2584

Clinical Characteristics of Clear Cell Carcinoma

of the Ovary
A Distinct Histologic Type with Poor Prognosis and Resistance to PlatinumBased Chemotherapy

Toru Sugiyama, M.D., Ph.D.1

Toshiharu Kamura, M.D., Ph.D. 1
Junzo Kigawa, M.D., Ph.D.2
Naoki Terakawa, M.D., Ph.D.2
Yoshihiro Kikuchi, M.D., Ph.D.3
Tunekazu Kita, M.D., Ph.D.3
Mitsuaki Suzuki, M.D., Ph.D.4
Ikuo Sato, M.D., Ph.D.4
Kouji Taguchi, M.D., Ph.D.5
1

Department of Obstetrics and Gynecology, Kurume University, Kurume City, Japan.

Department of Obstetrics and Gynecology, Tottori

University,Yonago, Japan.

Department of Obstetrics and Gynecology, National Defense Medical College, Tokorozawa, Japan.

Department of Obstetrics and Gynecology, Jichi

Medical School, Utsunomiya, Japan.

Department of Pathology, Okayama University,

Okayama, Japan.

BACKGROUND. A retrospective review of treatment results comparing women with

clear cell carcinoma of the ovary (CCC) with a group with serous adenocarcinoma
of the ovary (SAC) was conducted.
METHODS. Between 1988 1998, 662 patients with epithelial ovarian carcinoma
were identified through the medical records department and the tumor registry at
4 institutions. After the central pathologic review, 101 patients with pure or dominant ( 90%) CCC (15.3%) were entered into the current study. Two hundred
thirty five patients with pure SAC were selected as a group for comparison. All
patients underwent staging laparotomy followed by platinum-based chemotherapy. Distribution of the International Federation of Gynecology and Obstetrics
(FIGO) disease stage, response to chemotherapy, and prognosis for patients with
CCC were compared with the same values in patients with SAC.
RESULTS. Patients with CCC were significantly more likely to have FIGO Stage I
disease than were patients with SAC (48.5% vs. 16.6%). A high recurrence rate was
noted in those patients with Stage IC CCC (37%). In those patients with Stage IC
disease, the survival rates for patients with CCC were lower than those for patients
with SAC. The 3-year and 5-year survival rates for Stage III CCC patients were
significantly lower compared with Stage III SAC patients. The response rate to
platinum-based chemotherapy in patients with CCC was significantly lower than
that in patients with SAC.
CONCLUSIONS. CCC is an intriguing histologic type of epithelial ovarian cancer that
demonstrates a clinical behavior distinctly different from that of SAC. Cancer 2000;
88:2584 9. 2000 American Cancer Society.
KEYWORDS: clear cell carcinoma, ovary, survival, serous adenocarcinoma, chemotherapy.

Presented as a general poster presentation at the

1999 Annual Meeting of the American Society of
Clinical Oncology, Atlanta, Georgia.
Address for reprints: Toru Sugiyama, M.D., Department of Obstetrics and Gynecology, Kurume University School of Medicine, 67 Asahi-machi, Kurume City, 830-0011 Japan.
Received September 8, 1999; revision received
January 26, 2000; accepted January 26, 2000.
2000 American Cancer Society

lear cell carcinoma of the ovary (CCC) originally was termed

mesonephroid by Schiller in 1939 because it was believed to
originate from mesonephric structures and resembled renal carcinoma.1 Since 1973, CCC has been recognized as a distinct histologic
entity in the World Health Organization classification of ovarian tumors.2 The incidence of CCC among epithelial ovarian carcinomas is
3.712.1%.3-8 Recently, a body of evidence has accumulated to support the contention that CCC demonstrates a distinctly different
clinical behavior from other epithelial ovarian carcinomas4,5,7,9-11: 1)
it frequently presents as a large pelvic mass; 2) it rarely occurs bilaterally; 3) it often is associated with endometriosis; 4) it often is
accompanied by a thromboembolic complication; and 5) hypercalcemia is observed at a high frequency. In addition, CCC frequently

Clear Cell Carcinoma of the Ovary/Sugiyama et al.

presents at early stages. Several studies have discussed

the prognosis of CCC without much agreement, although there is general acceptance of CCCs insensitivity to conventional platinum-based chemotherapy
followed by poor prognosis.10,12,13
In the previous studies of CCC the number of
patients with CCC was too small to draw any conclusions regarding the impact of various clinicopathologic features. We conducted the current study to determine clinicopathologic features and to evaluate the
prognosis in 100 patients with CCC who underwent
complete surgical staging. The current study involved
what we believe to be the largest series of patients with
CCC reported to date.

2585

TABLE 1
Patient Characteristics

Total no. of patients

Median age (yrs) (range)
FIGO Stage Ia
IA
IB
IC
II
IIIa
IV

Clear cell

Serous

101
51 (3172)
49 (48.5%)
11 (10.9%)
0
38 (37.6%)
10 (9.9%)
31 (30.7%)
11 (10.9%)

235
54 (2382)
39 (16.6%)
15 (6.5%)
2 (0.9%)
22 (9.4%)
13 (5.5%)
145 (61.7%)
38 (16.2%)

FIGO: International Federation of Obstetrics and Gynecology.

a
P 0.0001.

MATERIALS AND METHODS

Between 1988 1997 a total of 662 patients with epithelial ovarian carcinoma underwent primary treatment at the Kurume University Hospital, the Tottori
University Hospital, the National Defense Medical
College Hospital, and the Jichi Medical School Hospital. Of this group of patients, 112 originally were diagnosed with CCC through the medical records department. Histologic evaluation was performed under
central pathologic review. All pathologic specimens
from primary surgery were reviewed by the pathologist at Okayama University who had no knowledge of
the histologic diagnosis previously made at each hospital. Tumors were diagnosed as CCC if the following
appeared in 90% of all histologic specimens: small
to large sheet of polyhedral clear cells with delicate
fibrovascular septa; tubules and papillae; clear, hobnail, or eosinophilic cells of organoid appearance; or
clear cells with coalescent vacuoles containing targetoid eosinophilic, periodic acidSchiff stain-positive
globules. After this review, 101 patients with CCC of
the 662 patients with epithelial ovarian carcinoma
(15.3%) were entered into the current study. Of the 662
patients, 235 with pure serous adenocarcinoma (SAC)
were selected as a control group for comparison of
prognosis.
All patients underwent complete surgical staging
including intraperitoneal cytology, bilateral salpingooophorectomy, hysterectomy, omentectomy, pelvic
and/or paraaortic lymphadenectomy, and aggressive
cytoreductive surgery for those patients with advanced disease.
Ninety-seven of the 101 patients with CCC (96%)
and 229 of 235 patients with SAC (97%) received platinum-based chemotherapy after initial surgery; this
was comprised of cyclophosphamide and platinum
(CP) or cyclophosphamide, doxorubicin, and platinum (CAP). Paclitaxel was not used as first-line therapy in this study because it was not approved by the

Ministry of Health and Welfare in Japan during the

period of the study.
For patients with measurable disease, response to
chemotherapy was evaluated by computed tomography. A complete response (CR) was defined as the
complete disappearance of all clinically detectable
disease for at least 4 weeks. A partial response (PR)
was defined as a 50% decrease in tumor size for at
least 4 weeks without an increase in the size of any
other known lesion or the appearance of a new lesion.
No change (NC) was defined as the absence of any
significant change in measurable lesions for at least 4
weeks. Progressive disease (PD) was defined as the
appearance of a new lesion or a 25% increase in
tumor size.
The time to recurrence was defined as the interval
from the date of primary surgery until the date of
documented recurrence. The duration of survival was
determined as the time from primary surgery until
death or the date of the last follow-up contact until
death.
Patient survival distribution was calculated using
the KaplanMeier method. The significance of the survival distribution in each group was tested by a generalized Wilcoxon test and the log rank test. The chisquare test and Student t test for unpaired data were
used for statistical analysis. A P value of 0.05 was
considered statistically significant.

RESULTS
Patient Characteristics
Patient characteristics are shown in Table 1. The median age of the patients did not differ between patients
with CCC and patients with SAC. The median duration
of follow-up was 37 months (range, 3121 months). Of
101 patients with CCC, 49 (48.5%) had Stage I disease
[T1N0M0] (Stage IA: 10.9%; and Stage IC: 37.6%), 10

2586

CANCER June 1, 2000 / Volume 88 / Number 11

TABLE 2
FIGO Stage of Ovarian Carcinoma versus Median Survival Time

TABLE 3
Estimated Survival Rate for Clear Cell Carcinoma versus Serous
Adenocarcinoma by Stage

Median survival time (mos) (range)

Clear cell
FIGO stage

Clear cell

Serous

P value

III
III
IV

31.8 (767)
12.7 (127)
17.8 (626)

42.3 (16101)
26.8 (0.591)
19.4 (0.268)

NS
0.0015
NS

FIGO: International Federation of Gynecology and Obstetrics; NS: not significant.

(9.9%) had Stage II disease [T2N0M0], 31 (30.7%) had

Stage III disease [T3N0M0 or any T, N1], and 11
(10.9%) had Stage IV disease [any T any N, M1] according to the classification of the International Federation of Obstetrics and Gynecology (FIGO). The percentage of patients with Stage I disease was
significantly higher in patients with CCC compared
with patients with SAC (16.6%), whereas that of patients with Stage III disease was significantly lower in
those patients with CCC compared with those patients
with SAC (61.7%). The percentage of patients with
Stage II or Stage IV disease did not differ between the
two groups. Twenty-seven patients with CCC (26.7%)
and 109 patients with SAC (46.4%) had measurable
residual tumor after the initial surgery.

Serous

FIGO stage

No. of
patients

3-year
survival

5-year
survival

No. of
patients

3-year
survival

5-year
survival

IA-B
IC
II
IIIa
IV
All stages

11
38
10
31
11
101

100%
76.8%
88.9%
23.5%
11.4%
57.9%

100%
60.1%
88.9%
23.5%
11.4%
52.0%

17
22
13
145
38
235

100%
80.4%
83.1%
54.1%
35.7%
58.6%

91.7%
80.4%
72.7%
34.1%
4.0%
44.1%

FIGO: International Federation of Gynecology and Obstetrics.

a
P 0.05 (clear cell vs. serous).

Clinical Outcome
Recurrence of CCC occurred in 29% of Stage I patients,
30% of Stage II patients, 62% of Stage III patients, and
73% of Stage IV patients. Although none of the patients with Stage IA CCC developed a recurrence, 14 of
38 patients with Stage IC disease (37%) did develop
disease recurrence. The recurrence rate increased as
the clinical stage advanced from Stage IC to Stage IV
(P 0.12). The median time to recurrence was 12.2
months in patients with Stage I/II CCC.
In the patients with CCC, the median survival time
was 31.8 months in those with Stage I/II disease, 12.7
months in those with Stage III disease, and 17.8
months in those with Stage IV disease. In the patients
with SAC, the median survival time was 42.3 months
in those with Stage I/II disease, 26.8 months in those
with Stage III disease, and 19.4 months in those with
Stage IV disease. With regard to Stage III disease, the
median survival time was significantly shorter in the
patients with CCC than in the patients with SAC (Table
2). The estimated 3-year and 5-year survival rates for
patients with CCC did not differ significantly from the
estimated 3-year and 5-year survival rates for patients
with SAC. The estimated survival rates by stage for
CCC versus SAC are outlined in Table 3. Survival rates
for patients with Stage IC and Stage IV disease were

FIGURE 1. KaplanMeier estimated survival by stage for patients with Stage

IC disease

poorer in the CCC group than in the SAC group, but

there were no significant statistical difference (Table
3) (Fig. 1). However, the survival rate for patients with
Stage III disease was significantly lower in the CCC
group than in the SAC group (Table 3) (Fig. 2). Table 4
shows the estimated survival rates in patients with
Stage III/IV disease when divided into 3 groups; they
included a group of patients with no macroscopic
tumor after initial surgery, one group with 2 cm
residual tumor, and one group with 2 cm residual
tumor. Although neither the estimated 3-year nor
5-year survival rates in those patients without macroscopic tumor significantly differed between the patients with CCC and those with SAC, both survival
rates in the patients with 2 cm residual tumor and
those with 2 cm residual tumor were significantly
lower in the CCC group compared with the SAC group.
Twenty-seven Stage III/IV patients with CCC had
measurable disease after initial surgery. Only 3 of 27
patients (11.1%) responded to platinum-based che-

Clear Cell Carcinoma of the Ovary/Sugiyama et al.

2587

TABLE 5
Response of Platinum-Based Chemotherapy for Measurable Residual
Tumor after Surgery
Response (%)

Clear cell
Serous

No. of
patients

CR

PR

NC

PD

Response
rate (%)

27
109

2 (7.4)
30 (27.5)

1 (3.7)
49 (45.0)

2 (7.4)
10 (9.2)

22 (81.5)
20 (18.3)

11.1
72.5

CR: complete response; PR: partial response; NC: no change; PD: progressive disease.
P 0.001.

FIGURE 2. KaplanMeier estimated survival by stage for patients with Stage

III disease.

TABLE 4
Estimated Survival Rate for FIGO Stage III/IV Disease by Size of
Residual Tumor
Clear cell

Serous

Initial surgery

3-year
survival

5-year
survival

3-year
survival

5-year
survival

No macroscopic tumor
2 cm residual tumora
2 cm residual tumora

40.6
18.6
10.2

40.6
18.6
10.2

73.5
53.2
45.9

47.2
36.2
23.9

FIGO: International Federation of Gynecology and Obstetrics.

a
Clear cell vs. serous ( 2 cm, P 0.0088; 2 cm, P 0.0005).

motherapy. PD was documented in 22 patients

(81.5%) and NC was documented in only 2 patients.
One hundred nine patients with SAC had measurable
disease after initial surgery. The overall clinical response rate was 72.5%, which included a CR in 30
patients and a PR in 49 patients. PD was documented
in 20 patients (18.3%) and NC was documented in 10
patients (9.2%) (Table 5).

DISCUSSION
CCC has been classified as a subgroup of epithelial
ovarian carcinoma and is reported to be an interesting
histologic type with unique clinical features. As many
investigators have stated,4,5,9,11 the percentage of patients with Stage I disease in the current study was
significantly higher in the CCC group (48.5%) compared with the SAC group (16.6%). Among patients
with Stage I CCC, the majority had Stage IC disease,
which has very interesting biologic characteristics. By
contrast, the rate of incidence of Stage III disease was

significantly lower in the CCC group (30.7%) compared with the SAC group (61.7%).
Several reports published since 1970 have suggested no differences in survival based on stage between patients with CCC and SAC.3,14 In contrast,
several recent reports indicate that CCC is a histologic
tumor type with a poor prognosis.4,6,7,9,15,16 Many authors have discussed the prognosis of patients with
CCC compared with that for patients with SAC; however, to our knowledge there had been no clear agreement in their findings. In the patients with Stage I
disease, it was reported that CCC was not a factor for
poor prognosis.5,11,17 In contrast, other authors reported that 7 of 12 patients with Stage IC disease died
of PD despite multiple aggressive adjuvant therapies4
and that a significantly lower 5-year survival rate was
determined in patients with CCC compared with
SAC.7 In the current study, a high recurrence rate was
observed in patients with Stage IC CCC, similar to the
studies discussed earlier, and the survival rate for
Stage IC CCC was lower than that of SAC. Jenison et
al.9 showed that the survival rates for CCC were consistently lower in each of the FIGO stages compared
with SAC, although there was no statistical significance. In their study, the median survival time for
Stage I patients with CCC was significantly worse than
that for patients with SAC.9 We found that the survival
rate for patients with Stage IC CCC was poorer compared with patients with Stage IC SAC. In addition, the
median survival time for Stage I patients with CCC was
worse than that for those with SAC (31.8 months vs.
42.3 months) and the time to recurrence in patients
with Stage I/II CCC was definitely short (12.2 months).
These findings suggest the susceptibility of CCC to
frequent and early recurrence, which may be one of
reasons for the poor prognosis of patients with CCC.
The median survival time of patients with advanced CCC (Stage III disease) was significantly
shorter (12.7 months) than that for patients with advanced SAC (26.8 months) in the current study. In
addition, the survival rates of patients with advanced

2588

CANCER June 1, 2000 / Volume 88 / Number 11

CCC were significantly lower than those of patients

with advanced SAC. These findings are supported by
the majority of previous studies.4,5,9,11,15,17 Thus, the
results of the current study confirmed that Stage III
CCC, especially in patients who undergo incomplete
resection, has an extremely poor prognosis among
advanced epithelial ovarian carcinomas. However,
CCC still is treated in the same manner as other epithelial ovarian carcinomas at the current time, without
any particular consideration because of its low rate of
incidence among epithelial ovarian carcinoma patients.
Because to our knowledge few clinical studies
have evaluated the response to platinum-based chemotherapy in CCC patients, we examined the clinical
response to this therapy in patients with measurable
residual CCC. Patients with CCC showed a very low
response rate of 11.1% (3 of 27), but a high incidence
rate of PD (81.5% [22 of 27]), whereas patients with
SAC had a high response rate of 72.5% (79 of 109) and
a low incidence rate of PD (20 of 109; 18.3%), a difference that was very significant. Similarly, what to our
knowledge is the only previous study to date on the
subject reported a higher rate of incidence of PD with
platinum-based chemotherapy in CCC patients with
measurable or nonmeasurable disease (16 of 23; 70%)
compared with SAC patients (10 of 34; 29%).10 Another
group of authors demonstrated that platinum-based
chemotherapy did not appear to improve the survival
of patients with CCC compared with the survival from
nonplatinum-based chemotherapy.12 In addition, no
patients with Stage IA CCC developed a recurrence,
but patients with Stage IC CCC frequently do develop
disease recurrence. Thus it was verified that CCC generally lacks sensitivity to conventional platinum-based
chemotherapy such as CAP or CP. In support of this
conclusion, an in vitro study by Gorai et al. indicated
that CCC cells exhibited resistance to cisplatin.13
The current study data are provocative and suggest that a new strategy for chemotherapy in CCC
should be adopted, one that focuses on new agents
without cross-resistance to platinum agents. The effects of new drugs should be evaluated in a prospective clinical trial as soon as possible. These drugs
include paclitaxel, which has been used as the firstline chemotherapy for ovarian carcinoma,18 and topoisomerase-I inhibitors, which also have been reported to be effective in the treatment of ovarian
carcinoma.19,20 In the current study the survival rate
was significantly lower in patients with residual tumors, particularly in those with a 2 cm residual
tumor burden who had a 3-year survival rate of 10%.
This again emphasizes the importance of an aggressive surgical approach in patients with Stage III CCC

prior to and integrated with an intensive postoperative

combination chemotherapy program.
CCC tumors have a more aggressive clinical
course and a more malignant behavior than SAC tumors. Therefore, a new treatment strategy for CCC,
including alternative regimens of chemotherapy,
should be established.

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