REVIEW ARTICLE
Gynecologic Cancer InterGroup (GCIG) Consensus Review for Ovarian Tumors of Low Malignant Potential (Borderline Ovarian Tumors) Philipp Harter, MD,* David Gershenson, MD, PhD,Þ Catherine Lhomme, MD, PhD,þ Fabrice Lecuru, MD, PhD,§ Jonathan Ledermann, MD, FRCP,|| Diane M. Provencher, MD, PhD,¶ Delia Mezzanzanica, MD, PhD,# Michael Quinn, MD, PhD,** Johanna Maenpaa, MD, PhD,ÞÞ Jae-Weon Kim, MD, PhD,þþ Sven Mahner, MD, PhD,§§ Felix Hilpert, MD, PhD,|||| Klaus Baumann, MD,¶¶ Jacobus Pfisterer, MD, PhD,## and Andreas du Bois, MD, PhD*
Abstract: Since the early 1970s, the World Health Organization and the International Federation of Gynecology and Obstetrics have classified borderline ovarian tumors as an independent group of ovarian epithelial tumors. A consensus statement of the Gynecologic Cancer Intergroup is reported. Key Words: Gynecologic Cancer InterGroup, GCIG, Ovarian tumor of low malignant potential, BOT Received April 23, 2014, and in revised form August 26, 2014. Accepted for publication August 26, 2014. (Int J Gynecol Cancer 2014;24: S5YS8)
the early 1970s, the World Health Organization and S ince the International Federation of Gynecology and Obstetrics
(FIGO) have classified borderline ovarian tumors (BOTs) as an independent group of ovarian epithelial tumors. *Kliniken-Essen-Mitte, AGO, Essen, Germany; †MD Andersen Cancer Center, GOG, Houston, TX; ‡Gustave Roussy, GINECO, Villejuif Cedex, France; §Universite´ Rene´ Descartes, GINECO, Paris, France; ||UCL Cancer Institute, MRC NCRI, London, United Kingdom; ¶CHUMYNotre-Dame Hospital, NCIC-CTG, Montreal, Quebec, Canada; #Fondazione IRCCS Istituto Nazionale dei Tumori, MITO, Milan, Italy; **ANZGOG, Parkville, Victoria, Australia; ††University and University Hospital of Tampere, NSGO, Tampere, Finland; ‡‡Seoul National University, KGOG, Seoul, South Korea; §§University Medical Center Hamburg-Eppendorf, AGO, Hamburg, Germany; ||||University Hospital Kiel, AGO, Kiel, Germany; ¶¶UKGM, Marburg, AGO, Marburg, Germany; and ##Gynecologic Oncology Center, Kiel, AGO, Kiel, Germany. Address correspondence and reprint requests to Dr Philipp Harter, Department of Gynecology and Gynecologic Oncology, Kliniken-Essen-Mitte, Henricistrasse 92, 45136 Essen, Germany. E-mail: [email protected]. The authors declare no conflicts of interest. Copyright * 2014 by IGCS and ESGO ISSN: 1048-891X DOI: 10.1097/IGC.0000000000000282 International Journal of Gynecological Cancer
Borderline ovarian tumors are characterized pathologically by mild nuclear abnormalities and modestly increased mitotic activity, but in contrast to malignant ovarian cancers, they do not exhibit infiltrative destructive growth or stromal invasion.1 Borderline ovarian tumors were first described in 1929 as ‘‘semimalignant’’ ovarian tumors.2 Since then, many different terms have been used to describe this subgroup of ovarian tumors, some of them misleading. For this reason, the term borderline ovarian tumors will be used throughout this review as it was introduced in the 2003 published World Health Organization classification.3
EPIDEMIOLOGY Borderline ovarian tumors represent about 10% to 20% of all ovarian epithelial tumors with an incidence of 1.8 to 4.8 per 100,000 women per year.4 They differ significantly from invasive ovarian carcinomas, and they usually affect patients at a younger age. One third of the patients are younger than 40 years, leading to specific issues in management with respect to preservation of fertility and ovarian function.
DIAGNOSIS Typically, patients present with nonspecific abnormalities of the ovaries on gynecologic examination and transvaginal
& Volume 24, Number S3, November 2014
Copyright © 2014 by IGCS and ESGO. Unauthorized reproduction of this article is prohibited.
S5
Harter et al
International Journal of Gynecological Cancer
ultrasound, about one third are asymptomatic.5 The definitive diagnosis is made on the pathologic specimen obtained intraoperatively, either by immediate frozen section analysis or ideally by permanent sections.6 Borderline ovarian tumors are staged using the FIGO classification for malignant epithelial ovarian tumors. Du Bois and colleagues7 have recently shown in a systematic review of 6362 cases that 78.9% of the patients with BOTs are diagnosed at FIGO stage I. Extension of tumor spread within the pelvis or beyond (FIGO stage II-III) is rarely seen at the time of diagnosis, and FIGO stage IV is even more uncommon.8
PATHOLOGY Histologically, BOTs exhibit an unusual degree of proliferation of the epithelial cells with cellular stratification including architectural atypia and the formation of papillary protuberances. The absence of obvious stromal invasion is the principal diagnostic criterion for a BOT. Nevertheless, microinvasion by cells with the same borderline cytologic features may be seen up to 5 mm maximal dimension or across an area not exceeding 10 mm2.3 As some of these criteria depend on individual decisions by the pathologist, the definitive diagnosis of BOT may be hard to establish, and interobserver reproducibility remains a concern. Peritoneal implants are classified into either invasive or noninvasive implants. Noninvasive implants share characteristics with the primary BOT, whereas invasive implants have features similar to infiltrating adenocarcinomas. Noninvasive implants are subclassified as epithelial, desmoplastic, or both.9 As in malignant ovarian cancers, every surface epithelial cell type (serous, mucinous, endometrioid, clear cell, transitional cell, and mixed epithelial cell) have been reported in BOTs as well. However, serous (S-BOT, 67%) and mucinous (M-BOT, 30%) BOTs are the most common by far. Interestingly, the incidence of M-BOT is reported to be higher in nonwhite patients comparable to invasive ovarian cancer.10 Serous BOTs are confined to 1 ovary in 75% of cases. Extraovarian distribution is more frequent in S-BOT (25%) represented by peritoneal implants (21.7% any implants, 3.6% invasive implants). The rate of extraovarian spread in M-BOT is far lower (3.4% any implant, 0.7% invasive implants).8 For this tumor entity in addition to careful examination of the intestine, appendectomy is recommended as these tumors may represent metastases from occult gastrointestinal primaries, most commonly in the appendix.11
PROGNOSTIC FACTORS Similar to ovarian cancer, FIGO stage at the time of diagnosis is 1 of the strongest prognostic factors.7 Although some authors have described micropapillary histology and microinvasion as risk factor, this could not be confirmed by others.8,12Y14 Peritoneal implants, especially invasive implants, are of prognostic significance.7 It has been postulated that the presence of invasive implants represent the most important risk factor besides the initial FIGO stage,15 so that these patients have to be followed up very closely. Invasive implants share many features with cancer, and they may already mark the transformation to invasive carcinoma. Interestingly,
S6
& Volume 24, Number S3, November 2014
histological subtype (serous or mucinous) itself or lymph node involvement could not convincingly be confirmed as independent risk factors.16
Molecular Biology Low-grade ovarian tumors and S-BOT have similar origins (2 pathway models). For details, see section Molecular Biology in the chapter Low-Grade Serous Carcinoma. 17
Initial Treatment Surgery When the diagnosis of BOT is made or suspected, gynecologic oncologists are confronted with the question of choosing conservative or radical surgery. Radical surgery with complete staging includes midline laparotomy, complete inspection, and palpation of the abdominal cavity, cytology, resection of all suspicious tissue, bilateral salpingo-oophorectomy, total hysterectomy, omentectomy, and multiple peritoneal biopsies. Beside of complete surgical staging, the aim is always complete resection of the tumor. However, the role of hysterectomy is not clearly demonstrated, but it is strongly recommended at least in endometrioid BOT, where simultaneous endometrial lesions are observed. Although even the most current FIGO recommendations include lymphadenectomy as part of complete staging in BOT, there is no rationale for systematic lymphadenectomy, and this procedure is routinely not indicated. The Retrospective Multicenter Outcome Survey in Borderline Tumors (ROBOT) study has shown that surgical staging is a significant prognostic factor regarding relapse (hazards ratio [HR], 0.443; 0.222Y0.884; P = 0.0209).8 Conservative surgery is defined as complete staging in which the uterus and at least a part of 1 ovary are preserved. Besides the fertility aspect, preserving hormonal function and the reduced morbidity for these patients play an important role in the planning of surgery. Available data suggest that in general, the rate of recurrence is higher after conservative management. In the German multicenter survey, it was shown that in premenopausal women, 65% of the treated patients underwent unilateral salpingooophorectomy, and only 34% underwent bilateral salpingooophorectomy (BSO). In contrast, 98% of postmenopausal women underwent BSO. Cystectomy was performed in only 19% of patients with a desire to preserve fertility.5 The ROBOT study has shown that unilateral salpingooophorectomy showed a 71% increased risk compared with BSO (HR, 1.713; 1.108Y2.649; P = 0.0155), and the highest risk was observed for cystectomy only with preservation of the primarily affected ovary (HR, 5.662; 3.154Y10.17; P G 0.0001). The impact of fertility-sparing surgery was analyzed in the subgroup of 601 patients who were younger than 55 years at diagnosis. Fertility-sparing surgery was applied in 129 (27.3%) of 473 and 37 (28.9%) of 128 patients with FIGO I and FIGO II/III, respectively. Progression free survival events were observed in 39 (23.5%) of 166 patients with fertility-sparing surgery, increasing the risk for recurrence with an HR of 3.813 (2.023Y7.188; P G 0.0001) and 3.956 (1.850Y8.461; P = 0.0004) in FIGO I and II/III, respectively.8 * 2014 IGCS and ESGO
Copyright © 2014 by IGCS and ESGO. Unauthorized reproduction of this article is prohibited.
International Journal of Gynecological Cancer
& Volume 24, Number S3, November 2014
The higher risk of relapse with conservative treatment has to be discussed versus the wish of fertility-sparing treatment. Some authors discuss restaging surgery including extirpation of the residual ovary after completion of family planning.7 Although midline laparotomy is the standard approach for staging in invasive ovarian cancer, laparoscopy seems to be an attractive approach for BOT as it is for benign ovarian tumors. Due to recent developments in oncologic surgery and considering the low malignant potential of BOT, this procedure seems to be safe and adequate, especially for conservatively treated patients.18 Nonetheless, because of fear of inadequate initial staging, tumor cell dissemination, port-side metastasis, and more frequent cyst ruptures compared with laparotomy, most gynecologic oncologists still regard laparoscopy with reservation. However, staging laparoscopy in stage I BOT seems to be acceptable, but an open approach or conversion is recommended in case of any findings suggesting metastases and thus higher stage disease. The potentially higher risk for relapse and the possible need for repeated surgery have to be discussed with the patient when defining the approach and kind of surgery.
Adjuvant Treatment To date, there are no data supporting any benefit from adjuvant therapy (chemotherapy or radiotherapy), even in advanced-stage disease and with the presence of invasive implants as these tumors have very low response rates (3%Y4%) with platinum-based and taxane-based chemotherapy.8,19,20 Therefore, adjuvant therapy is not indicated in patients with a BOT.
Follow-up For patients who undergo fertility-sparing surgery, the question will arise whether the remaining ovary and uterus should be resected once the family planning is complete. As mentioned earlier, the risk for recurrence is significantly higher in women who have conservative surgery although most recurrences remain BOT.21 For this reason, it seems acceptable to wait until recurrence develops.22 Nevertheless, the psychological impact of waiting for relapse may be considerable, and although the majority of relapses occur in the remaining ovary, there is still a risk for the development of invasive ovarian cancer. Therefore, we currently recommend discussion about definitive surgery after the childbearing is completed. Regular and intense follow-up including vaginal ultrasound of patients is essential for the early detection of BOT recurrence or malignant transformation. This has to be conducted for a longer period than in invasive ovarian cancer. The rate of relapse in the ROBOT study was 7.8%.8 A systematic review reports that 37.1% of the recurrences are diagnosed during the first 2 years, 31.8% of the patients experience relapse after 5 years, and 10.4% of the patients’ relapse occur after more than 10 years.7
Treatment of Relapse As in primary BOT, surgery remains the cornerstone for the treatment of recurrence. After conservative surgery, the patients should be treated with completion of the staging
GCIG Consensus BOT
and resection of all visible disease.18 About 70% of the recurrent tumors relapse as BOT. Malignant transformation with the subsequent development of an invasive ovarian cancer occurs in about 30% of relapses. Most of these are low-grade carcinomas, but up to 36% can relapse as high-grade invasive ovarian cancer, which significantly impacts on prognosis (P G 0.0001; HR, 26.0; 5-year survival rates 98% vs 50%).8
ACKNOWLEDGMENTS The authors would like to thank all the participants of the London meeting validating all GCIG reviews in November 2013. The authors would also like to thank the following: Isabelle Ray Coquard (GINECO); Monica Bacon (GCIG Canada); Eric Pujade-Lauraine (GINECO); William Small (RTOG); Gavin Stuart (NCIC CTG); Jan Vermorken (EORTC); Regina Berger, Christian Marth, and Karl Tamussino (AGO Au); Alexander Reuss, and Gabriele Elser (AGO); Alison Brand, Linda Mileshkin, and Clare Scott (ANZGOG); Jonathan Berek, Ashley Powell, and Wendy Fantl (COGi); Rudd Bekkers, Carien Creutzberg, and Els Witteveen (DGOG); Andres Poveda and Ignacio Romero (GEICO); David Isla and Dolores Gallardo (GICOM); Benedicte Votan, Emmanuel Kurtz, and Florence Joly (GINECO); Mark Brady, and David Miller (GOG); Keiichi Fujiwara, Kosei Hasegawa, and Yuji Takei (GOTIC); Dearbhaile O’Donnell, Noreen Gleeson, and Paula Calvert (ICORG); Satoru Sagae, Aikou Okamoto, and Tadao Takano (JGOG); Byung HO Nam and Sang Ryu (KGOG); Nicoletta Colombo, Roldano Fossati, and Dionyssios Katsaros (MaNGO); Domenica Lorusso, Georgia Mangili and Jane Bryce (MITO); Charles Gourley, Iain McNeish, Melanie Powell, and Max Parmar (MRC-NCRI); Hal Hirte and Marie Plante (NCIC CTG); Jalid Sehouli, Elena Braicu, and Mani Nassir (NOGGO); Gunnar Kristensen and Mansoor Mirza (NSGO); Amit Oza, Helen MacKay, and Steven Welch (PMHC); Patricia Eifel and Anuja Jhingran (RTOG); Ros Glasspool, David Millan, Nick Reed, and Jim Paul (SGCTG); Thomas Gross and Elise Kohn (NCI-US); and Michael Seckl (ISSTD).
REFERENCES 1. Acs G. Serous and mucinous borderline (low malignant potential) tumors of the ovary. Am J Clin Pathol. 2005;123:S13YS57. 2. Taylor HC Jr. Malignant and semi-malignant tumors of the ovary. Surg Gynecol Obstset. 1929;48:204Y230. 3. Tavassoli FA, Devilee P. Pathology and Genetics of Tumours of the Breast and Female Genital Organs. Lyon, France: IARC Press, 2003. 4. Skirnisdottir I, Garmo H, Wilander E, et al. Borderline ovarian tumors in Sweden 1960-2005: trends in incidence and age at diagnosis compared to ovarian cancer. Int J Cancer. 2008;123:1897Y1901. 5. Coumbos A, Sehouli J, Chekerov R, et al. Clinical management of borderline tumours of the ovary: results of a multicentre survey of 323 clinics in Germany. Br J Cancer. 2009;100:1731Y1738. 6. Baker P, Oliva E. A practical approach to intraoperative consultation in gynecological pathology. Int J Gynecol Pathol. 2008;27:353Y365.
* 2014 IGCS and ESGO
Copyright © 2014 by IGCS and ESGO. Unauthorized reproduction of this article is prohibited.
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7. Du Bois A, Ewald-Riegler N, du Bois O, et al. Borderline tumors of the ovaryVa systematic review [in German]. Geburtsh Frauenheilk. 2009;69:807Y833. 8. du Bois A, Ewald-Riegler N, de Gregorio N, et al. Borderline tumours of the ovary: a cohort study of the Arbeitsgemeinschaft Gyna¨kologische Onkologie (AGO) Study Group. Eur J Cancer. 2013;49:1905Y1914. 9. Bell DA, Weinstock MA, Scully RE. Peritoneal implants of ovarian serous borderline tumors. Histologic features and prognosis. Cancer. 1988;62:2212Y2222. 10. Song T, Lee YY, Choi CH, et al. Histologic distribution of borderline ovarian tumors worldwide: a systematic review. J Gynecol Oncol. 2013;24:44Y51. 11. Hart WR. Borderline epithelial tumors of the ovary. Mod Pathol. 2005;18(suppl 2):S33YS50. 12. Burks RT, Sherman ME, Kurman RJ. Micropapillary serous carcinoma of the ovary. A distinctive low-grade carcinoma related to serous borderline tumors. Am J Surg Pathol. 1996;20:1319Y1330. 13. Buttin BM, Herzog TJ, Powell MA, et al. Epithelial ovarian tumors of low malignant potential: the role of microinvasion. Obstet Gynecol. 2002;99:11Y17. 14. Morice P, Uzan C, Fauvet R, et al. Borderline ovarian tumour: pathological diagnostic dilemma and risk factors for invasive or lethal recurrence. Lancet Oncol. 2012;13:e103Ye115. 15. Kane A, Uzan C, Rey A, et al. Prognostic factors in patients with ovarian serous low malignant potential
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17.
18.
19.
20.
21.
22.
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(borderline) tumors with peritoneal implants. Oncologist. 2009;14:591Y600. Yokoyama Y, Moriya T, Takano T, et al. Clinical outcome and risk factors for recurrence in borderline ovarian tumours. Br J Cancer. 2006;94:1586Y1591. Meinhold-Heerlein I, Bauerschlag D, Hilpert F, et al. Molecular and prognostic distinction between serous ovarian carcinomas of varying grade and malignant potential. Oncogene. 2005;24:1053Y1065. Odegaard E, Staff AC, Langebrekke A, et al. Surgery of borderline tumors of the ovary: retrospective comparison of short-term outcome after laparoscopy or laparotomy. Acta Obstet Gynecol Scand. 2007;86:620Y626. Longacre TA, McKenney JK, Tazelaar HD, et al. Ovarian serous tumors of low malignant potential (borderline tumors): outcome-based study of 276 patients with long-term (9 or =5-year) follow-up. Am J Surg Pathol. 2005;29: 707Y723. Gershenson DM, Sun CC, Bodurka D, et al. Recurrent low-grade serous ovarian carcinoma is relatively chemoresistant. Gynecol Oncol. 2009;114:48Y52. DaraB E, Fauvet R, Uzan C, et al. Fertility and borderline ovarian tumor: a systematic review of conservative management, risk of recurrence and alternative options. Hum Reprod Update. 2013;19:151Y166. Cadron I, Leunen K, Van Gorp T, et al. Management of borderline ovarian neoplasms. J Clin Oncol. 2007;25:2928Y2937.
* 2014 IGCS and ESGO
Copyright © 2014 by IGCS and ESGO. Unauthorized reproduction of this article is prohibited.
Gynecologic Cancer InterGroup (GCIG) Consensus Review for Ovarian Tumors of Low Malignant Potential (Borderline Ovarian Tumors) Philipp Harter, MD,* David Gershenson, MD, PhD,Þ Catherine Lhomme, MD, PhD,þ Fabrice Lecuru, MD, PhD,§ Jonathan Ledermann, MD, FRCP,|| Diane M. Provencher, MD, PhD,¶ Delia Mezzanzanica, MD, PhD,# Michael Quinn, MD, PhD,** Johanna Maenpaa, MD, PhD,ÞÞ Jae-Weon Kim, MD, PhD,þþ Sven Mahner, MD, PhD,§§ Felix Hilpert, MD, PhD,|||| Klaus Baumann, MD,¶¶ Jacobus Pfisterer, MD, PhD,## and Andreas du Bois, MD, PhD*
Abstract: Since the early 1970s, the World Health Organization and the International Federation of Gynecology and Obstetrics have classified borderline ovarian tumors as an independent group of ovarian epithelial tumors. A consensus statement of the Gynecologic Cancer Intergroup is reported. Key Words: Gynecologic Cancer InterGroup, GCIG, Ovarian tumor of low malignant potential, BOT Received April 23, 2014, and in revised form August 26, 2014. Accepted for publication August 26, 2014. (Int J Gynecol Cancer 2014;24: S5YS8)
the early 1970s, the World Health Organization and S ince the International Federation of Gynecology and Obstetrics
(FIGO) have classified borderline ovarian tumors (BOTs) as an independent group of ovarian epithelial tumors. *Kliniken-Essen-Mitte, AGO, Essen, Germany; †MD Andersen Cancer Center, GOG, Houston, TX; ‡Gustave Roussy, GINECO, Villejuif Cedex, France; §Universite´ Rene´ Descartes, GINECO, Paris, France; ||UCL Cancer Institute, MRC NCRI, London, United Kingdom; ¶CHUMYNotre-Dame Hospital, NCIC-CTG, Montreal, Quebec, Canada; #Fondazione IRCCS Istituto Nazionale dei Tumori, MITO, Milan, Italy; **ANZGOG, Parkville, Victoria, Australia; ††University and University Hospital of Tampere, NSGO, Tampere, Finland; ‡‡Seoul National University, KGOG, Seoul, South Korea; §§University Medical Center Hamburg-Eppendorf, AGO, Hamburg, Germany; ||||University Hospital Kiel, AGO, Kiel, Germany; ¶¶UKGM, Marburg, AGO, Marburg, Germany; and ##Gynecologic Oncology Center, Kiel, AGO, Kiel, Germany. Address correspondence and reprint requests to Dr Philipp Harter, Department of Gynecology and Gynecologic Oncology, Kliniken-Essen-Mitte, Henricistrasse 92, 45136 Essen, Germany. E-mail: [email protected]. The authors declare no conflicts of interest. Copyright * 2014 by IGCS and ESGO ISSN: 1048-891X DOI: 10.1097/IGC.0000000000000282 International Journal of Gynecological Cancer
Borderline ovarian tumors are characterized pathologically by mild nuclear abnormalities and modestly increased mitotic activity, but in contrast to malignant ovarian cancers, they do not exhibit infiltrative destructive growth or stromal invasion.1 Borderline ovarian tumors were first described in 1929 as ‘‘semimalignant’’ ovarian tumors.2 Since then, many different terms have been used to describe this subgroup of ovarian tumors, some of them misleading. For this reason, the term borderline ovarian tumors will be used throughout this review as it was introduced in the 2003 published World Health Organization classification.3
EPIDEMIOLOGY Borderline ovarian tumors represent about 10% to 20% of all ovarian epithelial tumors with an incidence of 1.8 to 4.8 per 100,000 women per year.4 They differ significantly from invasive ovarian carcinomas, and they usually affect patients at a younger age. One third of the patients are younger than 40 years, leading to specific issues in management with respect to preservation of fertility and ovarian function.
DIAGNOSIS Typically, patients present with nonspecific abnormalities of the ovaries on gynecologic examination and transvaginal
& Volume 24, Number S3, November 2014
Copyright © 2014 by IGCS and ESGO. Unauthorized reproduction of this article is prohibited.
S5
Harter et al
International Journal of Gynecological Cancer
ultrasound, about one third are asymptomatic.5 The definitive diagnosis is made on the pathologic specimen obtained intraoperatively, either by immediate frozen section analysis or ideally by permanent sections.6 Borderline ovarian tumors are staged using the FIGO classification for malignant epithelial ovarian tumors. Du Bois and colleagues7 have recently shown in a systematic review of 6362 cases that 78.9% of the patients with BOTs are diagnosed at FIGO stage I. Extension of tumor spread within the pelvis or beyond (FIGO stage II-III) is rarely seen at the time of diagnosis, and FIGO stage IV is even more uncommon.8
PATHOLOGY Histologically, BOTs exhibit an unusual degree of proliferation of the epithelial cells with cellular stratification including architectural atypia and the formation of papillary protuberances. The absence of obvious stromal invasion is the principal diagnostic criterion for a BOT. Nevertheless, microinvasion by cells with the same borderline cytologic features may be seen up to 5 mm maximal dimension or across an area not exceeding 10 mm2.3 As some of these criteria depend on individual decisions by the pathologist, the definitive diagnosis of BOT may be hard to establish, and interobserver reproducibility remains a concern. Peritoneal implants are classified into either invasive or noninvasive implants. Noninvasive implants share characteristics with the primary BOT, whereas invasive implants have features similar to infiltrating adenocarcinomas. Noninvasive implants are subclassified as epithelial, desmoplastic, or both.9 As in malignant ovarian cancers, every surface epithelial cell type (serous, mucinous, endometrioid, clear cell, transitional cell, and mixed epithelial cell) have been reported in BOTs as well. However, serous (S-BOT, 67%) and mucinous (M-BOT, 30%) BOTs are the most common by far. Interestingly, the incidence of M-BOT is reported to be higher in nonwhite patients comparable to invasive ovarian cancer.10 Serous BOTs are confined to 1 ovary in 75% of cases. Extraovarian distribution is more frequent in S-BOT (25%) represented by peritoneal implants (21.7% any implants, 3.6% invasive implants). The rate of extraovarian spread in M-BOT is far lower (3.4% any implant, 0.7% invasive implants).8 For this tumor entity in addition to careful examination of the intestine, appendectomy is recommended as these tumors may represent metastases from occult gastrointestinal primaries, most commonly in the appendix.11
PROGNOSTIC FACTORS Similar to ovarian cancer, FIGO stage at the time of diagnosis is 1 of the strongest prognostic factors.7 Although some authors have described micropapillary histology and microinvasion as risk factor, this could not be confirmed by others.8,12Y14 Peritoneal implants, especially invasive implants, are of prognostic significance.7 It has been postulated that the presence of invasive implants represent the most important risk factor besides the initial FIGO stage,15 so that these patients have to be followed up very closely. Invasive implants share many features with cancer, and they may already mark the transformation to invasive carcinoma. Interestingly,
S6
& Volume 24, Number S3, November 2014
histological subtype (serous or mucinous) itself or lymph node involvement could not convincingly be confirmed as independent risk factors.16
Molecular Biology Low-grade ovarian tumors and S-BOT have similar origins (2 pathway models). For details, see section Molecular Biology in the chapter Low-Grade Serous Carcinoma. 17
Initial Treatment Surgery When the diagnosis of BOT is made or suspected, gynecologic oncologists are confronted with the question of choosing conservative or radical surgery. Radical surgery with complete staging includes midline laparotomy, complete inspection, and palpation of the abdominal cavity, cytology, resection of all suspicious tissue, bilateral salpingo-oophorectomy, total hysterectomy, omentectomy, and multiple peritoneal biopsies. Beside of complete surgical staging, the aim is always complete resection of the tumor. However, the role of hysterectomy is not clearly demonstrated, but it is strongly recommended at least in endometrioid BOT, where simultaneous endometrial lesions are observed. Although even the most current FIGO recommendations include lymphadenectomy as part of complete staging in BOT, there is no rationale for systematic lymphadenectomy, and this procedure is routinely not indicated. The Retrospective Multicenter Outcome Survey in Borderline Tumors (ROBOT) study has shown that surgical staging is a significant prognostic factor regarding relapse (hazards ratio [HR], 0.443; 0.222Y0.884; P = 0.0209).8 Conservative surgery is defined as complete staging in which the uterus and at least a part of 1 ovary are preserved. Besides the fertility aspect, preserving hormonal function and the reduced morbidity for these patients play an important role in the planning of surgery. Available data suggest that in general, the rate of recurrence is higher after conservative management. In the German multicenter survey, it was shown that in premenopausal women, 65% of the treated patients underwent unilateral salpingooophorectomy, and only 34% underwent bilateral salpingooophorectomy (BSO). In contrast, 98% of postmenopausal women underwent BSO. Cystectomy was performed in only 19% of patients with a desire to preserve fertility.5 The ROBOT study has shown that unilateral salpingooophorectomy showed a 71% increased risk compared with BSO (HR, 1.713; 1.108Y2.649; P = 0.0155), and the highest risk was observed for cystectomy only with preservation of the primarily affected ovary (HR, 5.662; 3.154Y10.17; P G 0.0001). The impact of fertility-sparing surgery was analyzed in the subgroup of 601 patients who were younger than 55 years at diagnosis. Fertility-sparing surgery was applied in 129 (27.3%) of 473 and 37 (28.9%) of 128 patients with FIGO I and FIGO II/III, respectively. Progression free survival events were observed in 39 (23.5%) of 166 patients with fertility-sparing surgery, increasing the risk for recurrence with an HR of 3.813 (2.023Y7.188; P G 0.0001) and 3.956 (1.850Y8.461; P = 0.0004) in FIGO I and II/III, respectively.8 * 2014 IGCS and ESGO
Copyright © 2014 by IGCS and ESGO. Unauthorized reproduction of this article is prohibited.
International Journal of Gynecological Cancer
& Volume 24, Number S3, November 2014
The higher risk of relapse with conservative treatment has to be discussed versus the wish of fertility-sparing treatment. Some authors discuss restaging surgery including extirpation of the residual ovary after completion of family planning.7 Although midline laparotomy is the standard approach for staging in invasive ovarian cancer, laparoscopy seems to be an attractive approach for BOT as it is for benign ovarian tumors. Due to recent developments in oncologic surgery and considering the low malignant potential of BOT, this procedure seems to be safe and adequate, especially for conservatively treated patients.18 Nonetheless, because of fear of inadequate initial staging, tumor cell dissemination, port-side metastasis, and more frequent cyst ruptures compared with laparotomy, most gynecologic oncologists still regard laparoscopy with reservation. However, staging laparoscopy in stage I BOT seems to be acceptable, but an open approach or conversion is recommended in case of any findings suggesting metastases and thus higher stage disease. The potentially higher risk for relapse and the possible need for repeated surgery have to be discussed with the patient when defining the approach and kind of surgery.
Adjuvant Treatment To date, there are no data supporting any benefit from adjuvant therapy (chemotherapy or radiotherapy), even in advanced-stage disease and with the presence of invasive implants as these tumors have very low response rates (3%Y4%) with platinum-based and taxane-based chemotherapy.8,19,20 Therefore, adjuvant therapy is not indicated in patients with a BOT.
Follow-up For patients who undergo fertility-sparing surgery, the question will arise whether the remaining ovary and uterus should be resected once the family planning is complete. As mentioned earlier, the risk for recurrence is significantly higher in women who have conservative surgery although most recurrences remain BOT.21 For this reason, it seems acceptable to wait until recurrence develops.22 Nevertheless, the psychological impact of waiting for relapse may be considerable, and although the majority of relapses occur in the remaining ovary, there is still a risk for the development of invasive ovarian cancer. Therefore, we currently recommend discussion about definitive surgery after the childbearing is completed. Regular and intense follow-up including vaginal ultrasound of patients is essential for the early detection of BOT recurrence or malignant transformation. This has to be conducted for a longer period than in invasive ovarian cancer. The rate of relapse in the ROBOT study was 7.8%.8 A systematic review reports that 37.1% of the recurrences are diagnosed during the first 2 years, 31.8% of the patients experience relapse after 5 years, and 10.4% of the patients’ relapse occur after more than 10 years.7
Treatment of Relapse As in primary BOT, surgery remains the cornerstone for the treatment of recurrence. After conservative surgery, the patients should be treated with completion of the staging
GCIG Consensus BOT
and resection of all visible disease.18 About 70% of the recurrent tumors relapse as BOT. Malignant transformation with the subsequent development of an invasive ovarian cancer occurs in about 30% of relapses. Most of these are low-grade carcinomas, but up to 36% can relapse as high-grade invasive ovarian cancer, which significantly impacts on prognosis (P G 0.0001; HR, 26.0; 5-year survival rates 98% vs 50%).8
ACKNOWLEDGMENTS The authors would like to thank all the participants of the London meeting validating all GCIG reviews in November 2013. The authors would also like to thank the following: Isabelle Ray Coquard (GINECO); Monica Bacon (GCIG Canada); Eric Pujade-Lauraine (GINECO); William Small (RTOG); Gavin Stuart (NCIC CTG); Jan Vermorken (EORTC); Regina Berger, Christian Marth, and Karl Tamussino (AGO Au); Alexander Reuss, and Gabriele Elser (AGO); Alison Brand, Linda Mileshkin, and Clare Scott (ANZGOG); Jonathan Berek, Ashley Powell, and Wendy Fantl (COGi); Rudd Bekkers, Carien Creutzberg, and Els Witteveen (DGOG); Andres Poveda and Ignacio Romero (GEICO); David Isla and Dolores Gallardo (GICOM); Benedicte Votan, Emmanuel Kurtz, and Florence Joly (GINECO); Mark Brady, and David Miller (GOG); Keiichi Fujiwara, Kosei Hasegawa, and Yuji Takei (GOTIC); Dearbhaile O’Donnell, Noreen Gleeson, and Paula Calvert (ICORG); Satoru Sagae, Aikou Okamoto, and Tadao Takano (JGOG); Byung HO Nam and Sang Ryu (KGOG); Nicoletta Colombo, Roldano Fossati, and Dionyssios Katsaros (MaNGO); Domenica Lorusso, Georgia Mangili and Jane Bryce (MITO); Charles Gourley, Iain McNeish, Melanie Powell, and Max Parmar (MRC-NCRI); Hal Hirte and Marie Plante (NCIC CTG); Jalid Sehouli, Elena Braicu, and Mani Nassir (NOGGO); Gunnar Kristensen and Mansoor Mirza (NSGO); Amit Oza, Helen MacKay, and Steven Welch (PMHC); Patricia Eifel and Anuja Jhingran (RTOG); Ros Glasspool, David Millan, Nick Reed, and Jim Paul (SGCTG); Thomas Gross and Elise Kohn (NCI-US); and Michael Seckl (ISSTD).
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