Arch Gynecol Obstet (2015) 291:123–130 DOI 10.1007/s00404-014-3381-7
GYNECOLOGIC ONCOLOGY
Retrospective evaluation of borderline ovarian tumors: single center experience of 183 cases Tayfun Gungor • Nilufer Cetinkaya • Hakan Yalcin • Bulent Ozdal • Emre Ozgu • Eralp Baser • Dilek Uygur Mete Caglar • Levent Sirvan • Salim Erkaya
•
Received: 29 January 2014 / Accepted: 10 July 2014 / Published online: 22 July 2014 Ó Springer-Verlag Berlin Heidelberg 2014
Abstract Purpose Borderline ovarian tumors (BOTs) constitute about a quarter of epithelial ovarian malignancies and require different treatment approaches. The present study aims to document the experience of a single center on the treatment outcome of women who had conservative or comprehensive surgery for BOTs. Methods One hundred eighty-three patients with BOTs, diagnosed and/or treated in our center between January of 2000 and March of 2013, were reviewed retrospectively. Results The mean age at diagnosis was 40.6 years old (range 17–78). Ninety-five patients (51 %) were B40 years. Comprehensive surgical staging and fertility sparing surgery were performed in 49 % (n = 91) and 48 % of patients (n = 89) respectively. A hundred and forty-seven patients had stage IA disease (80 %). The most common type of BOT was serous in histology with 18 % bilateralism. CA-125 and CA-199 levels were increased in 29 (19 %) and 15 (10 %) patients with stage IA disease. Non-invasive tumor implants were diagnosed in 9 patients (4 %) and uterine involvement was 2 % among BOT patients that underwent hysterectomies. The mean postT. Gungor N. Cetinkaya (&) H. Yalcin B. Ozdal E. Ozgu E. Baser D. Uygur S. Erkaya Department of Gynecologic Oncology, Zekai Tahir Burak Women’s Health Education and Research Hospital, 06230 Hamamonu, Ankara, Turkey e-mail: [email protected] M. Caglar Department of Obstetrics and Gynecology, Du¨zce University School of Medicine, Du¨zce, Turkey L. Sirvan Department of Pathology, Zekai Tahir Burak Women’s Health Education and Research Hospital, Ankara, Turkey
operative follow-up period was 20.4 months (range 6–78 months). Disease recurrence was seen in 5 patients indicating overall recurrence rate of 2.7 %. Conclusions In our study, we evaluated a large data pool of 183 patients diagnosed with borderline epithelial ovarian tumors. BOTs have a relatively better prognosis than invasive epithelial ovarian cancer. Surgery with proper staging is the cornerstone of treatment. Patients with BOTs at the early stage can undergo fertility sparing surgery with close follow-up. Keywords Ovarian cancer Borderline ovarian tumors Fertility sparing surgery
Introduction Borderline ovarian tumors (BOTs) constitute a special subgroup of epithelial ovarian tumors and generate about 10–20 % of diagnosed ovarian malignancies. These tumors have special histologic features like epithelial multilayering, moderate mitoses, mild nuclear atypia and lack of stromal invasion. Micro-invasive BOTs are a special subgroup of BOTs and have one or more foci of stromal invasion within a B3 mm diameter or B10 mm2 area [1]. BOTs are diagnosed in younger women more than invasive epithelial ovarian tumors and tend to have a better prognosis with an overall survival rate of 90–100 % [2, 3]. Patients present subtle pelvic symptoms or have a cystic mass discovered during pelvic examination or imaging. Tumor markers such as CA-125, CEA and CA-199 are elevated in 25–60 % of patients at diagnosis [4]. Follow-up in the post-operative period with tumor markers could have a role if the elevated values were diagnosed pre-operatively or more aggressive tumors recur after the initial surgery.
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Most tumors are diagnosed as stage I disease according to the International Federation of Gynecology and Obstetrics (FIGO) 2009 staging system. Higher stages of the disease with the involvement of extra-ovarian organs might be presented via invasive or non-invasive implants [5]. Surgical treatment is the same as for malignant ovarian tumors but there is no difference in the recurrence or survival rate whether lymphadenectomy is performed or not. Therefore, lymphadenectomy can be postponed [6]. Protection of fertility by preserving the uterus and contralateral ovary is preferable for young patients. Unilateral oophorectomy or cystectomy are safe options for the stage I disease if careful follow-up of the patient is possible [7–9]. However, the recurrence rate is 12–58 % after cystectomy [2]. Micro-invasive or micro-papillary histology, conservative procedures like cystectomy or unilateral salpingo-oophorectomy, cyst rupture, advanced stage disease and presence of tumor implants are prognostic factors affecting recurrence [10]. The aim of this study was to deal with BOTs based on a single center experience with 183 patient evaluations and call attention to the therapeutic approaches and prognostic values.
Patients and methods The present study was approved by the Institutional Review Board of Zekai Tahir Burak Women’s Health Education and Research Hospital where the study was conducted. Patients (n = 183) with BOTs diagnosed and/or treated in our center between Jan 2000 and Mar 2013 were reviewed retrospectively. From the hospital records, data related with the patients’ age, pre-operative CA-125 (Cancer Antigen-125), CEA (Carcinoembryonic Antigen), CA-199 (Cancer Antigen199) and CA-153 (Cancer Antigen-153) levels, were collected. Furthermore, type of surgical technique, primary lesion side, histologic type, mean tumor diameter, presence of and characteristics of tumor implants, results of the peritoneal washings, lymph node status, stage at diagnosis, frozen pathology records, permanent pathological diagnosis and accompanying pathologies if any, were reviewed. Additionally, chemotherapy requirements after surgery, postoperative follow-up periods, data related with the disease recurrence and conditions necessitating recurrent operations were evaluated. The patients were staged surgically according to FIGO 2009 guidelines for ovarian carcinoma. Comprehensive surgical staging with peritoneal sampling, total abdominal hysterectomy, bilateral salpingo-oophorectomy, pelvic and para-aortic lymphadenectomy, appendectomy and omentectomy were performed in patients who were
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postmenopausal, completed their fertility or had additional disease that require extensive surgery. Fertilitysparing surgery was performed in the form of one of the following techniques: unilateral salpingo-oophorectomy (USO), USO with contralateral ovarian biopsy, USO with contralateral cystectomy, cystectomy, bilateral cystectomy, cystectomy with contralateral ovarian biopsy and bilateral ovarian biopsy in patients who were premenopausal or wish to preserve their fertility. Three patients with a history of previous hysterectomy operations had been operated by excisional surgery without hysterectomy and staging. The patients that had comprehensive surgical staging or fertility-sparing surgery with lymph node dissection were operated using midline abdominal incisions. The patients that had fertility-sparing surgery without lymph node dissection (n = 21) were operated using pfannenstiel incisions. All of these patients with pfannenstiel incisions had negative pre-operative tumor markers. Statistical anaysis The statistical analysis was performed with SPSS for Mac version 20 (SPSS for Mac Inc., Chicago, IL, US). We computed descriptive statistics (mean and range). Independent samples t test was performed to compare the difference between the tumors’ histologic types.
Results A total of 183 patients were evaluated. The mean age at diagnosis was 40.6 (range 17–78). 51.9 % of the cases were B40 years (n = 95) old. There were two patients who had previously one-sided oophorectomy due to a somewhat unclear history and serous BOT on their contralateral ovary developed years later. Another three patients had previously hysterectomy operations due to abnormal uterine bleeding and an adnexal mass that was diagnosed as serous BOT developed years later. They underwent excisional surgery without hysterectomy and staging. Three other patients were diagnosed during cesarean section. A total of 91 hysterectomies, 176 peritoneal fluid washings, 153 appendectomies, 163 omentectomies and 159 pelvic and para-aortic lymph node dissections were performed. Ninety patients had unilateral right (49.1 %) and 70 patients had unilateral left sided (38.2 %) BOTs. Twenty-three patients’ BOT lesions were bilateral (12.5 %). There were 113 BOTs lesions on the right side and 93 BOTs lesions on the left side. The patient-related and the lesion-related data are presented in Tables 1 and 2. Moreover, Table 3 presents the clinical details of all patients.
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Table 1 Data present the number of patients, primary lesion side and histologic type of BOTs according to tumor localizations Primary lesion side
No. of patients
Percent
RO
90
49.1
LO
70
38.2
BO
23
12.5
T = 183 Tumor localizations
Histologic type
No. of patients
Percent
RO
Serous
49
26.7
Serous micro-papillary
1
0.5
Serous micro-invasive
2
1
Mucinous
32
17.4
Endometrioid Clear cell
5 1
2.7 0.5
Serous
40
21.8
Serous micro-invasive
2
1
Mucinous
25
13.6
Mucinous micro-invasive
1
0.5
Brenner
2
1
Serous
18
9.8
Serous micro-papillary
1
0.5
Serous micro-invasive
1
0.5
Mucinous
1
0.5
Serous micro-invasive and Mucinous
1
0.5
Serous micro-invasive and Serous
1 T = 183
0.5
LO
BO
RO right ovary, LO left ovary, BO bilateral ovarian, T total
Table 2 Data present the number of total lesions, total lesions per ovary and histologic type of BOTs per lesion
Total lesions per ovary RO LO
Histologic type per lesion Serous Serous micro-papillary Serous micro-invasive Mucinous Mucinous micro-invasive Endometrioid Brenner Clear cell
RO right ovary, LO left ovary, T total
No. of lesions
Percent
113 93 T = 206
61.7 45.1
126 3 8 60 1 5 2 1 T = 206
68.8 1.4 3.8 29.15 0.4 2.4 0.9 0.4
The most common type of BOT was serous in histology with 18 % bilateralism followed by mucinous, endometrioid, Brenner and clear cell BOTs. Serous BOTs was the leading (91 %) histologic type in bilateral tumors. There were 7 patients with serous micro-invasive and one patient with mucinous micro-invasive BOTs. Also two of them had synchronously mucinous or serous BOT on their contralateral ovaries. Additionally there were two patients with serous micro-papillary BOTs. The detailed clinical data of patients with micro-invasive and micro-papillary BOTs are presented in Table 4. Comprehensive surgical staging was performed in 49.7 % of the patients (n = 91). Fertility-sparing surgery with unilateral salpingo-oophorectomy or cystectomy with or without contralateral ovarian biopsy or cystectomy was performed in 48.6 % of the patients (n = 89). Lymph node dissection was done in 76.4 % of these patients (n = 68). The mean tumor diameter was 9.4 cm (range 1–27 cm), 14.8 cm (range 3–38 cm), 7.6 cm (range 0.8–13 cm) and 10.5 cm (range 9–12 cm) in serous, mucinous, endometrioid and Brenner type BOTs respectively. The tumor diameter of the clear cell BOT was 13 cm. Mucinous BOTs had significantly larger tumor diameters than serous BOTs (P \ 0.0001). A hundred and forty-seven patients’ disease was stage IA (80.3 %) and the remaining 36 patients’ were: stage IB (9.2 %, n = 17), stage IC (1.6 %, n = 3), stage IIC (2.1 %, n = 4) and stage IIIC (6.5 %, n = 12). There were ten patients that had synchronous ovarian and one patient with a para-tubal serous malignancy accompanying BOTs (Table 3). The malignant components were endometrioid (n = 4), serous (n = 2), mucinous (n = 2), clear cell (n = 1) and malign mixed Mullerian tumor (n = 1) in histology. Furthermore, one patient had BOT with concomitant gastric carcinoma. The minimum tumor diameter of the incidental ipsilateral and contralateral ovarian malignancies accompanying to BOTs were reported to be 8 mm and 1.2 cm respectively. Likewise the tumor diameter of the concomitant para-tubal serous malignancy was reported to be less than 10 mm. The mean preoperative CA-125, CEA, CA-199 and CA153 values were: 90.94 U/ml (range 4–1,556 U/ml), 2.02 ng/ml (range 0.01–33.5 ng/ml), 66.58 U/ml (range 0.02–1,000 U/ml) and 17.1 U/ml (range 0.5–83 U/ml) respectively. The values of CA-125, CEA, CA-199 and CA-153 were reported to be elevated in 20.7, 2.1, 10.9 and 1 % of patients respectively (Table 3). According to disease stages, CA-125 and CA-199 levels were increased in 29 (19 %) and 15 (10 %) patients with stage IA disease. There were 12 patients with positive peritoneal washings. The cytology reports of 9 patients were correlated with serous BOTs and 3 patients’ were correlated with malignancy (2 with bilateral serous BOTs and 1 with
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Table 3 Clinical details of patients with BOTs
Table 3 continued No. of patients
Percent
Age (17–78 years)
No. of patients
Percent
Follow-up (months)
B40 years
95
51.9
B3 mo
35
19.1
[40 years
88
48
[3 mo
148
80.8
5
2.7
9
4.9
Initial surgery
Disease recurrence
Comprehensive surgery
91
49.7
Fertility-sparing surgery ± PPLND
89
48.6
USO* USO and contralateral ovarian Bx
38 27
42.6 30.3
Unilateral cystectomy*
15
16.8
USO and contralateral cystectomy
3
3.3
Bilateral cystectomy*
3
3.3
Cystectomy and contralateral ovarian Bx*
2
2.2
Bilateral ovarian Bx*
1
1.1
3
1.6
38
20.7
4
2.1
20
10.9
2
1
Excisional surgery without hysterectomy and staging CA-125 U/ml : CEA ng/ml : CA-199 U/ml : CA-153 U/ml : Tumor implants Non-invasive
9
4.9
Invasive
0
0
Compatible with BOT
9
5.1
Malignant
3
1.7
10
6.2
IA
147
80.3
IB
17
9.2
IC IIC
3 4
1.6 2.1
IIIC
12
6.5
10
5.4
Para-tubal (serous tumor)
1
0.5
Other (gastric carcinoma)
1
0.5
Peritoneal cytology (N = 176)
Lymph node involvement ? Stage at diagnosis (FIGO 2009)
Accompanying malignancy Ovarian (serous, mucinous, endometrioid, clear, malign mixed Mullerian tumor)
Frozen pathology records (N = 111) Borderline
78
70.2
Suspicious for invasion
28
25.2
5
4.5
15
8.1
Malignant Adjuvant therapy CT
123
? Secondary surgery ?
USO unilateral salpingo-oopherectomy, Bx biopsy, RO right ovary, LO left ovary, BO bilateral ovarian, PPLND pelvic and para-aortic lymph node dissection, CT chemotherapy, N number * The types of surgeries in which some of the patients had no lymph node dissection
bilateral mucinous BOT) (Table 3). Hemorrhagic contaminations, mesothelial proliferations and sub-acute inflammatory reactions were other subtle changes. Non-invasive tumor implants were diagnosed in 9 patients (4.9 %): 5 with serous, 2 with micro-papillary serous, and 2 with mucinous BOTs (Table 3). Implants were mostly located on the Douglas pouch, uterine or tubal serosa, bladder serosa, sigmoid mesocolon, omentum, small intestine mesentery and the area surrounding the ureter. Frozen pathology records could be evaluated in 111 patients. Records were as follows: borderline, borderlinesuspicious for invasion and malignant in 78, 28 and 5 patients respectively (Table 3). There was only one patient that had a diagnosis of concomitant para-tubal serous malignancy in permanent pathology with a history of BOT diagnosis in frozen examination. The tumor diameter was less than 10 mm in the USO specimen. The frozen pathology results for eight patients with concomitant ovarian malignancy were given as borderline-suspicious for invasion or malignant in 3 and 5 patients respectively. The sensitivity and specificity values of frozen evaluation for borderline and malignant lesions were 100, 55.5 % and 55.5, 100 % respectively. There were 8 patients with micro-invasive BOT diagnosis in permanent pathology that all had history of suspicious for invasion reports in frozen examination. The mean number of dissected lymph nodes was 56.98 (range 12–173). Among the lymph node dissections of 159 patients, only 10 (6.2 %) had lymph node abnormalities other than lymphoid hyperplasia (Table 3). Of these, 4 patients had benign glands lined by tubal-type epithelium (also called endosalpingiosis); 3 patients had benign inclusional glandular implants; 2 patients had serous BOTs present and one patient with synchronous serous adenocarcinoma on the contralateral ovary had tumor-positive lymph nodes.
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Table 4 Characteristics of patients’ with micro-invasive or micro-papillary BOTs Age
RO
LO
Surgery
Stage
AT
Follow-up (months)
Recurrence
P1
50
Serous micro-invasive (9 cm)
Endometrioma and Endometrioid carcinoma (6 cm)
CS
IA (BOT)
CT
12
–
P2
32
Serous micro-invasive (17 cm)
–
USO
IA
–
28
–
P3
56
–
Serous micro-invasive (16 cm)
CS
IA
CT
19
?
P4
17
–
Serous micro-invasive (9 cm)
USO, CO-Bx, PPLND
IA
–
13
–
P5
50
Serous micro-invasive (10 cm)
Serous micro-invasive (12 cm)
CS
IB
CT
8
–
P6
31
Serous micro-invasive (15 cm)
Mucinous (6 cm)
CS
IB
–
74
–
P7
50
Serous micro-invasive (12 cm)
Serous (4.5 cm)
CS
IB
–
60
–
P8
46
–
Mucinous micro-invasive (10 cm)
CS
IA
–
8
–
P9
66
Serous micro-papillary (13 cm) Serous micro-papillary (9 cm)
Serous micro-papillary (14 cm)
CS
IIC
CT
13
–
–
CS
IIIC
CT
72
–
P10 32
Tumor diameters are presented in parenthesis P patient, RO right ovary, LO left ovary, CS Comprehensive surgery, USO unilateral salpingo-oopherectomy, CO-Bx contralateral ovarian biopsy, PPLND pelvic and para-aortic lymph node dissection, CT chemotherapy, BOT borderline ovarian tumor
The mean post-operative follow-up period was 20.4 months (range 6–78 months). According to patients’ data, 5 patients had never been in our clinic for regular post-operative check visits except in the early post-operative period at the 15th day and 30 had only one visit at 3 months after the operation (Table 3). During the surveillance, 15 patients that had peritoneal implants and/or lymph node positivity had post-operative chemotherapy (Table 3). Ten of the patients had concomitant ovarian, para-tubal or gastric malignancies; three of them had serous BOTs (two with micro-papillary architecture) with non-invasive implants or retroperitoneal positive lymph nodes and two of them had micro-invasive BOTs. During the follow-up period only 9 patients (4.9 %) had secondary operations (Table 3): five patients due to disease recurrence, one with recurrent serous ovarian malignancy with a history of serous BOT and concomitant serous ovarian malignancy, one with a benign ovarian cyst on the contralateral ovary with mucinous BOT history, one with bilateral benign ovarian cysts with a history of serous BOT and another one due to formation of 10 cm lymphocyst with a history of mucinous BOT. Only two patients were in the comprehensive surgery group requiring secondary surgery. Disease recurrence was seen in 5 of the 183 patients indicating overall recurrence rate of 2.7 % (Table 3). All of the recurrences except one were diagnosed after fertility-
Table 5 Characteristics of patients’ with recurrence Age
Histologystage
Initial surgery
Recurrence site
Recurrence interval (months)
16
Serous-IA
Unilateral cystectomy
Ipsilateral ovary
30
34
Serous-IB
Bilateral cystectomy
Pelvic peritoneum
18
39
Serous-IA
USO
Contralateral ovary
18
40
Serous-IA
USO
Contralateral ovary
22
56
Serous microinvasive-IA
Comprehensive staging
Bilateral pelvic wall
13
USO unilateral salpingo-oopherectomy
sparing surgery. Recurrent tumors had serous histology. Two patients that had USO previously had contralateral ovarian recurrence. A patient that had cystectomy previously had ipsilateral ovarian recurrence. Another patient with a history of cystectomy and chemotherapy due to serous BOT with implants had recurrent benign ovarian cysts and pelvic non-invasive BOT implants. There was only one patient in the comprehensive surgery group that developed recurrence after debulking surgery and chemotherapy for micro-invasive serous BOT. Recurrence was in
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the form of bilateral cystic masses simulating slowly enlarging lymphocysts with normal tumor markers. Fertility-sparing surgery with lymph node dissection was performed in these patients and secondary cyto-reductive surgery was performed in the previously staged patient. The characteristics of patients that developed recurrence are presented in Table 5.
Conclusions Borderline ovarian tumors are known to have usually an indolent nature with uncertain behaviors. Due to their atypical properties they are classified as a separate entity in the subject of ovarian malignancies. However, there are some features of BOTs that need special consideration such as peritoneal implants—invasive or non-invasive—, micropapillary architecture or presence of micro-invasion in serous BOTs [11]. Furthermore, there are still debates related with surgical management, re-staging or adjuvant therapy. In accordance to previous studies, the median age of patients with BOTs was 40.6 in our study. Of the 183 patients with the tumor, 95 patients (51.9 %) were B40 years old supporting the knowledge of the occurrence of BOTs more frequently in young adults [12, 13]. Our results also indicate that serous BOTs were more numerous than mucinous ones; endometrioid, Brenner and clear cell BOTs were diagnosed as a rare entity. Furthermore, bilateral tumors had more frequently serous histology and mucinous BOTs had larger tumor diameter than serous ones. These results were also compatible with the literature [14, 15]. One of the remarkable issues especially in serous BOTs is the presence of micro-invasive or micro-papillary architecture. Micro-invasion is defined by the presence of one or more foci of stromal invasion within a B3 mm diameter or B10 mm2 area [1]. Micro-papillary architecture is defined by the lack of hierarchically branching papillae, showing either elongate filiform ‘micropapillae’ or cribriform nests of epithelium. Also, one area of continuous micropapillary growth [5 mm must be present for the exact diagnosis [16]. The presence of micro-invasive or micro-papillary pattern is controversially linked to increased risk of invasive recurrence [11]. There were only 2 patients with micro-papillary serous BOT histology in our study. The disease was stage IIC at diagnosis, both having positive cytology and pelvic organ extension and one with bilateral involvement. The estimated incidence of micro-papillary serous BOT was 1 % in our study, which was much more lower than in the literature [17]. Moreover, there were 8 patients with micro-invasive BOTs (7 with serous, 1 with mucinous histology) at stage IA or IB of the
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disease, and the incidence of micro-invasive serous BOT was 6 % similar to other results in the literature [18]. We encountered only one patient (12.5 %) with a recurrence after surgery for serous micro-invasive BOT. However the recurrence occurred as a slowly enlarging bilateral pelvic cystic mass with non-invasive serous histology. The issue of tumor markers in BOT patients is handled in the literature. Based on previous findings abnormal concentrations of CA-125 were noted in 40 % of patients with stage I and in 83 % with advanced-stage disease. However there are limited data with the usage of various tumor markers such as CA-125, CA-199, CA-153 or CEA for high-risk BOTs identification [11]. In the present study, CA-125 and CA-199 levels were increased in 29 (19 %) and 15 (10 %) patients with stage IA disease. CEA values were elevated only in patients with mucinous BOTs and CA-153 levels were increased only in two patients one with endometrioid and the other with clear cell BOTs respectively. Another controversial issue in the management of BOTs is the surgical approach. Our study supports existing literature in that 147 patients’ diseases were stage IA (80 %). The accuracy of frozen section is sub-optimal with 45–64 % sensitivity, which makes the decision difficult to make during surgery [4, 10]. The lymph node involvement has been reported in up to 20 % of stage I, and 28.6 % of stage II–III serous BOTs respectively [2, 19]. However there is the literature data presenting no difference in overall survival between the patients with or without nodal disease in advanced stage BOTs [19]. The principles of surgical treatment of BOTs are similar to invasive ovarian carcinoma but lymphadenectomy can be omitted [6]. We performed systematic lymphadenectomy to 159 patients in our study. Reasons for lymphadenectomy were; enlarged nodes, accompanying ovarian or paratubal malignancies, presence of peritoneal implants, large ovarian tumors, increased tumor marker values, frozen reports of ‘suspicious for invasive disease’ and according to choices of the surgical teams. The lymph node abnormality was diagnosed in 6.2 % of our patients with BOTs but the lymph node involvement in serous BOTs was 1.8 %, much less than the reported incidence in the literature. However 91.1 % of our patients had stage I disease, supporting the decreased requirements for lymph node dissection in early stage disease. Furthermore, the sensitivity of frozen section for borderline ovarian lesions was 100 % in our study, higher than the literature, which permitted us confidence during surgery. Laparoscopic surgery can be performed successfully as well as laparotomy in the early stages of BOTs [20]. In women of more advanced ages, hysterectomy with bilateral salpingo-oophorectomy is preferred [5]. Appendectomy is essential in mucinous BOTs. The younger age of patients
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precludes protection of fertility by preserving uterus and contralateral ovary. Either unilateral oophorectomy or cystectomy is acceptable and safe for stage I disease in young women, provided that the patients undergo careful follow-up [7–9]. In this study all of our patients had laparotomy operation due to clinical obligation. Comprehensive surgical staging was performed in 49.7 % and fertilitysparing surgery with unilateral salpingo-oophorectomy or cystectomy with or without contralateral ovarian biopsy or cystectomy was performed in 48.6 % of the patients. Lymph node dissection was done in 76.4 % of patients with spared fertility. The mean age of patients in the fertility-sparing group was significantly lower than that of the patients in the comprehensive surgical staging group, 30 years (range 17–45 years) and 50 years (range 31–78 years) respectively. There were 14 patients in the comprehensive staging surgery group that were B40 years old due to concomitant uterine pathologies. The reasons for hysterectomy were secondary dysmenorrhea and abnormal uterine bleeding due to giant or multiple myoma, adenomyosis, endometrial polyps or simple endometrial hyperplasia without atypia. Moreover, our data indicate that uterine involvement is rare among patients with BOTs who underwent hysterectomy—only 2 % (3 patients), in which is consistent with the literature [5]. BOTs can spread throughout the peritoneum to form the so-called peritoneal implants. The waste majority of the implants have non-invasive nature with only about 15 % being invasive [11]. Non-invasive implants were seen in 4 % of patients in our study. However, we presented no invasive implants. Peritoneal cytology was positive for tumor cells mostly in patients with BOT implants. As it is known, persistence or recurrence rates are higher with more conservative surgery (recurrence rate: 12–58 % for cystectomy, 0–20 % for bilateral salpingo-ophorectomy) [2] or higher than stage IA disease even so without negative effects on survival. A recent study revealed higher stage, incomplete staging, tumor residuals, and organ preservation as independent prognostic factors for disease recurrence. Furthermore, neither micro-invasion nor micropapillary growth pattern showed any significant impact. They also confirm that presence of implants is a prognostic factor of both recurrence and malignant transformation of BOTs. However, in the sub-group analysis of FIGO II/III serous BOTs they found no significant impact on relapse rate if they compared patients with invasive implants to patients with no or non-invasive implants [21]. We demonstrated an overall 2.7 % recurrence of the disease among the 183 patients in our study. In the detailed analysis of the recurrences we recognized that the recurrence rates after comprehensive surgery, fertility-sparing surgery without lymphadenectomy and fertility-sparing surgery with lymphadenectomy were 1, 19 and 0 % respectively with the
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highest recurrence rates after fertility-sparing surgery without lymph node dissection. However, secondary surgery yielded negative lymph node involvements in those patients with disease recurrence limited to the ovaries or pelvic peritoneum. Thus the increased recurrence rate after fertility-sparing surgery without lymph node dissection cannot be attributed to the absence of lymphadenectomy. As can be seen in the Table 5, most of the recurrences are located in the same or contralateral ovaries. Thus, based on our findings similar to the literature [21], the surgeryrelated factors mainly affects the probability of recurrence. We also emphasize the importance of the contralateral ovarian evaluation during surgery. Also micro-papillary architecture and/or presence of non-invasive implants were not a risk factor for recurrence. Only one patient (12.5 %) with a micro-invasive serous BOT had recurrence. However we had limited patient numbers with the micro-papillary or micro-invasive BOTs to make a clear comment. Moreover, two patients in the fertility-sparing group were readmitted to the hospital due to new onset of cystic adnexal mass that necessitates surgery. Benign pathologies were diagnosed in these patients in the secondary surgery. We had previously reported that pregnancies usually occurred spontaneously after fertility-sparing surgery for BOTs and outcomes were seen to be promising [22]. At younger ages, non-serous histology and unilateral cystectomy were associated with favorable reproductive outcome in young women who underwent conservative surgery for borderline ovarian tumors [23]. BOT’s are relatively resistant to chemotherapy due to their low-malignant potential but still chemotherapeutics might have a role. Despite the beneficial reducing effect of adjuvant chemotherapy on persistent tumors, there is little effect on long-term survival in advanced stages of the disease [2]. The presence of risk factors for relapse or progression necessitates adjuvant platinum–taxane based chemotherapy. In our study, there were 15 patients that had postoperative chemotherapy due to concomitant malignant ovarian, para-tubal or gastric malignancies and BOTs with pelvic or abdominal implants and/or lymph node positivity. In our study, only two deaths were seen and these were the patient who had concomitant ovarian carcinoma and the other patient who had cerebrovascular hemorrhage. This study has some limitations. Due to its retrospective nature covering the last 13 years, large patient numbers and inadequacy of hospital records we couldn’t investigate the clinical parameters such as disease symptoms, history of gravidity, accompanying medical illness or suggested risk factors like obesity or smoking history. However, in our study, we as a single center gynecologic oncology clinic evaluated a large data pool of 183 patients diagnosed as borderline epithelial ovarian tumor, their pathologic characteristics, surgical techniques, and postoperative
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surveillance with management results. According to our knowledge, this study represents one of the largest series of cases with BOTs as a single center experience. In conclusion, BOTs have excellent prognosis with low recurrence rates and must be differentiated from their invasive epithelial counterparts with respect to treatment approaches such as fertility preservation and adjuvant chemotherapy. Further studies with larger samples are needed to overcome the current controversial issues related with management of BOTs. Conflict of interest of interest.
The authors declare that they have no conflict
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11. Morice P, Uzan C, Fauvet R, Gouy S, Duvillard P, Darai E (2012) Borderline ovarian tumour: pathological diagnostic dilemma and risk factors for invasive or lethal recurrence. Lancet Oncol 13(3):e103–e115. doi:10.1016/S1470-2045(11)70288-1 12. Gotlieb WH, Chetrit A, Menczer J, Hirsh-Yechezkel G, Lubin F, Friedman E, Modan B, Ben-Baruch G (2005) Demographic and genetic characteristics of patients with borderline ovarian tumors as compared to early stage invasive ovarian cancer. Gynecol Oncol 97(3):780–783. doi:10.1016/j.ygyno.2005.02.022 13. Romagnolo C, Gadducci A, Sartori E, Zola P, Maggino T (2006) Management of borderline ovarian tumors: results of an Italian multicenter study. Gynecol Oncol 101(2):255–260. doi:10.1016/j. ygyno.2005.10.014 14. Messalli EM, Grauso F, Balbi G, Napolitano A, Seguino E, Torella M (2013) Borderline ovarian tumors: features and controversial aspects. Eur J Obstet Gynecol Reprod Biol 167(1):86–89. doi:10.1016/j.ejogrb.2012.11.002 15. McCluggage WG (2010) The pathology of and controversial aspects of ovarian borderline tumours. Curr Opin Oncol 22(5):462–472. doi:10.1097/CCO.0b013e32833b0dc1 16. Avril S, Hahn E, Specht K, Hauptmann S, Hoss C, Kiechle M, Hofler H, Schmalfeldt B (2012) Histopathologic features of ovarian borderline tumors are not predictive of clinical outcome. Gynecol Oncol 127(3):516–524. doi:10.1016/j.ygyno.2012.08. 027 17. Park JY, Kim DY, Kim JH, Kim YM, Kim KR, Kim YT, Nam JH (2011) Micropapillary pattern in serous borderline ovarian tumors: does it matter? Gynecol Oncol 123(3):511–516. doi:10. 1016/j.ygyno.2011.08.008 18. Acs G (2005) Serous and mucinous borderline (low malignant potential) tumors of the ovary. Am J Clin Pathol 123(Suppl):S13– S57 19. Lesieur B, Kane A, Duvillard P, Gouy S, Pautier P, Lhomme C, Morice P, Uzan C (2011) Prognostic value of lymph node involvement in ovarian serous borderline tumors. Am J Obstet Gynecol 204(5):438 e1–438 e7. doi:10.1016/j.ajog.2010.12.055 20. Tinelli R, Malzoni M, Cosentino F, Perone C, Tinelli A, Malvasi A, Cicinelli E (2009) Feasibility, safety, and efficacy of conservative laparoscopic treatment of borderline ovarian tumors. Fertil Steril 92(2):736–741. doi:10.1016/j.fertnstert.2008.07.1716 21. du Bois A, Ewald-Riegler N, de Gregorio N, Reuss A, Mahner S, Fotopoulou C, Kommoss F, Schmalfeldt B, Hilpert F, Fehm T, Burges A, Meier W, Hillemanns P, Hanker L, Hasenburg A, Strauss HG, Hellriegel M, Wimberger P, Keyver-Paik MD, Baumann K, Canzler U, Wollschlaeger K, Forner D, Pfisterer J, Schroder W, Munstedt K, Richter B, Kommoss S, Hauptmann S, Arbeitsgmeinschaft Gynakologische Onkologie Study G (2013) Borderline tumours of the ovary: a cohort study of the Arbeitsgmeinschaft Gynakologische Onkologie (AGO) Study Group. Eur J Cancer 49(8):1905–1914. doi:10.1016/j.ejca.2013. 01.035 22. Nam JH (2010) Borderline ovarian tumors and fertility. Curr Opin Obstet Gynecol 22(3):227–234. doi:10.1097/GCO. 0b013e3283384928 23. Kanat-Pektas M, Ozat M, Gungor T, Dikici T, Yilmaz B, Mollamahmutoglu L (2011) Fertility outcome after conservative surgery for borderline ovarian tumors: a single center experience. Arch Gynecol Obstet 284(5):1253–1258. doi:10.1007/s00404010-1804-7
GYNECOLOGIC ONCOLOGY
Retrospective evaluation of borderline ovarian tumors: single center experience of 183 cases Tayfun Gungor • Nilufer Cetinkaya • Hakan Yalcin • Bulent Ozdal • Emre Ozgu • Eralp Baser • Dilek Uygur Mete Caglar • Levent Sirvan • Salim Erkaya
•
Received: 29 January 2014 / Accepted: 10 July 2014 / Published online: 22 July 2014 Ó Springer-Verlag Berlin Heidelberg 2014
Abstract Purpose Borderline ovarian tumors (BOTs) constitute about a quarter of epithelial ovarian malignancies and require different treatment approaches. The present study aims to document the experience of a single center on the treatment outcome of women who had conservative or comprehensive surgery for BOTs. Methods One hundred eighty-three patients with BOTs, diagnosed and/or treated in our center between January of 2000 and March of 2013, were reviewed retrospectively. Results The mean age at diagnosis was 40.6 years old (range 17–78). Ninety-five patients (51 %) were B40 years. Comprehensive surgical staging and fertility sparing surgery were performed in 49 % (n = 91) and 48 % of patients (n = 89) respectively. A hundred and forty-seven patients had stage IA disease (80 %). The most common type of BOT was serous in histology with 18 % bilateralism. CA-125 and CA-199 levels were increased in 29 (19 %) and 15 (10 %) patients with stage IA disease. Non-invasive tumor implants were diagnosed in 9 patients (4 %) and uterine involvement was 2 % among BOT patients that underwent hysterectomies. The mean postT. Gungor N. Cetinkaya (&) H. Yalcin B. Ozdal E. Ozgu E. Baser D. Uygur S. Erkaya Department of Gynecologic Oncology, Zekai Tahir Burak Women’s Health Education and Research Hospital, 06230 Hamamonu, Ankara, Turkey e-mail: [email protected] M. Caglar Department of Obstetrics and Gynecology, Du¨zce University School of Medicine, Du¨zce, Turkey L. Sirvan Department of Pathology, Zekai Tahir Burak Women’s Health Education and Research Hospital, Ankara, Turkey
operative follow-up period was 20.4 months (range 6–78 months). Disease recurrence was seen in 5 patients indicating overall recurrence rate of 2.7 %. Conclusions In our study, we evaluated a large data pool of 183 patients diagnosed with borderline epithelial ovarian tumors. BOTs have a relatively better prognosis than invasive epithelial ovarian cancer. Surgery with proper staging is the cornerstone of treatment. Patients with BOTs at the early stage can undergo fertility sparing surgery with close follow-up. Keywords Ovarian cancer Borderline ovarian tumors Fertility sparing surgery
Introduction Borderline ovarian tumors (BOTs) constitute a special subgroup of epithelial ovarian tumors and generate about 10–20 % of diagnosed ovarian malignancies. These tumors have special histologic features like epithelial multilayering, moderate mitoses, mild nuclear atypia and lack of stromal invasion. Micro-invasive BOTs are a special subgroup of BOTs and have one or more foci of stromal invasion within a B3 mm diameter or B10 mm2 area [1]. BOTs are diagnosed in younger women more than invasive epithelial ovarian tumors and tend to have a better prognosis with an overall survival rate of 90–100 % [2, 3]. Patients present subtle pelvic symptoms or have a cystic mass discovered during pelvic examination or imaging. Tumor markers such as CA-125, CEA and CA-199 are elevated in 25–60 % of patients at diagnosis [4]. Follow-up in the post-operative period with tumor markers could have a role if the elevated values were diagnosed pre-operatively or more aggressive tumors recur after the initial surgery.
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Most tumors are diagnosed as stage I disease according to the International Federation of Gynecology and Obstetrics (FIGO) 2009 staging system. Higher stages of the disease with the involvement of extra-ovarian organs might be presented via invasive or non-invasive implants [5]. Surgical treatment is the same as for malignant ovarian tumors but there is no difference in the recurrence or survival rate whether lymphadenectomy is performed or not. Therefore, lymphadenectomy can be postponed [6]. Protection of fertility by preserving the uterus and contralateral ovary is preferable for young patients. Unilateral oophorectomy or cystectomy are safe options for the stage I disease if careful follow-up of the patient is possible [7–9]. However, the recurrence rate is 12–58 % after cystectomy [2]. Micro-invasive or micro-papillary histology, conservative procedures like cystectomy or unilateral salpingo-oophorectomy, cyst rupture, advanced stage disease and presence of tumor implants are prognostic factors affecting recurrence [10]. The aim of this study was to deal with BOTs based on a single center experience with 183 patient evaluations and call attention to the therapeutic approaches and prognostic values.
Patients and methods The present study was approved by the Institutional Review Board of Zekai Tahir Burak Women’s Health Education and Research Hospital where the study was conducted. Patients (n = 183) with BOTs diagnosed and/or treated in our center between Jan 2000 and Mar 2013 were reviewed retrospectively. From the hospital records, data related with the patients’ age, pre-operative CA-125 (Cancer Antigen-125), CEA (Carcinoembryonic Antigen), CA-199 (Cancer Antigen199) and CA-153 (Cancer Antigen-153) levels, were collected. Furthermore, type of surgical technique, primary lesion side, histologic type, mean tumor diameter, presence of and characteristics of tumor implants, results of the peritoneal washings, lymph node status, stage at diagnosis, frozen pathology records, permanent pathological diagnosis and accompanying pathologies if any, were reviewed. Additionally, chemotherapy requirements after surgery, postoperative follow-up periods, data related with the disease recurrence and conditions necessitating recurrent operations were evaluated. The patients were staged surgically according to FIGO 2009 guidelines for ovarian carcinoma. Comprehensive surgical staging with peritoneal sampling, total abdominal hysterectomy, bilateral salpingo-oophorectomy, pelvic and para-aortic lymphadenectomy, appendectomy and omentectomy were performed in patients who were
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postmenopausal, completed their fertility or had additional disease that require extensive surgery. Fertilitysparing surgery was performed in the form of one of the following techniques: unilateral salpingo-oophorectomy (USO), USO with contralateral ovarian biopsy, USO with contralateral cystectomy, cystectomy, bilateral cystectomy, cystectomy with contralateral ovarian biopsy and bilateral ovarian biopsy in patients who were premenopausal or wish to preserve their fertility. Three patients with a history of previous hysterectomy operations had been operated by excisional surgery without hysterectomy and staging. The patients that had comprehensive surgical staging or fertility-sparing surgery with lymph node dissection were operated using midline abdominal incisions. The patients that had fertility-sparing surgery without lymph node dissection (n = 21) were operated using pfannenstiel incisions. All of these patients with pfannenstiel incisions had negative pre-operative tumor markers. Statistical anaysis The statistical analysis was performed with SPSS for Mac version 20 (SPSS for Mac Inc., Chicago, IL, US). We computed descriptive statistics (mean and range). Independent samples t test was performed to compare the difference between the tumors’ histologic types.
Results A total of 183 patients were evaluated. The mean age at diagnosis was 40.6 (range 17–78). 51.9 % of the cases were B40 years (n = 95) old. There were two patients who had previously one-sided oophorectomy due to a somewhat unclear history and serous BOT on their contralateral ovary developed years later. Another three patients had previously hysterectomy operations due to abnormal uterine bleeding and an adnexal mass that was diagnosed as serous BOT developed years later. They underwent excisional surgery without hysterectomy and staging. Three other patients were diagnosed during cesarean section. A total of 91 hysterectomies, 176 peritoneal fluid washings, 153 appendectomies, 163 omentectomies and 159 pelvic and para-aortic lymph node dissections were performed. Ninety patients had unilateral right (49.1 %) and 70 patients had unilateral left sided (38.2 %) BOTs. Twenty-three patients’ BOT lesions were bilateral (12.5 %). There were 113 BOTs lesions on the right side and 93 BOTs lesions on the left side. The patient-related and the lesion-related data are presented in Tables 1 and 2. Moreover, Table 3 presents the clinical details of all patients.
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Table 1 Data present the number of patients, primary lesion side and histologic type of BOTs according to tumor localizations Primary lesion side
No. of patients
Percent
RO
90
49.1
LO
70
38.2
BO
23
12.5
T = 183 Tumor localizations
Histologic type
No. of patients
Percent
RO
Serous
49
26.7
Serous micro-papillary
1
0.5
Serous micro-invasive
2
1
Mucinous
32
17.4
Endometrioid Clear cell
5 1
2.7 0.5
Serous
40
21.8
Serous micro-invasive
2
1
Mucinous
25
13.6
Mucinous micro-invasive
1
0.5
Brenner
2
1
Serous
18
9.8
Serous micro-papillary
1
0.5
Serous micro-invasive
1
0.5
Mucinous
1
0.5
Serous micro-invasive and Mucinous
1
0.5
Serous micro-invasive and Serous
1 T = 183
0.5
LO
BO
RO right ovary, LO left ovary, BO bilateral ovarian, T total
Table 2 Data present the number of total lesions, total lesions per ovary and histologic type of BOTs per lesion
Total lesions per ovary RO LO
Histologic type per lesion Serous Serous micro-papillary Serous micro-invasive Mucinous Mucinous micro-invasive Endometrioid Brenner Clear cell
RO right ovary, LO left ovary, T total
No. of lesions
Percent
113 93 T = 206
61.7 45.1
126 3 8 60 1 5 2 1 T = 206
68.8 1.4 3.8 29.15 0.4 2.4 0.9 0.4
The most common type of BOT was serous in histology with 18 % bilateralism followed by mucinous, endometrioid, Brenner and clear cell BOTs. Serous BOTs was the leading (91 %) histologic type in bilateral tumors. There were 7 patients with serous micro-invasive and one patient with mucinous micro-invasive BOTs. Also two of them had synchronously mucinous or serous BOT on their contralateral ovaries. Additionally there were two patients with serous micro-papillary BOTs. The detailed clinical data of patients with micro-invasive and micro-papillary BOTs are presented in Table 4. Comprehensive surgical staging was performed in 49.7 % of the patients (n = 91). Fertility-sparing surgery with unilateral salpingo-oophorectomy or cystectomy with or without contralateral ovarian biopsy or cystectomy was performed in 48.6 % of the patients (n = 89). Lymph node dissection was done in 76.4 % of these patients (n = 68). The mean tumor diameter was 9.4 cm (range 1–27 cm), 14.8 cm (range 3–38 cm), 7.6 cm (range 0.8–13 cm) and 10.5 cm (range 9–12 cm) in serous, mucinous, endometrioid and Brenner type BOTs respectively. The tumor diameter of the clear cell BOT was 13 cm. Mucinous BOTs had significantly larger tumor diameters than serous BOTs (P \ 0.0001). A hundred and forty-seven patients’ disease was stage IA (80.3 %) and the remaining 36 patients’ were: stage IB (9.2 %, n = 17), stage IC (1.6 %, n = 3), stage IIC (2.1 %, n = 4) and stage IIIC (6.5 %, n = 12). There were ten patients that had synchronous ovarian and one patient with a para-tubal serous malignancy accompanying BOTs (Table 3). The malignant components were endometrioid (n = 4), serous (n = 2), mucinous (n = 2), clear cell (n = 1) and malign mixed Mullerian tumor (n = 1) in histology. Furthermore, one patient had BOT with concomitant gastric carcinoma. The minimum tumor diameter of the incidental ipsilateral and contralateral ovarian malignancies accompanying to BOTs were reported to be 8 mm and 1.2 cm respectively. Likewise the tumor diameter of the concomitant para-tubal serous malignancy was reported to be less than 10 mm. The mean preoperative CA-125, CEA, CA-199 and CA153 values were: 90.94 U/ml (range 4–1,556 U/ml), 2.02 ng/ml (range 0.01–33.5 ng/ml), 66.58 U/ml (range 0.02–1,000 U/ml) and 17.1 U/ml (range 0.5–83 U/ml) respectively. The values of CA-125, CEA, CA-199 and CA-153 were reported to be elevated in 20.7, 2.1, 10.9 and 1 % of patients respectively (Table 3). According to disease stages, CA-125 and CA-199 levels were increased in 29 (19 %) and 15 (10 %) patients with stage IA disease. There were 12 patients with positive peritoneal washings. The cytology reports of 9 patients were correlated with serous BOTs and 3 patients’ were correlated with malignancy (2 with bilateral serous BOTs and 1 with
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Table 3 Clinical details of patients with BOTs
Table 3 continued No. of patients
Percent
Age (17–78 years)
No. of patients
Percent
Follow-up (months)
B40 years
95
51.9
B3 mo
35
19.1
[40 years
88
48
[3 mo
148
80.8
5
2.7
9
4.9
Initial surgery
Disease recurrence
Comprehensive surgery
91
49.7
Fertility-sparing surgery ± PPLND
89
48.6
USO* USO and contralateral ovarian Bx
38 27
42.6 30.3
Unilateral cystectomy*
15
16.8
USO and contralateral cystectomy
3
3.3
Bilateral cystectomy*
3
3.3
Cystectomy and contralateral ovarian Bx*
2
2.2
Bilateral ovarian Bx*
1
1.1
3
1.6
38
20.7
4
2.1
20
10.9
2
1
Excisional surgery without hysterectomy and staging CA-125 U/ml : CEA ng/ml : CA-199 U/ml : CA-153 U/ml : Tumor implants Non-invasive
9
4.9
Invasive
0
0
Compatible with BOT
9
5.1
Malignant
3
1.7
10
6.2
IA
147
80.3
IB
17
9.2
IC IIC
3 4
1.6 2.1
IIIC
12
6.5
10
5.4
Para-tubal (serous tumor)
1
0.5
Other (gastric carcinoma)
1
0.5
Peritoneal cytology (N = 176)
Lymph node involvement ? Stage at diagnosis (FIGO 2009)
Accompanying malignancy Ovarian (serous, mucinous, endometrioid, clear, malign mixed Mullerian tumor)
Frozen pathology records (N = 111) Borderline
78
70.2
Suspicious for invasion
28
25.2
5
4.5
15
8.1
Malignant Adjuvant therapy CT
123
? Secondary surgery ?
USO unilateral salpingo-oopherectomy, Bx biopsy, RO right ovary, LO left ovary, BO bilateral ovarian, PPLND pelvic and para-aortic lymph node dissection, CT chemotherapy, N number * The types of surgeries in which some of the patients had no lymph node dissection
bilateral mucinous BOT) (Table 3). Hemorrhagic contaminations, mesothelial proliferations and sub-acute inflammatory reactions were other subtle changes. Non-invasive tumor implants were diagnosed in 9 patients (4.9 %): 5 with serous, 2 with micro-papillary serous, and 2 with mucinous BOTs (Table 3). Implants were mostly located on the Douglas pouch, uterine or tubal serosa, bladder serosa, sigmoid mesocolon, omentum, small intestine mesentery and the area surrounding the ureter. Frozen pathology records could be evaluated in 111 patients. Records were as follows: borderline, borderlinesuspicious for invasion and malignant in 78, 28 and 5 patients respectively (Table 3). There was only one patient that had a diagnosis of concomitant para-tubal serous malignancy in permanent pathology with a history of BOT diagnosis in frozen examination. The tumor diameter was less than 10 mm in the USO specimen. The frozen pathology results for eight patients with concomitant ovarian malignancy were given as borderline-suspicious for invasion or malignant in 3 and 5 patients respectively. The sensitivity and specificity values of frozen evaluation for borderline and malignant lesions were 100, 55.5 % and 55.5, 100 % respectively. There were 8 patients with micro-invasive BOT diagnosis in permanent pathology that all had history of suspicious for invasion reports in frozen examination. The mean number of dissected lymph nodes was 56.98 (range 12–173). Among the lymph node dissections of 159 patients, only 10 (6.2 %) had lymph node abnormalities other than lymphoid hyperplasia (Table 3). Of these, 4 patients had benign glands lined by tubal-type epithelium (also called endosalpingiosis); 3 patients had benign inclusional glandular implants; 2 patients had serous BOTs present and one patient with synchronous serous adenocarcinoma on the contralateral ovary had tumor-positive lymph nodes.
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Table 4 Characteristics of patients’ with micro-invasive or micro-papillary BOTs Age
RO
LO
Surgery
Stage
AT
Follow-up (months)
Recurrence
P1
50
Serous micro-invasive (9 cm)
Endometrioma and Endometrioid carcinoma (6 cm)
CS
IA (BOT)
CT
12
–
P2
32
Serous micro-invasive (17 cm)
–
USO
IA
–
28
–
P3
56
–
Serous micro-invasive (16 cm)
CS
IA
CT
19
?
P4
17
–
Serous micro-invasive (9 cm)
USO, CO-Bx, PPLND
IA
–
13
–
P5
50
Serous micro-invasive (10 cm)
Serous micro-invasive (12 cm)
CS
IB
CT
8
–
P6
31
Serous micro-invasive (15 cm)
Mucinous (6 cm)
CS
IB
–
74
–
P7
50
Serous micro-invasive (12 cm)
Serous (4.5 cm)
CS
IB
–
60
–
P8
46
–
Mucinous micro-invasive (10 cm)
CS
IA
–
8
–
P9
66
Serous micro-papillary (13 cm) Serous micro-papillary (9 cm)
Serous micro-papillary (14 cm)
CS
IIC
CT
13
–
–
CS
IIIC
CT
72
–
P10 32
Tumor diameters are presented in parenthesis P patient, RO right ovary, LO left ovary, CS Comprehensive surgery, USO unilateral salpingo-oopherectomy, CO-Bx contralateral ovarian biopsy, PPLND pelvic and para-aortic lymph node dissection, CT chemotherapy, BOT borderline ovarian tumor
The mean post-operative follow-up period was 20.4 months (range 6–78 months). According to patients’ data, 5 patients had never been in our clinic for regular post-operative check visits except in the early post-operative period at the 15th day and 30 had only one visit at 3 months after the operation (Table 3). During the surveillance, 15 patients that had peritoneal implants and/or lymph node positivity had post-operative chemotherapy (Table 3). Ten of the patients had concomitant ovarian, para-tubal or gastric malignancies; three of them had serous BOTs (two with micro-papillary architecture) with non-invasive implants or retroperitoneal positive lymph nodes and two of them had micro-invasive BOTs. During the follow-up period only 9 patients (4.9 %) had secondary operations (Table 3): five patients due to disease recurrence, one with recurrent serous ovarian malignancy with a history of serous BOT and concomitant serous ovarian malignancy, one with a benign ovarian cyst on the contralateral ovary with mucinous BOT history, one with bilateral benign ovarian cysts with a history of serous BOT and another one due to formation of 10 cm lymphocyst with a history of mucinous BOT. Only two patients were in the comprehensive surgery group requiring secondary surgery. Disease recurrence was seen in 5 of the 183 patients indicating overall recurrence rate of 2.7 % (Table 3). All of the recurrences except one were diagnosed after fertility-
Table 5 Characteristics of patients’ with recurrence Age
Histologystage
Initial surgery
Recurrence site
Recurrence interval (months)
16
Serous-IA
Unilateral cystectomy
Ipsilateral ovary
30
34
Serous-IB
Bilateral cystectomy
Pelvic peritoneum
18
39
Serous-IA
USO
Contralateral ovary
18
40
Serous-IA
USO
Contralateral ovary
22
56
Serous microinvasive-IA
Comprehensive staging
Bilateral pelvic wall
13
USO unilateral salpingo-oopherectomy
sparing surgery. Recurrent tumors had serous histology. Two patients that had USO previously had contralateral ovarian recurrence. A patient that had cystectomy previously had ipsilateral ovarian recurrence. Another patient with a history of cystectomy and chemotherapy due to serous BOT with implants had recurrent benign ovarian cysts and pelvic non-invasive BOT implants. There was only one patient in the comprehensive surgery group that developed recurrence after debulking surgery and chemotherapy for micro-invasive serous BOT. Recurrence was in
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the form of bilateral cystic masses simulating slowly enlarging lymphocysts with normal tumor markers. Fertility-sparing surgery with lymph node dissection was performed in these patients and secondary cyto-reductive surgery was performed in the previously staged patient. The characteristics of patients that developed recurrence are presented in Table 5.
Conclusions Borderline ovarian tumors are known to have usually an indolent nature with uncertain behaviors. Due to their atypical properties they are classified as a separate entity in the subject of ovarian malignancies. However, there are some features of BOTs that need special consideration such as peritoneal implants—invasive or non-invasive—, micropapillary architecture or presence of micro-invasion in serous BOTs [11]. Furthermore, there are still debates related with surgical management, re-staging or adjuvant therapy. In accordance to previous studies, the median age of patients with BOTs was 40.6 in our study. Of the 183 patients with the tumor, 95 patients (51.9 %) were B40 years old supporting the knowledge of the occurrence of BOTs more frequently in young adults [12, 13]. Our results also indicate that serous BOTs were more numerous than mucinous ones; endometrioid, Brenner and clear cell BOTs were diagnosed as a rare entity. Furthermore, bilateral tumors had more frequently serous histology and mucinous BOTs had larger tumor diameter than serous ones. These results were also compatible with the literature [14, 15]. One of the remarkable issues especially in serous BOTs is the presence of micro-invasive or micro-papillary architecture. Micro-invasion is defined by the presence of one or more foci of stromal invasion within a B3 mm diameter or B10 mm2 area [1]. Micro-papillary architecture is defined by the lack of hierarchically branching papillae, showing either elongate filiform ‘micropapillae’ or cribriform nests of epithelium. Also, one area of continuous micropapillary growth [5 mm must be present for the exact diagnosis [16]. The presence of micro-invasive or micro-papillary pattern is controversially linked to increased risk of invasive recurrence [11]. There were only 2 patients with micro-papillary serous BOT histology in our study. The disease was stage IIC at diagnosis, both having positive cytology and pelvic organ extension and one with bilateral involvement. The estimated incidence of micro-papillary serous BOT was 1 % in our study, which was much more lower than in the literature [17]. Moreover, there were 8 patients with micro-invasive BOTs (7 with serous, 1 with mucinous histology) at stage IA or IB of the
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disease, and the incidence of micro-invasive serous BOT was 6 % similar to other results in the literature [18]. We encountered only one patient (12.5 %) with a recurrence after surgery for serous micro-invasive BOT. However the recurrence occurred as a slowly enlarging bilateral pelvic cystic mass with non-invasive serous histology. The issue of tumor markers in BOT patients is handled in the literature. Based on previous findings abnormal concentrations of CA-125 were noted in 40 % of patients with stage I and in 83 % with advanced-stage disease. However there are limited data with the usage of various tumor markers such as CA-125, CA-199, CA-153 or CEA for high-risk BOTs identification [11]. In the present study, CA-125 and CA-199 levels were increased in 29 (19 %) and 15 (10 %) patients with stage IA disease. CEA values were elevated only in patients with mucinous BOTs and CA-153 levels were increased only in two patients one with endometrioid and the other with clear cell BOTs respectively. Another controversial issue in the management of BOTs is the surgical approach. Our study supports existing literature in that 147 patients’ diseases were stage IA (80 %). The accuracy of frozen section is sub-optimal with 45–64 % sensitivity, which makes the decision difficult to make during surgery [4, 10]. The lymph node involvement has been reported in up to 20 % of stage I, and 28.6 % of stage II–III serous BOTs respectively [2, 19]. However there is the literature data presenting no difference in overall survival between the patients with or without nodal disease in advanced stage BOTs [19]. The principles of surgical treatment of BOTs are similar to invasive ovarian carcinoma but lymphadenectomy can be omitted [6]. We performed systematic lymphadenectomy to 159 patients in our study. Reasons for lymphadenectomy were; enlarged nodes, accompanying ovarian or paratubal malignancies, presence of peritoneal implants, large ovarian tumors, increased tumor marker values, frozen reports of ‘suspicious for invasive disease’ and according to choices of the surgical teams. The lymph node abnormality was diagnosed in 6.2 % of our patients with BOTs but the lymph node involvement in serous BOTs was 1.8 %, much less than the reported incidence in the literature. However 91.1 % of our patients had stage I disease, supporting the decreased requirements for lymph node dissection in early stage disease. Furthermore, the sensitivity of frozen section for borderline ovarian lesions was 100 % in our study, higher than the literature, which permitted us confidence during surgery. Laparoscopic surgery can be performed successfully as well as laparotomy in the early stages of BOTs [20]. In women of more advanced ages, hysterectomy with bilateral salpingo-oophorectomy is preferred [5]. Appendectomy is essential in mucinous BOTs. The younger age of patients
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precludes protection of fertility by preserving uterus and contralateral ovary. Either unilateral oophorectomy or cystectomy is acceptable and safe for stage I disease in young women, provided that the patients undergo careful follow-up [7–9]. In this study all of our patients had laparotomy operation due to clinical obligation. Comprehensive surgical staging was performed in 49.7 % and fertilitysparing surgery with unilateral salpingo-oophorectomy or cystectomy with or without contralateral ovarian biopsy or cystectomy was performed in 48.6 % of the patients. Lymph node dissection was done in 76.4 % of patients with spared fertility. The mean age of patients in the fertility-sparing group was significantly lower than that of the patients in the comprehensive surgical staging group, 30 years (range 17–45 years) and 50 years (range 31–78 years) respectively. There were 14 patients in the comprehensive staging surgery group that were B40 years old due to concomitant uterine pathologies. The reasons for hysterectomy were secondary dysmenorrhea and abnormal uterine bleeding due to giant or multiple myoma, adenomyosis, endometrial polyps or simple endometrial hyperplasia without atypia. Moreover, our data indicate that uterine involvement is rare among patients with BOTs who underwent hysterectomy—only 2 % (3 patients), in which is consistent with the literature [5]. BOTs can spread throughout the peritoneum to form the so-called peritoneal implants. The waste majority of the implants have non-invasive nature with only about 15 % being invasive [11]. Non-invasive implants were seen in 4 % of patients in our study. However, we presented no invasive implants. Peritoneal cytology was positive for tumor cells mostly in patients with BOT implants. As it is known, persistence or recurrence rates are higher with more conservative surgery (recurrence rate: 12–58 % for cystectomy, 0–20 % for bilateral salpingo-ophorectomy) [2] or higher than stage IA disease even so without negative effects on survival. A recent study revealed higher stage, incomplete staging, tumor residuals, and organ preservation as independent prognostic factors for disease recurrence. Furthermore, neither micro-invasion nor micropapillary growth pattern showed any significant impact. They also confirm that presence of implants is a prognostic factor of both recurrence and malignant transformation of BOTs. However, in the sub-group analysis of FIGO II/III serous BOTs they found no significant impact on relapse rate if they compared patients with invasive implants to patients with no or non-invasive implants [21]. We demonstrated an overall 2.7 % recurrence of the disease among the 183 patients in our study. In the detailed analysis of the recurrences we recognized that the recurrence rates after comprehensive surgery, fertility-sparing surgery without lymphadenectomy and fertility-sparing surgery with lymphadenectomy were 1, 19 and 0 % respectively with the
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highest recurrence rates after fertility-sparing surgery without lymph node dissection. However, secondary surgery yielded negative lymph node involvements in those patients with disease recurrence limited to the ovaries or pelvic peritoneum. Thus the increased recurrence rate after fertility-sparing surgery without lymph node dissection cannot be attributed to the absence of lymphadenectomy. As can be seen in the Table 5, most of the recurrences are located in the same or contralateral ovaries. Thus, based on our findings similar to the literature [21], the surgeryrelated factors mainly affects the probability of recurrence. We also emphasize the importance of the contralateral ovarian evaluation during surgery. Also micro-papillary architecture and/or presence of non-invasive implants were not a risk factor for recurrence. Only one patient (12.5 %) with a micro-invasive serous BOT had recurrence. However we had limited patient numbers with the micro-papillary or micro-invasive BOTs to make a clear comment. Moreover, two patients in the fertility-sparing group were readmitted to the hospital due to new onset of cystic adnexal mass that necessitates surgery. Benign pathologies were diagnosed in these patients in the secondary surgery. We had previously reported that pregnancies usually occurred spontaneously after fertility-sparing surgery for BOTs and outcomes were seen to be promising [22]. At younger ages, non-serous histology and unilateral cystectomy were associated with favorable reproductive outcome in young women who underwent conservative surgery for borderline ovarian tumors [23]. BOT’s are relatively resistant to chemotherapy due to their low-malignant potential but still chemotherapeutics might have a role. Despite the beneficial reducing effect of adjuvant chemotherapy on persistent tumors, there is little effect on long-term survival in advanced stages of the disease [2]. The presence of risk factors for relapse or progression necessitates adjuvant platinum–taxane based chemotherapy. In our study, there were 15 patients that had postoperative chemotherapy due to concomitant malignant ovarian, para-tubal or gastric malignancies and BOTs with pelvic or abdominal implants and/or lymph node positivity. In our study, only two deaths were seen and these were the patient who had concomitant ovarian carcinoma and the other patient who had cerebrovascular hemorrhage. This study has some limitations. Due to its retrospective nature covering the last 13 years, large patient numbers and inadequacy of hospital records we couldn’t investigate the clinical parameters such as disease symptoms, history of gravidity, accompanying medical illness or suggested risk factors like obesity or smoking history. However, in our study, we as a single center gynecologic oncology clinic evaluated a large data pool of 183 patients diagnosed as borderline epithelial ovarian tumor, their pathologic characteristics, surgical techniques, and postoperative
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surveillance with management results. According to our knowledge, this study represents one of the largest series of cases with BOTs as a single center experience. In conclusion, BOTs have excellent prognosis with low recurrence rates and must be differentiated from their invasive epithelial counterparts with respect to treatment approaches such as fertility preservation and adjuvant chemotherapy. Further studies with larger samples are needed to overcome the current controversial issues related with management of BOTs. Conflict of interest of interest.
The authors declare that they have no conflict
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