Int J Clin Oncol (2014) 19:921–927 DOI 10.1007/s10147-013-0645-3
ORIGINAL ARTICLE
A recurrence-predicting prognostic factor for patients with ovarian clear-cell adenocarcinoma at reproductive age Hiroaki Kajiyama • Mika Mizuno • Kiyosumi Shibata • Tomokazu Umezu Shiro Suzuki • Eiko Yamamoto • Hiroko Mitsui • Ryuichiro Sekiya • Kaoru Niimi • Michiyasu Kawai • Tetsuro Nagasaka • Fumitaka Kikkawa
•
Received: 7 September 2013 / Accepted: 11 November 2013 / Published online: 5 December 2013 Ó Japan Society of Clinical Oncology 2013
Abstract Objectives We retrospectively analyzed the clinicopathological features and evaluated the prognostic indicators of recurrence in 132 patients with clear cell adenocarcinoma (CCC) of the ovary at reproductive age. Patients and methods Between 1986 and 2011, as a regional population-based study, clinicopathological data on 132 young patients with CCC, collected under the central pathological review system, were subjected to uniand multivariable analyses to evaluate recurrence-free survival (RFS). Results The median age was 40 (27–45) years. The median follow-up period for surviving patients was 46.4 months. During the observation period, there were 16 recurrences in 87 patients with stage I tumors (18.4 %), 8 in 17 with stage II (47.1 %), and 16 in 28 with III–IV (57.1 %). Subsequently, 35 patients died of the disease. Those with stage I or II did not reach the median RFS. The median RFS of stage III–IV was 21.6 months. When
H. Kajiyama (&) M. Mizuno K. Shibata T. Umezu S. Suzuki E. Yamamoto H. Mitsui R. Sekiya K. Niimi F. Kikkawa Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya 466-8550, Japan e-mail: [email protected] M. Kawai Department of Obstetrics and Gynecology, Toyohashi Municipal Hospital, 50 Hakkenn-nishi, Aotake-cho, Toyohashi 441-8570, Japan T. Nagasaka Department of Medical Technology, Nagoya University School of Health Science, Daiko-minami 1-1-20, Higashi-ku, Nagoya, Japan
analysis was confined to stage I patients, there was no significant difference in the RFS of CCC patients between IA and IC(r) (intraoperative capsule rupture) (P = 0.7957). In contrast, CCC patients with IC excluding IC(r) [IC(nonr)] showed a poorer RFS than those with IC(r) (P \ 0.0001). In multivariable analysis confined to stage I patients, the substage group was only an independent prognostic factor for RFS [IA vs. IC(non-r)] [hazard ratio (HR) = 9.394; 95 % CI, 1.445–61.070; P = 0.0190]. Conclusion We should keep in mind the greater risk of recurrence in patients with stage IC disease or higher, other than those stage IC patients with intraoperative rupture. Keywords Clear cell carcinoma of ovary Reproductive age Capsule status Recurrence-free survival Fertility Abbreviations CCC Clear cell adenocarcinoma of the ovary EOC Epithelial ovarian carcinoma RFS Recurrence-free survival
Introduction Epithelial ovarian cancer (EOC) is the leading cause of gynecological cancer death. Based on pathological criteria, there are several major types of primary EOC, and the chemosensitivity and biological nature differ among these histological types. Clear cell adenocarcinoma of the ovary (CCC), which is the second most frequent subtype of EOC, accounts for 24.5 % of all malignant neoplasms diagnosed in Japan [1]. However, CCC is a comparatively uncommon tumor worldwide, found in 7.6 % of 40,571 women
123
922
with EOC identified by The Surveillance, Epidemiology, and End Results database in the USA [2]. Moreover, this tumor tends to be diagnosed at stage I without peritoneal metastasis, and is often associated with endometriosis, which causes dense adhesion to the uterus, peritoneum, and adjacent bowel [3–5]. Therefore, pre- or intraoperative capsule rupture is likely to occur regardless of capsule surface involvement and/or positive cytology of ascites [6, 7]. On the other hand, based on earlier reports, 3–17 % of patients with EOC are of reproductive age [8–12]. Similarly, in Japan, around 10 % of women with malignant ovarian neoplasm were reported to be diagnosed at 40 years old or younger [13]. Therefore, since there has been an increase in the total number of EOC patients, CCC at reproductive age is increasing. Indeed, previous prospective studies support the hypothesis that ovarian endometrioma, which is a common gynecological disease and cause of infertility in women of childbearing age, is associated with a subsequent risk of CCC [14–16]. Thus, CCC will become an increasingly serious problems in this reproductive generation. Nevertheless, based on previous investigations of CCC, the number of young patients with CCC was too small to come to any conclusions about whether there were any unique characteristics regarding various clinicopathological features. In the present study, we retrospectively analyzed clinicopathological features and evaluated prognostic indicators of recurrence in 132 CCC patients of reproductive age. The current study includes, to our knowledge, the largest series of young women with CCC.
Materials and methods Patients The Tokai Ovarian Tumor Study Group, consisting of Nagoya University Hospital and thirteen affiliated institutions, has accumulated clinical data on malignant ovarian tumors under the central pathological review system as a regional population-based registry. Between 1986 and 2011, 593 patients with pure type CCC were registered in this original registry. Eight patients were excluded from this study due to insufficient clinical data or loss to followup immediately after surgery. Of the remaining patients, we finally extracted 132 CCC patients who were 45 years of age or younger at the time of the initial diagnosis. Clinical data were collected through a periodic prognosis survey of medical records and clinical follow-up visits. This study was approved by the ethics committee of Nagoya University. Pure type CCC was pathologically diagnosed if typical clear or hobnail cells growing in a
123
Int J Clin Oncol (2014) 19:921–927
papillary, solid, or tubulocystic pattern appeared in [90 % of all pathological specimens. When there were more than 10 % of other histological types, those cases were excluded and classed as mixed pathological type. The histological cell types were assigned according to the criteria of the World Health Organization (WHO). The staging was based on the FIGO (International Federation of Gynecology and Obstetrics, 1988) staging system. Histological slides were reviewed by one or two expert pathologists regarding gynecological malignancy, under a central pathological review system with no knowledge of the patients’ clinical data. Moreover, in this study, we classified patients with stage IC into two sub-groups: IC(r) – patients with only intraoperative capsule rupture (no surface involvement and negative cytology); IC (non-r) – IC excluding IC(r), including patients with preoperative capsule rupture, or surface involvement irrespective of cytological washings/ ascites. Treatment Primary laparotomy was conducted in all patients for assessment of the abdominal contents. In principle, standard primary surgical treatment consisted of hysterectomy, bilateral salpingo-oophorectomy, infracolic omentectomy, retroperitoneal lymphadenectomy, or sampling. Sixteen patients underwent fertility-sparing surgery, including at least unilateral salpingo-oophorectomy with peritoneal staging. Detailed criteria of fertility-sparing surgery have been described previously [17]. Peritoneal washing was routinely carried out. If patients were at an advanced age with a gross residual tumor, or showed severe complications that were a physical burden for radical surgery, retroperitoneal lymphadenectomy was omitted. When retroperitoneal lymphadenectomy was omitted, the absence of swollen lymph nodes more than 1 cm in diameter was confirmed by a preoperative CT scan, and, if present, palpable nodes were sampled. Of all patients, 122 were treated postoperatively with at least 3 cycles of adjuvant chemotherapy; 45 patients (34.1 %) received conventional platinum-based chemotherapy, and 77 patients (58.3 %) received taxane plus platinum chemotherapy. Ten patients (7.6 %) did not receive adjuvant chemotherapy due to severe complications, the patients’ strong wishes, or at the physician’s discretion in each institution. Details of the chemotherapy regimen in each period have been described previously [7]. Briefly, patients received first-line chemotherapy as follows: CAP [cyclophosphamide (300 mg/m2), adriamycin (30 mg/m2), and cisplatin (70 mg/m2)]; (1986–1989): CAP or PVB [cisplatin (70 mg/m2), vinblastine (6 mg/m2), and bleomycin (12 mg/m2)]; (1989–1991): PVB or PP [carboplatin (300 mg/m2) and cisplatin (70 mg/m2)];
Int J Clin Oncol (2014) 19:921–927
Follow-up and analysis At the end of treatment, all patients underwent a strict follow-up, consisting of clinical checkups, such as a pelvic examination, transvaginal and/or transabdominal ultrasonographic scan, cancer antigen (CA)125 evaluation, magnetic resonance imaging (MRI), and a periodic computed tomography (CT) scan of the entire chest and abdomen. When an elevated CA125 value was continuously detected, the presence or absence of a tumor was radiologically confirmed. Recurrence was diagnosed radiologically and/or clinically. Recurrence/progressionfree survival (RFS) was defined as the time interval between the date of surgery and that of recurrence/retrogression or the last follow-up or death from any cause. Survival curves were based on the Kaplan–Meier method. Comparison between the curves was conducted using the log-rank test. Multivariable analysis was performed with the Cox proportional hazards model to evaluate independent factors affecting survival. A P value of \0.05 was considered significant.
Results Patients’ characteristics Patients’ characteristics are summarized in Table 1. The median age was 40 years, ranging from 27 to 45. The median follow-up for surviving patients was 46.4 months. Among the 132 patients, the stage distribution was as follows: IA in 20 patients (15.2 %), IC in 67 (50.8 %), II in 17 (12.9 %), III in 25 (18.9 %), and IV in 3 (2.3 %). Regarding the IC substage, 7 patients showed surface involvement/preoperative capsule rupture, 48 showed intraoperative capsule rupture/negative cytology/no surface involvement, and 12 showed positive ascites/washing cytology. Of the total patients, 16 who were 40 years old or less underwent fertility-sparing surgery because they hoped to preserve fertility. One hundred and eleven patients had no residual tumor. In addition, 21 patients had a residual tumor [maximal tumor diameter \1 cm (N = 5), C1 cm (N = 16)].
Table 1 Patients’ characteristics (N = 132) Characteristic
N
%
Age Mean (range)
40.0 (27–45)
FIGO stage IA
20
15.2
IC(r)
48
36.4
IC(non-r)
19
14.4
II
17
12.9
III
25
18.9
IV
3
2.3
Conservative
16
12.1
Radical
116
87.9
B35 [35
27 101
20.5 76.5
Unknown
4
Surgery
CA125 value (U/ml)
3.0
Residual tumor None
111
\1 cm
5
3.8
C1 cm
16
12.1
84.1
10
7.6
Chemotherapy None Conventional platinum based
45
34.1
Taxane plus platinum
77
58.3
IC(r) patients who had only intraoperative capsule rupture (no surface involvement and negative cytology); IC(non-r) as IC excluding IC(r), including patients with preoperative capsule rupture, or surface involvement irrespective of cytological washings/ascites
100
Recurrence-free survival (%)
(1992–2000): TC [paclitaxel (180 mg/m2) and carboplatin (AUC 5)]; (2000–2002): and TC or DC [docetaxel (70 mg/ m2) and carboplatin (AUC 5)]; (2003 onward).
923
80
60
40
Stage I
20
(N=87)
P
ORIGINAL ARTICLE
A recurrence-predicting prognostic factor for patients with ovarian clear-cell adenocarcinoma at reproductive age Hiroaki Kajiyama • Mika Mizuno • Kiyosumi Shibata • Tomokazu Umezu Shiro Suzuki • Eiko Yamamoto • Hiroko Mitsui • Ryuichiro Sekiya • Kaoru Niimi • Michiyasu Kawai • Tetsuro Nagasaka • Fumitaka Kikkawa
•
Received: 7 September 2013 / Accepted: 11 November 2013 / Published online: 5 December 2013 Ó Japan Society of Clinical Oncology 2013
Abstract Objectives We retrospectively analyzed the clinicopathological features and evaluated the prognostic indicators of recurrence in 132 patients with clear cell adenocarcinoma (CCC) of the ovary at reproductive age. Patients and methods Between 1986 and 2011, as a regional population-based study, clinicopathological data on 132 young patients with CCC, collected under the central pathological review system, were subjected to uniand multivariable analyses to evaluate recurrence-free survival (RFS). Results The median age was 40 (27–45) years. The median follow-up period for surviving patients was 46.4 months. During the observation period, there were 16 recurrences in 87 patients with stage I tumors (18.4 %), 8 in 17 with stage II (47.1 %), and 16 in 28 with III–IV (57.1 %). Subsequently, 35 patients died of the disease. Those with stage I or II did not reach the median RFS. The median RFS of stage III–IV was 21.6 months. When
H. Kajiyama (&) M. Mizuno K. Shibata T. Umezu S. Suzuki E. Yamamoto H. Mitsui R. Sekiya K. Niimi F. Kikkawa Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya 466-8550, Japan e-mail: [email protected] M. Kawai Department of Obstetrics and Gynecology, Toyohashi Municipal Hospital, 50 Hakkenn-nishi, Aotake-cho, Toyohashi 441-8570, Japan T. Nagasaka Department of Medical Technology, Nagoya University School of Health Science, Daiko-minami 1-1-20, Higashi-ku, Nagoya, Japan
analysis was confined to stage I patients, there was no significant difference in the RFS of CCC patients between IA and IC(r) (intraoperative capsule rupture) (P = 0.7957). In contrast, CCC patients with IC excluding IC(r) [IC(nonr)] showed a poorer RFS than those with IC(r) (P \ 0.0001). In multivariable analysis confined to stage I patients, the substage group was only an independent prognostic factor for RFS [IA vs. IC(non-r)] [hazard ratio (HR) = 9.394; 95 % CI, 1.445–61.070; P = 0.0190]. Conclusion We should keep in mind the greater risk of recurrence in patients with stage IC disease or higher, other than those stage IC patients with intraoperative rupture. Keywords Clear cell carcinoma of ovary Reproductive age Capsule status Recurrence-free survival Fertility Abbreviations CCC Clear cell adenocarcinoma of the ovary EOC Epithelial ovarian carcinoma RFS Recurrence-free survival
Introduction Epithelial ovarian cancer (EOC) is the leading cause of gynecological cancer death. Based on pathological criteria, there are several major types of primary EOC, and the chemosensitivity and biological nature differ among these histological types. Clear cell adenocarcinoma of the ovary (CCC), which is the second most frequent subtype of EOC, accounts for 24.5 % of all malignant neoplasms diagnosed in Japan [1]. However, CCC is a comparatively uncommon tumor worldwide, found in 7.6 % of 40,571 women
123
922
with EOC identified by The Surveillance, Epidemiology, and End Results database in the USA [2]. Moreover, this tumor tends to be diagnosed at stage I without peritoneal metastasis, and is often associated with endometriosis, which causes dense adhesion to the uterus, peritoneum, and adjacent bowel [3–5]. Therefore, pre- or intraoperative capsule rupture is likely to occur regardless of capsule surface involvement and/or positive cytology of ascites [6, 7]. On the other hand, based on earlier reports, 3–17 % of patients with EOC are of reproductive age [8–12]. Similarly, in Japan, around 10 % of women with malignant ovarian neoplasm were reported to be diagnosed at 40 years old or younger [13]. Therefore, since there has been an increase in the total number of EOC patients, CCC at reproductive age is increasing. Indeed, previous prospective studies support the hypothesis that ovarian endometrioma, which is a common gynecological disease and cause of infertility in women of childbearing age, is associated with a subsequent risk of CCC [14–16]. Thus, CCC will become an increasingly serious problems in this reproductive generation. Nevertheless, based on previous investigations of CCC, the number of young patients with CCC was too small to come to any conclusions about whether there were any unique characteristics regarding various clinicopathological features. In the present study, we retrospectively analyzed clinicopathological features and evaluated prognostic indicators of recurrence in 132 CCC patients of reproductive age. The current study includes, to our knowledge, the largest series of young women with CCC.
Materials and methods Patients The Tokai Ovarian Tumor Study Group, consisting of Nagoya University Hospital and thirteen affiliated institutions, has accumulated clinical data on malignant ovarian tumors under the central pathological review system as a regional population-based registry. Between 1986 and 2011, 593 patients with pure type CCC were registered in this original registry. Eight patients were excluded from this study due to insufficient clinical data or loss to followup immediately after surgery. Of the remaining patients, we finally extracted 132 CCC patients who were 45 years of age or younger at the time of the initial diagnosis. Clinical data were collected through a periodic prognosis survey of medical records and clinical follow-up visits. This study was approved by the ethics committee of Nagoya University. Pure type CCC was pathologically diagnosed if typical clear or hobnail cells growing in a
123
Int J Clin Oncol (2014) 19:921–927
papillary, solid, or tubulocystic pattern appeared in [90 % of all pathological specimens. When there were more than 10 % of other histological types, those cases were excluded and classed as mixed pathological type. The histological cell types were assigned according to the criteria of the World Health Organization (WHO). The staging was based on the FIGO (International Federation of Gynecology and Obstetrics, 1988) staging system. Histological slides were reviewed by one or two expert pathologists regarding gynecological malignancy, under a central pathological review system with no knowledge of the patients’ clinical data. Moreover, in this study, we classified patients with stage IC into two sub-groups: IC(r) – patients with only intraoperative capsule rupture (no surface involvement and negative cytology); IC (non-r) – IC excluding IC(r), including patients with preoperative capsule rupture, or surface involvement irrespective of cytological washings/ ascites. Treatment Primary laparotomy was conducted in all patients for assessment of the abdominal contents. In principle, standard primary surgical treatment consisted of hysterectomy, bilateral salpingo-oophorectomy, infracolic omentectomy, retroperitoneal lymphadenectomy, or sampling. Sixteen patients underwent fertility-sparing surgery, including at least unilateral salpingo-oophorectomy with peritoneal staging. Detailed criteria of fertility-sparing surgery have been described previously [17]. Peritoneal washing was routinely carried out. If patients were at an advanced age with a gross residual tumor, or showed severe complications that were a physical burden for radical surgery, retroperitoneal lymphadenectomy was omitted. When retroperitoneal lymphadenectomy was omitted, the absence of swollen lymph nodes more than 1 cm in diameter was confirmed by a preoperative CT scan, and, if present, palpable nodes were sampled. Of all patients, 122 were treated postoperatively with at least 3 cycles of adjuvant chemotherapy; 45 patients (34.1 %) received conventional platinum-based chemotherapy, and 77 patients (58.3 %) received taxane plus platinum chemotherapy. Ten patients (7.6 %) did not receive adjuvant chemotherapy due to severe complications, the patients’ strong wishes, or at the physician’s discretion in each institution. Details of the chemotherapy regimen in each period have been described previously [7]. Briefly, patients received first-line chemotherapy as follows: CAP [cyclophosphamide (300 mg/m2), adriamycin (30 mg/m2), and cisplatin (70 mg/m2)]; (1986–1989): CAP or PVB [cisplatin (70 mg/m2), vinblastine (6 mg/m2), and bleomycin (12 mg/m2)]; (1989–1991): PVB or PP [carboplatin (300 mg/m2) and cisplatin (70 mg/m2)];
Int J Clin Oncol (2014) 19:921–927
Follow-up and analysis At the end of treatment, all patients underwent a strict follow-up, consisting of clinical checkups, such as a pelvic examination, transvaginal and/or transabdominal ultrasonographic scan, cancer antigen (CA)125 evaluation, magnetic resonance imaging (MRI), and a periodic computed tomography (CT) scan of the entire chest and abdomen. When an elevated CA125 value was continuously detected, the presence or absence of a tumor was radiologically confirmed. Recurrence was diagnosed radiologically and/or clinically. Recurrence/progressionfree survival (RFS) was defined as the time interval between the date of surgery and that of recurrence/retrogression or the last follow-up or death from any cause. Survival curves were based on the Kaplan–Meier method. Comparison between the curves was conducted using the log-rank test. Multivariable analysis was performed with the Cox proportional hazards model to evaluate independent factors affecting survival. A P value of \0.05 was considered significant.
Results Patients’ characteristics Patients’ characteristics are summarized in Table 1. The median age was 40 years, ranging from 27 to 45. The median follow-up for surviving patients was 46.4 months. Among the 132 patients, the stage distribution was as follows: IA in 20 patients (15.2 %), IC in 67 (50.8 %), II in 17 (12.9 %), III in 25 (18.9 %), and IV in 3 (2.3 %). Regarding the IC substage, 7 patients showed surface involvement/preoperative capsule rupture, 48 showed intraoperative capsule rupture/negative cytology/no surface involvement, and 12 showed positive ascites/washing cytology. Of the total patients, 16 who were 40 years old or less underwent fertility-sparing surgery because they hoped to preserve fertility. One hundred and eleven patients had no residual tumor. In addition, 21 patients had a residual tumor [maximal tumor diameter \1 cm (N = 5), C1 cm (N = 16)].
Table 1 Patients’ characteristics (N = 132) Characteristic
N
%
Age Mean (range)
40.0 (27–45)
FIGO stage IA
20
15.2
IC(r)
48
36.4
IC(non-r)
19
14.4
II
17
12.9
III
25
18.9
IV
3
2.3
Conservative
16
12.1
Radical
116
87.9
B35 [35
27 101
20.5 76.5
Unknown
4
Surgery
CA125 value (U/ml)
3.0
Residual tumor None
111
\1 cm
5
3.8
C1 cm
16
12.1
84.1
10
7.6
Chemotherapy None Conventional platinum based
45
34.1
Taxane plus platinum
77
58.3
IC(r) patients who had only intraoperative capsule rupture (no surface involvement and negative cytology); IC(non-r) as IC excluding IC(r), including patients with preoperative capsule rupture, or surface involvement irrespective of cytological washings/ascites
100
Recurrence-free survival (%)
(1992–2000): TC [paclitaxel (180 mg/m2) and carboplatin (AUC 5)]; (2000–2002): and TC or DC [docetaxel (70 mg/ m2) and carboplatin (AUC 5)]; (2003 onward).
923
80
60
40
Stage I
20
(N=87)
P
