.
2. Materials and methods 2.1. Animals This study protocol was approved by the Committee for Animal Research of Hirosaki University and conducted in accordance with the Guidelines for Animal Experimentation, Hirosaki University. Eight-week-old female F344 rnu/rnu rats weighing 180–200 g were used in this study. All rats were group housed in plastic cages with stainless-steel grid tops in an air-conditioned and 12 h–lightdark–cycle–maintained room and fed with water and food ad libitum in the Institute for Animal Experiments of Hirosaki University. 2.2. Cell line and cell culture DISS was kindly provided by Dr. Saga (Jichi Medical School, Tochigi, Japan). This cell line was derived from human epithelial ovarian adenocarcinoma, grown in RPMI 1640 medium supplemented with 10% fetal bovine serum (FBS), 100 U/ml penicillin and 100 mg/ml streptomycin at 37 8C in a water-saturated atmosphere with 5% CO2/95% air [5]. 2.3. Study design Firstly, the rats were divided into two groups: one in which laparotomy and omentectomy were performed (primary omentectomy group, n = 6) and one in which laparotomy but not omentectomy was performed (sham operation group, n = 12). During the operation, DISS cells were transplanted intraperitoneally to all 18 rats at a concentration of 1 106 cells/ml. After three weeks, the 12 rats without omentectomy were further divided into two groups: one in which the omentum with tumor was resected (sham operation/omentectomy group, n = 6) and one without omentectomy (sham operation alone group, n = 6). Survival was compared among the three groups and the characteristics of the intraperitoneal disseminated foci were observed.
3. Results 3.1. Comparison of survival The survival of the sham operation alone group was shortest with a median of 35 days (28–37 days), while the median of the primary omentectomy group was 42 days (39–54 days) (p < 0.005) (Fig. 1). Two rats in the sham operation/omentectomy group died on Day 42 while the remaining four rats survived until Day 90, the day on which the observation was terminated (p < 0.005 as compared with the sham operation alone group and p < 0.01 as compared with the primary omentectomy group) (Fig. 1). 3.2. Intraperitoneal findings The intraperitoneal findings in the groups that were examined three weeks after intraperitoneal administration of cancer cells and conservation of the omentum (sham operation/omentectomy group and sham operation alone group) demonstrated that the tumor was restricted to the omentum without obvious dissemination to the mesentery (Fig. 2A). The intraperitoneal findings in the primary omentectomy group revealed extensive disseminated foci on the mesentery and under the abdominal wall (Fig. 2B). By the end the sham operation alone group showed only development of the omental mass and was characterized by jaundice resulting from the compression of the biliary system at the liver hilum (Fig. 2C). Disseminated foci were not observed in the peritoneal cavity of the rats from the sham operation/omentectomy group that survived for a long period (Fig. 2D), indicating that the omentum caught all cancer cells. 4. Comment When cancer cells were transplanted intraperitoneally to the rats subjected to omentectomy, the foci disseminated extensively on the mesentery and under the abdominal wall, but the intraperitoneal findings in the rats whose omentum was conserved demonstrated that the tumor was restricted to the omentum after the transplantation of the cancer cells. This result clearly indicates that the omentum plays an important role in capturing intraperitoneal cancer cells. The present results, which show the shortest survival in the primary omentectomy group, raise the question of
2.4. Omentectomy and sham operation Laparotomy was performed under pentobarbital anesthesia and sterile conditions. The omentum was reached via a 4-cm midline incision in the abdomen and subsequently extirpated by ligating the gastroepiploic vessels and hilum of the spleen. Sham operation was done by a similar incision. After hemostasis, the abdominal wall was closed in two layers using 3/0 polyglactin (Vicryl1, Ethicon, Tokyo, Japan). No animal died as a result of the operative procedure. 2.5. Statistical analysis The survival curves were calculated by the Kaplan–Meier method, and the statistical significance of differences in the cumulative survival curves between the groups was evaluated by logrank test. A result was deemed significant at P < 0.05.
Fig. 1. Comparison of survival. The sham operation/omentectomy group survived significantly longer than the sham operation alone group and the primary omentectomy group (p < 0.005 and p < 0.01, respectively). There is also a significant difference in survival period between the sham operation alone group and the primary omentectomy group (p < 0.005).
Y. Yokoyama et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 164 (2012) 89–92
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Fig. 2. The intraperitoneal findings in each group. (A) The intraperitoneal findings in the sham operation/omentectomy group three weeks after intraperitoneal administration of cancer cells. The tumor was restricted to the omentum without obvious dissemination to the mesentery. (B) The intraperitoneal findings in the primary omentectomy group. Arrows indicate disseminated foci on the mesentery and under the abdominal wall. (C) The intraperitoneal finding in the sham operation alone group. Only development of the omental mass was shown. The finding was characterized by jaundice resulting from the compression of the biliary system at the liver hilum. (D) The peritoneal cavity of the rat from the sham operation/omentectomy group that survived for a long period. Disseminated foci are not observed.
whether omentectomy should be included in the initial standard procedure even in cases of epithelial ovarian cancer restricted to the pelvis. Oosterling et al. [6] have demonstrated that the proliferation of an omental tumor is formed mainly at the liver hilum, which is the gateway to the portal vein, hepatic artery, and bile duct. The present study confirmed this and further revealed that dissemination on the mesentery and under the abdominal wall and diaphragm was not evident even when the omental tumor was advanced, suggesting that the cause of death by omental tumor may be attributed to liver dysfunction. With regard to tumor toxic effects of the omentum, Koenen et al. [4] reported that the addition of granulocyte/macrophagecolony-stimulating factor (GM-CSF) to the macrophages isolated from the so-called omental milky spot potentiates the cytotoxicity against tumor cells, and showed that the administration of GM-CSF into the rat peritoneal cavity enhances the antitumor effect of milky spot macrophages and increases the population, suggesting that omental macrophages have an important role in inhibiting intraperitoneal cancer proliferation. On the other hand, Oosterling et al. [6] have shown that omental milky spots are insufficient to prevent peritoneal tumor outgrowth of the minimal residual lesion, and recommended omentectomy in surgical treatment of intra-abdominal tumors that are prone to disseminate intraperitoneally. They have also demonstrated, however, that intraperitoneally injected tumor cells predominantly adhered on the milky spots and the number of cells thereafter declined, suggesting that the omentum efficiently captures tumor cells that are floating in
the abdominal cavity [6]. Accordingly, if the omentum has such a function, it is relevant to delay omentectomy until floating tumor cells are maximally captured by the omentum. Why has omentectomy been included in the standard procedures for ovarian cancer, in particular early stages? To the best of our knowledge, omentectomy is required for determining stages and there has been no randomized controlled trial which has proved that omental resection correlates with the prognosis of ovarian cancer. In a recent retrospective analysis of 211 apparent early stage epithelial ovarian cancers, only 2% (4/196) were upstaged due to omental biopsy, suggesting that random peritoneal biopsy including omentum has limited value in staging of apparent early stage epithelial ovarian cancer after thorough exploration [7]. Trimbos et al. [8] showed in a randomized clinical trial that optimal surgery and appropriate adjuvant chemotherapy had significantly improved the prognosis of early-stage ovarian cancers. In that study, infracolic omentectomy was included in optimal surgery and was performed in 90% of patients. That study, however, was not designed to clarify the effect of omentectomy on prognosis, and whether omentectomy at an early stage of ovarian cancer improves the prognosis remains unclear. Omentectomy may be mandatory for assessing clinical stage at the present time, but the results of the present study revealed for the first time that omentectomy at an early stage adversely affects the prognosis. Although the present study could not show the appropriate timing for omentectomy, it casts doubt on its routine performance in cases of early-stage ovarian cancer. We propose that omentectomy should be restricted in early-stage ovarian
Y. Yokoyama et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 164 (2012) 89–92
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cancer unless macroscopic dissemination is present, and that omentectomy should be done secondarily as necessary. Partial omentectomy for microscopic stating may be another option. Conflict of interest
[2]
[3] [4]
The authors report no conflicts of interest. Acknowledgments This study was supported by a Grant-in Aid for Cancer Research (No. 20591935) from the Ministry of Education, Science and Culture of Japan and by the Karoji Memorial Fund of the Hirosaki University Graduate School of Medicine. References [1] Benedet JL, Bender H, Jones III H, et al. FIGO staging classifications and clinical practice guidelines in the management of gynecologic cancers. FIGO committee
[5]
[6]
[7]
[8]
on gynecologic oncology. International Journal of Gynaecology and Obstetrics 2000;70:209–62. Agca B, Paksoy M, Polat E, et al. Influence of omentectomy on peritoneal defense mechanisms in an experimental model of intra-abdominal infection. European Surgical Research 2003;35:35–40. Cerci C, Eroglu E, Sutcu R, et al. Effects of omentectomy on the peritoneal fibrinolytic system. Surgery Today 2008;38:711–5. Koenen HJPM, Smit MJ, Simmelink MMJA, et al. Effect of intraperitoneal administration of granulocyte/macrophage-colony-stimulating factor in rats on omental milky-spot composition and tumoricidal activity in vivo and in vitro. Cancer Immunology Immunotherapy 1996;42:310–6. Yokoyama Y, Xin B, Shigeto T, et al. Clofibric acid, a peroxisome proliferatoractivated receptor a ligand, inhibits growth of human ovarian cancer. Molecular Cancer Therapeutics 2007;6:1379–86. Oosterling SJ, van der Bij GJ, Bo¨gels M, et al. Insufficient ability of omental milky spots to prevent peritoneal tumor outgrowth supports omentectomy in minimal residual disease. Cancer Immunology Immunotherapy 2006;55:1043–51. Powless CA, Bakkum-Gamez JN, Aletti GD, et al. Random peritoneal biopsies have limited value in staging of apparent early stage epithelial ovarian cancer after thorough exploration. Gynecologic Oncology 2009;115:86–9. Trimbos JB, Vergote I, Bolis G, et al. Impact of adjuvant chemotherapy and surgical staging inn early-stage ovarian carcinoma: European organisation for research and treatment of cancer-adjuvant chemotherapy in ovarian neoplasm trial. Journal of the National Cancer Institute 2003;95:113–25.
Contents lists available at SciVerse ScienceDirect
European Journal of Obstetrics & Gynecology and Reproductive Biology journal homepage: www.elsevier.com/locate/ejogrb
Is omentectomy mandatory in the operation for ovarian cancer? Preliminary results in a rat study Yoshihito Yokoyama *, Hachidai Hirakawa, Hui Wang, Hideki Mizunuma Department of Obstetrics and Gynecology, Hirosaki University Graduate School of Medicine, 5-Zaifu-cho, Hirosaki 036-8562, Japan
A R T I C L E I N F O
A B S T R A C T
Article history: Received 29 October 2011 Received in revised form 20 February 2012 Accepted 5 May 2012
Objective: To investigate whether omentectomy is required in the operation for ovarian cancer, in particular at the early stage. Study design: F344 nude rats were divided into two groups: one in which laparotomy and omentectomy were performed (primary omentectomy group, n = 6) and one without omentectomy (n = 12). Concurrently, DISS cells derived from ovarian cancer were transplanted intraperitoneally. After three weeks, the 12 rats without omentectomy were divided into two more groups: one in which the omentum was resected together with the tumor (sham operation/omentectomy group, n = 6) and one without omentectomy (sham operation alone group, n = 6). Results: The survival of the sham operation alone group was shortest with a median of 35 days, while the median of the primary omentectomy group was 42 days. In the sham operation/omentectomy group, four rats survived beyond Day 90, which was significant compared with other two groups. The intraperitoneal findings in the primary omentectomy group revealed extensive disseminated foci on the mesentery and under the abdominal wall. The sham operation alone group was characterized by jaundice resulting from the compression of the biliary system at the liver hilum by the omental mass. Disseminated foci were not observed in the peritoneal cavity from the sham operation/omentectomy group. Conclusions: This study suggests the possibility that the omentum has a role in capturing cancer cells and suppressing further peritoneal dissemination. Therefore, although omentectomy is rewarding if disseminated foci are present in the omentum, it is suggested that the timing of omentectomy requires reconsideration in the absence of omental metastasis. ß 2012 Elsevier Ireland Ltd. All rights reserved.
Keywords: Ovarian cancer Timing of omentectomy Dissemination Survival
1. Introduction Because the diameter of a residual tumor correlates closely with the prognosis in stages III–IV advanced epithelial ovarian cancer, surgeons aim to perform a complete operation that does not leave any gross residual tumor. Omental metastasis occurs in 70–80% of advanced ovarian cancer cases and omentectomy is considered as a procedure required to achieve a complete operation in the advanced stages. However, the guideline of the International Federation of Gynecology and Obstetrics recommends omentectomy at the first operation for the purpose of reasonable staging even if clinical stage I is speculated [1], and
* Corresponding author at: Department of Obstetrics and Gynecology, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki, Aomori 036-8562, Japan. Tel.: +81 172 39 5107; fax: +81 172 37 6842. E-mail address: [email protected] (Y. Yokoyama). 0301-2115/$ – see front matter ß 2012 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ejogrb.2012.05.020
omentectomy is recognized as one of the standard procedures for ovarian cancer. The omentum is a peritoneal organ that hangs inferiorly from the greater curvature of the stomach to the front of the transverse colon. The omentum is thin and translucent in the early stage of development, but gradually becomes yellow-brown because adipose tissue, lymphocytes, and plasma cells accumulate toward the blood vessels that run in the membranous connective tissue. The omentum wraps the source of inflammation and prevents it spreading over the entire peritoneal cavity. It has been shown that resection of the omentum in rodents results in collapse of the protection against intraperitoneal inflammation [2]. Moreover, the omentum is suggested to have a protective function against fibrous peritoneal adhesions [3]. Hence, the omentum plays an important role in the immunological defence mechanism of the organism. Furthermore, the omentum contains a large number of so-called milky spots, which are rich in macrophages and lymphocytes, and it is said that omental immune cells such as macrophages and
90
Y. Yokoyama et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 164 (2012) 89–92
lymphocytes have a function of attacking cytotoxically and capturing tumor cells in the peritoneal cavity [4]. It is believed that the omentum may have a role of local prevention against peritoneal dissemination. Thus, omentectomy in theory possibly weakens protection against exfoliated tumor cells. Is omentectomy mandatory in the operation for ovarian cancer? This question was addressed by using a rat model of carcinomatous peritonitis.
2. Materials and methods 2.1. Animals This study protocol was approved by the Committee for Animal Research of Hirosaki University and conducted in accordance with the Guidelines for Animal Experimentation, Hirosaki University. Eight-week-old female F344 rnu/rnu rats weighing 180–200 g were used in this study. All rats were group housed in plastic cages with stainless-steel grid tops in an air-conditioned and 12 h–lightdark–cycle–maintained room and fed with water and food ad libitum in the Institute for Animal Experiments of Hirosaki University. 2.2. Cell line and cell culture DISS was kindly provided by Dr. Saga (Jichi Medical School, Tochigi, Japan). This cell line was derived from human epithelial ovarian adenocarcinoma, grown in RPMI 1640 medium supplemented with 10% fetal bovine serum (FBS), 100 U/ml penicillin and 100 mg/ml streptomycin at 37 8C in a water-saturated atmosphere with 5% CO2/95% air [5]. 2.3. Study design Firstly, the rats were divided into two groups: one in which laparotomy and omentectomy were performed (primary omentectomy group, n = 6) and one in which laparotomy but not omentectomy was performed (sham operation group, n = 12). During the operation, DISS cells were transplanted intraperitoneally to all 18 rats at a concentration of 1 106 cells/ml. After three weeks, the 12 rats without omentectomy were further divided into two groups: one in which the omentum with tumor was resected (sham operation/omentectomy group, n = 6) and one without omentectomy (sham operation alone group, n = 6). Survival was compared among the three groups and the characteristics of the intraperitoneal disseminated foci were observed.
3. Results 3.1. Comparison of survival The survival of the sham operation alone group was shortest with a median of 35 days (28–37 days), while the median of the primary omentectomy group was 42 days (39–54 days) (p < 0.005) (Fig. 1). Two rats in the sham operation/omentectomy group died on Day 42 while the remaining four rats survived until Day 90, the day on which the observation was terminated (p < 0.005 as compared with the sham operation alone group and p < 0.01 as compared with the primary omentectomy group) (Fig. 1). 3.2. Intraperitoneal findings The intraperitoneal findings in the groups that were examined three weeks after intraperitoneal administration of cancer cells and conservation of the omentum (sham operation/omentectomy group and sham operation alone group) demonstrated that the tumor was restricted to the omentum without obvious dissemination to the mesentery (Fig. 2A). The intraperitoneal findings in the primary omentectomy group revealed extensive disseminated foci on the mesentery and under the abdominal wall (Fig. 2B). By the end the sham operation alone group showed only development of the omental mass and was characterized by jaundice resulting from the compression of the biliary system at the liver hilum (Fig. 2C). Disseminated foci were not observed in the peritoneal cavity of the rats from the sham operation/omentectomy group that survived for a long period (Fig. 2D), indicating that the omentum caught all cancer cells. 4. Comment When cancer cells were transplanted intraperitoneally to the rats subjected to omentectomy, the foci disseminated extensively on the mesentery and under the abdominal wall, but the intraperitoneal findings in the rats whose omentum was conserved demonstrated that the tumor was restricted to the omentum after the transplantation of the cancer cells. This result clearly indicates that the omentum plays an important role in capturing intraperitoneal cancer cells. The present results, which show the shortest survival in the primary omentectomy group, raise the question of
2.4. Omentectomy and sham operation Laparotomy was performed under pentobarbital anesthesia and sterile conditions. The omentum was reached via a 4-cm midline incision in the abdomen and subsequently extirpated by ligating the gastroepiploic vessels and hilum of the spleen. Sham operation was done by a similar incision. After hemostasis, the abdominal wall was closed in two layers using 3/0 polyglactin (Vicryl1, Ethicon, Tokyo, Japan). No animal died as a result of the operative procedure. 2.5. Statistical analysis The survival curves were calculated by the Kaplan–Meier method, and the statistical significance of differences in the cumulative survival curves between the groups was evaluated by logrank test. A result was deemed significant at P < 0.05.
Fig. 1. Comparison of survival. The sham operation/omentectomy group survived significantly longer than the sham operation alone group and the primary omentectomy group (p < 0.005 and p < 0.01, respectively). There is also a significant difference in survival period between the sham operation alone group and the primary omentectomy group (p < 0.005).
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Fig. 2. The intraperitoneal findings in each group. (A) The intraperitoneal findings in the sham operation/omentectomy group three weeks after intraperitoneal administration of cancer cells. The tumor was restricted to the omentum without obvious dissemination to the mesentery. (B) The intraperitoneal findings in the primary omentectomy group. Arrows indicate disseminated foci on the mesentery and under the abdominal wall. (C) The intraperitoneal finding in the sham operation alone group. Only development of the omental mass was shown. The finding was characterized by jaundice resulting from the compression of the biliary system at the liver hilum. (D) The peritoneal cavity of the rat from the sham operation/omentectomy group that survived for a long period. Disseminated foci are not observed.
whether omentectomy should be included in the initial standard procedure even in cases of epithelial ovarian cancer restricted to the pelvis. Oosterling et al. [6] have demonstrated that the proliferation of an omental tumor is formed mainly at the liver hilum, which is the gateway to the portal vein, hepatic artery, and bile duct. The present study confirmed this and further revealed that dissemination on the mesentery and under the abdominal wall and diaphragm was not evident even when the omental tumor was advanced, suggesting that the cause of death by omental tumor may be attributed to liver dysfunction. With regard to tumor toxic effects of the omentum, Koenen et al. [4] reported that the addition of granulocyte/macrophagecolony-stimulating factor (GM-CSF) to the macrophages isolated from the so-called omental milky spot potentiates the cytotoxicity against tumor cells, and showed that the administration of GM-CSF into the rat peritoneal cavity enhances the antitumor effect of milky spot macrophages and increases the population, suggesting that omental macrophages have an important role in inhibiting intraperitoneal cancer proliferation. On the other hand, Oosterling et al. [6] have shown that omental milky spots are insufficient to prevent peritoneal tumor outgrowth of the minimal residual lesion, and recommended omentectomy in surgical treatment of intra-abdominal tumors that are prone to disseminate intraperitoneally. They have also demonstrated, however, that intraperitoneally injected tumor cells predominantly adhered on the milky spots and the number of cells thereafter declined, suggesting that the omentum efficiently captures tumor cells that are floating in
the abdominal cavity [6]. Accordingly, if the omentum has such a function, it is relevant to delay omentectomy until floating tumor cells are maximally captured by the omentum. Why has omentectomy been included in the standard procedures for ovarian cancer, in particular early stages? To the best of our knowledge, omentectomy is required for determining stages and there has been no randomized controlled trial which has proved that omental resection correlates with the prognosis of ovarian cancer. In a recent retrospective analysis of 211 apparent early stage epithelial ovarian cancers, only 2% (4/196) were upstaged due to omental biopsy, suggesting that random peritoneal biopsy including omentum has limited value in staging of apparent early stage epithelial ovarian cancer after thorough exploration [7]. Trimbos et al. [8] showed in a randomized clinical trial that optimal surgery and appropriate adjuvant chemotherapy had significantly improved the prognosis of early-stage ovarian cancers. In that study, infracolic omentectomy was included in optimal surgery and was performed in 90% of patients. That study, however, was not designed to clarify the effect of omentectomy on prognosis, and whether omentectomy at an early stage of ovarian cancer improves the prognosis remains unclear. Omentectomy may be mandatory for assessing clinical stage at the present time, but the results of the present study revealed for the first time that omentectomy at an early stage adversely affects the prognosis. Although the present study could not show the appropriate timing for omentectomy, it casts doubt on its routine performance in cases of early-stage ovarian cancer. We propose that omentectomy should be restricted in early-stage ovarian
Y. Yokoyama et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 164 (2012) 89–92
92
cancer unless macroscopic dissemination is present, and that omentectomy should be done secondarily as necessary. Partial omentectomy for microscopic stating may be another option. Conflict of interest
[2]
[3] [4]
The authors report no conflicts of interest. Acknowledgments This study was supported by a Grant-in Aid for Cancer Research (No. 20591935) from the Ministry of Education, Science and Culture of Japan and by the Karoji Memorial Fund of the Hirosaki University Graduate School of Medicine. References [1] Benedet JL, Bender H, Jones III H, et al. FIGO staging classifications and clinical practice guidelines in the management of gynecologic cancers. FIGO committee
[5]
[6]
[7]
[8]
on gynecologic oncology. International Journal of Gynaecology and Obstetrics 2000;70:209–62. Agca B, Paksoy M, Polat E, et al. Influence of omentectomy on peritoneal defense mechanisms in an experimental model of intra-abdominal infection. European Surgical Research 2003;35:35–40. Cerci C, Eroglu E, Sutcu R, et al. Effects of omentectomy on the peritoneal fibrinolytic system. Surgery Today 2008;38:711–5. Koenen HJPM, Smit MJ, Simmelink MMJA, et al. Effect of intraperitoneal administration of granulocyte/macrophage-colony-stimulating factor in rats on omental milky-spot composition and tumoricidal activity in vivo and in vitro. Cancer Immunology Immunotherapy 1996;42:310–6. Yokoyama Y, Xin B, Shigeto T, et al. Clofibric acid, a peroxisome proliferatoractivated receptor a ligand, inhibits growth of human ovarian cancer. Molecular Cancer Therapeutics 2007;6:1379–86. Oosterling SJ, van der Bij GJ, Bo¨gels M, et al. Insufficient ability of omental milky spots to prevent peritoneal tumor outgrowth supports omentectomy in minimal residual disease. Cancer Immunology Immunotherapy 2006;55:1043–51. Powless CA, Bakkum-Gamez JN, Aletti GD, et al. Random peritoneal biopsies have limited value in staging of apparent early stage epithelial ovarian cancer after thorough exploration. Gynecologic Oncology 2009;115:86–9. Trimbos JB, Vergote I, Bolis G, et al. Impact of adjuvant chemotherapy and surgical staging inn early-stage ovarian carcinoma: European organisation for research and treatment of cancer-adjuvant chemotherapy in ovarian neoplasm trial. Journal of the National Cancer Institute 2003;95:113–25.