- Email: [email protected]
Age-dependent differences in borderline ovarian tumours (BOT) regarding clinical characteristics and outcome: results from a sub-analysis of the Arbeitsgemeinschaft Gynaekologische Onkologie (AGO) ROBOT study
Annals of Oncology Advance Access published March 11, 2014
1 Age-dependent differences in borderline ovarian tumours (BOT) regarding clinical characteristics and outcome: Results from a subanalysis of the Arbeitsgemeinschaft Gynaekologische Onkologie (AGO) ROBOT Study
F. Trillsch1,#, S. Mahner1,#, L. Woelber1, E. Vettorazzi2, A. Reuss3, N. EwaldRiegler4, N. de Gregorio5, C. Fotopoulou6, B. Schmalfeldt7, A. Burges8, F. Hilpert9, T. Fehm10, W. Meier11, P. Hillemanns12, L. Hanker13,14, A. Hasenburg15,
Paik21, U. Canzler19, K. Wollschlaeger22, D. Forner23, J. Pfisterer24,25, W. Schroeder26, K. Muenstedt27, B. Richter28, F. Kommoss29, S. Hauptmann16,30, A. du Bois31 1 Department of Gynaecology and Gynaecologic Oncology, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany 2 Department of Medical Biometry and Epidemiology, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany 3 Coordinating Center for Clinical Trials, Marburg, Germany 4 Department of Gynaecology and Gynaecologic Oncology, Dr. Horst Schmidt Klinik GmbH, Wiesbaden, Germany 5 Department of Gynaecolgy and Obstetrics, Universitätsklinikum Ulm, Ulm, Germany 6 Department of Gynaecolgy, Charité, Campus Virchow Klinikum, Berlin, Germany 7 Department of Obstetrics and Gynaecolgy, Klinikum rechts der Isar der Technischen Universität, Munich, Germany 8 Department of Obstetrics and Gynaecolgy, Klinikum der Universität München, Campus Großhadern, Munich, Germany 9 Department of Gynaecolgy and Obstetrics, Universitätsklinikum Schleswig-Holstein, Campus Kiel, Kiel, Germany 10 Department of Gynaecolgy and Obstetrics, Universitätsklinikum Tübingen, Tuebingen, Germany 11 Department of Gynaecolgy and Obstetrics, Evangelisches Krankenhaus, Duesseldorf, Germany 12 Department of Gynaecolgy and Obstetrics, Medizinische Hochschule Hannover, Hannover, Germany 13 Department of Gynaecolgy and Obstetrics, Klinikum der J.W. Goethe-Universität, Frankfurt/M., Germany 14 Department of Gynaecolgy and Obstetrics, Universitätsklinikum Schleswig-Holstein, Campus Lübeck, Luebeck, Germany 15 Department of Obstetrics and Gynaecolgy, Universitätsklinikum Freiburg, Freiburg, Germany 16 Department of Gynaecolgy and Obstetrics, Universitätsklinikum Halle/S., Halle/S., Germany 17 Department of Gynaecolgy and Obstetrics, Georg-August-Universität Göttingen, Goettingen, Germany 18 Clinic of Gynaecolgy and Obstetrics, Universitätsklinikum Essen, Essen, Germany 19 Department of Gynaecolgy and Obstetrics, Universitätsklinikum Carl Gustav Carus, Dresden, Germany 20 Department of Gynaecolgy, Endocrinology and Oncology, Universitätsklinikum Gießen u. Marburg GmbH, Marburg, Germany 21 Department of Obstetrics and Gynaecolgy, Rheinische Friedrich-Wilhelms-Universität, Bonn, Germany 22 Department of Gynaecolgy and Obstetrics, Universitätsklinikum Magdeburg, Magdeburg, Germany 23 Department of Gynaecolgy and Obstetrics, Sana-Klinikum Remscheid, Remscheid, Germany
© The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected].
Downloaded from http://annonc.oxfordjournals.org/ at Anadolu University on April 29, 2014
H.G. Strauss16, M. Hellriegel17, P. Wimberger18,19, K. Baumann20, M.D. Keyver-
2 24
Department of Gynaecolgy and Obstetrics, Städtisches Klinikum Solingen gGmbH, Solingen, Germany 25 Zentrum für Gynäkologische Onkologie, Kiel, Germany 26 GYNAEKOLOGICUM Bremen, Bremen, Germany 27 Department of Obstetrics and Gynaecolgy, Universitätsklinikum Gießen, Gießen, Germany 28 Department of Gynaecology and Obstetrics, Elblandkliniken Meißen-Radebeul GmbH & Co. KG, Radebeul, Germany 29 Institute of Pathology, Referenzzentrum für Gynäkopathologie, Mannheim, Germany 30 Institute of Pathology Trier-Dueren-Duesseldorf, Dueren, Germany 31 Department of Gynaecolgy and Gynaecolgic Oncology, Kliniken Essen-Mitte, Essen, Germany Corresponding author: Dr. Sven Mahner, Department of Gynaecology and Gynaecologic Oncology, University Medical Centre Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany, Tel:
#
both authors contributed equally to this work
Key message This subgroup analysis of the AGO ROBOT study demonstrates that BOT patients with childbearing potential and fertility sparing management have a higher risk for disease recurrence. However, relapses usually remain BOT in the preserved ovaries as opposed to older patients being at higher risk for malignant transformation in peritoneal or distant localisation. Therefore, fertility sparing approach can be justified for younger patients after thorough consultation.
Key words borderline ovarian tumour, surgical treatment, fertility preservation, recurrence, malignant transformation
Downloaded from http://annonc.oxfordjournals.org/ at Anadolu University on April 29, 2014
+49 40 7410 52510, Fax: +49 40 7410 40070, E-mail: [email protected]
3 Abstract Background: Approximately one third of all borderline ovarian tumours (BOT) are diagnosed in patients with childbearing potential. Detailed information regarding their specific characteristics and prognostic factors is limited. Methods: Clinical parameters of BOT patients treated between 1998 and 2008 in 24 German centres were retrospectively investigated. Central pathology review and prospective follow-up were performed. Patients <40 versus ≥40 years were analysed
Results: A total of 950 BOT patients with a median age of 49.1 (14.1-91.5) years were analysed (280 patients <40 years [29.5%], 670 patients ≥40 years [70.5%]). Fertility-preserving surgery was performed in 53.2% (149/280) of patients <40 years with preservation of the primarily affected ovary in 32 of these 149 cases (21.5%). Recurrence was significantly more frequent in patients <40 years (19.0% vs 10.1% 5year-recurrence-rate, p<0.001), usually in ovarian tissue, whereas disease-specific overall survival did not differ between the subgroups. In case of recurrent disease, malignant transformation was less frequent in younger than in older patients (12.0% vs. 62.5%, p<0.001), mostly presenting as invasive peritoneal carcinomatosis. Multivariate analysis for patients <40 years identified advanced FIGO stage and fertility-sparing approach as independent prognostic factors negatively affecting PFS, while for patients ≥40 years higher FIGO stage and incomplete staging was associated with impaired PFS. Conclusions: Despite favourable survival, young BOT patients with childbearing potential are at higher risk for disease recurrence. However, relapses usually remain BOT in the preserved ovaries as opposed to older patients being at higher risk for malignant transformation in peritoneal or distant localisation. Therefore, fertility sparing approach can be justified for younger patients after thorough consultation.
Downloaded from http://annonc.oxfordjournals.org/ at Anadolu University on April 29, 2014
separately and then compared regarding clinicopathological variables and prognosis.
4 Introduction
Borderline ovarian tumours (BOT) represent a distinct tumour entity of epithelial origin accounting for approximately 10-20% of all ovarian neoplasms [1, 2]. In contrast to ovarian cancer they are characterised by the absence of destructive stromal invasion. They are distinct by an epidemiological shift towards younger women and an excellent overall prognosis with a 5-year-survival rate of more than
than ten years and undergo malignant transformation in selected cases [6]. Since approximately one third of BOT patients is younger than 40 years and the incidence of BOT has been rising over the past decades, fertility preserving aspects have become a considerable issue when the treatment plan is defined [7, 8]. Besides higher FIGO stage, incomplete surgical staging and residual tumour, fertility preservation was recently confirmed to be an independent prognostic factor for disease recurrence in the large cohort study on BOT of the Arbeitsgemeinschaft Gynaekologische Onkologie (AGO ROBOT study) [9]. With respect to the excellent overall prognosis, the risk of malignant transformation in case of relapse needs to be carefully investigated. We therefore performed a focused analysis of the AGO cohort study [9] to reveal potential age-specific differences of treatment and clinical course of BOT patients. A special focus was put on patients in reproductive age to generate a possible base for treatment recommendations in this specific subgroup.
Downloaded from http://annonc.oxfordjournals.org/ at Anadolu University on April 29, 2014
90% across all tumour stages [3-5]. Nevertheless, BOT may recur even after more
5 Methods
Patients All consecutive patients with primary diagnosis of BOT in the 11-year period between 1998 and 2008 from twenty-four participating member institutions of the Arbeitsgemeinschaft Gynaekologische Onkologie (AGO) study group were included in this recently published multicentre study (AGO ROBOT study) [9]. Patient cases
investigators. Clinical data was then retrieved from hospital records and/or clinical tumour registries. Patients without available paraffin embedded material or with coincident invasive cancer were excluded. The prospective part of this study included an active follow-up and an independent central pathology review by one of the two specialised gynaecopathologists (FK and SH) strictly following current WHO diagnostic criteria [10]. In case of discrepancies with initial diagnosis the primary pathologist at the participating centre was contacted, the diagnosis was discussed and consented. Only confirmed cases with BOT were included in the present analysis. Therapeutic strategies were documented according to patients' charts and surgery reports and aligned with pathology reports. Staging quality was considered comprehensive following German guidelines [11]. This includes bilateral salpingooophorectomy in patients ≥55 years or younger patients without attempted organ preservation, omentectomy or omental biopsy, peritoneal biopsies, peritoneal cytology, and, for cases with mucinous histology, appendectomy. Neither removal of the uterus nor lymphadenectomy were regarded necessary parts of staging procedures. Fertility sparing surgery was assumed in patients who were younger than 55 years at diagnosis and had the uterus and at least parts of one ovary left
Downloaded from http://annonc.oxfordjournals.org/ at Anadolu University on April 29, 2014
eligible for study participation at each centre were retrospectively identified by local
6 after operation. For patients with fertility preservation, surgical staging was considered comprehensive when apart from the reproductive organs the same surgical steps as described above were performed. The study protocol was approved by local ethics committees at each participating centre and written informed consent was obtained from all patients to access their tissue and review their medical records.
Statistical analysis
2.15.2 (R Foundation for Statistical Computing, Vienna). P values <0.05 were considered statistically significant. Age-dependent differences regarding clinical characteristics and outcome were evaluated separately for patients <40 years and ≥40 years according to the cut-off for primary ovarian insufficiency [12] to put a special focus on patients in reproductive age. Both groups were compared regarding clinicopathological variables and treatment parameters by applying Student’s t test or chi square test, as appropriate. Unless otherwise specified, surgical parameters are provided taken together primary and a possible secondary re-staging procedure. Kaplan-Meier method and log-rank test were used to analyse and illustrate progression-free (PFS) and disease-specific overall survival. For multivariate analysis regarding PFS Cox regression models were calculated and then presented via forest plots. These models were applied separately for the whole patient cohort as well as for patients <40 and ≥40 years only.
Downloaded from http://annonc.oxfordjournals.org/ at Anadolu University on April 29, 2014
All statistical analyses were conducted using IBM® SPSS® Statistics 19 and R
7 Results
A total of 950 patients met the inclusion criteria with confirmed diagnosis of BOT in central pathological review. Median age of the total cohort was 49.1 (14.1-91.5) years with 280 patients <40 years (29.5%) and 670 patients ≥40 years (70.5%). Detailed clinical and treatment-related parameters are provided in Tables 1 and 2. While histological subtype did not significantly differ between the groups with serous
significantly higher in younger patients (FIGO stage ≥II 25.7 vs. 14.3% in patients ≥40 years of age, p<0.001). Peritoneal implants were more frequent in patients <40 years (24.3% vs. 12.1%, p<0.001) with comparable distribution of invasive vs. non-invasive implants in both age groups (Table 1). Regarding the primary surgical approach, patients <40 years were more likely to undergo primary laparoscopy compared to patients ≥40 years (43.9% vs. 26.0%, p<0.001, Table 2, Figure S1). A fertility-sparing approach was conducted in 168 of all 950 patients (17.7%), and in 149 of the 280 patients <40 years (53.2%). Therefore, surgical procedures affecting fertility such as hysterectomy (26.8% vs. 87.2%, p<0.001) and bilateral salpingo-oophorectomy (31.1% vs. 92.7%, p<0.001) were significantly less frequent in younger patients compared to patients ≥40 years. Consequently, an inverse distribution of fertility-preserving procedures like unilateral salpingo-oophorectomy (57.5% vs. 5.7%, p<0.001) as well as unilateral or bilateral ovarian cystectomy (37.5% vs. 2.8%, p<0.001) was seen in younger patients as opposed to patients 40 years and older. In general, Preservation of a primarily affected ovary after completed surgical treatment was seen in 43 of 168 cases with a fertility-sparing approach (25.6%) sub-dividing into 32 of the 149 patients <40 years (21.5%) and 11 of the 19 patients ≥40 years (57.8%, Table 2, Figure S1).
Downloaded from http://annonc.oxfordjournals.org/ at Anadolu University on April 29, 2014
histology in 64.3% and mucinous histology in 30.5% of all patients, FIGO stage was
8 Further surgical interventions were equally distributed between the two subgroups except for a higher rate of peritoneal biopsies in younger patients (70.0% vs. 61.6%, p=0.01). Significantly more patients <40 years underwent re-staging procedures following incomplete primary surgery (48.6% vs. 27.3%, p<0.001) with the consequence of upstaging in 13.2% vs. 8.7% (Table 2, Figure S1). However, surgical outcome in terms of complete cytoreduction (91.8% vs. 92.5%, p=0.80) and adequate surgical staging (39.6% vs. 41.6%, p=0.57) did not differ between the two
Of all 950 patients, 74 patients (7.8%) experienced recurrent disease (Table 3). Among cases with tumour relapse, invasive carcinoma was detected in 22 of these 74 cases (29.7%) with a rate of 22.4% for serous, 60.0% for mucinous, and 50% for endometroid relapse. While the recurrence rate was significantly higher in the younger patient cohort (17.9% vs. 3.6%, p<0.001; 19.0% vs. 10.1% 5-yearrecurrence-rate, p<0.001), malignant transformation was significantly less often observed compared to patients ≥40 years (6 of 50, 12.0% vs. 16 of 24, 66.7%, p<0.001; table 3). In the younger patient subgroup almost two thirds of all relapses were diagnosed in remaining ovarian tissue without any case of malignant transformation, while this localization was significantly less frequent in patients ≥40 years (64% vs. 12.5% of patients with recurrent disease, p<0.001). Contrarily, recurrent disease in peritoneal implants or distant localization was more frequent among older patients compared to younger patients (87.5% vs. 36.0%, p<0.001) with a significantly higher rate of malignant histology in these cases (71.4% vs. 33.3%, p<0.001). Focussing on the 11 patients <40 years who experienced recurrent disease following organ preserving approach (11/32, 34.4%) BOT recurrence was diagnosed in the remaining ipsilateral
Downloaded from http://annonc.oxfordjournals.org/ at Anadolu University on April 29, 2014
age groups (Table 2, Figure S1).
9 ovary in four and in the contralateral ovary in seven patients. Initial histologic subtypes did not significantly differ between the two age groups for patients diagnosed with malignant transformation. Of note, in 9 of all 22 patients with malignant transformation (40.9%) the diagnosed invasive carcinoma was of high grade, especially in patients ≥40 years with 8 of the 16 cases (50%, Table 3).
As a consequence of the described results, rates for progression-free survival (PFS)
patients ≥40 years, p<0.001; Table 3, Figure S2A) while disease-specific overall survival (DSS) as assessed by the local investigators did not significantly differ between the two age groups (5-year-DSS-rate 98.9% vs. 97.7%, p=0.12; Table 3, Figure S2B). In multivariate analyses (Figure 1A-C), higher FIGO stage (IIA-C vs. IA/B HR 2.80, 95%CI 1.56, 5.01; IIIA-C vs. IA/B HR 3.38 95%CI 1.91, 5.98), postoperative residual tumour (HR 2.59, 95%CI 1.09, 6.19), incomplete staging (HR 2.27, 95%CI 1.44, 3.57), and fertility preservation (HR 2.15, 95%CI 1.25, 3.70) could be confirmed as independent prognostic factors for unfavourable PFS in the overall cohort (n=950) (Figure 1A). Focussing on the patient cohort <40 years, higher FIGO stage (IIA-C vs. IA/B HR 3.00, 95%CI 1.39, 6.48; IIIA-C vs. IA/B HR 3.38 95%CI 1.42, 8.09) and fertility preservation (HR 2.31, 95%CI 1.23, 4.33) remained statistically significant prognostic factors for impaired PFS (Figure 1B), while for the patients ≥40 years only staging quality was an independent prognostic factor (HR 0.36, 95%CI 0.18, 0.70; Figure 1C).
Downloaded from http://annonc.oxfordjournals.org/ at Anadolu University on April 29, 2014
were significantly lower in patients <40 years (5-year-PFS-rate 81.0% vs. 89.9% in
10 Discussion
With this subgroup analysis of the AGO ROBOT study we could observe that BOT patients with childbearing potential and fertility sparing management have a higher risk for disease recurrence in the remaining ovarian tissue. The risk for malignant transformation is however lower than in older patients resulting in an oncologic outcome comparable to the overall cohort.
AGO ROBOT study and were characterised by significantly higher FIGO stage and more peritoneal implants at first diagnosis compared to older patients. In contrast to ovarian cancer where fertility preservation is only reserved for special constellations, conservative surgical treatment represents an important option for patients with BOT [13]. In our cohort, fertility-sparing strategy was followed in more than half of the patients <40 years with preservation of parts of an BOT-affected ovary in 20% of these cases. Surgical outcome in terms of postoperative residual tumour and staging quality did not differ between the age groups. The individual extent of "adequate" staging procedures might, however, be different in both age groups as more younger patients underwent re-staging surgery when the diagnosis of BOT had already been confirmed. This could have led to more rigorous staging in these cases potentially explaining the higher FIGO stage and the higher rates of up-staging following restaging procedures in this younger patient cohort. Overall, an almost three-fold higher risk of recurrence without significant impact on overall survival has been previously described [6, 14]. In the present multivariate analysis of patients <40 years fertility preservation and FIGO stage remained independent prognostic factors for recurrence, seemingly explaining the significantly higher recurrence rates with 19.0% in younger patients compared to 10.1% for
Downloaded from http://annonc.oxfordjournals.org/ at Anadolu University on April 29, 2014
Patients <40 years represent about one third of all patients in the large cohort of the
11 patients ≥40 years. Of note, relapses of younger patients presented in 80% as BOT potentially cured by single secondary surgery with again a favourable prognosis [9]. We observed that these recurrences were mostly diagnosed in remaining ovarian tissue without an elevated risk of malignant transformation. Following organ preserving approach relapses were diagnosed as BOT in both, the ipsilateral remaining ovarian tissue and the contralateral ovary but not as invasive carcinoma. In contrast, two thirds of patients ≥40 years experiencing recurrent disease were
all of these 16 patients had relapse in form of peritoneal or distant tumour manifestations although initial FIGO stage was lower compared to younger patients. It can be speculated that biologic factors influence the clinical course of BOT patients leading to different tumour biology in older patients with recurrent BOT. So far, mutation analyses have shown that both, serous BOT and low-grade serous carcinoma may exhibit mutations in KRAS, BRAF and ERBB2 supporting the stepwise pathway from BOT to low-grade carcinoma [15-17]. In general, mutations in oncogenes have been observed to appear more frequently over lifespan [18] but it has to be suspected that further intracellular processes and changed transduction pathways are responsible for the different behaviour of recurrent BOT in older patients [19]. This is further supported by the fact that half of the patients ≥40 years with recurrent disease were diagnosed with high grade ovarian carcinoma which is in conflict with the stepwise-progression model of ovarian tumour development [17, 20] and warrants future investigations. In these cases a second primary tumour cannot be ruled out since high grade serous carcinomas tend to develop de novo and not stepwise with an intermediate borderline lesion [21]. Since all cases were subject to reference pathology the risk of missed primary diagnosis of cancer as described previously should be of low impact in the current
Downloaded from http://annonc.oxfordjournals.org/ at Anadolu University on April 29, 2014
diagnosed with invasive carcinoma and a consecutively impaired prognosis. Almost
12 study [22]. Nevertheless, patients were retrospectively included and not randomly assigned to one or another treatment strategy so that the results have to be cautiously interpreted to avoid possible selection bias. However, the AGO-ROBOT dataset represents a very large and in detail documented cohort of 950 BOT patients. The participating centres included all consecutive patients during the study period and all cases were subject to central pathological review leading to a homogenous well-characterized cohort of BOT patients.
of recurrent disease in this study provides evidence to justify fertility-sparing surgery for patients with childbearing potential. Tumourbiological mechanisms, reproductive outcome and the role of completion surgery, however, should now be systematically assessed to further substantiate treatment recommendations.
Acknowledgements
The following additional collaborators contributed to this work: J.D. Ruetzel (Hamburg), P. Harter and O. du Bois (HSK Wiesbaden), C. Kurzeder (Ulm), J. Sehouli (Berlin), S. Avril (TU Muenchen), E. Kuehnle (Kiel), R. Rothmund (Tuebingen), D. Mayr (LMU Muenchen), M. Tjahadi (Hannover), S. Markert (Freiburg), C. Thomssen and C. Richter (Halle), M. Peters (Solingen), G. Emons (Goettingen), R. Kimmig (Essen). C. Nasemann supported the data clarification process.
Funding No external funding sources were involved during this analysis.
Downloaded from http://annonc.oxfordjournals.org/ at Anadolu University on April 29, 2014
The observed age-specific risk of malignant transformation for BOT patients in case
13 Disclosure The authors have declared no conflicts of interest.
References
1. Skirnisdottir I, Garmo H, Wilander E, Holmberg L. Borderline ovarian tumors in Sweden 1960-2005: trends in incidence and age at diagnosis compared to ovarian cancer. Int J Cancer 2008; 123: 1897-1901.
3. Heintz AP, Odicino F, Maisonneuve P et al. Carcinoma of the ovary. FIGO 6th Annual Report on the Results of Treatment in Gynecological Cancer. Int J Gynaecol Obstet 2006; 95 Suppl 1: S161-192. 4. Tavassoli FA, Devilee P. Pathology and genetics of tumours of the breast and female genital organs. Lyon: IARC Press 2003. 5. Tang A, Kondalsamy-Chennakesavan S, Ngan H et al. Prognostic value of elevated preoperative serum CA125 in ovarian tumors of low malignant potential: a multinational collaborative study (ANZGOG0801). Gynecol Oncol 2012; 126: 36-40. 6. Du Bois A, Ewald-Riegler N, du Bois O, Harter P. Borderline Tumors of the Ovary - A Systematic Review [German]. Geburtsh Frauenheilk 2009; 69: 807-833. 7. Sherman ME, Mink PJ, Curtis R et al. Survival among women with borderline ovarian tumors and ovarian carcinoma: a population-based analysis. Cancer 2004; 100: 1045-1052. 8. Trillsch F, Mahner S, Ruetzel J et al. Clinical management of borderline ovarian tumors. Expert Rev Anticancer Ther 2010; 10: 1115-1124. 9. du Bois A, Ewald-Riegler N, de Gregorio N et al. Borderline tumours of the ovary: A cohort study of the Arbeitsgmeinschaft Gynakologische Onkologie (AGO) Study Group. Eur J Cancer 2013; 49: 1905-1914. 10. Tavassoli FA, Devilee P, International Agency for Research on Cancer., World Health Organization. Pathology and genetics of tumours of the breast and female genital organs. Lyon: IAPS Press 2003. 11. Deutsche Krebsgesellschaft DK, AWMF. S3-Leitlinie Diagnostik, Therapie und Nachsorge maligner Ovarialtumoren, Langversion 1.0; http://leitlinienprogrammonkologie.de/Leitlinien.7.0.html. AWMF Registrierungsnummer: 032-035OL 2013. 12. De Vos M, Devroey P, Fauser BC. Primary ovarian insufficiency. Lancet 2010; 376: 911-921.
Downloaded from http://annonc.oxfordjournals.org/ at Anadolu University on April 29, 2014
2. Trope C, Kaern J. Management of borderline tumors of the ovary: state of the art. Semin Oncol 1998; 25: 372-380.
14 13. Cadron I, Leunen K, Van Gorp T et al. Management of borderline ovarian neoplasms. J Clin Oncol 2007; 25: 2928-2937. 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: e103-115. 15. Kurman RJ, Shih Ie M. Molecular pathogenesis and extraovarian origin of epithelial ovarian cancer--shifting the paradigm. Hum Pathol 2011; 42: 918-931. 16.
Trillsch F, Aberle J, Regier M et al. Lost in effusion. Lancet 2012; 380: 620.
18. Bouchardy C, Rapiti E, Blagojevic S et al. Older female cancer patients: importance, causes, and consequences of undertreatment. J Clin Oncol 2007; 25: 1858-1869. 19. Farley J, Smith LM, Darcy KM et al. Nuclear P27 expression in benign, borderline (LMP) and invasive tumors of the ovary and its association with prognosis: a gynecologic oncology group study. Gynecol Oncol 2011; 121: 395-401. 20. Kurman RJ, Shih Ie M. Pathogenesis of ovarian cancer: lessons from morphology and molecular biology and their clinical implications. Int J Gynecol Pathol 2008; 27: 151-160. 21. Kurman RJ, Shih Ie M. The origin and pathogenesis of epithelial ovarian cancer: a proposed unifying theory. Am J Surg Pathol 2010; 34: 433-443. 22. Fischerova D, Zikan M, Dundr P, Cibula D. Diagnosis, treatment, and follow-up of borderline ovarian tumors. Oncologist 2012; 17: 1515-1533.
Downloaded from http://annonc.oxfordjournals.org/ at Anadolu University on April 29, 2014
17. May T, Virtanen C, Sharma M et al. Low malignant potential tumors with micropapillary features are molecularly similar to low-grade serous carcinoma of the ovary. Gynecol Oncol 2010; 117: 9-17.
15 Figure legends
Table 1: Clinical patient characteristics. Overview of the clinical characteristics of all included patients with primary BOT (n=950). A total of 280 patients <40 years are opposed to 670 patients 40 years and older.
Detailed overview of surgical procedures and outcome as well as the therapeutic intention. Parameters are separately analysed for patients <40 years (n=280) and patients ≥40 years (n=670).
Table 3: Clinical course and prognosis. Overview illustrating the clinical course of the included patients. Besides information on recurrence and malignant transformation with histological subtypes, survival rates are provided for progression-free and disease-specific overall survival. Parameters are separately analysed for patients <40 years (n=280) and patients ≥40 years (n=670).
Figure 1: Multivariate analysis of prognostic factors regarding progression-free survival (PFS). Forest plots illustrating analysis of possible prognostic factors regarding their statistical significance and independence in terms of PFS by cox regression model. These models were separately calculated for the overall patient cohort (A, n=950), for patients <40 years (B, n=280) and for patients ≥40 years (C, n=280). FIGO = International Federation of Gynecology and Obstetrics LSC = laparoscopy, LAP = laparotomy, LSC->LAP = laparoscopy converted to laparotomy
Downloaded from http://annonc.oxfordjournals.org/ at Anadolu University on April 29, 2014
Table 2: Treatment-related patient characteristics.
16
Downloaded from http://annonc.oxfordjournals.org/ at Anadolu University on April 29, 2014
17
Downloaded from http://annonc.oxfordjournals.org/ at Anadolu University on April 29, 2014
18
Downloaded from http://annonc.oxfordjournals.org/ at Anadolu University on April 29, 2014
Table 1: Clinical patient characteristics. total (%) n=950 Age at first diagnosis median years (range)
age <40y (%) n=280 (29.5)
age ≥40y (%) n=670 (70.5)
<0.001a 49.1 (14.1-91.5) 31.0 (14.1-40.0) 55.5 (40.0-91.5) b
<0.001 578 (60.8) 204 (21.5) 72 (7.6) 96 (10.1) 0 (0.0)
144 64 31 41 0
(51.4) (22.9) (11.1) (14.6) (0.0)
434 140 41 55 0
(64.8) (20.9) (6.1) (8.2) (0.0)
Histological subtype serous seromucinous mucinous endometroid other
611 (64.3) 33 (3.5) 290 (30.5) 10 (1.1) 6 (0.6)
194 (69.3) 4 (1.4) 77 (27.5) 3 (1.1) 2 (0.7)
417 29 213 7 4
(62.2) (4.3) (31.8) (1.0) (0.6)
Peritoneal implants Yes - non-invasive - invasive - both No
149 (15.7) - 123 (82.6) - 17 (11.4) - 9 (6.0) 801 (84.3)
68 (24.3) - 55 (80.9) - 9 (13.2) - 4 (5.9) 212 (75.7)
81 (12.1) - 68 (84.0) - 8 (9.9) - 5 (6.2) 589 (87.9)
CA125 levels preoperative elevated within normal limits not determined
83 (8.7) 44 (4.6) 823 (86.6)
30 (10.7) 12 (4.3) 238 (85.0)
53 32 585
b
0.078b
<0.001b
0.380b
Student's t-test, Chi²-test FIGO = International Federation of Gynecology and Obstetrics
(7.9) (4.8) (87.3)
Downloaded from http://annonc.oxfordjournals.org/ at Anadolu University on April 29, 2014
FIGO stage IA/B IC IIA-IIC IIIA-IIIC IV
a
p value
Table 2: Treatment-related patient characteristics.
Primary surgical approach laparoscopy converted (laparoscopy to laparotomy) laparotomy other (vaginal)
Re-staging surgery yes - up-staging - no up-staging no Surgical cytoreduction complete incomplete unknown
age <40y (%) n=280 (29.5)
age ≥40y (%) n=670 (70.5)
297 (31.3) 67 (7.1)
123 (43.9) 22 (7.9)
174 (26.0) 45 (6.7)
585 (61.6) 1 (0.1)
135 (48.2) 0 (0.0)
450 (67.2) 1 (0.1)
659 (69.4) 708 (74.5)
75 (26.8) 87 (31.1)
584 (87.2) 621 (92.7)
<0.001b <0.001b
199 (20.9)
161 (57.5)
38 (5.7)
<0.001
124 (13.1)
105 (37.5)
19 (2.8)
<0.001b
718 (75.6) 609 (64.1) 635 (66.8) 315 (33.2) 186 (19.6)
205 (73.2) 196 (70.0) 184 (65.7) 88 (31.4) 49 (17.5)
513 (76.6) 413 (61.6) 451 (67.3) 227 (33.9) 137 (20.4)
0.276 b 0.014 0.634b 0.463b 0.292b
115 (12.1)
29 (10.4)
86 (12.8)
0.279
<0.001b
319 (33.6) -34/319 (10.7) - 285/319 (89.3) 631 (66.4)
136 (48.6) -18/136 (13.2) -118/136 (86.8) 144 (51.4)
b
b
183 (27.3) 16/183 (8.7) 167/183 (91.3) 487 (72.7) 0.800b
877 (92.3) 12 (1.3) 61 (6.4)
257 (91.8) 3 (1.1) 20 (7.1)
620 (92.5) 9 (1.3) 41 (6.1) 0.568b
390 (41.1) 560 (58.9)
111 (39.6) 169 (60.4)
279 (41.6) 391 (58.4)
Fertility-sparing surgery yes no
168 (17.7) 782 (82.3)
149 (53.2) 131 (46.8)
19 (2.8) 651 (97.2)
Organ-preserving surgery yes no
43 (4.5) 907 (95.5)
32 (11.4) 248 (88.6)
11 (1.6) 659 (98.4)
Chemotherapy yes - for primary BOT - for recurrent BOT no
50 (5.3) - 35/50 (70.0) - 15/50 (30.0) 900 (94.7)
18 (6.4) - 14 (77.8) - 4 (22.2) 262 (93.6)
32 (4.8) - 21/32 (65.6) - 11/32 (34.4) 638 (95.2)
b
b
<0.001b
Staging quality adequate incomplete
a
p value
<0.001b
<0.001b
0.307b
Student's t-test, Chi²-test LND=lymph node dissection, LN=lymph node, BOT=borderline ovarian tumour
Downloaded from http://annonc.oxfordjournals.org/ at Anadolu University on April 29, 2014
Surgical interventions hysterectomy bilateral salpingooophorectomy unilateral salpingooophorectomy unilateral or bilateral cystectomy omentectomy peritoneal biopsies peritoneal cytology appendectomy pelvic LND/ LN biopsies para-aortic LND/ LN biopsies
total (%) n=950
Table 3: Clinical course and prognosis. Total (%) n=950 FIGO stage IA/B IC IIA-IIC IIIA-IIIC IV
-- low grade -- high grade -- unknown
- unknown no Overall rate of malignant transformation Site and dignity of recurrent disease ovarian tissue - BOT - invasive carcinoma other (peritoneum, distant) - BOT - invasive carcinoma - unknown Initial histology of cases with recurrent BOT serous - BOT again - invasive carcinoma
seromucinous mucinous - BOT again - invasive carcinoma
endometroid - BOT again - invasive carcinoma
other Initial histology of cases with malignant transformation serous mucinous endometroid other Progression-free survival 5-year-rate Disease-specific overall survival 5-year-rate b
c
age ≥40y (%) n=670 (70.5)
p value
<0.001b 578 (60.8) 204 (21.5) 72 (7.6) 96 (10.1) 0 (0.0)
144 64 31 41 0
(51.4) (22.9) (11.1) (14.6) (0.0)
434 (64.8) 140 (20.9) 41 (6.1) 55 (8.2) 0 (0.0) b
<0.001 74 (7.8) - 45/74 (60.8) - 3/74 (4.1) - 22/74 (29.7) --11/22 (50.0) -- 9/22 (40.1) -- 2/22 (9.1)
- 4/74 (5.4) 876 (92.2)
22/950 (2.3)
50 (17.9) - 40/50 (80.0) - 2/50 (4.0) - 6/50 (12.0)
24 (3.6) - 5/24 (20.8) - 1/24 (4.2) - 16/24 (66.7)
-- 5/6 (83.3) -- 1/6 (16.7)
- 2/50 (4.0) 230 (82.1)
-- 6/16 (37.5) -- 8/16 (50.0) -- 2/16 (12.5)
- 2/24 (8.3) 646 (96.4)
6/280 (2.1)
16/670 (2.4)
0.410b b
<0.001 35/74 (47.3) - 34/35 (97.1) - 1/35 (2.9) 39/74 (52.3) - 17/39 (43.6) - 21/39 (53.8) - 1/39 (2.6)
32/50 (64.0) 3/24 (12.5) - 32/32(100.0) - 2/3 (66.7) - 0/32 (0.0) - 1/3 (33.3) 18/50 (36.0) 21/24 (87.5) - 12/18 (66.7) - 5/21 (23.8) - 6/18 (33.3) - 15/21 (71.4) - 1/21 (4.8) b
<0.001 58/74 (78.4)
44/50 (88.0)
14/24 (58.3)
5/50 (10.0)
1/24 (4.2) 5/24 (20.8)
1/50 ( 2.0)
3/24 (12.5)
- 35/58 (77.6) - 13/58 (22.4)
1/74 (1.4) 10/74 (13.5) - 4/10 (40.0) - 6/10 (60.0)
4/74 (5.4) - 2/4 (50.0) - 2/4 (50.0)
1/74 (1.4)
13/22 (59.1) 6/22 (27.3) 2/22 (9.1) 1/22 (4.5)
1/24 (4.2)
4/6 (66.7) 2/6 (33.3)
9/16 (60.0) 4/16 (26.7) 2/16 (13.3) 1/16 (6.7) <0.001c
87.3
81.0
89.9 c
0.199 98.1
98.9
Chi²-test, log-rank test FIGO = International Federation of Gynecology and Obstetrics, BOT=borderline ovarian tumour
97.7
Downloaded from http://annonc.oxfordjournals.org/ at Anadolu University on April 29, 2014
Recurrent disease yes - BOT w/o microinvasion - BOT with microinvasion - invasive carcinoma
age <40y (%) n=280 (29.5)
1 Age-dependent differences in borderline ovarian tumours (BOT) regarding clinical characteristics and outcome: Results from a subanalysis of the Arbeitsgemeinschaft Gynaekologische Onkologie (AGO) ROBOT Study
F. Trillsch1,#, S. Mahner1,#, L. Woelber1, E. Vettorazzi2, A. Reuss3, N. EwaldRiegler4, N. de Gregorio5, C. Fotopoulou6, B. Schmalfeldt7, A. Burges8, F. Hilpert9, T. Fehm10, W. Meier11, P. Hillemanns12, L. Hanker13,14, A. Hasenburg15,
Paik21, U. Canzler19, K. Wollschlaeger22, D. Forner23, J. Pfisterer24,25, W. Schroeder26, K. Muenstedt27, B. Richter28, F. Kommoss29, S. Hauptmann16,30, A. du Bois31 1 Department of Gynaecology and Gynaecologic Oncology, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany 2 Department of Medical Biometry and Epidemiology, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany 3 Coordinating Center for Clinical Trials, Marburg, Germany 4 Department of Gynaecology and Gynaecologic Oncology, Dr. Horst Schmidt Klinik GmbH, Wiesbaden, Germany 5 Department of Gynaecolgy and Obstetrics, Universitätsklinikum Ulm, Ulm, Germany 6 Department of Gynaecolgy, Charité, Campus Virchow Klinikum, Berlin, Germany 7 Department of Obstetrics and Gynaecolgy, Klinikum rechts der Isar der Technischen Universität, Munich, Germany 8 Department of Obstetrics and Gynaecolgy, Klinikum der Universität München, Campus Großhadern, Munich, Germany 9 Department of Gynaecolgy and Obstetrics, Universitätsklinikum Schleswig-Holstein, Campus Kiel, Kiel, Germany 10 Department of Gynaecolgy and Obstetrics, Universitätsklinikum Tübingen, Tuebingen, Germany 11 Department of Gynaecolgy and Obstetrics, Evangelisches Krankenhaus, Duesseldorf, Germany 12 Department of Gynaecolgy and Obstetrics, Medizinische Hochschule Hannover, Hannover, Germany 13 Department of Gynaecolgy and Obstetrics, Klinikum der J.W. Goethe-Universität, Frankfurt/M., Germany 14 Department of Gynaecolgy and Obstetrics, Universitätsklinikum Schleswig-Holstein, Campus Lübeck, Luebeck, Germany 15 Department of Obstetrics and Gynaecolgy, Universitätsklinikum Freiburg, Freiburg, Germany 16 Department of Gynaecolgy and Obstetrics, Universitätsklinikum Halle/S., Halle/S., Germany 17 Department of Gynaecolgy and Obstetrics, Georg-August-Universität Göttingen, Goettingen, Germany 18 Clinic of Gynaecolgy and Obstetrics, Universitätsklinikum Essen, Essen, Germany 19 Department of Gynaecolgy and Obstetrics, Universitätsklinikum Carl Gustav Carus, Dresden, Germany 20 Department of Gynaecolgy, Endocrinology and Oncology, Universitätsklinikum Gießen u. Marburg GmbH, Marburg, Germany 21 Department of Obstetrics and Gynaecolgy, Rheinische Friedrich-Wilhelms-Universität, Bonn, Germany 22 Department of Gynaecolgy and Obstetrics, Universitätsklinikum Magdeburg, Magdeburg, Germany 23 Department of Gynaecolgy and Obstetrics, Sana-Klinikum Remscheid, Remscheid, Germany
© The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected].
Downloaded from http://annonc.oxfordjournals.org/ at Anadolu University on April 29, 2014
H.G. Strauss16, M. Hellriegel17, P. Wimberger18,19, K. Baumann20, M.D. Keyver-
2 24
Department of Gynaecolgy and Obstetrics, Städtisches Klinikum Solingen gGmbH, Solingen, Germany 25 Zentrum für Gynäkologische Onkologie, Kiel, Germany 26 GYNAEKOLOGICUM Bremen, Bremen, Germany 27 Department of Obstetrics and Gynaecolgy, Universitätsklinikum Gießen, Gießen, Germany 28 Department of Gynaecology and Obstetrics, Elblandkliniken Meißen-Radebeul GmbH & Co. KG, Radebeul, Germany 29 Institute of Pathology, Referenzzentrum für Gynäkopathologie, Mannheim, Germany 30 Institute of Pathology Trier-Dueren-Duesseldorf, Dueren, Germany 31 Department of Gynaecolgy and Gynaecolgic Oncology, Kliniken Essen-Mitte, Essen, Germany Corresponding author: Dr. Sven Mahner, Department of Gynaecology and Gynaecologic Oncology, University Medical Centre Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany, Tel:
#
both authors contributed equally to this work
Key message This subgroup analysis of the AGO ROBOT study demonstrates that BOT patients with childbearing potential and fertility sparing management have a higher risk for disease recurrence. However, relapses usually remain BOT in the preserved ovaries as opposed to older patients being at higher risk for malignant transformation in peritoneal or distant localisation. Therefore, fertility sparing approach can be justified for younger patients after thorough consultation.
Key words borderline ovarian tumour, surgical treatment, fertility preservation, recurrence, malignant transformation
Downloaded from http://annonc.oxfordjournals.org/ at Anadolu University on April 29, 2014
+49 40 7410 52510, Fax: +49 40 7410 40070, E-mail: [email protected]
3 Abstract Background: Approximately one third of all borderline ovarian tumours (BOT) are diagnosed in patients with childbearing potential. Detailed information regarding their specific characteristics and prognostic factors is limited. Methods: Clinical parameters of BOT patients treated between 1998 and 2008 in 24 German centres were retrospectively investigated. Central pathology review and prospective follow-up were performed. Patients <40 versus ≥40 years were analysed
Results: A total of 950 BOT patients with a median age of 49.1 (14.1-91.5) years were analysed (280 patients <40 years [29.5%], 670 patients ≥40 years [70.5%]). Fertility-preserving surgery was performed in 53.2% (149/280) of patients <40 years with preservation of the primarily affected ovary in 32 of these 149 cases (21.5%). Recurrence was significantly more frequent in patients <40 years (19.0% vs 10.1% 5year-recurrence-rate, p<0.001), usually in ovarian tissue, whereas disease-specific overall survival did not differ between the subgroups. In case of recurrent disease, malignant transformation was less frequent in younger than in older patients (12.0% vs. 62.5%, p<0.001), mostly presenting as invasive peritoneal carcinomatosis. Multivariate analysis for patients <40 years identified advanced FIGO stage and fertility-sparing approach as independent prognostic factors negatively affecting PFS, while for patients ≥40 years higher FIGO stage and incomplete staging was associated with impaired PFS. Conclusions: Despite favourable survival, young BOT patients with childbearing potential are at higher risk for disease recurrence. However, relapses usually remain BOT in the preserved ovaries as opposed to older patients being at higher risk for malignant transformation in peritoneal or distant localisation. Therefore, fertility sparing approach can be justified for younger patients after thorough consultation.
Downloaded from http://annonc.oxfordjournals.org/ at Anadolu University on April 29, 2014
separately and then compared regarding clinicopathological variables and prognosis.
4 Introduction
Borderline ovarian tumours (BOT) represent a distinct tumour entity of epithelial origin accounting for approximately 10-20% of all ovarian neoplasms [1, 2]. In contrast to ovarian cancer they are characterised by the absence of destructive stromal invasion. They are distinct by an epidemiological shift towards younger women and an excellent overall prognosis with a 5-year-survival rate of more than
than ten years and undergo malignant transformation in selected cases [6]. Since approximately one third of BOT patients is younger than 40 years and the incidence of BOT has been rising over the past decades, fertility preserving aspects have become a considerable issue when the treatment plan is defined [7, 8]. Besides higher FIGO stage, incomplete surgical staging and residual tumour, fertility preservation was recently confirmed to be an independent prognostic factor for disease recurrence in the large cohort study on BOT of the Arbeitsgemeinschaft Gynaekologische Onkologie (AGO ROBOT study) [9]. With respect to the excellent overall prognosis, the risk of malignant transformation in case of relapse needs to be carefully investigated. We therefore performed a focused analysis of the AGO cohort study [9] to reveal potential age-specific differences of treatment and clinical course of BOT patients. A special focus was put on patients in reproductive age to generate a possible base for treatment recommendations in this specific subgroup.
Downloaded from http://annonc.oxfordjournals.org/ at Anadolu University on April 29, 2014
90% across all tumour stages [3-5]. Nevertheless, BOT may recur even after more
5 Methods
Patients All consecutive patients with primary diagnosis of BOT in the 11-year period between 1998 and 2008 from twenty-four participating member institutions of the Arbeitsgemeinschaft Gynaekologische Onkologie (AGO) study group were included in this recently published multicentre study (AGO ROBOT study) [9]. Patient cases
investigators. Clinical data was then retrieved from hospital records and/or clinical tumour registries. Patients without available paraffin embedded material or with coincident invasive cancer were excluded. The prospective part of this study included an active follow-up and an independent central pathology review by one of the two specialised gynaecopathologists (FK and SH) strictly following current WHO diagnostic criteria [10]. In case of discrepancies with initial diagnosis the primary pathologist at the participating centre was contacted, the diagnosis was discussed and consented. Only confirmed cases with BOT were included in the present analysis. Therapeutic strategies were documented according to patients' charts and surgery reports and aligned with pathology reports. Staging quality was considered comprehensive following German guidelines [11]. This includes bilateral salpingooophorectomy in patients ≥55 years or younger patients without attempted organ preservation, omentectomy or omental biopsy, peritoneal biopsies, peritoneal cytology, and, for cases with mucinous histology, appendectomy. Neither removal of the uterus nor lymphadenectomy were regarded necessary parts of staging procedures. Fertility sparing surgery was assumed in patients who were younger than 55 years at diagnosis and had the uterus and at least parts of one ovary left
Downloaded from http://annonc.oxfordjournals.org/ at Anadolu University on April 29, 2014
eligible for study participation at each centre were retrospectively identified by local
6 after operation. For patients with fertility preservation, surgical staging was considered comprehensive when apart from the reproductive organs the same surgical steps as described above were performed. The study protocol was approved by local ethics committees at each participating centre and written informed consent was obtained from all patients to access their tissue and review their medical records.
Statistical analysis
2.15.2 (R Foundation for Statistical Computing, Vienna). P values <0.05 were considered statistically significant. Age-dependent differences regarding clinical characteristics and outcome were evaluated separately for patients <40 years and ≥40 years according to the cut-off for primary ovarian insufficiency [12] to put a special focus on patients in reproductive age. Both groups were compared regarding clinicopathological variables and treatment parameters by applying Student’s t test or chi square test, as appropriate. Unless otherwise specified, surgical parameters are provided taken together primary and a possible secondary re-staging procedure. Kaplan-Meier method and log-rank test were used to analyse and illustrate progression-free (PFS) and disease-specific overall survival. For multivariate analysis regarding PFS Cox regression models were calculated and then presented via forest plots. These models were applied separately for the whole patient cohort as well as for patients <40 and ≥40 years only.
Downloaded from http://annonc.oxfordjournals.org/ at Anadolu University on April 29, 2014
All statistical analyses were conducted using IBM® SPSS® Statistics 19 and R
7 Results
A total of 950 patients met the inclusion criteria with confirmed diagnosis of BOT in central pathological review. Median age of the total cohort was 49.1 (14.1-91.5) years with 280 patients <40 years (29.5%) and 670 patients ≥40 years (70.5%). Detailed clinical and treatment-related parameters are provided in Tables 1 and 2. While histological subtype did not significantly differ between the groups with serous
significantly higher in younger patients (FIGO stage ≥II 25.7 vs. 14.3% in patients ≥40 years of age, p<0.001). Peritoneal implants were more frequent in patients <40 years (24.3% vs. 12.1%, p<0.001) with comparable distribution of invasive vs. non-invasive implants in both age groups (Table 1). Regarding the primary surgical approach, patients <40 years were more likely to undergo primary laparoscopy compared to patients ≥40 years (43.9% vs. 26.0%, p<0.001, Table 2, Figure S1). A fertility-sparing approach was conducted in 168 of all 950 patients (17.7%), and in 149 of the 280 patients <40 years (53.2%). Therefore, surgical procedures affecting fertility such as hysterectomy (26.8% vs. 87.2%, p<0.001) and bilateral salpingo-oophorectomy (31.1% vs. 92.7%, p<0.001) were significantly less frequent in younger patients compared to patients ≥40 years. Consequently, an inverse distribution of fertility-preserving procedures like unilateral salpingo-oophorectomy (57.5% vs. 5.7%, p<0.001) as well as unilateral or bilateral ovarian cystectomy (37.5% vs. 2.8%, p<0.001) was seen in younger patients as opposed to patients 40 years and older. In general, Preservation of a primarily affected ovary after completed surgical treatment was seen in 43 of 168 cases with a fertility-sparing approach (25.6%) sub-dividing into 32 of the 149 patients <40 years (21.5%) and 11 of the 19 patients ≥40 years (57.8%, Table 2, Figure S1).
Downloaded from http://annonc.oxfordjournals.org/ at Anadolu University on April 29, 2014
histology in 64.3% and mucinous histology in 30.5% of all patients, FIGO stage was
8 Further surgical interventions were equally distributed between the two subgroups except for a higher rate of peritoneal biopsies in younger patients (70.0% vs. 61.6%, p=0.01). Significantly more patients <40 years underwent re-staging procedures following incomplete primary surgery (48.6% vs. 27.3%, p<0.001) with the consequence of upstaging in 13.2% vs. 8.7% (Table 2, Figure S1). However, surgical outcome in terms of complete cytoreduction (91.8% vs. 92.5%, p=0.80) and adequate surgical staging (39.6% vs. 41.6%, p=0.57) did not differ between the two
Of all 950 patients, 74 patients (7.8%) experienced recurrent disease (Table 3). Among cases with tumour relapse, invasive carcinoma was detected in 22 of these 74 cases (29.7%) with a rate of 22.4% for serous, 60.0% for mucinous, and 50% for endometroid relapse. While the recurrence rate was significantly higher in the younger patient cohort (17.9% vs. 3.6%, p<0.001; 19.0% vs. 10.1% 5-yearrecurrence-rate, p<0.001), malignant transformation was significantly less often observed compared to patients ≥40 years (6 of 50, 12.0% vs. 16 of 24, 66.7%, p<0.001; table 3). In the younger patient subgroup almost two thirds of all relapses were diagnosed in remaining ovarian tissue without any case of malignant transformation, while this localization was significantly less frequent in patients ≥40 years (64% vs. 12.5% of patients with recurrent disease, p<0.001). Contrarily, recurrent disease in peritoneal implants or distant localization was more frequent among older patients compared to younger patients (87.5% vs. 36.0%, p<0.001) with a significantly higher rate of malignant histology in these cases (71.4% vs. 33.3%, p<0.001). Focussing on the 11 patients <40 years who experienced recurrent disease following organ preserving approach (11/32, 34.4%) BOT recurrence was diagnosed in the remaining ipsilateral
Downloaded from http://annonc.oxfordjournals.org/ at Anadolu University on April 29, 2014
age groups (Table 2, Figure S1).
9 ovary in four and in the contralateral ovary in seven patients. Initial histologic subtypes did not significantly differ between the two age groups for patients diagnosed with malignant transformation. Of note, in 9 of all 22 patients with malignant transformation (40.9%) the diagnosed invasive carcinoma was of high grade, especially in patients ≥40 years with 8 of the 16 cases (50%, Table 3).
As a consequence of the described results, rates for progression-free survival (PFS)
patients ≥40 years, p<0.001; Table 3, Figure S2A) while disease-specific overall survival (DSS) as assessed by the local investigators did not significantly differ between the two age groups (5-year-DSS-rate 98.9% vs. 97.7%, p=0.12; Table 3, Figure S2B). In multivariate analyses (Figure 1A-C), higher FIGO stage (IIA-C vs. IA/B HR 2.80, 95%CI 1.56, 5.01; IIIA-C vs. IA/B HR 3.38 95%CI 1.91, 5.98), postoperative residual tumour (HR 2.59, 95%CI 1.09, 6.19), incomplete staging (HR 2.27, 95%CI 1.44, 3.57), and fertility preservation (HR 2.15, 95%CI 1.25, 3.70) could be confirmed as independent prognostic factors for unfavourable PFS in the overall cohort (n=950) (Figure 1A). Focussing on the patient cohort <40 years, higher FIGO stage (IIA-C vs. IA/B HR 3.00, 95%CI 1.39, 6.48; IIIA-C vs. IA/B HR 3.38 95%CI 1.42, 8.09) and fertility preservation (HR 2.31, 95%CI 1.23, 4.33) remained statistically significant prognostic factors for impaired PFS (Figure 1B), while for the patients ≥40 years only staging quality was an independent prognostic factor (HR 0.36, 95%CI 0.18, 0.70; Figure 1C).
Downloaded from http://annonc.oxfordjournals.org/ at Anadolu University on April 29, 2014
were significantly lower in patients <40 years (5-year-PFS-rate 81.0% vs. 89.9% in
10 Discussion
With this subgroup analysis of the AGO ROBOT study we could observe that BOT patients with childbearing potential and fertility sparing management have a higher risk for disease recurrence in the remaining ovarian tissue. The risk for malignant transformation is however lower than in older patients resulting in an oncologic outcome comparable to the overall cohort.
AGO ROBOT study and were characterised by significantly higher FIGO stage and more peritoneal implants at first diagnosis compared to older patients. In contrast to ovarian cancer where fertility preservation is only reserved for special constellations, conservative surgical treatment represents an important option for patients with BOT [13]. In our cohort, fertility-sparing strategy was followed in more than half of the patients <40 years with preservation of parts of an BOT-affected ovary in 20% of these cases. Surgical outcome in terms of postoperative residual tumour and staging quality did not differ between the age groups. The individual extent of "adequate" staging procedures might, however, be different in both age groups as more younger patients underwent re-staging surgery when the diagnosis of BOT had already been confirmed. This could have led to more rigorous staging in these cases potentially explaining the higher FIGO stage and the higher rates of up-staging following restaging procedures in this younger patient cohort. Overall, an almost three-fold higher risk of recurrence without significant impact on overall survival has been previously described [6, 14]. In the present multivariate analysis of patients <40 years fertility preservation and FIGO stage remained independent prognostic factors for recurrence, seemingly explaining the significantly higher recurrence rates with 19.0% in younger patients compared to 10.1% for
Downloaded from http://annonc.oxfordjournals.org/ at Anadolu University on April 29, 2014
Patients <40 years represent about one third of all patients in the large cohort of the
11 patients ≥40 years. Of note, relapses of younger patients presented in 80% as BOT potentially cured by single secondary surgery with again a favourable prognosis [9]. We observed that these recurrences were mostly diagnosed in remaining ovarian tissue without an elevated risk of malignant transformation. Following organ preserving approach relapses were diagnosed as BOT in both, the ipsilateral remaining ovarian tissue and the contralateral ovary but not as invasive carcinoma. In contrast, two thirds of patients ≥40 years experiencing recurrent disease were
all of these 16 patients had relapse in form of peritoneal or distant tumour manifestations although initial FIGO stage was lower compared to younger patients. It can be speculated that biologic factors influence the clinical course of BOT patients leading to different tumour biology in older patients with recurrent BOT. So far, mutation analyses have shown that both, serous BOT and low-grade serous carcinoma may exhibit mutations in KRAS, BRAF and ERBB2 supporting the stepwise pathway from BOT to low-grade carcinoma [15-17]. In general, mutations in oncogenes have been observed to appear more frequently over lifespan [18] but it has to be suspected that further intracellular processes and changed transduction pathways are responsible for the different behaviour of recurrent BOT in older patients [19]. This is further supported by the fact that half of the patients ≥40 years with recurrent disease were diagnosed with high grade ovarian carcinoma which is in conflict with the stepwise-progression model of ovarian tumour development [17, 20] and warrants future investigations. In these cases a second primary tumour cannot be ruled out since high grade serous carcinomas tend to develop de novo and not stepwise with an intermediate borderline lesion [21]. Since all cases were subject to reference pathology the risk of missed primary diagnosis of cancer as described previously should be of low impact in the current
Downloaded from http://annonc.oxfordjournals.org/ at Anadolu University on April 29, 2014
diagnosed with invasive carcinoma and a consecutively impaired prognosis. Almost
12 study [22]. Nevertheless, patients were retrospectively included and not randomly assigned to one or another treatment strategy so that the results have to be cautiously interpreted to avoid possible selection bias. However, the AGO-ROBOT dataset represents a very large and in detail documented cohort of 950 BOT patients. The participating centres included all consecutive patients during the study period and all cases were subject to central pathological review leading to a homogenous well-characterized cohort of BOT patients.
of recurrent disease in this study provides evidence to justify fertility-sparing surgery for patients with childbearing potential. Tumourbiological mechanisms, reproductive outcome and the role of completion surgery, however, should now be systematically assessed to further substantiate treatment recommendations.
Acknowledgements
The following additional collaborators contributed to this work: J.D. Ruetzel (Hamburg), P. Harter and O. du Bois (HSK Wiesbaden), C. Kurzeder (Ulm), J. Sehouli (Berlin), S. Avril (TU Muenchen), E. Kuehnle (Kiel), R. Rothmund (Tuebingen), D. Mayr (LMU Muenchen), M. Tjahadi (Hannover), S. Markert (Freiburg), C. Thomssen and C. Richter (Halle), M. Peters (Solingen), G. Emons (Goettingen), R. Kimmig (Essen). C. Nasemann supported the data clarification process.
Funding No external funding sources were involved during this analysis.
Downloaded from http://annonc.oxfordjournals.org/ at Anadolu University on April 29, 2014
The observed age-specific risk of malignant transformation for BOT patients in case
13 Disclosure The authors have declared no conflicts of interest.
References
1. Skirnisdottir I, Garmo H, Wilander E, Holmberg L. Borderline ovarian tumors in Sweden 1960-2005: trends in incidence and age at diagnosis compared to ovarian cancer. Int J Cancer 2008; 123: 1897-1901.
3. Heintz AP, Odicino F, Maisonneuve P et al. Carcinoma of the ovary. FIGO 6th Annual Report on the Results of Treatment in Gynecological Cancer. Int J Gynaecol Obstet 2006; 95 Suppl 1: S161-192. 4. Tavassoli FA, Devilee P. Pathology and genetics of tumours of the breast and female genital organs. Lyon: IARC Press 2003. 5. Tang A, Kondalsamy-Chennakesavan S, Ngan H et al. Prognostic value of elevated preoperative serum CA125 in ovarian tumors of low malignant potential: a multinational collaborative study (ANZGOG0801). Gynecol Oncol 2012; 126: 36-40. 6. Du Bois A, Ewald-Riegler N, du Bois O, Harter P. Borderline Tumors of the Ovary - A Systematic Review [German]. Geburtsh Frauenheilk 2009; 69: 807-833. 7. Sherman ME, Mink PJ, Curtis R et al. Survival among women with borderline ovarian tumors and ovarian carcinoma: a population-based analysis. Cancer 2004; 100: 1045-1052. 8. Trillsch F, Mahner S, Ruetzel J et al. Clinical management of borderline ovarian tumors. Expert Rev Anticancer Ther 2010; 10: 1115-1124. 9. du Bois A, Ewald-Riegler N, de Gregorio N et al. Borderline tumours of the ovary: A cohort study of the Arbeitsgmeinschaft Gynakologische Onkologie (AGO) Study Group. Eur J Cancer 2013; 49: 1905-1914. 10. Tavassoli FA, Devilee P, International Agency for Research on Cancer., World Health Organization. Pathology and genetics of tumours of the breast and female genital organs. Lyon: IAPS Press 2003. 11. Deutsche Krebsgesellschaft DK, AWMF. S3-Leitlinie Diagnostik, Therapie und Nachsorge maligner Ovarialtumoren, Langversion 1.0; http://leitlinienprogrammonkologie.de/Leitlinien.7.0.html. AWMF Registrierungsnummer: 032-035OL 2013. 12. De Vos M, Devroey P, Fauser BC. Primary ovarian insufficiency. Lancet 2010; 376: 911-921.
Downloaded from http://annonc.oxfordjournals.org/ at Anadolu University on April 29, 2014
2. Trope C, Kaern J. Management of borderline tumors of the ovary: state of the art. Semin Oncol 1998; 25: 372-380.
14 13. Cadron I, Leunen K, Van Gorp T et al. Management of borderline ovarian neoplasms. J Clin Oncol 2007; 25: 2928-2937. 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: e103-115. 15. Kurman RJ, Shih Ie M. Molecular pathogenesis and extraovarian origin of epithelial ovarian cancer--shifting the paradigm. Hum Pathol 2011; 42: 918-931. 16.
Trillsch F, Aberle J, Regier M et al. Lost in effusion. Lancet 2012; 380: 620.
18. Bouchardy C, Rapiti E, Blagojevic S et al. Older female cancer patients: importance, causes, and consequences of undertreatment. J Clin Oncol 2007; 25: 1858-1869. 19. Farley J, Smith LM, Darcy KM et al. Nuclear P27 expression in benign, borderline (LMP) and invasive tumors of the ovary and its association with prognosis: a gynecologic oncology group study. Gynecol Oncol 2011; 121: 395-401. 20. Kurman RJ, Shih Ie M. Pathogenesis of ovarian cancer: lessons from morphology and molecular biology and their clinical implications. Int J Gynecol Pathol 2008; 27: 151-160. 21. Kurman RJ, Shih Ie M. The origin and pathogenesis of epithelial ovarian cancer: a proposed unifying theory. Am J Surg Pathol 2010; 34: 433-443. 22. Fischerova D, Zikan M, Dundr P, Cibula D. Diagnosis, treatment, and follow-up of borderline ovarian tumors. Oncologist 2012; 17: 1515-1533.
Downloaded from http://annonc.oxfordjournals.org/ at Anadolu University on April 29, 2014
17. May T, Virtanen C, Sharma M et al. Low malignant potential tumors with micropapillary features are molecularly similar to low-grade serous carcinoma of the ovary. Gynecol Oncol 2010; 117: 9-17.
15 Figure legends
Table 1: Clinical patient characteristics. Overview of the clinical characteristics of all included patients with primary BOT (n=950). A total of 280 patients <40 years are opposed to 670 patients 40 years and older.
Detailed overview of surgical procedures and outcome as well as the therapeutic intention. Parameters are separately analysed for patients <40 years (n=280) and patients ≥40 years (n=670).
Table 3: Clinical course and prognosis. Overview illustrating the clinical course of the included patients. Besides information on recurrence and malignant transformation with histological subtypes, survival rates are provided for progression-free and disease-specific overall survival. Parameters are separately analysed for patients <40 years (n=280) and patients ≥40 years (n=670).
Figure 1: Multivariate analysis of prognostic factors regarding progression-free survival (PFS). Forest plots illustrating analysis of possible prognostic factors regarding their statistical significance and independence in terms of PFS by cox regression model. These models were separately calculated for the overall patient cohort (A, n=950), for patients <40 years (B, n=280) and for patients ≥40 years (C, n=280). FIGO = International Federation of Gynecology and Obstetrics LSC = laparoscopy, LAP = laparotomy, LSC->LAP = laparoscopy converted to laparotomy
Downloaded from http://annonc.oxfordjournals.org/ at Anadolu University on April 29, 2014
Table 2: Treatment-related patient characteristics.
16
Downloaded from http://annonc.oxfordjournals.org/ at Anadolu University on April 29, 2014
17
Downloaded from http://annonc.oxfordjournals.org/ at Anadolu University on April 29, 2014
18
Downloaded from http://annonc.oxfordjournals.org/ at Anadolu University on April 29, 2014
Table 1: Clinical patient characteristics. total (%) n=950 Age at first diagnosis median years (range)
age <40y (%) n=280 (29.5)
age ≥40y (%) n=670 (70.5)
<0.001a 49.1 (14.1-91.5) 31.0 (14.1-40.0) 55.5 (40.0-91.5) b
<0.001 578 (60.8) 204 (21.5) 72 (7.6) 96 (10.1) 0 (0.0)
144 64 31 41 0
(51.4) (22.9) (11.1) (14.6) (0.0)
434 140 41 55 0
(64.8) (20.9) (6.1) (8.2) (0.0)
Histological subtype serous seromucinous mucinous endometroid other
611 (64.3) 33 (3.5) 290 (30.5) 10 (1.1) 6 (0.6)
194 (69.3) 4 (1.4) 77 (27.5) 3 (1.1) 2 (0.7)
417 29 213 7 4
(62.2) (4.3) (31.8) (1.0) (0.6)
Peritoneal implants Yes - non-invasive - invasive - both No
149 (15.7) - 123 (82.6) - 17 (11.4) - 9 (6.0) 801 (84.3)
68 (24.3) - 55 (80.9) - 9 (13.2) - 4 (5.9) 212 (75.7)
81 (12.1) - 68 (84.0) - 8 (9.9) - 5 (6.2) 589 (87.9)
CA125 levels preoperative elevated within normal limits not determined
83 (8.7) 44 (4.6) 823 (86.6)
30 (10.7) 12 (4.3) 238 (85.0)
53 32 585
b
0.078b
<0.001b
0.380b
Student's t-test, Chi²-test FIGO = International Federation of Gynecology and Obstetrics
(7.9) (4.8) (87.3)
Downloaded from http://annonc.oxfordjournals.org/ at Anadolu University on April 29, 2014
FIGO stage IA/B IC IIA-IIC IIIA-IIIC IV
a
p value
Table 2: Treatment-related patient characteristics.
Primary surgical approach laparoscopy converted (laparoscopy to laparotomy) laparotomy other (vaginal)
Re-staging surgery yes - up-staging - no up-staging no Surgical cytoreduction complete incomplete unknown
age <40y (%) n=280 (29.5)
age ≥40y (%) n=670 (70.5)
297 (31.3) 67 (7.1)
123 (43.9) 22 (7.9)
174 (26.0) 45 (6.7)
585 (61.6) 1 (0.1)
135 (48.2) 0 (0.0)
450 (67.2) 1 (0.1)
659 (69.4) 708 (74.5)
75 (26.8) 87 (31.1)
584 (87.2) 621 (92.7)
<0.001b <0.001b
199 (20.9)
161 (57.5)
38 (5.7)
<0.001
124 (13.1)
105 (37.5)
19 (2.8)
<0.001b
718 (75.6) 609 (64.1) 635 (66.8) 315 (33.2) 186 (19.6)
205 (73.2) 196 (70.0) 184 (65.7) 88 (31.4) 49 (17.5)
513 (76.6) 413 (61.6) 451 (67.3) 227 (33.9) 137 (20.4)
0.276 b 0.014 0.634b 0.463b 0.292b
115 (12.1)
29 (10.4)
86 (12.8)
0.279
<0.001b
319 (33.6) -34/319 (10.7) - 285/319 (89.3) 631 (66.4)
136 (48.6) -18/136 (13.2) -118/136 (86.8) 144 (51.4)
b
b
183 (27.3) 16/183 (8.7) 167/183 (91.3) 487 (72.7) 0.800b
877 (92.3) 12 (1.3) 61 (6.4)
257 (91.8) 3 (1.1) 20 (7.1)
620 (92.5) 9 (1.3) 41 (6.1) 0.568b
390 (41.1) 560 (58.9)
111 (39.6) 169 (60.4)
279 (41.6) 391 (58.4)
Fertility-sparing surgery yes no
168 (17.7) 782 (82.3)
149 (53.2) 131 (46.8)
19 (2.8) 651 (97.2)
Organ-preserving surgery yes no
43 (4.5) 907 (95.5)
32 (11.4) 248 (88.6)
11 (1.6) 659 (98.4)
Chemotherapy yes - for primary BOT - for recurrent BOT no
50 (5.3) - 35/50 (70.0) - 15/50 (30.0) 900 (94.7)
18 (6.4) - 14 (77.8) - 4 (22.2) 262 (93.6)
32 (4.8) - 21/32 (65.6) - 11/32 (34.4) 638 (95.2)
b
b
<0.001b
Staging quality adequate incomplete
a
p value
<0.001b
<0.001b
0.307b
Student's t-test, Chi²-test LND=lymph node dissection, LN=lymph node, BOT=borderline ovarian tumour
Downloaded from http://annonc.oxfordjournals.org/ at Anadolu University on April 29, 2014
Surgical interventions hysterectomy bilateral salpingooophorectomy unilateral salpingooophorectomy unilateral or bilateral cystectomy omentectomy peritoneal biopsies peritoneal cytology appendectomy pelvic LND/ LN biopsies para-aortic LND/ LN biopsies
total (%) n=950
Table 3: Clinical course and prognosis. Total (%) n=950 FIGO stage IA/B IC IIA-IIC IIIA-IIIC IV
-- low grade -- high grade -- unknown
- unknown no Overall rate of malignant transformation Site and dignity of recurrent disease ovarian tissue - BOT - invasive carcinoma other (peritoneum, distant) - BOT - invasive carcinoma - unknown Initial histology of cases with recurrent BOT serous - BOT again - invasive carcinoma
seromucinous mucinous - BOT again - invasive carcinoma
endometroid - BOT again - invasive carcinoma
other Initial histology of cases with malignant transformation serous mucinous endometroid other Progression-free survival 5-year-rate Disease-specific overall survival 5-year-rate b
c
age ≥40y (%) n=670 (70.5)
p value
<0.001b 578 (60.8) 204 (21.5) 72 (7.6) 96 (10.1) 0 (0.0)
144 64 31 41 0
(51.4) (22.9) (11.1) (14.6) (0.0)
434 (64.8) 140 (20.9) 41 (6.1) 55 (8.2) 0 (0.0) b
<0.001 74 (7.8) - 45/74 (60.8) - 3/74 (4.1) - 22/74 (29.7) --11/22 (50.0) -- 9/22 (40.1) -- 2/22 (9.1)
- 4/74 (5.4) 876 (92.2)
22/950 (2.3)
50 (17.9) - 40/50 (80.0) - 2/50 (4.0) - 6/50 (12.0)
24 (3.6) - 5/24 (20.8) - 1/24 (4.2) - 16/24 (66.7)
-- 5/6 (83.3) -- 1/6 (16.7)
- 2/50 (4.0) 230 (82.1)
-- 6/16 (37.5) -- 8/16 (50.0) -- 2/16 (12.5)
- 2/24 (8.3) 646 (96.4)
6/280 (2.1)
16/670 (2.4)
0.410b b
<0.001 35/74 (47.3) - 34/35 (97.1) - 1/35 (2.9) 39/74 (52.3) - 17/39 (43.6) - 21/39 (53.8) - 1/39 (2.6)
32/50 (64.0) 3/24 (12.5) - 32/32(100.0) - 2/3 (66.7) - 0/32 (0.0) - 1/3 (33.3) 18/50 (36.0) 21/24 (87.5) - 12/18 (66.7) - 5/21 (23.8) - 6/18 (33.3) - 15/21 (71.4) - 1/21 (4.8) b
<0.001 58/74 (78.4)
44/50 (88.0)
14/24 (58.3)
5/50 (10.0)
1/24 (4.2) 5/24 (20.8)
1/50 ( 2.0)
3/24 (12.5)
- 35/58 (77.6) - 13/58 (22.4)
1/74 (1.4) 10/74 (13.5) - 4/10 (40.0) - 6/10 (60.0)
4/74 (5.4) - 2/4 (50.0) - 2/4 (50.0)
1/74 (1.4)
13/22 (59.1) 6/22 (27.3) 2/22 (9.1) 1/22 (4.5)
1/24 (4.2)
4/6 (66.7) 2/6 (33.3)
9/16 (60.0) 4/16 (26.7) 2/16 (13.3) 1/16 (6.7) <0.001c
87.3
81.0
89.9 c
0.199 98.1
98.9
Chi²-test, log-rank test FIGO = International Federation of Gynecology and Obstetrics, BOT=borderline ovarian tumour
97.7
Downloaded from http://annonc.oxfordjournals.org/ at Anadolu University on April 29, 2014
Recurrent disease yes - BOT w/o microinvasion - BOT with microinvasion - invasive carcinoma
age <40y (%) n=280 (29.5)