Synchronous primary cancers of the endometrium

and ovary
Y.-C. CHIANG, C.-A. CHEN, C.-Y. HUANG, C.-Y. HSIEH & W.-F. CHENG
Department of Obstetrics and Gynecology, College of Medicine, National Taiwan University, Taipei, Taiwan
Abstract. Chiang Y-C, Chen C-A, Huang C-Y, Hsieh C-Y, Cheng W-F. Synchronous primary cancers of the
endometrium and ovary. Int J Gynecol Cancer 2008;18:159164.
Simultaneous detection of malignancy in the endometrium and ovary represents an uncommon event. The
objective of the study was to clarify the possible factors that inuenced on the survival. From 1977 to 2005,
totally 27 patients fullled the criteria and were included in the study. The medical records and the patho-
logic reports were reviewed. The histologic determination was followed by the World Health Organization
Committee classication, and cancer stage was based on the staging system of the FIGO. The Kaplan
Meier survival analyses were generated and compared by the log-rank test. The incidence of synchronous
primary endometrial and ovarian cancers was 3.3% in patients with endometrial cancer and 2.7% in patients
with ovarian cancer. The mean survival in the group of similar histology (n 15) was 63 months, and 48
months in the group of dissimilar histology (n 12) (P 0.63). The mean survival in the group of early
stage (n 21) was 68 months and 15 months in the group of advanced stage (n 6) with statistic signi-
cance (P 0.0003). However, the impact of adjuvant therapy on survival did not reach statistic signicance
(P 0.15 for chemotherapy; P 0.69 for radiotherapy). We conclude that the majority of the patients be-
longed to concordant endometrioid histology in endometrium and ovary, and it tends to be early stage and
low grade with favorable prognosis. The stage had more signicant inuence on the survival than the his-
tology. Adjuvant therapy should be given especially in patients with advanced stage although the optimal
management remained to be determined.
KEYWORDS: endometrial cancer, ovarian cancer, synchronous cancers.
Simultaneous detection of malignancy in the endome-
trium and ovary represent an uncommon event. It
occurred in 5% of the patients with endometrial cancer
and 10% of the patients with ovarian cancer
(1)
. It is
possible to encounter difculty in denite diagnosis of
simultaneously detected cancers in both endometrium
and ovary, which could present one of the three con-
ditions: primary endometrial cancer with ovarian
metastasis, primary ovarian cancer with endometrial
metastasis, or synchronous primary endometrial and
ovarian cancers. However, the differentiation is impor-
tant because it would inuence on cancer staging,
management, and prognosis. Pathologic criteria to dis-
tinguish synchronous primary cancers from metastatic
lesions were proposed by Ulbright and Roth
(2)
rst,
and were revised in more detail by Scully et al.
(3)
. Sev-
eral authors described methods of molecular analysis
in order to differentiate the dilemma of diagnosis
more denitely, but there is no consensus about the
most appropriate method now. Previous studies
pointed out that the prognosis of synchronous pri-
mary cancers of the endometrium and ovary is favor-
able, especially for early stage and low grade
(1,4)
. In
this retrospective study, we reviewed the records of
the patients with synchronous primary endometrial
and ovarian cancers in past three decades to study the
characteristics and prognosis of the patients with this
unusual diagnosis.
Materials and methods
From the National Taiwan University Hospital Cancer
Registry database, we retrospectively reviewed the
medical records and pathologic reports during the
Address correspondence and reprint requests to: Wen-Fang Cheng,
MD, PhD, Department of Obstetrics and Gynecology, College of
Medicine, National Taiwan University, No. 7, Chung-Shan South
Road, Taipei 10016, Taiwan. Email: wenfangcheng@yahoo.com
doi:10.1111/j.1525-1438.2007.00975.x
#
2007, Copyright the Authors
Journal compilation
#
2007, IGCS and ESGO
Int J Gynecol Cancer 2008, 18, 159164
period from 1977 to 2005. The pathologic specimens
were diagnosed by our pathologists with the patho-
logical criteria proposed by Ulbright and Roth
(2)
and
Scully et al.
(3)
. Totally 27 patients fullled the criteria,
and they were included in the study. All of these 27
patients received management and were followed up
at our institution. The basic information including ini-
tial presenting symptoms, age at diagnosis, parity,
menstrual status, hormone use, medical comorbidities
(such as diabetes mellitus or hypertension), and family
history of malignancy were collected from medical re-
cords. The pathologic ndings including histology,
grade, invasion of myometrium, lymphovascular per-
meation, involvement of lymph nodes, and extrapelvic
extension were obtained from pathologic reports. The
histologic determination followed the World Health
Organization Committee classication, and cancer
stage was based on the staging system of the FIGO.
For analysis of possible prognostic factors to overall
survival, the patients were assigned to subgroups
based on the symptoms, the histology, the stage, and
the adjuvant therapy. The data were analyzed by Sta-
tistical Package of Social Studies software (SPSS for
Windows, version 10.0.7C, SPSS Inc., Chicago, IL). The
KaplanMeier survival analyses were generated and
compared by the log-rank test. The probability value
of less than 0.05 was dened as statistical signicance.
Results
Totally 844 patients had endometrial cancer and 1004
patients had ovarian cancer in our institution during
the period. Twenty-seven patients fullled the patho-
logic criteria proposed by Ulbright and Roth
(2)
and
Scully et al.
(3)
, and they were included in the study. Of
these patients enrolled in our studies, the mean age at
diagnosis was 47 years (range: 3159 years). The inci-
dence of synchronous primary endometrial and ovar-
ian cancers was 3.3% in patients with endometrial
cancer and 2.7% in patients with ovarian cancer. The
mean body mass index was 26.5 kg/m
2
(range: 2033
kg/m
2
). Diabetes mellitus was noted in six patients
(22%), and endometriosis was also noted in six pa-
tients (22%). Nine patients were nulliparous (33%),
and ten patients were menopausal (37%). None had
used hormone agent, such as hormone replacement
therapy or oral pills. The common presenting symp-
toms were abnormal uterine bleeding (AUB) (41%),
abdominal pain (22%), abdominal fullness (18%), ele-
vated CA-125 level (7%), abdominal mass (4%), body
weight loss (4%), and constipation (4%). The histology
of endometrial cancer consisted of clear cell carcinoma
(4%) and endometrioid adenocarcinoma (96%), includ-
ing grade 1 (64%), 2 (24%), and 3 (12%). The FIGO
stage of the endometrial cancer consists of IA (48%),
IB (40%), IIA (4%), IIB (4%), and IIIA (4%). The histol-
ogy of ovarian cancer includes endometrioid (58%),
clear cell (11%), mixed endometrioid and clear cell
(11%), mixed mucinous and endometrioid (4%), se-
rous adenocarcinoma (4%), malignant mixed mu llerian
tumor (4%), Brenner tumor (4%), and granulosa cell
tumor (4%). The grade of histology included grade 1
(62%), 2 (28%), 3 (10%). The FIGO stage of ovarian
cancer consists of IA (44%), IC (24%), IIA (4%), IIC
(8%), IIIA (4%), and IIIC (16%) (Table 1). Fifteen pa-
tients (56%) had similar histology in both primaries.
However, dissimilar histology was noted in the other
12 patients (44%). All of the patients received surgical
intervention (at least hysterectomy and bilateral sal-
pingo-oophorectomy). Four patients did not receive
any postoperative adjuvant therapy. Seventeen pa-
tients received platin-based adjuvant chemotherapy,
and seven patients received adjuvant radiotherapy
postoperatively. Two patients received both adjuvant
chemotherapy and radiotherapy. Five patients had
recurrence (18%), including abdomen (three patients
with the mean interval of 15 months), vagina (one
patient with the interval of 10 months), and neck
lymphadenopathy (one patient with the interval of 3
months). One patient died of acute renal failure in
postoperational period, and another patient died of
recurrence 8 months after initial treatment. The mean
duration of follow-up was 59 months (range: 6153
months). The mean survival was 56 months. The ve-
year survival rate was about 85%. If dividing to two
groups upon initial presentation of AUB, there were
11 patients in the AUB group and 16 patients in the
non-AUB group. The mean survival in the AUB group
was 60 months, and 54 months in the non-AUB group.
Table 1. FIGO stage of the 27 patients with synchronous
endometrial and ovarian cancers
Endometrium Ovary
Stage I 88 (%) 68 (%)
A 48 44
B 40 0
C 0 24
Stage II 8 (%) 12 (%)
A 4 4
B 4 0
C 8
Stage III 4 (%) 20 (%)
A 4 4
B 0 0
C 0 16
Stage IV 0% 0%
160 Y.-C. Chiang et al.
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2007 IGCS and ESGO, International Journal of Gynecological Cancer 18, 159164
It did not reach statistic signicance (P 0.90). Classi-
ed upon histology on each primary site of malig-
nancy, the group of similar histology (n 15) meant
the same histology of endometrium and ovary, and
different histology in the dissimilar group (n 12).
The mean survival in the group of similar histology
was 63 months, and 48 months in the group of dissim-
ilar histology. It also did not reach statistic signicance
(P 0.63). Based upon FIGO stage, the group of
advanced stage included stage III/IVendometrial (n
1) or ovarian cancer (n 5) and stage I/II endometrial
or ovarian cancer in the group of early stage (n 21).
The mean survival in the group of early stage was 68
months, and 15 months in the group of advanced
stage. Statistic signicance was noted (P 0.0003,
Fig. 1). However, the impact of adjuvant therapy on
survival did not reach statistic signicance (P 0.15
for chemotherapy, Fig. 2a; P 0.69 for radiotherapy,
Fig. 2b). The results of survival analysis based on
these factors were summarized in Table 2.
Discussion
Synchronous primary cancers of the endometrium and
ovary represent an uncommon event. According to
previous literature, coexistence of carcinoma in endo-
metrium and ovary occurred in about 5% of the pa-
tients with endometrial cancer and 10% of the patients
of ovarian cancer
(1)
. In our study, the incidence was
3.3% of patients with endometrial cancer and 2.7% of
patients with ovarian cancer. Our study was con-
ducted in a single institution rather than multicenter
analysis, and we only included cases with conrmed
diagnosis of synchronous tumors and excluded other
conditions such as primary endometrial cancer with
ovarian metastasis or primary ovarian cancer with
endometrial metastasis. It might explain why the inci-
dence of synchronous endometrial and ovarian can-
cers was lower in our series.
Simultaneous detection of malignancy at endome-
trium and ovary often challenges the clinicians and
pathologists to make correct diagnosis and arrange
appropriate managements. It consists of one of the fol-
lowing conditions: primary endometrial cancer with
ovarian metastasis, primary ovarian cancer with endo-
metrial metastasis, or synchronous primary endome-
trial and ovarian cancer. If the histology of both sites is
Figure 1. Survival analysis of 27 patients with synchronous endo-
metrial and ovarian cancers in stage. Patients with advanced stage
showed signicantly poorer overall survival than those with early
stage (P 0.0003, log-rank test).
Figure 2. Survival analysis of 27 patients with synchronous endo-
metrial and ovarian cancers with adjuvant chemotherapy or radio-
therapy. a) Adjuvant chemotherapy. There was no statistical
difference in the overall survival of patients with or without adju-
vant chemotherapy (P 0.15, log-rank test). b) Adjuvant radiother-
apy. There was no statistical difference in the overall survival of
patients with or without adjuvant radiotherapy, either (P 0.69,
log-rank test).
Synchronous cancers with endometrial and ovarian cancers 161
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2007 IGCS and ESGO, International Journal of Gynecological Cancer 18, 159164
dissimilar, the answer is straightforward. However,
the problem occurs especially when the histology of
both sites are similar like the 15 patients in our series.
According to cancer staging system, it may represent
more advanced stage of single cancer, such as stage
IIIA endometrial cancer or stage IIA ovarian cancer,
in spite of synchronous primary double cancers.
The majority of previous reports enrolled patients
with similar histology of malignancy at endometrium
and ovary synchronously, especially endometrioid
adenocarcinoma.
The prognosis of these patients was more favorable
than stage II ovarian cancer or stage III endometrial
cancer, and therefore, it seemed to represent another
entity other than single cancer with metastasis.
Ulbright and Roth
(2)
proposed pathologic criteria for
differentiation in 1985, including either a multinodular
ovarian pattern (major criterion) or two or more of the
following minor criteria: small (less than 5 cm) ovary
(ies), bilateral ovarian involvement, deep myometrial
invasion, vascular invasion, and tubal lumen involve-
ment. Scully et al.
(3)
further developed the pathologic
criteria in detail to more extensive degree. Several
methods of molecular analysis had been developed to
add in differentiating synchronous primary tumors
from metastatic disease, such as DNA ow cy-
tometry
(5)
, loss of heterozygosity on chromosome
(6)
,
X-chromosome inactivation
(7)
, PTEN/MMAC1
(8,9)
,
beta-catenin
(10)
, and microsatellite instability
(11)
. How-
ever, the numbers of cases in these studies are small,
and there is still no consensus about the most appro-
priate method. To date, the majority of published
studies like our study depended mainly on morpho-
logic pathologic criteria.
The pathogenesis of synchronous endometrial and
ovarian cancer is unclear. The theory of secondary
Mu llerian system proposed that the epithelia of cer-
vix, uterus, fallopian tubes, ovaries, and peritoneal
surface had shared molecular receptors responding to
carcinogenic stimulus leading to the development of
multiple primary malignancies synchronously
(1215)
.
The hypothesis could provide explanation to synchro-
nous malignancies of similar histology. It may not be
the case in synchronous cancers of dissimilar histol-
ogy, and there should be another mechanism underly-
ing the interesting phenomenon. Further studies are
needed to disclose the possible pathogenesis of syn-
chronous endometrial and ovarian cancer.
The mean age at diagnosis was 47.2 years in our
series and comparable to previous reports
(1,4)
. It is
younger than that of ovarian or endometrial cancer
occurring predominantly in women during 60 or 70
years. In synchronous endometrial and ovarian prima-
ries of endometrioid histology, the age at diagnosis
tended to be younger. In contrast, the age was older in
patients of dissimilar histology. In the study of Soliman
et al.
(4)
, women with synchronous endometrioid/
endometrioid tumors (50-year-old) were younger than
those with synchronous endometrioid/serous tumors
(63-year-old). They thought this difference could indi-
cate different pathogenesis in these two groups of pa-
tients. In our study, the mean age of diagnosis was 48
years in the 15 patients of similar histology. Twelve
patients had dissimilar histology with the mean age of
46.3 years (range: 2858 years) at diagnosis. It differed
from previous literature and the exact cause was
unknown. Early presentation of AUB may contribute
to the incidental simultaneous ovarian malignancy of
dissimilar histology. In addition, limited case numbers
with wide age range could also have inuence on it.
The most common presenting symptoms were AUB
(41%), abdominal pain (22%), and abdominal fullness
(18%) in our study. Endometrial cancer usually produ-
ces early symptoms like AUB even when malignancy
is still conned to the uterus. In contrast to vague
symptoms of ovarian cancer and generally late detec-
tion of disease, AUB usually causes these women to
seek for help that results in detecting the disease ear-
lier. In other words, the silent ovarian malignancy was
diagnosed earlier due to the symptomatic endometrial
malignancy
(1518)
. In our study, there were 11 patients
presenting with AUB. The mean survival in the AUB
group was 60 months, and 54 months in the non-AUB
group. The results supported the viewpoint as men-
tioned above although it did not reach the statistic sig-
nicance (P 0.90). It also partially accounts for
favorable prognosis of these patients because of early
detection and treatment.
Table 2. Survival analysis based on prognostic risk factors
Mean survival (months) P value
Initial presentation AUB (n 11):60 Non-AUB (n 16):54 0.90
Histology Similar (n 15):63 Dissimilar (n 12):48 0.63
Stage Early (n 21):68 Advanced (n 6):15 0.0003
Adjuvant therapy Chemotherapy (n 17):47 No chemotherapy (n 10):74 0.15
Radiotherapy (n 7):63 No radiotherapy (n 20):55 0.69
162 Y.-C. Chiang et al.
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2007 IGCS and ESGO, International Journal of Gynecological Cancer 18, 159164
Early stage and low histologic grade are also the
characteristics of synchronous endometrial and ovarian
tumors, especially in subtype of endometrioid/endo-
metrioid histology
(1)
, to have favored overall prognosis
of these patients. Ayhan et al.
(19)
concluded that stage of
ovarian cancer and grade of endometrial cancer are
important prognostic factors.The histology of endome-
trial cancer was almost endometrioid adenocarcinoma
with low grade and early stage in our series. The
majority of ovarian cancer was endometrioid adenocar-
cinoma with low grade and early stage. The mean sur-
vival in the group of similar histology (n 15) was 63
months, and 48 months in the group of dissimilar his-
tology (n 12). The mean survival in the group of
early stage (n 21) was 68 months, and 15 months in
the group of advanced stage (n 6). Our results
showed that the stage had more signicant inuence
on the survival than the histology. The patients of con-
cordant endometrial and ovarian endometrioid adeno-
carcinoma had good survival potential and favorable
prognosis. We think that the advanced stage would
have detrimental inuence on survival and was exactly
a poor prognostic indicator.
Primary surgical staging is the mainstay of the man-
agement for the patients of synchronous endometrial
and ovarian cancers
(2,13,19,20)
. However, the adjuvant
treatment for these patients is still controversial
(2,13,21)
.
In our study, the patients all received surgical in-
tervention, and the majority received postoperative
platinum-based chemotherapy. It is difcult to evaluate
the prognosis of these patients without consideration of
the impact of adjuvant chemotherapy. Although the
optimal management needed to be determined, we
believed that the adjuvant therapy should be given es-
pecially in patients with advanced stage of ovarian can-
cer in addition to primary surgical staging procedure.
Cancer occurring at younger age and multiple sites
would make us think of the possibility of familial can-
cer syndrome. Women with Lynch syndrome (heredi-
tary nonpolyposis colorectal cancer) would have
a lifetime risk of 60% to develop endometrial cancer
and 12% lifetime risk of ovarian cancer. Are the pa-
tients of synchronous primary endometrial and ovarian
cancers related to Lynch syndrome? Shannon et al.
(22)
thought that synchronous primary carcinomas of the
ovary and endometrium are unlikely to be part of the
hereditary nonpolyposis colorectal cancer syndrome in
their study of microsatellite instability in synchronous
tumors. Soliman et al.
(23)
found that only 7% of women
with synchronous endometrial and ovarian cancer had
either clinical or molecular criteria suggestive of Lynch
syndrome. As mentioned previously, several molecular
methods are proposed to assist diagnosis, but there is
still no consensus about the most appropriate method.
The possible genetic defect underlying this phenome-
non needs further evaluation.
The major limitations of the study are limited num-
bers and retrospective review. The diagnosis of syn-
chronous malignancy was conrmed only after
pathologic examinations and it was hard to predict
before surgical staging. In addition, the incidence of
the disease was truly low. Therefore, it was difcult to
conduct a prospective study for the uncommon condi-
tion in a single institution. Although the retrospective
study could help to have an idea of the synchronous
dual primary cancer, there should be further studies to
nd out the possible etiology, mechanism of pathogen-
esis, and the optimal treatment plans.
In summary, the synchronous primary endometrial
and ovarian cancer was an unusual condition. AUB
was the most frequent complaint, and it helped for
early detection and treatment. The majority of the pa-
tients belonged to concordant endometrioid histology
in endometrium and ovary, and it tends to be early
stage and low grade with favorable prognosis. The
optimal management remained to be determined, but
the adjuvant therapy should be given especially in pa-
tients with advanced stage that would have detrimen-
tal inuence on survival.
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