Prognostic value of lymph node involvement in ovarian serous borderline tumors

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Prognostic value of lymph node involvement in ovarian serous borderline tumors Benedicte Lesieur, MD; Aminata Kane, MD; Pierre Duvillard, MD; Sebastien Gouy, MD; Patricia Pautier, MD; Catherine Lhommé, MD; Philippe Morice, MD, PhD; Catherine Uzan, MD, PhD OBJECTIVE: This study was conducted to evaluate the prognosis value

of lymph node involvement (LN positive) lymph node involvement for borderline ovarian tumor (BOT). STUDY DESIGN: This was a retrospective study on 49 patients treated

at our institution for advanced-stage serous BOT (International Federation of Gynecology and Obstetrics [FIGO] III or IV). Pathological characteristics and survival were compared according to the lymph node status. The same analysis was performed on 1503 patients of the Surveillance, Epidemiology, and End Results (SEER) database. RESULTS: In our institution, 14 patients were LN positive. Eight pa-

tients have been upstaged after lymph node dissection. No patient

has died during follow-up (median 53 months). LN positivity was not associated with recurrence. In the SEER registry, 93 patients (6.2%) had LN positivity. These patients were younger and with more advanced local extension. Survival curves were similar after adjustment for FIGO stage. CONCLUSION: Lymph node involvement does not appear as a progno-

sis factor for advanced-stage BOT. Key words: advanced stage, borderline ovarian tumor, endosalpingiosis, lymphadenectomy, prognosis

Cite this article as: Lesieur B, Kane A, Duvillard P, et al. Prognostic value of lymph node involvement in ovarian serous borderline tumors. Am J Obstet Gynecol 2011;204:438.e1-7.

B

orderline tumors of the ovary (BOTs) or ovarian tumors of low malignant potential represent 15-20% of epithelial ovarian tumors. Described for the first time by Taylor in 1929, they are characterized by a slow clinical course with a potential for peritoneal extension but have an excellent prognosis (overall survival estimated 90% at 10 years), which differentiates them from ovarian cancer. BOTs are also distinct from invasive cancer of the ovary because of the age at onset, which is about 10 years younger. Extraovarian spread is found in about 35% of cases in the form of peri-

From the Departments of Gynecologic Surgery (Drs Lesieur, Kane, Gouy, Morice, and Uzan), Pathology (Dr Duvillard), and Oncology (Dr Pautier and Lhommé), Institut Gustave Roussy, Villejuif, France. Received Aug. 12, 2010; revised Oct. 1, 2010; accepted Dec. 29, 2010. Reprints: Catherine Uzan, MD, PhD, Institut Gustave Roussy, 39 Rue Camille Desmoulins, 94805 Villejuif, France. [email protected] 0002-9378/$36.00 © 2011 Mosby, Inc. All rights reserved. doi: 10.1016/j.ajog.2010.12.055

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toneal implants. According to their microscopic characteristics, these implants can be divided into noninvasive (papillary structure similar to that of the BOT) or invasive (a similar structure to that of a well-differentiated invasive adenocarcinoma). Invasive peritoneal implants are associated with a poor prognosis.1-3 Although the most frequent extraovarian site of BOT is the peritoneum, pelvic and retroperitoneal lymph node involvement has been described.1,2,4-9 Since 1995, surgical lymph node staging is no longer among the recommendations for the management of BOTs.10 Nevertheless, a number of patients undergo lymph node sampling at the time of surgery and lymph node involvement is described in 15-35% of BOTs.1,2,4,7,8 We retrospectively collected data on a large series of patients with advancedstage serous BOTs, all treated in or referred to our institute. The objective of this study was to focus on the prognostic impact of nodal involvement in patients treated for advanced-stage serous BOTs. We completed this study by consulting the US Surveillance, Epidemiology, and End Results (SEER) database to

American Journal of Obstetrics & Gynecology MAY 2011

evaluate the prognosis of patients with BOTs and documented lymph node involvement.

M ATERIALS AND M ETHODS From January 1973 to February 2006, 171 patients treated in or referred to our institution for a serous BOT with peritoneal implants had their histological slides reviewed by the same pathologist in our center. BOT was defined as an ovarian tumor with the following: (1) a stratified epithelial lining; (2) the formation of microscopic papillary projections; (3) nuclear atypia; and (4) above all, the absence of frank stromal invasion.11 The micropapillary pattern was evaluated according to criteria of Kurman et al.12 A serous BOT with a micropapillary pattern was confirmed if this appearance continuously occupied greater than 5 mm and greater than 10% of the ovarian tumor. Stromal microinvasion can be observed on the ovarian tumor and was defined as the presence of stromal invasion less than 10 mm2. The staging classification used was the 2000 classification International Federation of Gynecology and Obstetrics (FIGO).13 The tumor stage was recorded

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www.AJOG.org using the macroscopic description during the surgical procedure and reviewing the pathology records. Peritoneal implants were classified as noninvasive (epithelial or desmoplastic type) or invasive according to the criteria previously described by Bell and Scully.14 Surgery had consisted of either radical (bilateral salpingo-oophorectomy with or without hysterectomy) or conservative treatment (defined as conservation of the uterus and salvaging at least a portion of 1 ovary). Additional staging surgical procedures had occasionally been performed. This was dependent on the surgical teams, on whether the BOT was diagnosed during or after the surgical procedure, and on disease extension. Patients had undergone either an open or laparoscopic approach performed either during a 1-step surgical procedure, if the diagnosis of BOT was made at a frozen section analysis during the operation, or during restaging surgery. Lymphadenectomy, although not recommended, could have been performed because of enlarged nodes or misdiagnosis of invasive carcinoma. Adjuvant treatment (chemotherapy, external radiation therapy, and chemotherapy with external radiation therapy) had been administered until 1985. The indications for and the type of adjuvant treatment depended on the pathological results (characteristics of peritoneal implants: noninvasive vs invasive), persistent residual tumor, and the date that treatment had been administered.

Seer program database Case ascertainment. The SEER Program (http://seer.cancer.gov/) currently collects and publishes cancer incidence and survival data from 15 population-based cancer registries that cover one quarter of the US population. Data on more than 6 million in situ and invasive cancer cases are included in the database. The SEER Program is the only source of population-based historical as well as current information on patient survival and disease stage. The mortality data reported by SEER are provided by the National Center for Health Statistics. From a total of 95,000 ovarian tumors registered, we selected 6017 for further

analysis based on the following International Classification of Diseases for Oncology (third edition) codes: 8442 (serous cystadenoma of borderline malignancy), 8451 (papillary cystadenoma of borderline malignancy), 8462 (serous papillary cystic tumor of borderline malignancy), 8472 (mucinous cystic tumor of borderline malignancy), and 8473 (papillay mucinous cystadenoma of borderline malignancy). Only histopathologically diagnosed tumors that represented either the only primary tumor or the first primary tumor diagnosed for each patient were included. Analysis of vital status data were collected until death or the last contact before or until December 2004. For descriptive purposes, we tabulated data using SEER*Stat software (National Cancer Institute, Bethesda, MD): the variables studied were age, stage (American Joint Committee on Cancer stage third edition), number of lymph nodes examined, number of positive lymph nodes, cause of death, and survival time at recode. Staging of BOT was based exclusively on histologically diagnosed extraovarian lesions (called implants). Implants removed from undesignated sites were coded as abdominal involvement. The presence of implants increased the stage of a BOT, but the data on the subclassification of noninvasive or invasive implants were unavailable.

Statistical analysis Recurrence-free interval rates were determined using the Kaplan-Meier method. Recurrence-free intervals were calculated including patients who had relapsed. Patients who had died of intercurrent disease were censored at the time of their death. Univariate analysis was performed. The log-rank test was used to compare the survival curves and to determine the P value. A P ⬍ .05 was considered significant. Categorical variables were compared using the ␹2 or Fisher’s test, when appropriate. Continuous variables were compared using the Student t test, the Mann-Whitney U test, or the analysis of variance test, when appropriate.

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R ESULTS Our series concerned 49 patients who had undergone a lymphadenectomy and had a final diagnosis of BOT: 14 of them (28.6%) had lymph node metastases from BOT. Patient characteristics and histopathological results are detailed in Table 1. Forty-five patients had undergone removal of pelvic lymph nodes (PN), 29 removals of paraaortic nodes (PAN): 20 patients had undergone resection of PN alone, 25 had PN plus PAN surgery, and 4 patients had PAN surgery alone. The proportion of patients who had undergone PAN surgery in the group of patients with involved lymph nodes (LN positive) was statistically significantly higher (12 of 14, 85.7%) than in the group with no lymph node involvement (LN negative) with only 18 of 31 patients with PAN (48.6%) (P ⫽ .024). The mean number of nodes removed was 24.1 in the LN-positive group and 11.3 in the LN-negative group, and this parameter was significantly different (P ⫽ .006). The 5 patients who had undergone fertility-sparing surgery did not have lymph node involvement. Regarding operative findings at the time of surgery, macroscopic implants on the omentum were significantly associated with lymph node involvement (28.6% in the LN-positive group, 2.9% in the LN-negative group, P ⫽ .021). The presence of macroscopic implants on the ovary surface was not associated with LN positivity. The recurrence rate over the follow-up period was 25% in the LN-positive group (3 of 12) and 23.5% in the LN-negative group (8 of 34). Two of the 3 patients in the LN-positive group had developed an invasive recurrence vs 2 of 8 in the LNnegative group. Only 1 patient had died during the follow-up period, and this death was in the LN-negative group (invasive recurrence 56 months after fertility-sparing surgery when she was 16 years old). Recurrence-free survival and overall survival curves are shown in Figures 1 and 2: 10 year disease-free survival was 67.5% for the LN-negative group vs 79.5% in the LN-positive group; 10 year overall survival was 92.8% for LN-nega-

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TABLE 1

Characteristics of the Institute Gustave Roussy patients according to lymph node involvement Characteristics

All

Lymph node not involved (n ⴝ 35)

Lymph node involved (n ⴝ 14)

Age (mean) (y)

36.6

37.0

35.6

Age (median) (y)

34.9

31.4

36.0

Infertility

16.7%

P value

................................................................................................................................................................................................................................................................................................................................................................................

.94

................................................................................................................................................................................................................................................................................................................................................................................

6 of 29

1/13

.41

1/13

1.00

................................................................................................................................................................................................................................................................................................................................................................................

Ovulation induction

7.5%

2 of 27

................................................................................................................................................................................................................................................................................................................................................................................

CA 125 (median)

257

179

417.5

.22

................................................................................................................................................................................................................................................................................................................................................................................

Type of surgery

.......................................................................................................................................................................................................................................................................................................................................................................

Radical

89.8%

30 of 35

14 of 14

Conservative

10.2%

5 of 35

0 of 14

.30

....................................................................................................................................................................................................................................................................................................................................................................... ................................................................................................................................................................................................................................................................................................................................................................................

Type of lymph node surgery

.......................................................................................................................................................................................................................................................................................................................................................................

Pelvic

91.8%

33 of 35

12 of 14

.56

Lumbar-aortic

59.2%

17 of 35

12 of 14

.024

....................................................................................................................................................................................................................................................................................................................................................................... ................................................................................................................................................................................................................................................................................................................................................................................

Number of nodes removed

.......................................................................................................................................................................................................................................................................................................................................................................

Mean

15.3

11.3

24.1

Median

11.0

4.0

20.0

.......................................................................................................................................................................................................................................................................................................................................................................

.006

................................................................................................................................................................................................................................................................................................................................................................................

No residual disease (R0)

65.3%

23 of 35

9 of 14

1.00

Adjuvant chemotherapy

44.9%

15 of 35

7 of 14

.75

................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................

Pathological results (%)

.......................................................................................................................................................................................................................................................................................................................................................................

Microinvasion

51.1

16 of 32

7 of 13

1.00

Micropapillary pattern

53.3

15 of 31

9 of 14

.36

Noninvasive implants

93.6

32 of 33

12 of 14

.21

Invasive implants

23.4

7 of 33

4 of 14

.71

Endosalpingiosis

57.1

14 of 29

10 of 13

1.00

Number of sites greater than 3

68.8

23 of 34

10 of 14

1.00

Omentum microscopically involved

54.2

19 of 34

7 of 14

.76

Omentum macroscopically involved

10.4

1 of 34

4 of 14

.021

Serosa of the corpus uteri

37.5

12 of 34

6 of 14

.75

Douglas pouch

20.8

7 of 34

3 of 14

1.00

Peritoneum between bladder and uterus

27.1

8 of 34

5 of 14

.48

Pelvic peritoneum

41.7

17 of 34

3 of 14

.11

Paracolic gutters

22.9

6 of 34

5 of 14

.26

4.2

2 of 34

0

1.00

Diaphragmatic peritoneum

10.4

5 of 34

0

.30

Salpinx

38.8

13 of 34

6 of 14

1.00

Nodal endosalpingiosis

28.6

7 of 35

7 of 14

.08

Ovarian macroscopic implants

83.7

30 of 35

11 of 14

.67

Peritoneal washing positive

73.2

21 of 28

9 of 13

.72

....................................................................................................................................................................................................................................................................................................................................................................... ....................................................................................................................................................................................................................................................................................................................................................................... ....................................................................................................................................................................................................................................................................................................................................................................... ....................................................................................................................................................................................................................................................................................................................................................................... ....................................................................................................................................................................................................................................................................................................................................................................... ....................................................................................................................................................................................................................................................................................................................................................................... ....................................................................................................................................................................................................................................................................................................................................................................... ....................................................................................................................................................................................................................................................................................................................................................................... ....................................................................................................................................................................................................................................................................................................................................................................... ....................................................................................................................................................................................................................................................................................................................................................................... ....................................................................................................................................................................................................................................................................................................................................................................... ....................................................................................................................................................................................................................................................................................................................................................................... .......................................................................................................................................................................................................................................................................................................................................................................

Rectum

....................................................................................................................................................................................................................................................................................................................................................................... ....................................................................................................................................................................................................................................................................................................................................................................... ....................................................................................................................................................................................................................................................................................................................................................................... ....................................................................................................................................................................................................................................................................................................................................................................... ....................................................................................................................................................................................................................................................................................................................................................................... ................................................................................................................................................................................................................................................................................................................................................................................

Recurrence

23.9%

8 of 34

3 of 12

1.00

Invasive recurrence (per recurrences)

36.4%

2 of 7

2 of 3

.50

................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................

A P ⬍ .05 was considered significant. Lesieur. Prognosis value of lymph node involvement in borderline tumors. Am J Obstet Gynecol 2011.

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FIGURE 1

Disease-free survival according to lymph node status in IGR patients

Disease-free survival according to lymph node status for the IGR patients (the Kaplan Meier method was used). Curves were compared using the log-rank test. The P value was .8793. IGR, Institute Gustave Roussy; LN⫹, involved lymph nodes; LN–, lymph nodes not involved. Lesieur. Prognosis value of lymph node involvement in borderline tumors. Am J Obstet Gynecol 2011.

tive and 100% for LN-positive patients. These findings were not statistically different. The SEER database identified 6017 cases of BOTs between 1973 and 2004. Among these cases, 25% (n ⫽ 1503) had FIGURE 2

Overall survival according to lymph node status in IGR patients

documented lymph node removal, 93 of 1496 had histological evidence of lymph node metastases from the BOT, and information was not available for 7 patients. Patients with lymph node involvement had been diagnosed between 1988 and 2000. We observed a significant increase in the proportion of patients who had undergone lymph node surgery during that period (P ⬍ .001, Figure 3). Information about the type of lymph node removed (ie, pelvic and/or paraaortic) was not available among the database items. Patient characteristics in the SEER database are described in Table 2. The mean age of the patients in the LN-positive group was younger (40.4 vs 48.2, P ⬍ .001). When we compared stage III and IV groups exclusively, this parameter was still significant (39.3 vs 44.5, P ⫽ .02). There was a trend toward a higher number of nodes examined in the LNpositive group (13.3 vs 10.5, P ⫽ .057). The survival curves of patients in the SEER database are shown in Figure 4. We analyzed disease-specific survival (the cause of death was ovarian disease) for all patients according to lymph node management. Five and 10 year disease-specific survival rates were 98% and 97%, respectively, in the LN-negative group and 95% and 89%, respectively, in the LN-positive group. No significant difference was found after adjustment for the FIGO stage (Figure 4). We then analyzed the serous subtype of BOT and found comparable results with disease-specific survival rate of 94.7% and 92.2% in the LN-negative group and 93.3% and 83.8% in the LN-positive group for FIGO III and IV groups. These were not significantly different (P ⫽ .56).

C OMMENT Overall survival according to lymph node status for the IGR patients (the Kaplan Meier method was used). Curves were compared using the logrank test. The P value was .5127. IGR, Institute Gustave Roussy; LN⫹, involved lymph nodes; LN–, lymph nodes not involved. Lesieur. Prognosis value of lymph node involvement in borderline tumors. Am J Obstet Gynecol 2011.

The series from the Institute Gustave Roussy (IGR) concerned 14 cases of lymph node metastases from BOTs accounting for 28.6% of patients with serous advanced-stage BOT. Although this series is limited, this is 1 of the largest ever published. Our study on the series from the IGR and larger-scale data from the SEER database found that there was no significant difference in overall sur-

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FIGURE 3

Evolution of the management of lymph node surgery

Evolution of the management of lymph node surgery according to the year of diagnosis for patients diagnosed with a borderline ovarian tumor in the SEER database. The P value is for the ␹2 test for trend. SEER, Surveillance, Epidemiology, and End Results. Lesieur. Prognosis value of lymph node involvement in borderline tumors. Am J Obstet Gynecol 2011.

vival when the group with nodal disease was compared with the group without nodal disease. In the IGR series, there was no significant difference in survival between patients treated with or without adjuvant chemotherapy following surgery (1 of 3 patients with LN positivity who developed a recurrence had received chemotherapy). The study of the SEER database showed that survival is related to the FIGO stage, regardless of the nodal status, because survival adjusted on the stage was identical in the 2 groups of patients with advanced-stage BOT. The rate of lymph node involvement among women submitted to lymph node surgery was 28.6% in our series, which is slightly higher than that reported by previous series.4,7,8,15,16 Most of the patients in our series had FIGO stage III or IV disease. A series by Rao et al3 reported an LN-positive rate of only 3.2% among 183 patients with BOT who had undergone lymph node staging. In that series, most of the patients had FIGO stage I disease, and only 23% had FIGO stage III. Reports describing a higher rate of lymph node metastases from BOT mainly concerned advanced-stage disease (40-67% of stage III/IV). SEER data showed an LN rate of 6.2%, but 73.6% of patients who had undergone lymph node staging had FIGO stage I disease. If FIGO stages III and IV are considered, 28.3% of patients had lymph node involvement.

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TABLE 2

Characteristics of the patients in the SEER database according to lymph node surgery Characteristics Mean age

Total (n ⴝ 6017) 48.1

LNS done (n ⴝ 1503) 47.78

No LNS (n ⴝ 4514) 48.2

P value .3673

LN positive (n ⴝ 93) 40.39

LN negative (n ⴝ 1403) 48.25

P value ⬍ .0001

................................................................................................................................................................................................................................................................................................................................................................................

⬍40 y

2180 (36.2%)

511 (34.0%) 1669 (37.0%) ⬍ .0001

53 (57.0%)

456 (32.5%)

40-60 y

2387 (39.7%)

672 (44.7%) 1715 (38.0%)

28 (30.1%)

642 (45.8%)

⬎60 y

1450 (24.1%)

320 (21.3%) 1130 (25.0%)

12 (12.9%)

305 (21.7%)

⬍ .0001

................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................

FIGO stage

.......................................................................................................................................................................................................................................................................................................................................................................

4943 (82.2%) 1104 (73.5%) 3839 (85.0%) ⬍ .0001

I

17 (18.3%)

1084 (77.3%)

⬍ .0001

.......................................................................................................................................................................................................................................................................................................................................................................

II

351 (5.8%)

144 (9.6%)

207 (4.6%)

8 (8.6%)

136 (9.7%)

III

494 (8.2%)

204 (13.6%)

290 (6.4%)

50 (53.8%)

150 (10.7%)

IV

121 (2.0%)

37 (2.5%)

84 (1.9%)

17 (18.3%)

20 (1.4%)

Not available

108 (1.8%)

14 (0.9%)

94 (2.1%)

1 (1.1%)

13 (0.9%)

....................................................................................................................................................................................................................................................................................................................................................................... ....................................................................................................................................................................................................................................................................................................................................................................... ....................................................................................................................................................................................................................................................................................................................................................................... ................................................................................................................................................................................................................................................................................................................................................................................

Pathology

.......................................................................................................................................................................................................................................................................................................................................................................

Serous cystadenoma

1458 (24.2%)

Papillary cystadenoma

103 (1.7%)

375 (25.0%) 1083 (24.0%) ⬍ .0001

29 (31.2%)

345 (24.6%)

3 (3.2%)

17 (1.2%)

⬍ .0001

.......................................................................................................................................................................................................................................................................................................................................................................

20 (1.3%)

83 (1.8%)

.......................................................................................................................................................................................................................................................................................................................................................................

Serous papillary cystadenoma

2240 (37.2%)

672 (44.7%) 1568 (34.7%)

56 (60.2%)

611 (43.5%)

Mucinous cystadenoma

2076 (34.5%)

414 (27.5%) 1662 (36.8%)

4 (4.3%)

409 (29.2%)

....................................................................................................................................................................................................................................................................................................................................................................... .......................................................................................................................................................................................................................................................................................................................................................................

Mucinous papillary cystadenoma

140 (2.3%)

22 (1.5%)

118 (2.6%)

1 (1.1%)

21 (1.5%)

.......................................................................................................................................................................................................................................................................................................................................................................

Number of nodes examined

13.34 (1-59)

10.52 (1-77)

.0572

................................................................................................................................................................................................................................................................................................................................................................................

FIGO, International Federation of Gynecology and Obstetrics; LNS, lymph node sampling; LN positive, involved lymph nodes; LN negative, lymph nodes not involved; SEER, Surveillance, Epidemiology, and End Results. Lesieur. Prognosis value of lymph node involvement in borderline tumors. Am J Obstet Gynecol 2011.

The various studies published in the literature mentioned no impact of lymph node involvement on survival in BOTs,1,2,4,7 particularly the 2 largest series, namely that by McKenney et al8 and the one by Djordjevic and Malpica5 concerning 31 patients with lymph node involvement and 36 cases of lymph node involvement, respectively. Leake et al7 found an association between nodal involvement and the risk of recurrence. In our series, this association was not found despite a median follow-up of 105 months in the LN-positive group. The study reported by McKenney et al8 analyzed more precisely the morphology of the lymph node involvement in 31 cases of serous BOT with LN positivity. This study found a significant decrease in disease-free survival among patients with nodular lymph node involvement exceeding 1 mm in size (6 cases, 19% of patients). However, most of the patients had single buds or clusters of cells in the sinus nodes. Our study did not specify the type of lymph node involvement. 438.e5

Studying the US registry SEER database allowed us to establish a survival curve of a number of patients that exceeds that of the series published to date. The results showed no difference in survival between patients with FIGO stage III or IV disease with or without lymph node involvement. These data showed that LN-positive patients were younger. This finding is supported by a recent study by Djordjevic and Malpica,5 which found a mean age that was 10 years younger for patients with LN positivity.5 However, the use of this database has many limitations: histology cannot be verified, data on administration of adjuvant chemotherapy and which drugs were used are not available, and the analysis of the type of surgery performed is too complex because of the multiplicity and vagueness of the headings concerning the surgical procedures and changes in codes over time. Many interesting details were not included: micropapillary pattern and pres-

American Journal of Obstetrics & Gynecology MAY 2011

ence of peritoneal or lymph node endosalpingiosis. Another main limitation of the database was the potential unreliability of the staging because some patients reported with lymph node involvement were not classified as having stage III or IV disease (as they should have been). This is why we limited the study to these advanced stages. Our IGR database was created to exclusively study serous borderline tumors. In the literature, all the series reporting on lymph node metastases from BOT found the serous type, except in 2 cases (1 mucinous tumor17 and 1 seromucinous tumor7). In the SEER database, only 5 patients with mucinous tumors were reported as LN positive (1.15% of patients with mucinous BOT had undergone a lymph node dissection): none of those patients had early stage (FIGO I) disease. Lymph node dissection in patients with mucinous BOT does not appear relevant to the risk of nodal involvement.

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FIGURE 4

Disease-specific survival according to lymph node status for SEER patients with FIGO III or IV BOT

Disease-specific survival according to lymph node status for the SEER database patients with FIGO stage III or IV BOT (the Kaplan-Meier method was used). Curves were compared using the log-rank test. The P value was .29. Zero indicates that lymph nodes not involved; 1 indicates involved lymph nodes; 2 indicates that lymph node sampling was not done. BOT, borderline tumors of the ovary; FIGO, International Federation of Gynecology and Obstetrics; SEER, Surveillance, Epidemiology, and End Results. Lesieur. Prognosis value of lymph node involvement in borderline tumors. Am J Obstet Gynecol 2011.

In the series presented here, 90% of patients had peritoneal implants and 31% of the patients with lymph node involvement had invasive implants. We found no significant difference between the 2 groups regarding the presence of invasive implants. The series published by McKenney et al8 reported 31 cases of BOT with LN positivity: 87% of LN-positive patients had peritoneal implants vs only 54% of LN-negative patients. A significant association was found between nodal involvement and the presence of invasive implants (22% for LN positive, 0% for LN negative). The limitation of this study was that 79% of the LN-negative patients had FIGO stage I and II disease, and the two groups (LN positive or negative) were not comparable in terms of the rate of advanced stages. The particularity of our study is its homogeneity: only advanced stages (III or IV) were taken into ac-

count; thus, the two groups (LN positive or negative) were comparable. The presence of lymph node endosalpingiosis is frequently described in the literature as being associated with lymph node involvement in BOT. The pathogenesis of this node involvement is poorly understood, and there are 2 opposite theories about the origin of lymph node lesions: a metastatic theory by analogy with invasive tumors and the local transformation theory of initially benign glandular inclusion.18-22 Most studies have described the simultaneous presence of endosalpingiosis and papillae that were histologically similar to the BOT in the node. Indeed, some authors suggested that glandular lesions may occur through local metaplasia from the endosalpingiosis in the lymph node. Several teams18,19 have described their observations of what they believe to be malignant transformation of intranodal endosalpingiosis. Other studies sought to highlight the fact that lymph node metastases do not occur through lymphatic spread by producing evidence of the nonclonal origin of glandular lesions compared with the primary lesion. Emerson et al22 studied the polymorphism of X chromosome inactivation in primary borderline tumors and lymph node inclusions (endosalpingiosis or serous BOT) in 13 patients. They found a possible clonal origin in 8 of 13 cases and therefore could not rule out a type of metastatic process. One of the main limitations of our series is that the mean number of nodes examined was higher in patients with lymph node involvement with a higher rate of paraaortic lymph node sampling. The only series published to date that focused on the same question8 found a comparable number of lymph nodes examined in both groups (10.3 and 11.1 for LN-negative and LN-positive patients, respectively). Di Re et al6 found 50% of lymph node involvement in a series of 18 lymphadenectomies with an average of 46.5 lymph nodes analyzed. These data suggest that the probability of finding lymph node metastases from BOTs might also depend on the completeness of lymph node sampling. In our study,

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many patients had sampling of 4 enlarged nodes or fewer. Lymph node involvement is not so rare in advanced-stage BOT because it is observed in approximately 25% of patients with FIGO stage III or IV disease. Lymph node lesions from BOT are frequently associated with the presence of lymph node endosalpingiosis. In our study, we did not find that lymph node involvement was associated with a worse prognosis. The nodal status does not appear to provide relevant additional prognostic information because, as suggested by data in the literature, patients with a borderline ovarian tumor and nodal involvement already exhibit other poor prognostic factors. In conclusion, systematic lymphadenectomy cannot be recommended in advanced-stage BOT, even in the presence of invasive implants. The principle of treatment of borderline ovarian tumors is based on the complete surgical resection of all lesions. The interest of lymph node dissection could therefore be considered as curative in patients with LN positivity. One can only guess the potential benefit of surgery as a curative treatment of suspicious lymph nodes, but prospective studies are needed to subf stantiate this hypothesis. ACKNOWLEDGMENT We thank Lorna Sant Ange for editing.

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