Bendifallah2015

Ann Surg Oncol DOI 10.1245/s10434-015-4784-9

ORIGINAL ARTICLE – GYNECOLOGIC ONCOLOGY

New Pointers for Surgical Staging of Borderline Ovarian Tumors Sofiane Bendifallah1,2,3,4, Myriam Nikpayam1,2,3, Marcos Ballester1,2,3,5, Catherine Uzan6,7,8, Raffaele Fauvet9, Philippe Morice6,7,8, and Emile Darai1,2,3,5 Department of Obstetrics and Gynaecology, University Hospital of Tenon, Paris, France; 2Assistance Publique des Hoˆpitaux de Paris, Universite´ Pierre et Marie Curie, Paris 6, France; 3Institut Universitaire de Cance´rologie, Paris, France; 4 INSERM UMR_S 707, ‘‘Epidemiology, Information Systems, Modeling’’, University Pierre and Marie Curie, Paris, France; 5INSERM UMR_S 938, Universite´ Pierre et Marie Curie, Paris, France; 6Department of Gynaecological Surgery, Institut Gustave Roussy, Villejuif, France; 7INSERM U 10-30, Institut Gustave Roussy, Villejuif, France; 8Universite´ Paris-Sud, Le Kremlin Biceˆtre, France; 9Department of Obstetrics and Gynaecology, University Hospital of Caen, Caen, France 1

ABSTRACT Background. Surgical management of borderline ovarian tumors (BOTs) is similar to that of ovarian cancer apart from lymphadenectomy. However, the complete procedure including peritoneal washing, infracolic omentectomy and random peritoneal biopsies remains a subject of controversy especially in presumed early stage BOTs. To evaluate the prognostic value of complete surgical staging on recurrence rates, recurrence free (RFS) and overall survival (OS) in a multicentre cohort of BOTs. Methods. This retrospective multicentre study included 428 patients with BOTs diagnosed from January 1980 to December 2008. Survival estimates were based on Kaplan– Meier calculations and RFS defined as the time from the date of surgery to the date of recurrence.

Results. The median time of follow-up was 94.9 months (range: 60.00–207.3). The overall recurrence rate was 23.8 %. There was no difference in 5-year RFS between patients with and without complete surgical staging 78.1 % (95 % CI 68.9–88.6) and 70.9 % (95 % CI 64.6–77.8), (p = 0.0806). In the whole cohort, 5-year OS was higher for patients with complete surgical staging 98.4 % (95 % CI 96.8–1.0) and 93.8 % (95 % CI 88.1–1), (p = 0.0182) but this difference was not significant for patients with FIGO stage I 98.6 % (95 % CI 96.7–1) and 92.7 % (95 % CI 83.4–1.0), p = 0.1275, respectively.

Ó Society of Surgical Oncology 2015 First Received: 1 April 2015 S. Bendifallah e-mail: sofiane.bendifallah@tnn.aphp.fr

Conclusions. Complete staging surgery should be considered as a cornerstone treatment for patients with advanced stage BOT but not for those with stage I disease.

Borderline ovarian tumors (BOTs), which account for 15 % of epithelial ovarian tumors, are defined by the presence of cellular proliferation and nuclear atypia without an infiltrative pattern or stromal invasion.1 Compared to invasive ovarian tumors (IOTs), BOTs have been described with different clinical and pathological characteristics associated with better long-term prognosis.

Indeed, 5-and 10-year survival rates for FIGO (International Federation of Gynecology and Obstetrics) stages I, II, and III disease are 99% and 97, 98 and 90 %, and 96 and 88 %, respectively.2 The standard of care for BOTs is complete comprehensive staging surgery, defined as the exploration of the entire abdominal cavity, infracolic omentectomy, peritoneal biopsies, peritoneal washings, removal of all suspicious macroscopic peritoneal lesions and, for mucinous tumours, appendectomy with or without fertilitysparing surgery for the uterus and the ovaries.3 International Guidelines recommend performing complete and systematic staging procedures whatever the presumed or confirmed risk for recurrence as for ovarian cancer.1,4 This can either be performed at the time of primary treatment (when the diagnosis of BOTs is suspected or confirmed) or during a second-surgical surgery (for undiagnosed BOTs at the time of the first surgery but found on histologic analysis, or in the event inconclusive intraoperative histology).5–9 Although complete surgical staging advocates argue its crucial role in identifying high-risk patients for invasive

S. Bendifallah et al.

recurrence and detecting occult infracolic or peritoneal location of BOTs 6,10–12 its prognostic value has never been reported. Furthermore, its benefits could be potentially limited especially in early stages (FIGO I and II) BOTs, as adjuvant treatment has not been proved to show any benefit in this setting and the prognosis of second surgery for recurrence is favourable.

The aim of this multicentre retrospective study of patients with BOTs was to examine the prognostic value of complete surgical staging in terms of recurrence rates, recurrence free (RFS) and overall survival (OS).

were suspect palpable lymph nodes at intra-operative examination).

Recurrence Event and Recurrence-Free Survival (RFS) Primary outcome was the recurrence-free survival (RFS) defined as the time from the date of surgery to the date of recurrence. RFS and overall survival (OS) were assessed using the Kaplan Meyer method and the log-rank test. The associations of clinical, pathological and surgical variables with the recurrence free survival were assessed using the Cox proportional hazards methods.14

MATERIALS AND METHODS Patients and Data We retrospectively studied data from patients with BOTs who had received primary surgical treatment between January 1980 and December 2008 in two referenced centers (Tenon University Hospital and the Institut Gustave Roussy). Medical records, including patient charts, operative, pathological and follow-up records, were reviewed. Data included clinical, surgical, pathological and demographic variables at presentation: age, preoperative serum CA 125, type of surgery (fertility-sparing intention or not), pathological type (serous or mucinous), pathological characteristics of omentectomy, peritoneal biopsies and cytology analysis. The staging system was based on the 2006 FIGO stage system for ovarian cancer.13 Surgical Management Fertility-sparing surgery (conservative treatment) was defined as a procedure in which the uterus and at least part of one ovary are preserved (i.e., unilateral salpingooophorectomy (USO) and cystectomy). Surgical treatment was considered non-conservative when bilateral salpingooophorectomy (BSO) was performed with or without associated hysterectomy.

Surgical staging was considered complete when all peritoneal surfaces were carefully inspected and peritoneal washing, random or oriented multiple biopsies, and infracolic omentectomy were performed independently of whether they were performed in one or two interventions (that is, a second procedure after childbearing). Systematic appendectomy was also a criterion for complete staging especially for mucinous BOTs. Initial surgical staging was considered incomplete in all other cases, independently of its radical or conservative nature. Pelvic and paraaortic lymphadenectomy was performed according to institutional guidelines and the surgeon’s preference (if malignant disease was suspected at frozen section analysis or if there

Other Statistical Analysis Statistical analysis was based on Student’s t test and the Mann–Whitney test for parametric and nonparametric continuous variables, respectively, and the Chi square test or Fisher’s exact test, as appropriate, for categorical variables. Values of p \ 0.05 were considered to denote significant differences. Data were managed with an Excel database (Microsoft, Redmond, WA) and analyzed using R 2.15 software packages (http://lib.stat.cmu.edu/R/CRAN).

RESULTS Description of the Population Among the 704 who underwent histological diagnosis of BOT in both centers, 428 patients with primary surgical treatment for BOTs were included in the study. The median age of the patients was 34 years (range 18–75 years).

Among the 428 patients, 58.8, 9.1 and 32.2 % had FIGO stage I, II and III, respectively. About half of the tumors (216, 50.5 %) were of mucinous histology and 23 (10.6 %) of these had features of intraepithelial carcinoma (IEC).

The remaining 212 tumors were serous and 69 (32.5 %) of these had a micropapillary pattern. Microinvasion was reported in 98 (22.9 %) of the BOTs overall (mucinous and serous). Detailed patients’ characteristics at baseline are shown in Table 1.

Staging Surgery The initial surgical approach was laparoscopy (in 57.5 %) and laparotomy (in 38.1 %). Data were not available in 4.4 %. Bilateral salpingo-oophorectomy, unilateral salpingooophorectomy and cystectomy were performed in 40, 23.1 and 36.9 % of cases, respectively. Three hundred and nine (72.2 %) underwent incomplete surgical staging. Independently of each other, peritoneal washings, peritoneal biopsy,

Staging of Borderline Ovarian Tumors TABLE 1 Epidemiological, surgical and histological characteristics in the whole population of patients with BOTs Parameters

Baseline characteristics

p value

Overall cohort N % N = 428

No recurrence N % N = 326

Recurrence N % N = 102

37.17 (18–98)

38.23 (18–95)

33.64 (18–98)

I

251 (58.7)

203 (62.3)

48 (47.0)

II

39 (9.1)

26 (7.9)

13 (12.8)

III

138 (32.2)

97 (29.8)

41 (40.2)

Serous

212 (49.5)

144 (44.2)

68 (66.7)

Mucinous

216 (50.5)

182 (55.8)

34 (33.3)

Mean age years (range)

0.002

FIGO staging

0.022

Histologic subtype \0.001

Micropapillary architecture Yes

69 (16.1)

47 (14.4)

22 (21.6)

No

166 (38.8)

111 (34.1)

55 (53.9)

NA

193 (45.1)

168 (51.5)

25 (24.5)

Yes No

98 (22.9) 275 (64.3)

69 (21.2) 213 (65.3)

29 (28.4) 62 (60.8)

NA

55 (12.8)

44 (13.5)

11 (10.8)

Complete

119 (27.8)

94 (28.8)

25 (24.5)

Incomplete

309 (72.2)

232 (71.2)

77 (75.5)

Laparoscopy

246 (57.5)

196 (60.1)

50 (37.2)

Laparotomy

163 (38.1)

125 (38.4)

38 (49.1)

NA

19 (4.4)

5 (1.5)

14 (13.7)

\0.001

Micro invasion

0.288

Completeness of surgical staging 0.890

Surgical route

\0.001

Surgery procedure Bilateral SO ± HT

12 (2.8)

8 (2.5)

4 (3.9)

Unilateral SO

301 (70.3)

244 (74.8)

57 (55.9)

Cystectomy

115 (26.9)

74 (22.7)

41 (40.2)

No Pelvic ± para-aortic

352 (82.2) 58 (13.6)

276 (84.7) 44 (13.5)

76 (74.5) 14 (13.7)

NA

18 (4.2)

6 (1.8)

12 (11.8)

No

408 (95.3)

312 (95.7)

96 (94.1)

Yes

20 (4.7)

14 (4.3)

6 (5.9)

0.001

Lymphadenectomy

\0.001

CA 125 [ 35 IU/mL 0.507

FIGO International Federation of Gynecology and Obstetrics, NA not available, BOTs borderline ovarian tumors, SO salpingo-oophorectomy, HT hysterectomy

omentectomy were performed in 52.8, 55.4, and 27.8 % of cases, respectively (Table 2). Appendectomy was performed in 38 of the 216 patients (17.6 %) with mucinous BOTs and no lesions were found in the appendectomy samples. Final pathology results on random biopsies revealed occult presence of BOTs in 38.9 and 35.3 % of peritoneal washing and omentectomy none of which were invasive. Peritoneal biopsies were performed in 55.4 % of the cohort with 22.7 % positive results on final histology: 81.5 % (44/54) of

these were non-invasive and the remaining 18.5 % (10/54) invasive. Lymphadenectomy was performed in 58 of the 428 patients (13.6 %), all of which included pelvic ± paraaortic areas, with positive lymph nodes in 18.9 % (11/58).

Recurrence Rate, RFS and OS The median time of follow-up (from diagnosis to recurrence or last date of follow-up) was 94.9 months

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TABLE 2 Results of staging procedures according to the FIGO stage and histology type Overall

Complete staging

FIGO staging

Histology

I N = 251

II N = 39

III N = 138

Serous N = 212

Mucinous N = 216

30.1 % (129/428)

13.5 % (34/251)

38.5 % (15/39)

50.7 % (70/138)

42.9 % (91/212)

12.9 % (28/216)

52.8 % (226/428) 38.9 % (88/226)

28.3 % (71/251) 8.4 % (6/71)

71.8 % (28/39) 60.7 % (17/28)

89.1 % (123/138) 52.8 % (65/123)

23.6 % (50/212) 6.0 % (3/50)

79.6 % (172/216) 49.4 % (85/172)

Peritoneal washings Performed Positive Peritoneal biopsy Performed

55.4 % (237/428)

35.8 % (90/251)

71.8 % (28/39)

86.2 % (119/138)

76.4 % (162/212)

34.7 % (75/216)

Positive

22.7 % (54/237)

0 % (10/100)

0 % (1/31)

45.3 % (54/119)

30.2 % (49/162)

6.7 % (5/75)

Omentectomy Performed

27.8 % (119/428)

13.5 % (34/251)

38.4 %( 15/39)

50.7 % (70/138)

42.9 % (91/212)

12.9 % (28/216)

Positive

35.3 % (42/119)

0 % (0/36)

0 % (0/15)

60.0 % (42/70)

45.1 % (41/91)

3.5 % (1/28)

0.6 0.4 0.0

0.2

Overall Survival

0.8

1.0

regression analysis (Table 3). There was no difference in 5-year RFS in the whole population between patients who had received complete staging surgery and those who had not (78.1 % (95 % CI 68.9–88.6) and 70.9 % (95 % CI 64.6–77.8), p = 0.080). Similar results were observed according to the FIGO stage (p = 0.765) and histological type (p = 0.0733). Concerning 5-year OS, in the whole cohort there was a difference between patients who had received complete staging surgery and patients who had not (98.4 % (95 % CI 96.8–1.0) and 93.8 % (95 % CI 88.1–1), p = 0.018). However, this significant difference was not observed in FIGO stage I patients 98.6 % (95 % CI 96.7–1) and 92.7 % (95 % CI 83.4–1.0), p = 0.127, respectively.

0

12

24

36

48

60

Comment

Time (months) FIG. 1 5-Years overall survival curves according to the staging surgery. Complete staging yellow line, incomplete staging blue line

(range: 60.00–207.3). The overall recurrence rate was 23.8 % (102/428), with non-invasive and invasive forms in 20.3 % (87/428) and 5.4 % (15/428) of cases, respectively.

Recurrences were diagnosed in 19.1, 33.3 and 29.7 % of patients with FIGO stage I, II and III, respectively. For the whole population, 5- and 10-year RFS was 100 and 94.7 % (95 % CI 88.9–100), respectively. For OS, 5- and 10-year rates were 97.4 % (95 % CI 95.7–99.2) and 94.7 % (95 % CI 88.9 –100), respectively (Fig. 1).

Recurrence Prognostic Factors No significant differences were found depending on the histology type, FIGO stage, complete staging, micropapillary architecture, microinvasion, intraepithelial carcinoma, invasive implant or type of surgery procedure using cox

Even though a lot is known about the clinical behaviour and prognosis of BOTs, there is still no consensus about the most optimal staging surgery.3,12 We report here one of the largest studies that specifically focused on findings related to the uterus, the ovaries, the omentum, cytology and multiple peritoneal surfaces during surgery. We report that the omission of such surgery is not associated with a lower 5-year RFS or OS in patients with presumed stage I BOTs. Conversely, complete staging seems to be associated with an improvement in survival rates for patients with presumed advanced stages (FIGO stages II and III BOTs).

While complete surgical staging is currently recommended for all patients with BOTs,3 this is not always applied in real-life practice. In the current study, only 27.8 % of the patients were completely staged, which is low compared with some studies.12 However, several other authors have also reported low rates (38.1 %) of complete staging (at least peritoneal cytological analysis, omentectomy, and peritoneal biopsy) during initial surgery, even

Staging of Borderline Ovarian Tumors TABLE 3 Univariate analysis of RFS according to tumor characteristics and surgery interventions Factor

Hazard ratio (HR) 95 % confidence interval (CI)

p value

FIGO staging I

–

II

0.91 (0.49–1.69)

0.765

III

0.92 (0.59–1.44)

0.728

Histological subtype Mucinous

–

Serous

1.47 (0.96–2.25)

0.073

Microinvasion Without microinvasion

–

With microinvasion

1.23 (0.79–1.92)

0.359

1.74 (1.13–2.70)

0.012

Surgical access Laparotomy Laparoscopy Completeness of surgical staging Incomplete

–

Complete

0.67 (0.42–1.05)

0.080

Surgery Fertility-sparing surgery

–

No conservative surgery

0.93 (0.34–2.56)

0.893

Lymphadenectomy No

–

Yes

0.94 (0.53–1.67)

0.834

Micropapillary architecture No Yes Intraepithelial carcinoma

– 1.11 (0.67–1.82)

No

–

Yes

0.18 (0.03–1.25)

0.684

0.082

when the borderline nature of the lesion is assessed by intraoperative histology.5,6 Similarly, Fauvet et al.6 reported 4.6 % of complete staging by laparoscopy during initial surgery, 21.4 % after conversion to open surgery, and 25.4 % by laparotomy. Lin et al.5 recorded a 12 % rate of complete staging by laparotomy, 7 % for general surgeons, and 50 % for oncological surgeons. This illustrates that BOT staging management remains controversial and practice patterns vary widely among gynecologic oncologists.

In theory, complete staging is carried out to determine whether implants are present which would point towards further adjuvant treatment. However, for BOTs, the treatment is almost always surgical3 which puts into question the benefits of such primary surgery if it has little effect on management and prognosis. When focusing especially on stage I BOTs (presumed or after complete staging showing

no invasive implants) incomplete staging was not related to a lower 5-year RFS or OS. In contrast, complete staging did have an impact on 5-year OS in patients with advanced stage BOTs (FIGO stage III). These results are in accordance with several studies.8,12 Indeed, Seidman and Kurman15 reported a recurrence rate of 1.7 % in patients with advance stage BOTs with complete staging versus 9.9 % in those with incomplete staging. Similarly, Camatte et al.8 reported no recurrence after complete staging compared with a rate of 8 % after incomplete staging. However, in contrast with du Bois et al.,16 we did not find that incomplete staging had an impact on disease recurrence (in our study, the recurrence rate in patients with and without complete surgical staging was 21.0 (25/119) and 24.9 (77/ 309), respectively). This apparent discrepancy could be explained by a bias of analysis in the previous studies which included BOTs both at early and advanced stages of the disease.

Numerous studies suggest that comprehensive staging surgery could be of particular importance only for patients with peritoneal implants.4,17–19 This hypothesis is reinforced by the fact that the benefits of complete staging in patients with BOTs without implants could be limited for two reasons: it might not modify the decision for adjuvant treatment; and most observed recurrences can be surgically salvaged secondarily.12 Morice et al.12 demonstrated that the main predictive factor of survival was the presence of invasive implants.

In the current study peritoneal implants were reported in 22.7 % of the explored cohort with 18.5 % found to be invasive. However, no difference in 5-year RFS or OS was observed in this subset of patient. In addition, invasive recurrence represented 5.4 % (15/428) of cases. Remarkably, 46.6 % (7/15) of these patients who experienced invasive recurrence had previously undergone complete surgical staging implying a contrario that most of the patients underwent complete staging without benefit.

Despite a relative high rate of positive cytology, no impact on survival was observed in our study. This could be partly explained by difficulties in distinguishing nonmesothelial cells from reactive mesothelial cells that can be observed in benign conditions such as endometriosis. The presence of cilia, lack of single atypical cells, prominent cytoplasmic vacuolation, marked nuclear atypia or two distinct cell populations are features favouring a benign process.20 Moreover, as recently underlined in comments on the new 2014 FIGO classification for ovarian cancer, the significance of positive cytology is poorly understood and is one of the reasons that the committee elected to divide it into three categories21 with a worse prognosis in the event of intraoperative rupture than when the capsule is unruptured. Similarly, our results are in agreement with those of a previous study showing that peritoneal surfaces with a

S. Bendifallah et al.

macroscopically normal appearance rarely contain a microscopic focus of BOTs.22 Similarly to our findings, microscopic disease in the omentum is reported in between 0–22 % of cases of apparently early-stage epithelial ovarian cancer; however extra-ovarian disease isolated in the omentum is found in only 2–7 % of cases. We report that occult omental disease was found in 0, 0 and 60.0 % of patients with stage I, II, III, respectively. More interestingly only 3.5 % of patients with mucinous BOTs had omental disease compared to 45.1 % of those with serous BOTs. Finally, for the purpose of staging, omental biopsies are probably sufficient in a grossly normal appearing omentum.

Our data suggest that complete staging including peritoneal cytology, random peritoneal biopsies and omentectomy could be omitted for presumed stage I BOTs and should not be an indication for restaging operations. Only a few settings may argue in favour of restaging surgery. These would include mucinous BOTs treated by cystectomy, a micropapillary pattern often associated with peritoneal implants, microinvasion, incomplete excision of peritoneal implants, and the indeterminate nature of peritoneal implants, attributable to absence of adjacent and underlying tissue.12 Some limitations of this study deserve to be mentioned.

First, its retrospective nature which included heterogeneous data from multicenter cohort especially concerning the omission of the stadification surgery. Although, the complete staging was not associated with a lower 5-year RFS or OS in patients with presumed stage I BOTs, the current study included only 27.8 % of patients who underwent the complete staging procedure. Second, another source of bias could be due to modifications in staging modalities and surgical techniques (surgical sparing surgery or laparoscopy) which occurred during the data collection period. Third, a follow-up period of more than 5 years has been claimed to be crucial to properly evaluate the recurrence rate, due to the high number of late recurrences.17,23 Indeed, recurrence rates range from 5 % in series with a median follow-up of less than 3 years to 30 % in series with a median follow-up of more than 5 years.12,17,24 Fourth, we did not include rare entities such as endometrioid, Brenner, or clear-cell BOTs because of their very low incidence (\5 % of BOTs). Fifth, in the current study microinvasion was not found to be an independent prognostic factor for RFS. However, the analysis of the effect of microinvasion on the rate of invasive recurrences and disease-related death is especially difficult because of potential confounding factors (micropapillary patterns, presence of peritoneal implants) especially for serous BOT.12 To conclude, one pragmatic way of better identifying patients who may benefit from staging or restaging surgery seems to rely on a more accurate selection of patients who are at high risk of advanced stages of BOT and

invasive recurrence. Finally, most patients without implants or micropapillary patterns,12 intraepithelial carcinoma,12 stromal microinvasion,12 as well as patient with stage I BOT have appear not to benefit from complete staging putting into question the necessity of restaging operations.

CONFLICT OF INTEREST The authors declared no conflicts of interest. No financial support for the research.

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