Archives of Gynecology and Obstetrics

https://doi.org/10.1007/s00404-018-4789-2

GYNECOLOGIC ONCOLOGY

Does tumor grade influence the rate of lymph node metastasis

in apparent early stage ovarian cancer?
Dimitrios Nasioudis1   · Spyridon A. Mastroyannis1 · Emily M. Ko1 · Nawar A. Latif1

Received: 25 December 2017 / Accepted: 16 May 2018

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Abstract
Purpose  To evaluate the prevalence of regional lymph node (LN) metastasis in patients with non-clear cell epithelial ovarian
cancer apparently confined to the ovary, stratified by tumor grade.
Methods  The National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) database was accessed
(1988–2014). We identified patients with epithelial ovarian carcinoma of serous, endometrioid and mucinous histology
apparently confined to the ovary who underwent extensive lymphadenectomy (defined as at least 20 lymph nodes removed).
Demographics, tumor histology, grade and lymph node status were collected. Comparisons were made with Chi square and
Mann–Whitney U tests.
Results  A total of 1242 women met the inclusion criteria. Endometrioid adenocarcinoma was the most common histology
(564 patients (45.4%)) while 443 (35.7%) and 235 (18.9%) patients had serous, and mucinous adenocarcinoma, respectively.
The rate of LN metastasis in low-grade serous was 9.0% (6/67) vs. 14.4% (54/376) in high-grade serous histology (OR, 1.71,
95% CI 0.70, 4.14, p = 0.24). In patients with low-grade endometrioid tumors, the rate of LN metastasis was 1.7% (7/407)
vs. 5.1% (8/157) observed in those with high-grade tumors (OR: 3.07, 95% CI 1.09, 8.61, p = 0.033). Lastly, the rate of LN
metastasis in mucinous histology was 1.7% (3/177) in low-grade vs. 8.6% (5/58) in high-grade tumors (OR: 5.47, 95% CI
1.27, 23.66, p = 0.024).
Conclusions  Regional LN metastasis in apparent stage I low-grade mucinous and endometrioid ovarian tumors is infrequent.

Keywords  Ovarian cancer · Grade · Lymph node · Lymphadenectomy

Introduction recommendations. Patients with favorable characteristics

Ovarian cancer is currently the fifth leading cause of can-
cer-related death among women in the United States [1].
Approximately 30% of the patients with (EOC) present
with disease confined to the ovary or pelvis [2]. According
to FIGO guidelines every patient diagnosed with ovarian
cancer should undergo a complete surgical staging proce-
dure that includes omentectomy, biopsy of all suspicious
lesions, peritoneal washings and lymph node sampling/dis-
section (LND). Surgical staging provides valuable informa-
tion on tumor dissemination thus guiding adjuvant treatment
* Dimitrios Nasioudis
dimitrios.nasioudis@uphs.upenn.edu
1
Department of Obstetrics and Gynecology, Hospital
of the University of Pennsylvania, Helen O’Dickens
Women’s Health Center, 3400 Spruce Street, Philadelphia,
PA, USA
(stage IA, low-grade, non-clear cell histology) can be safely
spared of adjuvant chemotherapy [3]. However, systematic
LN dissection of pelvic and para-aortic LNs can be associ-
ated with a prolonged operative time, increased blood loss
and significant morbidity [4]. The aim of the present report
was to investigate the prevalence of regional LN metas-
tasis in apparent early-stage non-clear cell EOC stratified
by tumor histology and grade, using a multi-institutional
population-based database.
Materials and methods
The National Cancer Institute’s SEER database was accessed
and using the ICD-O-3/WHO 2008 site code “C.569/ovary”
a cohort of patients with ovarian cancer diagnosis between
1988 and 2014 was abstracted. Data deriving from 18 can-
cer registries as released on April 2017 were used [5]. All

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patient data are de-identified and available to the public for
research purposes. The ICD-O-3 morphology codes “8441,
8460–8463, 9014”, “8470–8490, 9015” and “8380–8381,
8560, 8570” as grouped by the International Agency for
Research on Cancer (IARC) were used to identify women
with serous, mucinous and endometrioid ovarian tumors,
respectively [6]. Using the Collaborative staging (CS) and
the Extent of Disease (EOD)-10 fields, those with disease
apparently confined to the ovary and documented absence of
distant metastasis were selected for further analysis. Patients
who did not undergo cancer-directed surgery, those who
were upstaged due to microscopic peritoneal implants, cases
without histologic confirmation or without tumor grade
information were excluded. In addition, from the present
study we opted to exclude clear cell tumors given that they
are currently not deemed histologically gradable. Tumor
grade was recoded from a 4-tier into a 3-tier system that
included grade 1 (well differentiated), grade 2 (moderately
differentiated) and grade 3 (poorly differentiated and undif-
ferentiated, combined). We opted to exclude from our analy-
sis cases with grade 2 tumors given significant variations in
their classification into low and high grade [7]. Information
derived from the histopathology report was employed to
identify women who underwent lymphadenectomy (LND).
In the present report, we opted to include only patients who
had extensive LND defined as at least 20 LNs removed and
examined. Comparison of categorical and continuous vari-
ables was made with the Fisher’s exact or Chi square tests
and Mann–Whitney U test, respectively while odds ratio and
95% confidence intervals were calculated. Statistical analysis
was performed with the SPSS v.24 statistical package. The
alpha level of statistical significance was set at 0.05.
Results
A total of 1242 women met the inclusion criteria. The
median age at diagnosis was 53 years (range 18–88), and the
majority of patients were White (84.9%). Endometrioid ade-
nocarcinoma was the most common histology [564 patients
(45.4%)] while 443 (35.7%) and 235 (18.9%) patients had
serous, and mucinous adenocarcinoma, respectively. In our
cohort, 84.9% of serous tumors were high grade compared
to 27.8% of endometrioid and 24.7% of mucinous tumors
(p < 0.001). A total of 633 (51%) patients had apparent stage
IA disease while 486 (39.1%), 105 (8.5%) and 18 (1.4%) had
apparent IC, IB and INOS (not otherwise specified) disease,
respectively. Table 1 summarizes the clinico-pathological
characteristics of the study population stratified by tumor
grade. Patients with serous histology were older (median
age 57 years) than those with endometrioid and mucinous
tumors (51 and 50 years, respectively p < 0.001) and pre-
sented more commonly with apparent stage IC disease
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Archives of Gynecology and Obstetrics
(49.9%) compared to those with endometrioid (34.8%) and
mucinous (29.4%) tumors, p < 0.001.
The median number of LN removed and examined was 27
(IQR:10). No statistically significant difference in the extent
of LND was found based on tumor grade following stratifi-
cation by histology. Rate of LN metastasis was 6.7% while
median number of positive LNs removed was 2 (IQR:4).
Median lymph node ratio (LNR, ratio of the number of
positive lymph nodes to the total number of lymph nodes
removed) was 0.048 (IQR: 0.13). Figure 1 depicts the dis-
tribution of LNR in our cohort. The rate of LN metastasis in
low-grade serous tumors was 9.0% (6/67) vs. 14.4% (54/376)
in high-grade serous histology (OR, 171, 95% CI 0.70, 4.14,
p = 0.24). For patients with low-grade endometrioid tumors,
the rate of LN metastasis was 1.7% (7/407) vs. 5.1% (8/157)
observed in those with high-grade tumors (OR: 3.07, 95%
CI 1.09, 8.61, p = 0.033). Lastly, the rate of LN metastasis in
mucinous histology was 1.7% (3/177) in low-grade vs. 8.6%
(5/58) in high-grade tumors (OR: 5.47, 95% CI 1.27, 23.66,
p = 0.024). Table 2 summarizes the rate of LN metastasis
stratified by tumor histology and grade.
Discussion
The results of the present report further support the grow-
ing body of evidence that the prevalence of occult regional
LN metastases in low grade, endometrioid and mucinous
EOC apparently confined to the ovary is very low. A recent
meta-analysis of retrospective studies that included data
from 273 patients with apparent stage I–II, low-grade
ovarian tumors (of any histology) who underwent sys-
tematic LND revealed that rate of occult LN metastases
was 2.9% [8]. However, in that study, limited information
on tumor histology was available. In a multi-center study
that examined 107 patients with apparent stage I disease
and low-grade mucinous and endometriod histology who
underwent systematic LND, LN metastasis was extremely
rare occurring in only one patient [9]. In the same study,
contrary to our results, the prevalence of LN metasta-
sis among patients with low-grade serous and apparent
stage I disease was 2.4%, which was significantly lower
than the rate observed in our cohort (9.0%). It should be
underlined that low and high grade serous tumors are
characterized by unique molecular profiles and clinico-
pathological characteristics indicating that these tumors
are two distinct entities and not the ends of the same dis-
ease [10]. Interestingly, a previous analysis of the SEER
database failed to demonstrate a survival benefit of LND
for patients with apparent stage I mucinous tumors [11].
As such, omitting LND (in the absence of grossly abnor-
mal lymph nodes) when staging low grade mucinous and
endometrioid EOCs may potentially shorten operative time
Archives of Gynecology and Obstetrics

Table 1  Clinical characteristics Low-grade High-grade p value* Overall

of study cohort stratified by
tumor grade Age (median, IQR, years) 51 (16) 56 (15) < 0.001 53 (16)
Age (years) < 0.001
 <50 290 (44.5%) 155 (26.2%) 445 (35.8%)
 ≥ 50 361 (55.1%) 436 (73.8%) 797 (64.2%)
Race 0.88
 White 551 (84.6%) 504 (85.3%) 1055 (84.9%)
 Black 24 (3.7%) 23 (3.9%) 47 (3.8%)
 Other/unknown 76 (11.7%) 64 (10.8%) 140 (11.3%)
Histology < 0.001
 Serous 67 (10.3%) 376 (63.6%) 443 (35.7%)
 Endometrioid 407 (62.5%) 157 (26.6%) 564 (45.4%)
 Mucinous 177 (27.2%) 58 (9.8%) 235 (18.9%)
Laterality < 0.001
 Unilateral 589 (90.5%) 442 (74.8%) 1031 (83%)
 Bilateral 62 (9.5%) 149 (25.2%) 211 (17%)
Substage
 IA 411 (63.1%) 222 (37.6%) < 0.001 633 (51%)
 IB 33 (5.1%) 72 (12.2%) 105 (8.5%)
 IC 197 (30.3%) 289 (48.9%) 486 (39.1%)
 INOS 10 (1.5%) 8 (1.4%) 18 (1.4%)
LN removed (median, IQR) 27 (11) 27 (10) 0.28 27 (10)
LN status
 Negative 635 (97.5%) 524 (88.7%) < 0.001 1159 (93.3%)
 Positive 16 (2.5%) 67 (11.3%) 83 (6.7%)
LN positive (median, IQR) 1 (1) 2 (4) 0.64 2 (4)
LN ratio (median, IQR) 0.045 (0.05) 0.071 (0.16) 0.14 0.048 (0.13)

Bold values indicate p < 0.05

*p value from Chi square or Mann–Whitney U test

and minimize post-operative complications without jeop-

Fig. 1  Lymph node ratio distribution in study population
ardizing the oncological outcomes of these patients. The
above data support omitting a second surgery to perform
LND after a first procedure in which low-grade endometri-
oid or muinous ovarian cancer is discovered in an adnexal
mass. The challenge, however, may be reliably diagnosing
low-grade histology based on frozen section analysis at
the time of surgery. A complete staging procedure should
be performed when a malignancy is diagnosed, but there
is uncertainty regarding tumor histology or grade on the
frozen section. The limitations of the current study is the
retrospective nature and the lack of specific information on
the surgical staging technique employed at each reporting
site as well as the exact anatomical location (pelvic and/
or para-aortic) of the harvested LNs as well as their gross
appearance. Lastly, variations in specimen handling by
different pathology laboratories may have influenced the
final reported LN count. While given the lack of central
pathology report possible tumor misclassification cannot
be excluded. Regional lymph node involvement in appar-
ent stage I low-grade mucinous and endometrioid ovarian

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Table 2  Rate of regional lymph Serous
node (LN) metastasis stratified
by tumor histology and grade Low grade
LN status
 Positive 6 (9%)
 Negative 61 (91%)
cancer is infrequent. International collaborations may aid
in identifying patients with apparent early stage EOC who
may be safely spared of systematic LND.
Author contributions  DN: Conception, Protocol/project development,
Data collection and management, Data analysis, Manuscript writing/
editing, SAM: Data analysis, Manuscript writing/editing, EMK: Data
analysis, Manuscript writing/editing, NAL: Protocol/project develop-
ment, Data analysis, Manuscript writing/editing.
Funding  The authors declare no source of funding for the research
conducted.
Compliance with ethical standards  epithelial ovarian cancer. Obstet Gynecol 129(3):439–447
Conflict of interest  All authors declare no potential conflict of interest,
including and financial or personal relationship which could viewed
as one.
Ethical standards  The SEER is a public dataset available to the public
for research purpose. All patient data are de-identified. The present
study was deemed exempt by the institutional review board.
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