GYNECOLOGIC ONCOLOGY 70, 183–187 (1998)
ARTICLE NO. GO985086
Ovarian Metastasis in Endometrial Carcinoma
Nobuhiro Takeshima, Yasuo Hirai, Kenji Yano, Naotake Tanaka, Kazuhiro Yamauchi, and Katsuhiko Hasumi
Department of Gynecology, Cancer Institute Hospital, 1-37-1, Kami-Ikebukuro, Toshima-Ku, Tokyo, 170, Japan
Received May 27, 1997
A retrospective study was conducted to investigate the clinical
significance of ovarian metastasis in 439 patients with clinical
stage I endometrial cancer surgically treated by performing total
abdominal hysterectomy, bilateral salpingo-oophorectomy, and
pelvic lymphadenectomy. Histologic examination revealed that 22
patients (5%) had ovarian metastasis. The maximum diameter of
the ovarian metastases ranged from 1 to 100 mm. In 18.2% (4/22)
of patients with ovarian metastasis, the maximum diameter was
less than 2 mm. Patients with metastasis limited to the ovarian
surface showed 100% positive peritoneal cytology, 0% lymph node
metastases, and 50% recurrence, while patients with metastasis
inside the ovary showed 10% positive peritoneal cytology, 36%
lymph node metastases, and 53% recurrence. The prognosis of
patients with ovarian metastasis alone was situated midway be-
tween that of patients with cancer limited to the uterus and that of
patients with lymph node metastasis alone. The lymph node status
was of importance to determine the prognosis of patients with
ovarian metastasis. The series also suggests that there may be two
routes for ovarian metastasis; one is a route via the fallopian tube
to the ovarian surface and the other is a route via the lymphatics
to the inside of the ovary. © 1998 Academic Press
INTRODUCTION
A number of prognostic factors have been reported in
the management of early endometrial cancer. Among them,
extrauterine spread, such as lymph node metastasis or
adnexal metastasis, has been recognized as a major adverse
factor [1–3]. In the case of adnexal metastasis, however, it is
well known that there are a variety of pathological types
encountered in surgical specimens of endometrial cancer.
Since the clinical significance of these various types observed
in adnexal metastasis has not been fully clarified, the question
arises as to whether all of these different cases can be treated
in the same way.
We recently have completed clinicopathologic analyses of
487 consecutive patients with clinical stage I endometrial can-
cer treated at a single institute. In all cases, systemic pelvic
lymphadenectomy was performed. The current study focuses
on ovarian metastasis in endometrial carcinoma. It is hoped
that this information will serve to provide a better understand-
ing of the natural history of this particular extrauterine spread.
183
MATERIALS AND METHODS
Between 1969 and 1990, 487 consecutive patients with
clinical stage I endometrial carcinoma undergoing total abdom-
inal hysterectomy, bilateral salpingo-oophorectomy, and pelvic
lymphadenectomy were treated at the Cancer Institute Hospi-
tal, Tokyo, Japan. None of these patients had any synchronous
primary neoplasm nor had they received any treatment before
surgery. All of the operative specimens were pathologically
reviewed. Nine cases with serous papillary adenocarcinoma, 5
cases with clear cell adenocarcinoma, and 15 cases with ade-
nosquamous carcinoma were excluded from this study. Eigh-
teen cases with extrauterine spread other than to the ovary and
pelvic lymph nodes, such as peritoneal surface seeding, were
also excluded. Although two cases who had metastases to both
the ovary and the fallopian tube were included, one case with
metastases to the fallopian tube alone was excluded from this
series. The remaining 439 patients, all with adenocarcinoma
(endometrioid type), formed the study population.
With respect to ovarian metastasis, if present, only tumors
which were pathologically considered as metastatic sites from
endometrial carcinoma were enrolled as ovarian metastasis in
this study. The criteria proposed by Ulbright and Roth were
employed for this classification with minor modification [4].
Briefly, the criteria were either a multinodular ovarian pattern
(major criterion) or two or more of the following minor crite-
ria: small (,5 cm) ovary(ies), bilateral ovarian involvement,
deep myometrial invasion, vascular invasion, and tubal lumen
involvement. In this study, cases in which an ovarian lesion
exhibited a nonendometrioid morphology were also excluded.
A complete bilateral pelvic lymphadenectomy was per-
formed with the aim of removing all external iliac, internal
iliac, common iliac, and obturator lymph nodes. A median
number of 27 lymph nodes per patient was removed. In 38
cases, a para-aortic lymphadenectomy with the aim of remov-
ing all lymph nodes between the bifurcation of the aorta and
the renal vein was performed in addition to pelvic lymphade-
nectomy. A median number of 57 lymph nodes per patient was
obtained in this group.
As for adjuvant therapy, all of the patients with pelvic lymph
node metastasis, whether the ovary was concurrently involved
or not, received pelvic external beam irradiation (50 Gy). No
0090-8258/98 $25.00
Copyright © 1998 by Academic Press
All rights of reproduction in any form reserved.
184 TAKESHIMA ET AL.

TABLE 1 (continuous), vessel permeation, depth of myometrial invasion

Profile of Patients with Stage I Endometrial Cancer (continuous), cervical extension, lymph node metastasis, and
in This Study ovarian metastasis.
Pathological classification, adenocarcinoma
G1a 253 RESULTS
G2 122
G3 64 Table 1 shows the profile of 439 patients with stage I
Extrauterine spread endometrial cancer in this study. Twenty-two cases (5%) were
Ovary alone 15 identified to have ovarian implants. The incidence of pelvic
Pelvic lymph node alone 36
lymph metastasis was 9.8% (43/439). In 381 patients, no
Both 7
None 381 extrauterine spread was observed.
Total cases 439 Table 2 shows the pathologic findings of the 22 patients with
ovarian metastasis. The incidence of pelvic lymph metastasis
a
Combined grade. was 31.8% (7/22) in patients with ovarian metastasis. Nineteen
patients (86.4%) had a single ovarian involvement. In 4 pa-
adjuvant therapy was provided for any patients with the other tients (18.2%), ovarian implants were limited to the ovarian
adverse factors, such as ovarian metastasis alone, deep myo- surface; 2 of the 4 patients also had metastases to the fallopian
metrial invasion, or grade 3 tumors. tube. The maximum diameter of the ovarian metastases ranged
The grade (1–3) of adenocarcinoma was established accord- from 1 to 100 mm. In 4 patients (18.2%), the maximum
ing to FIGO (International Federation of Gynecology and diameter was less than 2 mm.
Obstetrics) criteria [5]. Nuclear grade was assigned as pro- Table 3 shows the positive rates of peritoneal cytology,
posed by Zaino et al.: grade 1, uniform round to oval nuclei, lymph node metastasis, and recurrence in relation to the met-
with even distribution of chromatin and inconspicuous nucle- astatic positions at the ovary. All of the 4 patients with metas-
oli; grade 2, irregular oval nuclei, with chromatin clumping and tasis limited to the ovarian surface showed positive peritoneal
moderate size nucleoli; and grade 3, large, pleomorphic nuclei, cytology. Although none of these 4 patients had pelvic lymph
with coarse chromatin, and large irregular nucleoli [6]. All node metastasis, 2 of them developed a recurrence. On the
cases have been followed for 5 to 25 years or until death. No other hand, only 10% of patients with metastasis inside the
patients were lost to follow-up. ovary showed positive peritoneal cytology. However, 36% of
In patients having ovarian implants, the position and the size the patients had lymph node metastasis and 57% developed
of the ovarian metastases were investigated. The size of ovar- recurrence. One patient, of the 3 patients with bilateral ovarian
ian lesions was presented as the maximum diameter of meta- involvement, in whom a pelvic lymph node metastasis was also
static sites in the ovary. When the size of ovarian lesions was revealed, developed a recurrence. The overall incidence of
less than 5 mm on a representative section, additional sections
were obtained to confirm the size of metastatic sites. Peritoneal
washings were obtained in 16 (72.7%) of 22 patients with TABLE 2
ovarian metastasis. The relapse rates in relation to pathologic Pathologic Findings of Endometrial Cancer Patients
findings in patients with ovarian metastasis were analyzed. The with Ovarian Metastasis
x2 test was used to examine the effects of these pathological
Grade of the uterine tumor
factors on the relapse rates. The sites of recurrence in patients 1 13
with ovarian metastasis were also surveyed. 2 6
To determine the prognostic significance of ovarian metas- 3 3
tasis, disease-free survival was comparatively analyzed be- Pelvic lymph node metastasis
Positive 7
tween patients with carcinoma limited to the uterus, patients
Negative 15
with ovarian metastasis alone, patients with lymph node me- Metastatic position
tastasis alone, and patients having both ovarian metastasis and Single ovary 19
lymph node metastasis using the Kaplan-Meier method. The Bilateral ovaries 3
generalized Wilcoxon method was used for the statistical anal- Ovarian surface 4
Inside of ovary 14
ysis. Cox’s proportional hazards model was used to identify the
Both 4
independent prognostic factors in clinical stage I endometrial Size of ovarian metastasis (maximum diameter)
cancer. A standard step-up procedure was employed, entering ,2 mm 4
statistically significant factors in the model based on the like- 2 to ,5 mm 7
lihood ratio test. The pathological findings entered in the 5 to ,20 mm 7
20 mm or greater 4
multivariate analysis were age (continuous), architectural
Total cases 22
grade, nuclear grade, the presence of hyperplasia, tumor size
 OVARIAN METASTASIS IN ENDOMETRIAL CARCINOMA 185

TABLE 3 TABLE 5
The Incidence of Positive Peritoneal Cytology, Lymph Node Sites of Recurrence Relative to Pelvic Lymph Node Metastasis
Metastasis, and Recurrence in Relation to the Positions of Ovarian in Endometrial Cancer with Ovarian Metastasis
Metastases
Nodal metastasis Nodal metastasis
Positive peritoneal Sites of recurrence (1) (2)
Position cytology Nodal metastasis Recurrence
Intrapelvic recurrence 0 1
Surface 4/4 (100%) 0/4 (0%) 2/4 (50%) Extrapelvic recurrence 5 4
Inside 1/10 (10%) 5/14 (36%) 8/14 (57%) Both 2 0
Both 1/2 (50%) 2/4 (50%) 2/4 (50%) Total cases 7 5
Single ovary 5/14 (36%) 6/19 (32%) 11/19 (58%)
Bilateral ovaries 1/2 (50%) 1/3 (33%) 1/3 (33%)
Total 6/16 (38%) 7/22 (32%) 12/22 (55%)
metastasis and lymph node metastasis (P 5 0.0001), and
between patients with lymph node metastasis alone and pa-
positive peritoneal cytology, pelvic lymph node metastasis, and tients with carcinoma limited to the uterus (P 5 0.0001). No
recurrence in patients with ovarian metastasis was 38% (6/16), significant difference was noted between patients with ovarian
32% (7/22), and 55% (12/22), respectively. metastasis alone and patients with lymph node metastasis alone
Table 4 shows the relapse rates relative to histologic param- (P 5 0.3766).
eters in endometrial cancer with ovarian metastasis. A large Table 6 shows the results of the multivariant analysis per-
incidence of recurrence was observed in patients with G2 or G3 formed. Pelvic lymph node metastasis and ovarian metastasis
tumors (66.7%), deep myometrial invasion (70%), and pelvic were recognized as independent prognostic factors. To a lesser
lymph node metastasis (100%). Only pelvic lymph node me- degree, the importance of nuclear grade was noted as an
tastasis was found to have a significant effect on the relapse independent prognostic variable.
rates of endometrial cancer with ovarian metastasis (P 5
0.0137). DISCUSSION
Table 5 shows the sites of recurrence relative to pelvic
lymph node metastasis in endometrial cancer with ovarian The incidence of ovarian metastasis in clinical stage I en-
metastasis. The majority of the patients with recurrent disease, dometrial cancer has been reported to be 1.7–11% [7–11].
whether lymph nodes were concurrently involved or not, were Mannel et al. reported that 8% of stage II cases had metastasis
found to have had an extrapelvic relapse. Only 1 of the 12 to adnexa [12]. In this series, the incidence of ovarian metas-
recurrent cases was exclusively found to have had an intrapel- tasis was approximately 5% in clinical stage I disease.
vic recurrence. From a pathological point of view, there seem to be two
The 5-year disease-free survival rates were 92.1% in patients possible routes for ovarian metastasis. One seems to occur
with carcinoma limited to the uterus, 72.2% in patients with when cancer cells pass through the fallopian tube onto the
ovarian metastasis alone, 59.6% in patients with pelvic lymph ovarian surface. Positive peritoneal cytology in the absence of
node metastasis alone, and 0% in patients having both ovarian nodal metastasis is usually observed and concurrent metastases
metastasis and pelvic lymph node metastasis (Fig. 1). There is to the fallopian tube are also sometimes seen for this metastatic
a significant difference in disease-free survival between pa- route. The other route occurs when cancer cells form a meta-
tients with ovarian metastasis alone and patients with carci- static lesion inside the ovary probably via the lymphatics.
noma limited to the uterus (P 5 0.002), between patients with Lymph nodes are often concomitantly involved and positive
ovarian metastasis alone and patients having both ovarian peritoneal cytology is rarely seen for this route. However, our
data do not disclose much difference in patient survival be-
tween the two routes of metastasis. The rate of recurrence was
TABLE 4 approximately 50% in both groups.
Relapse Rates Relative to Histologic Parameters We also reported that the maximum diameter of the ovarian
in Endometrial Cancer with Ovarian Metastasis lesions was less than 2 mm in 18.2% of cases with ovarian
metastasis. Since the overall incidence of ovarian metastasis
Histologic parameter (1) (2) P was 5% in this study, it is considered that approximately 1% of
Grade 2 or 3 tumor 66.7 (6/9) 46.2% (6/13) 0.6068 patients with clinical stage I endometrial cancer have micro-
Vessel involvement 50% (6/12) 60% (6/10) 0.9688 metastases in the ovary. These data indicate that this small risk
Depth of myometrial invasion 70% (7/10) 41.7% (5/12) 0.3687 should be taken into consideration when preserving the ovary
(.50%) in the treatment of young patients. Clinicians cannot rely on the
Positive peritoneal cytology 50% (3/6) 60% (6/10) 0.8965
macroscopic appearance of the involved ovary or even on
Pelvic lymph node metastasis 100% (7/7) 33.3% (5/15) 0.0137
intraoperative analysis using frozen sections.
186 TAKESHIMA ET AL.

FIG. 1. Disease-free survival in stage I endometrial cancer. The 5-year disease-free survival rates were 92.1% in patients with cancer limited to the uterus
(N 5 381), 72.2% in patients with ovarian metastasis alone (N 5 15), 59.6% in patients with lymph node metastasis alone (N 5 36), and 0% in patients having
both ovarian metastasis and lymph node metastasis (N 5 7).

With respect to the prognostic significance of ovarian me- incidence was 31.8% in patients with ovarian metastasis, while
tastasis, our multivariate analysis confirmed that this factor and it was 8.6% in patients without ovarian metastasis. Chen has
lymph node metastasis were independent prognostic factors in reported poor survival in patients with isolated or concomitant
clinical stage I endometrial cancer (endometrioid type). Since adnexal involvement in endometrial cancer with deep myome-
these extrauterine factors exhibit a large influence on survival, trial invasion and/or grade 3 tumors [16]. Although this trend
only nuclear grade from intrauterine factors remains as an was also noted in our series, the lymph node status seems to be
independent prognostic variable. These results suggest that of more value to determine the prognosis of patients with
architectural grade or the other factors commonly reported to ovarian metastasis.
be of prognostic significance are closely associated with met- With respect to the adjuvant therapy for endometrial
astatic disease. Zaino et al. investigated the prognostic signif- cancer, Ackerman et al. performed postoperative irradiation
icance of pathologic factors using a multivariate analysis in for high-risk patients who had grade 3 tumors with any
their GOG (Gynecologic Oncology Group) study [13]. They myometrial invasion or any grade with greater than 50%
reported that only age and depth of myometrial invasion were myometrial invasion [17]. In the analysis of their recurrent
independent indicators of outcome in surgical stage I and II cases, isolated pelvic recurrence was the predominate re-
endometrial cancer, while in clinical stage I and II endometrial lapse site in low-risk patients who had not received adjuvant
cancer histologic grade, cell type, positive washings, and vas- radiotherapy, whereas distant relapse predominated in high-
cular space involvement were also noted as independent prog- risk patients who had received radiotherapy. Similar find-
nostic factors. These data also suggest that the prognostic
factors except for age and depth of myometrial invasion cor-
TABLE 6
relate with the extrauterine spread.
The Proportional Hazards Model of Disease-Free Interval in
From a clinical standpoint, it seems to be logical to separate Patients with Stage I Endometrial Cancer (Endometrioid Type)
patients with ovarian metastasis into two groups with widely
differing prognoses. Bruckman et al. and Grigsby et al. em- Variable Coefficient Relative risk 95% CIa P
phasized that the prognosis of patients with extrauterine dis-
ease limited to ovary and/or fallopian tube is significantly Age 0.023 1.023 0.989–1.059 0.183
Architectural grade 0.140 1.150 0.719–1.835 0.557
better than that of patients who demonstrate multiple intrapel-
Nuclear grade 0.798 2.222 1.009–4.897 0.047
vic lesions [14, 15]. Similar results were obtained in our study. Hyperplasia 20.164 0.848 0.327–2.641 0.757
The 5-year disease-free survival rate was 72.2% in patients Tumor size 0.181 1.199 0.943–1.514 0.135
with ovarian metastasis alone, while it was 0% in patients Vessel permeation 20.068 0.934 0.427–1.977 0.860
having both ovarian metastasis and lymph node metastasis. Myometrial invasion 0.007 1.007 0.991–1.024 0.372
Cervical extension 0.531 1.700 0.673–3.906 0.248
Creasman et al. reported that the incidence of pelvic lymph
Lymph node metastasis 0.986 2.680 1.231–5.611 0.014
node metastasis in patients with adnexal involvement was 32% Ovarian metastasis 1.569 4.803 1.597–12.57 0.007
compared to 8% in those patients without adnexal involvement
[10]. A very similar incidence rate was found in our series. The a
Confidence interval.
 OVARIAN METASTASIS IN ENDOMETRIAL CARCINOMA
ings were also reported by Podczaski et al. [18]. These data
suggest that pelvic radiotherapy can only improve survival
in patients with disease confined to the pelvis. In our series,
four of the five recurrent cases with ovarian metastasis
showed extrapelvic recurrence in the absence of pelvic
radiation, suggesting that pelvic radiation will be of little
value as adjuvant therapy. In addition, all seven cases, in
whom pelvic lymph nodes were concurrently involved and
pelvic radiation was performed, also showed extrapelvic
recurrence and subsequently died of the disease. It is then
considered that the value of cytotoxic chemotherapy as
adjuvant therapy must be examined to reduce the relapse
rate of endometrial cancer with ovarian metastasis, partic-
ularly when lymph nodes are concomitantly involved.
ACKNOWLEDGMENT
We thank Miss S. Kontani for secretarial assistance in this work.
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