Introduction
The role of systematic lymphadenectomy in primary
advanced ovarian cancer and its prognostic effect remain
controversial and there are currently no available results from
randomised controlled studies. There is an increased tendency for
nodal invasion in advanced ovarian cancer (1,2). Panici
et al described a positive prognostic effect of systematic
lymphadenectomy on progression-free survival (PFS) compared with
resection of bulky nodes, but not on overall survival (OS)
(3). By contrast, other studies
reported a positive prognostic effect on OS after systematic
lymphadenectomy in this subgroup (4).
Therefore, it remains unclear whether complete staging with
systematic lymphadenectomy and its associated morbidity is
beneficial in this subgroup. Little is known on the extent of lymph
node metastases, or which lymph node region is affected depending
on histological subtype. The objective of this study was to
delineate the prevalence and distribution pattern of pelvic and
para-aortic lymph node metastases and the tumour characteristics,
such as histological subtype, affecting survival in primary
advanced ovarian cancer.
Patients and methods
Patients
A total of 130 consecutive patients with primary
International Federation of Gynecology and Obstetrics (FIGO) stage
IIIC/IV advanced epithelial ovarian cancer who were treated at the
Department of Gynecology, University of Tübingen (Tübingen,
Germany), were retrospectively analysed. Each patient underwent
surgical staging following hysterectomy, bilateral adnexectomy,
supracolic omentectomy and cytoreduction, as indicated. Pelvic and
para-aortic lymphadenectomy was performed up to the level of the
renal vessels in all patients with optimally cytoreduced ovarian
cancer. All the patients were treated with an adjuvant standard
platinum-based chemotherapy, according to the AGO guidelines
(http://www.ago-online.de/de/infothek-fuer-aerzte/leitlinienempfehlungen/ovar/).
A total of 130 patients met the inclusion criteria and were
enrolled. The affected region of nodal metastasis (pelvic or
para-aortic) and the clinicopathological factors that were
associated with nodal involvement were identified (Table I). All the patients provided informed
consent for data acquisition prior to their inclusion in the
evaluation. For evaluation of the affected lymph node region
depending on histology, data on 2 patients were missing and were
not further evaluated in this subgroup.
 | Table I.Clinicopathological characteristics of
patients with FIGO stage IIIC/IV primary ovarian cancer. |
Table I.
Clinicopathological characteristics of
patients with FIGO stage IIIC/IV primary ovarian cancer.
| Characteristics | n (%) |
|---|
| Histologic grade |
|
| 1/2 | 59 (45.38) |
| 3 | 71 (54.62) |
| Histology |
|
|
Serous | 111 (85.38) |
|
Mucinous | 3 (2.3) |
| Clear
cell | 2 (1.5) |
|
Endometrioid | 8 (6.2) |
|
Undifferentiated | 6 (4.62) |
| Node involvement |
|
| N0 | 33 (25.38) |
| N+ | 97 (74.62) |
| R-status |
|
| R0 (0
mm) | 39 (30.0) |
|
R>0-<10 mm | 69 (53.07) |
| R≥10
mm | 22 (16.93) |
| Region with node
involvementa
(n=128) |
|
| Pelvic
-/paraaortic − | 33 (25.78) |
| Pelvic
+/paraaortic − | 17 (13.3) |
| Pelvic
+/paraaortic + | 46 (35.9) |
| Pelvic
-/paraaortic + | 17 (13.3) |
| Pelvic
+/paraaortic x | 13 (10.16) |
| Pelvic
x/paraaortic + | 2 (1.56) |
The present study was conducted in compliance with
the current national laws and the principles laid down in the
Declaration of Helsinki and was approved by the Ethics Committee of
the University of Tübingen (no. 244/2015R).
Histology
All surgical tissues were examined by a pathologist
and the final pathology reports were obtained. All the surgical
pathology samples were examined by a gynaecological pathologist and
each diagnosis was reviewed and classified as benign or malignant.
The histological diagnosis was classified according to the FIGO
staging guidelines (5).
Follow-up
Follow-up data were collected at presentation in our
outpatient department. The mean follow-up time was 53.5 months.
Statistical analysis
Statistical analyses (multivariate) were performed
using PASW Statistics, version 22 (PASW Inc., Chicago, IL, USA).
The Student's t-test was used for testing significant differences
between the examined groups. The significance level was set at
P<0.05.
Results
Patient characteristics
Of the 130 enrolled patients, the majority (n=108)
were classified as FIGO stage IIIC and the remaining (n=22) as FIGO
stage IV. The patient characteristics are summarised in Table I. Overall, the most common
histological grade was 3 (54.62%) and the most common histological
type was serous (85.38%), followed by the undifferentiated (4.62%)
and endometrioid (6.2%) subtypes (Table
I); the mucinous and clear cell subtypes were rarely detected
(Table I). Lymph node metastases were
detected in 74.62% of the cases (Table
I).
Considering the affected lymph node regions, the
following were observed: The most frequent pattern was invasion of
both the pelvic and para-aortic nodes (35.9% of the patients);
isolated involvement of the pelvic or para-aortic lymph nodes was
detected in 13.3% of the patients, whereas 13 patients had positive
pelvic nodes with unknown status of the para-aortic nodes and 2
patients had positive para-aortic nodes with unknown status of the
pelvic nodes (Table I).
On multivariate analysis, histological grade 1/2 and
3, and serous and endometrioid histology were found to be
independent predictors of nodal metastasis (Table II). Serous histology is most commonly
associated with nodal metastasis; however, patients with advanced
ovarian cancer with mucinous, clear cell and endometrioid histology
also had node metastases (Table II).
Considering the limited number of cases, mucinous cancers rarely
led to nodal metastasis, whereas metastasis was detected in 84.2%
(n=16) of non-serous cancers (Table
II).
| Table II.Evaluation of lymph node metastases in
correlation with clinicopathological parameters, such as histology
(serous vs. non-serous) and histological grade in 130 FIGO stage
IIIC/IV ovarian cancer patients. |
Table II.
Evaluation of lymph node metastases in
correlation with clinicopathological parameters, such as histology
(serous vs. non-serous) and histological grade in 130 FIGO stage
IIIC/IV ovarian cancer patients.
| Parameters | N0, n (%) | N+, n (%) |
|---|
| Histologic grade |
|
|
| 1/2 | 21 (16.2) | 38 (29.2) |
| 3 | 12 (9.2) | 59 (45.4) |
| Histology |
|
|
Serous | 30 (23.1) | 81 (62.3) |
|
Mucinous | 2 (1.5) | 1 (0.8) |
| Clear
cell | 0 (0) | 2 (1.5) |
|
Endometrioid | 0 (0) | 8 (6.2) |
|
Undifferentiated | 0 (0.8) | 5 (3.8) |
Serous cancers were associated with metastasis to
the pelvic lymph nodes alone, the para-aortic nodes alone, and both
the pelvic and para-aortic nodes; a combined involvement of the
pelvic and para-aortic nodes was the most frequent pattern in this
subgroup (Table III). Of the
patients with non-serous cancers, 27.77% (n=5) exhibited
involvement of the pelvic and para-aortic nodes (Table III). Patients with endometrioid
histology had exhibited metastases to the pelvic nodes alone, or to
both the pelvic and para-aortic nodes; isolated involvement of the
para-aortic lymph nodes was the most frequent pattern detected in
this subgroup (Table III). Among
patients with mucinous cancers (n=3), 1 had metastatic pelvic nodes
and 2 had negative nodes (Table
III). Of the 2 patients with the clear cell subtype, 1
exhibited combined involvement of the pelvic and para-aortic nodes
and 1 had involvement of the para-aortic nodes alone (Table III).
| Table III.Description of lymph node metastases
in correlation with histological subtype (serous vs. non-serous)
and the affected region (pelvic/para-aortic) in 128 patients with
FIGO stage IIIC/IV primary ovarian cancer. |
Table III.
Description of lymph node metastases
in correlation with histological subtype (serous vs. non-serous)
and the affected region (pelvic/para-aortic) in 128 patients with
FIGO stage IIIC/IV primary ovarian cancer.
| Histology | Pelvic-/para-aortic -
(n) | Pelvic +/para-aortic
-, n (%) | Pelvic +/para-aortic
+, n (%) | Pelvic-/para-aortic
+, n (%) | Pelvic +/para-aortic
x, n (%) | Pelvic x/para-aortic
+, n (%) |
|---|
| Serous | 30 (23.44) | 16 (12.5) | 41 | 13 (10.16) | 9 (7.05) | 1 (0.78) |
| Mucinous | 2 (1.56) | 0 (0.0) | (32.03) | 0 (0.0) | 1 (0.78) | 0 (0.0) |
| Clear cell | 0 (0.0) | 0 (0.0) | 0 (0.0) | 1 (0.78) | 0 (0.0) | 0 (0.0) |
| Endometrioid | 0 (0.0) | 1 (0.78) | 2 (1.56) | 3 (2.34) | 2 (1.56) | 0 (0.0) |
|
Undifferentiated | 1 (0.78) | 0 (0.0) | 2 (1.56) | 0 (0.0) | 1 (0.78) | 1 (0.78) |
A significant positive effect on OS was observed for
patients with serous cancers and nodal metastases, compared with
node-negative and non-serous cancers (P=0.043); there was no
significant difference in terms of PFS (Table IV).
| Table IV.Prognostic effect (OS and PFS) of the
histological subtype (serous vs. non-serous) and lymph node
metastatic status (N0 vs. N+) in 129 patients with FIGO stage
IIIC/IV primary ovarian cancer. |
Table IV.
Prognostic effect (OS and PFS) of the
histological subtype (serous vs. non-serous) and lymph node
metastatic status (N0 vs. N+) in 129 patients with FIGO stage
IIIC/IV primary ovarian cancer.
| Nodal status | PFS, months (95%
CI) | P-value | OS, months (95%
CI) | P-value |
|---|
| N0 |
|
| Serous,
n=29 | 13.27
(11.8–14.72) |
| 25.97
(21.85–30.1) |
|
| Othera,
n=3 | 15.83
(13.01–15.8) |
| 16.0
(11.8–20.2) |
|
| N+ |
| N.S. |
| 0.043 |
| Serous,
n=81 | 15.433
(13.071–17.8) |
| 47.97
(13.9–48.8) |
|
Othera, n=16 | 12.167
(10.3–14.04) |
| 25.7
(11.5–39.8) |
Discussion
Complete cytoreduction (R=0 mm), compared with
R>0 mm -≤1 cm, exerts a significantly better prognostic effect
on PFS and OS in advanced ovarian cancer (6–8). The
relevance of lymphadenectomy in the primary surgical management of
ovarian cancer remains unclear (9,10) and is
currently investigated in the prospective LION study (AGO-Ovar).
Results from randomised controlled studies are currently lacking
(11,12). The randomised trial of Panici et
al revealed a positive effect of systemic lymphadenectomy on
PFS compared with resection of bulky nodes in optimally cytoreduced
patients, but no effect on OS (2–4).
Therefore, pelvic and para-aortic lymphadenectomy following optimal
cytoreduction is recommended, with a positive prognostic effect on
primary advanced ovarian cancer (11,13). By
contrast, another report showed a significant positive prognostic
effect of systematic lymphadenectomy on OS in advanced ovarian
cancer (4).
Overall, previous studies reported a rate of ~45–60%
nodal involvement in advanced ovarian cancer (2,3,9,14). In the
present study, collective nodal metastases were detected in 74.62%
of the cases (Table I). Involvement
of the pelvic and/or para-aortic region was also described
(2,3,9), which was
confirmed in our study (Table I).
Thus, accurate surgical staging, including lymphadenectomy,
reliably detects the true extent of the disease with detection of
occult nodal metastases.
The prognostic relevance of nodal metastases in
primary ovarian cancer remains unclear (4). It was previously reported that the
impact of lymph node metastasis on prognosis decreases with an
increase of residual tumour mass (15). As there are several risk factors for
ovarian cancer, it remains questionable whether lymphadenectomy in
advanced ovarian cancer improves prognosis. The results of the
ongoing prospective LION study (AGO-Ovar) may help to assess the
validity of lymphadenectomy as part of the treatment strategy in
optimally cytoreduced patients.
Additionally, the association of nodal metastasis
with clinicopathological parameters must be investigated.
Di Re et al reported that the incidence of
metastatic lymph nodes significantly increased with advanced stage,
serous histology and greater amount of residual tumour (10). On multivariate analysis, histological
grade 3, serous and endometrioid histology, were found to be
independent predictors of lymph node metastasis in advanced ovarian
cancer (Table II). However, even in
the less common subtype of non-serous cancers, 84.2% of the
patients with advanced ovarian cancer had nodal metastases
(Table II).
Since ovarian cancer is known to spread
simultaneously intra- and retroperitoneally, the presence of tumour
spreading mainly through the lymphatic channels without
intraperitoneal dissemination suggests that such tumours may be
associated with a favourable biological behaviour (16). A previous study described that ovarian
serous carcinoma patients with only extrapelvic peritoneal
involvement have a more favorable survival compared with those with
extrapelvic peritoneal involvement and lymph node metastases
(17). Therefore, the extent to which
lymphadenectomy may be considered as reasonable has yet to be
determined, and it may depend on the histological findings.
It has been previously described that nodal
metastases to both the pelvic and para-aortic nodes, as well as to
the pelvic or para-aortic region alone, may be found in advanced
ovarian cancer (3,12,18), as
was observed in our study (Table I).
Both the pelvic and para-aortic nodes were affected in 35.9% of the
patients in our study, with isolated involvement of the pelvic or
para-aortic nodes detected in 13.3% of the patients (Table I).
Serous cancers were associated with all distribution
patterns of nodal involvement, although most frequently combined
involvement of the pelvic and para-aortic region was observed
(Table III). Other histological
subtypes, such as endometrioid and mucinous cancers, are associated
with metastases to the pelvic and para-aortic lymph nodes. Patients
with the endometrioid subtype exhibited all patterns of lymph node
metastasis (Table III). The rare
mucinous subtype only showed a predilection for the pelvic nodes,
without involvement of the para-aortic nodes (Table III). Lymphadenectomy leads to
accurate staging with detection of occult node metastases. In our
study there was a significant effect on OS in serous cancers with
nodal metastases compared with node-negative patients and
non-serous cancers (P=0.043; Table
IV). The removal of positive lymph nodes in the pelvic or
para-aortic region may explain the positive prognostic effect of
lymphadenectomy in advanced-stage disease (3,10,19). This effect is possibly caused by
affected nodes in the para-aortic region, which are not removed by
pelvic lymphadenectomy alone. This fact supports the hypothesis
that adequate staging may be achieved by performing lymphadenectomy
(19). Chang et al described
involvement of para-aortic nodes and recommended a para-aortic
lymphadenectomy up to the level of the renal vessels, which may
detect occult metastases and be helpful in tailoring appropriate
adjuvant treatment, as well as providing useful prognostic
information (20).
Our findings suggest that pelvic and para-aortic
lymphadenectomy in advanced ovarian cancer leads to adequate
staging and may detect occult node metastases. Consequently, the
effect of systematic lymphadenectomy on prognosis in advanced
ovarian cancer remains unknown, due to the lack of prospective
randomised controlled studies.
Prospective studies are required to investigate the
prognostic effect of lymphadenectomy in cases with advanced ovarian
cancer depending on histology and distribution pattern of nodal
metastases. The stratification of this subpopulation of
node-positive epithelial ovarian cancer based on nodal burden may
be of significant prognostic value, and it may be considered in
future staging and aid with management decisions.
Optimal cytoreduction is the main intention of
primary surgery in advanced ovarian cancer, with a significant
positive effect on prognosis. There is a need to investigate the
risk factors and metastatic patterns of such patients in a
multicenter analysis. More extensive lymphadenectomy appears to
play an important role through achieving accurate staging by
detection of occult metastases. Prospective studies are required to
investigate the prognostic effect of lymphadenectomy on advanced
ovarian cancer depending on histology and distribution pattern of
nodal metastases.
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