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Is there any possibility of fertility-sparing surgery in patients with clear-cell carcinoma of the ovary?
Available online at www.sciencedirect.com
Gynecologic Oncology 111 (2008) 523 – 526 www.elsevier.com/locate/ygyno
Case Report
Is there any possibility of fertility-sparing surgery in patients with clear-cell carcinoma of the ovary? Hiroaki Kajiyama a,⁎, Kiyosumi Shibata a , Shiro Suzuki a , Kazuhiko Ino a , Eiko Yamamoto a , Kimio Mizuno b , Katsumi Sakakibara c , Katsuji Matsuzawa d , Akihiro Takeda e , Yoshito Kinoshita f , Michiyasu Kawai g , Tetsuro Nagasaka h , Akihiro Nawa a , Fumitaka Kikkawa a a
Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, Japan b Department of Obstetrics and Gynecology, Japanese Red Cross Nagoya First Hospital, Japan c Department of Obstetrics and Gynecology, Okazaki Municipal Hospital, Japan d Department of Obstetrics and Gynecology, Anjyo Kosei Hospital, Japan e Department of Obstetrics and Gynecology, Gifu Prefectural Tajimi Hospital, Japan f Department of Obstetrics and Gynecology, Ogaki Municipal Hospital, Japan g Department of Obstetrics and Gynecology, Toyohashi Municipal Hospital, Japan h Division of Pathology, Clinical Laboratory, Nagoya University Hospital, Japan Received 30 January 2008 Available online 9 June 2008
Abstract Background. In epithelial ovarian cancer (EOC), fertility-sparing surgery (FSS) has mainly been chosen for stage IA disease. The purpose of this study was to clarify the clinical outcome of patients with clear-cell carcinoma of the ovary (CCC) who would usually undergo radical surgery. Cases. After a central pathological review and search of the medical records from multiple institutions between 1988 and 2005, a total of 10 CCC patients treated with FSS were retrospectively evaluated in the current study. The mean age was 35.9 years (range: 32–39 years). The median follow-up time was 35.4 months (range: 21.7–153.2 months). The stage was IA in 4 patients, and IC in 6 patients {IC(b) in 5 patients, and IC(2) in one}. Nine patients received adjuvant chemotherapy. Nine patients were alive and one patient with stage IC(2) died of the disease at a follow-up time of 36.8 months. Five pregnancies were observed in 4 patients. Conclusions. Although there is no worldwide criterion for FSS in CCC patients at present, it seems that, in selected patients, this surgical approach could be adopted. This should be investigated by additional studies in a larger series. © 2008 Elsevier Inc. All rights reserved. Keywords: Clear-cell carcinoma of the ovary (CCC); Fertility-sparing surgery; Pregnancy; Clinical outcome
Background Epithelial ovarian carcinoma (EOC) is the leading cause of death from gynecological malignancy [1]. The standard surgical treatment of patients with EOC is based on hysterectomy and
⁎ Corresponding author. Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, Tsuruma-cho 65, Showa-ku, Nagoya 466-8550, Japan. Fax: +81 52 744 2268. E-mail address: [email protected] (H. Kajiyama). 0090-8258/$ - see front matter © 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.ygyno.2008.04.001
bilateral salpingo-oophorectomy with peritoneal sampling (peritoneal washing, omentectomy, multiple peritoneal biopsies, and the removal of peritoneal implants) with or without lymph-node sampling [2]. However, several reports have estimated that 3–17% of all EOCs occur in women under 40 years of age [3–7]. In these patients, the preservation of the reproductive and endocrine functions is crucial. Therefore, fertility-sparing surgery (FSS) has become important in the treatment of borderline, germ cell, and early-stage/grade invasive EOC despite several unresolved points regarding the management of these patients.
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Table 1 Clinical outcome of the 10 CCC patients who underwent fertility-sparing surgery Case
Age
Initial surgery
PT
Substage
Prognosis
Follow-up (months)
Chemotherapy
Recurrence
Pregnancy
1 2 3 4 5 6 7 8 9 10
39 38 37 37 33 35 32 36 39 34
LSO + wedge RSO RSO + OM RSO + OM LSO + OM + PLA LSO + wedge RSO + wedge LSO + RPN sampling LSO + wedge RSO + wedge
IC IA IC IA IA IC IC IA IC IC
IC(2) (–) IC(b) (–) (–) IC(b) IC(b) (–) IC(b) IC(b)
DOD NED NED NED NED NED NED NED NED NED
36.8 68.5 21.7 75.9 95.4 153.2 24.3 29.9 33.9 29.2
CAP PP TC N.D. PP EP DC TC TC TC
Brain, pelvic wall (–) (–) Second cancer (–) (–) (–) (–) (–) (−)
No No No Yes No No Yes Yes No Yes
Fertility
G2P2
G1P1 G1P1 G2P0
Clinical staging was defined according to the International Federation of Gynecology and Obstetrics (FIGO, 1985) criteria without considering the pathologic findings of the lymph nodes, using the macroscopic description during the surgical procedure and histological analysis of specimens removed during initial or restaging surgery (if the initial procedure was incomplete). IC(b), patients with intraoperative capsule rupture and negative peritoneal cytology; IC (2), those with positive malignant cells in the ascites. LSO, left salpingo-oophorectomy; RSO, right salpingo-oophorectomy; OM, omentectomy; wedge, wedge resection of the contralateral ovary; PLA, pelvic lymphadenectomy; RPN, retroperitoneal lymph node; DOD, died of the disease; NED, no evidence of the disease; CAP, cisplatin + adriamycin + cyclophosphamide; PP, cisplatin + carboplatin; EP, etoposide + cisplatin; DC, docetaxel + carboplatin; TC, paclitaxel + carboplatin; N.D., not done.
Clear-cell carcinoma of the ovary (CCC) is a distinctive subtype of EOC which was strictly defined by the World Health Organization (WHO) as a lesion characterized by clear-cell growth in solid/tubular or glandular patterns as well as hobnail cells lining tubules and cysts [8]. CCC is more likely to be diagnosed at an earlier stage, bilateral occurrence is rare, and it is frequently associated with endometriosis, hypercalcemia, and thromboembolic complications [9–12]. According to the highly malignant potential of CCC due to its comparative resistance to platinum-based chemotherapy [13], FSS has tended to be avoided as a rule, despite its frequent diagnosis at an earlier stage. Between 1988 and 2005, a total of 10 patients treated with FSS by the Tokai Ovarian Tumor Study Group and diagnosed with pure-type CCC under a central pathological review system were picked up after searching the medical records. In the present study, we retrospectively analyzed these patients to clarify the clinical outcome of CCC patients who would usually undergo radical surgery. Cases In the current study, FSS was carried out only when we could not obtain informed consent for our recommended surgical procedure from CCC patients who strongly desired to preserve fertility. As shown in Table 1, the mean age was 35.9 years (range: 32–39 years). The median follow-up time was 35.4 months (range: 21.7–153.2 months). All patients were nulliparous and received unilateral salpingo-oophorectomy. Two patients received laparoscopic cystectomy as an initial surgery prior to
secondary salpingo-oophorectomy. During initial or restaging surgery, all patients underwent salpingo-oophorectomy on the side of the ovarian tumor with at least peritoneal staging including cytology of peritoneal washing or ascites, careful palpation and inspection throughout the peritoneal cavity, and multiple peritoneal biopsies. Retroperitoneal lymphadenectomy (Case No. 5 and 8), wedge resection of the remaining ovary, omentectomy, and appendectomy were optional (Table 1). Five patients underwent a routine wedge resection of the contralateral ovary (normal in all cases). None were re-classified at a higher stage following the histological analysis of lymph nodes. The FIGO stage (International Federation of Gynecology and Obstetrics) was IA in 4 patients and IC in 6. In addition, patients with Stage IC were classified into four subtypes according to their pathological characteristics: IC(b) for patients with intraoperative capsule rupture and negative cytology, IC(a) for those with a tumor on the ovarian surface or preoperative capsule rupture, and IC(1) or IC(2) for those with positive malignant cells in the positive peritoneal washing or ascites, respectively. As a result, 5 patients were at stage IC(b), and one patient was at IC(2). In our current series, there were no patients with IC(a) and IC(1). Nine patients (90.0%) received adjuvant chemotherapy: four underwent adjuvant cisplatin-based combination chemotherapy, and five received taxan/platinum-based chemotherapy. One patient rejected additional treatment. One patient was diagnosed during pregnancy (at 18 gestational weeks), and underwent right salpingo-oophorectomy and omentectomy. No additional therapy was given to this patient based on her wishes (case no.4).
Table 2 Clinical outcomes and fertility results in CCC patients treated conservatively in the literature Reference
Patients (n)
Age
FIGO stage
Prognosis
Adjuvant chemotherapy
Recurrence
Pregnancy
Schilder et al. [16] Morice et al. [2] Eitan et al. [17] Current report
5 1 1 10
N.D. 33 30 32–39
IA–IC IA IA 4, IA; 6, IC
NED AWD NED 9, NED; 1, DOD
Yes Yes Yes 9, Yes; 1, No
None RLN, liver None 1, distant; 9, none
N.D. No Yes Yes (4/10)
RLN, retroperitoneal lymph node; DOD, died of the disease; NED, no evidence of the disease; AWD, alive with the disease; N.D., not precisely documented.
H. Kajiyama et al. / Gynecologic Oncology 111 (2008) 523–526
After the childbirth, she became pregnant again, and delivered 25.9 months after the initial treatment. However, she developed a stage IA adenocarcinoma of the uterine cervix 34.0 months after initial FSS and was treated with total abdominal hysterectomy, contralateral salpingo-oophorectomy, and then 3 cycles of taxan/platinum chemotherapy. Since the histological types of the primary and secondary tumors were different, she was thought to have another malignancy rather than recurrence. She is currently alive with no evidence of disease 75.6 months after the initial treatment. Nine patients were alive without evidence of recurrence 21.7–153.2 months (median: 33.9 months) after the initial surgery. One patient with stage IC(2) showed recurrence in the brain and abdominal wall 20.3 months after the initial surgery, and died of the disease at a follow-up time of 36.8 months. However, excluding this case, all patients were alive without evidence of disease. Following treatment, five pregnancies were observed in four patients (40.0%). These patients showed two full-term pregnancies, one premature delivery at 35 gestational weeks, and 2 spontaneous abortions. There were no congenital anomalies reported in any of the babies. Conclusions In general, patients with CCC have a poorer prognosis compared with those with other pathological types of EOC [14,15]. Ordinary, standard surgery for stage I-CCC includes intact tumor removal, total abdominal hysterectomy and bilateral salpingo-oophorectomy, omentectomy, lymph-node sampling, peritoneal and diaphragmatic sampling, and multiple washing for cytology. Although CCC generally affects older women, it can also be observed in women of childbearing age, frequently associated with a clinical history of endometriosis. Needless to say, preservation of the reproductive function is a crucial consideration at this age, however FSS has rarely been chosen in almost all juvenile patients with CCC, even if it is at an earlier stage, owing to its assembly poorer clinical outcome. Indeed, it is plausible that the potential risks may be an increase in the probability of recurrence and death if we adopt this surgical procedure. Nevertheless, if we could carry out FSS without compromising the curability of selected CCC cases, this would be an ideal therapeutic choice. In the current study, we reported the clinical courses of 10 stage I-CCC patients treated with FSS: 4 stage IA, 6 stage IC. While only the stage IC(2) patient experienced a recurrence in the distant organs and died of disease, the other 9 patients showed no evidence of disease. Four patients became pregnant, and 3 of them achieved successful childbearing. Indeed, there was the limitation of the small number of patients for retrospective analysis and the possibility of a selection bias. However, FSS may not worsen the prognosis of these patients despite the use of chemotherapy in almost all cases. Very few previous reports have demonstrated the role of FSS in early-stage CCC. Table 2 summarizes the CCC patients treated with conservative surgery in the literature [2,16,17]. All of them are similar to case reports. Especially, Schilder et al.
525
reported 52 patients with stage I EOC, including 5 stage IA/IC CCC cases, who were treated with unilateral salpingooophorectomy. They observed no CCC relapses, while 5/47 (10.6%) patients with other histological types of EOC such as serous, mucinous, and endometrioid types developed tumor recurrence 8–78 months after initial surgery [16]. Of all the 17 CCC patients treated with FSS listed in Table 2, including our current cases, only 2 showed a relapse (11.8%) without any involvement of the preserved ovary or uterus. Therefore, a question arises as to whether recurrence could have been avoided in these two cases, if radical surgery had been performed in the initial operation. In particular, regarding the indication of FSS for Stage IC(2) patients, it appears that the existence of tumor cells in ascites has the potential risk of disseminating the tumor throughout the peritoneal cavity or to distant organs. We should keep in mind that the abovementioned risk is quite different from the risk that accompanies FSS. Nevertheless, since our case (No.1) actually developed tumor recurrence despite at a distant site, it would be better to exclude Stage IC(2) CCC patients from candidates for FSS due to the lack of sufficient evidence at present. Taken together, confined to these analyses, we may conclude that CCC patients with at least stage IA and IC(b) treated with FSS have an acceptable prognosis, although there was the limitation of indirect aggregation. In the present examination, adjuvant chemotherapy was conducted in 9 patients (90.0%). ICON 1-Action combined analysis showed that patients with early-stage EOC have a better prognosis when they receive platinum-based chemotherapy after surgery [18]. Indeed, it is widely accepted that CCC is resistant to a variety of chemotherapeutic agents, including platinum or taxane compounds. However, we think that it would be better to perform adjuvant chemotherapy in all CCC patients undergoing FSS because of its possible efficacy. In summary, although there is no established criterion for FSS in CCC patients at present, it seems that, in selected patients, it may be an option in young women presenting with early-stage CCC. However, this is based on a very small number of investigations, and further studies should be conducted with a larger-scale, prospective clinical trial in the future. Conflict of interest statement The authors declare that they have no conflicts of interest to disclose.
References [1] Greenlee RT, Hill-Harmon MB, Murray T, Thun M. Cancer statistics, 2001. CA Cancer J Clin 2001;51:15–36. [2] Morice P, Leblanc E, Rey A, Baron M, Querleu D, Blanchot J, et al. Conservative treatment in epithelial ovarian cancer: results of a multicentre study of the GCCLCC (Groupe des Chirurgiens de Centre de Lutte Contre le Cancer) and SFOG (Societe Francaise d'Oncologie Gynecologique). Hum Reprod 2005;20:1379–85. [3] Duska LR, Chang YC, Flynn CE, Chen AH, Goodman A, Fuller AF, et al. Epithelial ovarian carcinoma in the reproductive age group. Cancer 1999;85:2623–9. [4] Plaxe SC, Braly PS, Freddo JL, McClay E, Kirmani S, Howell SB. Profiles of women age 30–39 and age less than 30 with epithelial ovarian cancer. Obstet Gynecol 1993;81:651–4.
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[5] Rodriguez M, Nguyen HN, Averette HE, Steren AJ, Penalver MA, Harrison T, et al. National survey of ovarian carcinoma XII. Epithelial ovarian malignancies in women less than or equal to 25 years of age. Cancer 1994;73:1245–50. [6] Swenerton KD, Hislop TG, Spinelli J, LeRiche JC, Yang N, Boyes DA. Ovarian carcinoma: a multivariate analysis of prognostic factors. Obstet Gynecol 1985;65:264–70. [7] Smedley H, Sikora K. Age as a prognostic factor in epithelial ovarian carcinoma. Br J Obstet Gynaecol 1985;92:839–42. [8] Serov SFSR, Sobin LH, editors. International histologic classification of tumors., Vol. 9. Geneva: World Health Organization; 1973. [9] Kennedy AW, Biscotti CV, Hart WR, Webster KD. Ovarian clear cell adenocarcinoma. Gynecol Oncol 1989;32:342–9. [10] Goff BA, Sainz de la Cuesta R, Muntz HG, Fleischhacker D, Ek M, Rice LW, et al. Clear cell carcinoma of the ovary: a distinct histologic type with poor prognosis and resistance to platinum-based chemotherapy in stage III disease. Gynecol Oncol 1996;60:412–7. [11] Czernobilsky B, Silverman BB, Enterline HT. Clear-cell carcinoma of the ovary. A clinicopathologic analysis of pure and mixed forms and comparison with endometrioid carcinoma. Cancer 1970;25:762–72. [12] Matsuura Y, Robertson G, Marsden DE, Kim SN, Gebski V, Hacker NF. Thromboembolic complications in patients with clear cell carcinoma of the ovary. Gynecol Oncol 2007;104:406–10.
[13] Sugiyama T, Kamura T, Kigawa J, Terakawa N, Kikuchi Y, Kita T, et al. Clinical characteristics of clear cell carcinoma of the ovary: a distinct histologic type with poor prognosis and resistance to platinum-based chemotherapy. Cancer 2000;88:2584–9. [14] O'Brien ME, Schofield JB, Tan S, Fryatt I, Fisher C, Wiltshaw E. Clear cell epithelial ovarian cancer (mesonephroid): bad prognosis only in early stages. Gynecol Oncol 1993;49:250–4. [15] Omura GA, Brady MF, Homesley HD, Yordan E, Major FJ, Buchsbaum HJ, et al. Long-term follow-up and prognostic factor analysis in advanced ovarian carcinoma: the Gynecologic Oncology Group experience. J Clin Oncol 1991;9:1138–50. [16] Schilder JM, Thompson AM, DePriest PD, Ueland FR, Cibull ML, Kryscio RJ, et al. Outcome of reproductive age women with stage IA or IC invasive epithelial ovarian cancer treated with fertility-sparing therapy. Gynecol Oncol 2002;87:1–7. [17] Eitan R, Chi DS. Successful pregnancies following fertility-preserving treatment for ovarian carcinoma. Nat Clin Pract Oncol 2005;2:647–51 quiz 652. [18] Trimbos JB, Parmar M, Vergote I, Guthrie D, Bolis G, Colombo N, et al. International Collaborative Ovarian Neoplasm trial 1 and Adjuvant ChemoTherapy In Ovarian Neoplasm trial: two parallel randomized phase III trials of adjuvant chemotherapy in patients with early-stage ovarian carcinoma. J Natl Cancer Inst 2003;95:105–12.
Gynecologic Oncology 111 (2008) 523 – 526 www.elsevier.com/locate/ygyno
Case Report
Is there any possibility of fertility-sparing surgery in patients with clear-cell carcinoma of the ovary? Hiroaki Kajiyama a,⁎, Kiyosumi Shibata a , Shiro Suzuki a , Kazuhiko Ino a , Eiko Yamamoto a , Kimio Mizuno b , Katsumi Sakakibara c , Katsuji Matsuzawa d , Akihiro Takeda e , Yoshito Kinoshita f , Michiyasu Kawai g , Tetsuro Nagasaka h , Akihiro Nawa a , Fumitaka Kikkawa a a
Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, Japan b Department of Obstetrics and Gynecology, Japanese Red Cross Nagoya First Hospital, Japan c Department of Obstetrics and Gynecology, Okazaki Municipal Hospital, Japan d Department of Obstetrics and Gynecology, Anjyo Kosei Hospital, Japan e Department of Obstetrics and Gynecology, Gifu Prefectural Tajimi Hospital, Japan f Department of Obstetrics and Gynecology, Ogaki Municipal Hospital, Japan g Department of Obstetrics and Gynecology, Toyohashi Municipal Hospital, Japan h Division of Pathology, Clinical Laboratory, Nagoya University Hospital, Japan Received 30 January 2008 Available online 9 June 2008
Abstract Background. In epithelial ovarian cancer (EOC), fertility-sparing surgery (FSS) has mainly been chosen for stage IA disease. The purpose of this study was to clarify the clinical outcome of patients with clear-cell carcinoma of the ovary (CCC) who would usually undergo radical surgery. Cases. After a central pathological review and search of the medical records from multiple institutions between 1988 and 2005, a total of 10 CCC patients treated with FSS were retrospectively evaluated in the current study. The mean age was 35.9 years (range: 32–39 years). The median follow-up time was 35.4 months (range: 21.7–153.2 months). The stage was IA in 4 patients, and IC in 6 patients {IC(b) in 5 patients, and IC(2) in one}. Nine patients received adjuvant chemotherapy. Nine patients were alive and one patient with stage IC(2) died of the disease at a follow-up time of 36.8 months. Five pregnancies were observed in 4 patients. Conclusions. Although there is no worldwide criterion for FSS in CCC patients at present, it seems that, in selected patients, this surgical approach could be adopted. This should be investigated by additional studies in a larger series. © 2008 Elsevier Inc. All rights reserved. Keywords: Clear-cell carcinoma of the ovary (CCC); Fertility-sparing surgery; Pregnancy; Clinical outcome
Background Epithelial ovarian carcinoma (EOC) is the leading cause of death from gynecological malignancy [1]. The standard surgical treatment of patients with EOC is based on hysterectomy and
⁎ Corresponding author. Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, Tsuruma-cho 65, Showa-ku, Nagoya 466-8550, Japan. Fax: +81 52 744 2268. E-mail address: [email protected] (H. Kajiyama). 0090-8258/$ - see front matter © 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.ygyno.2008.04.001
bilateral salpingo-oophorectomy with peritoneal sampling (peritoneal washing, omentectomy, multiple peritoneal biopsies, and the removal of peritoneal implants) with or without lymph-node sampling [2]. However, several reports have estimated that 3–17% of all EOCs occur in women under 40 years of age [3–7]. In these patients, the preservation of the reproductive and endocrine functions is crucial. Therefore, fertility-sparing surgery (FSS) has become important in the treatment of borderline, germ cell, and early-stage/grade invasive EOC despite several unresolved points regarding the management of these patients.
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H. Kajiyama et al. / Gynecologic Oncology 111 (2008) 523–526
Table 1 Clinical outcome of the 10 CCC patients who underwent fertility-sparing surgery Case
Age
Initial surgery
PT
Substage
Prognosis
Follow-up (months)
Chemotherapy
Recurrence
Pregnancy
1 2 3 4 5 6 7 8 9 10
39 38 37 37 33 35 32 36 39 34
LSO + wedge RSO RSO + OM RSO + OM LSO + OM + PLA LSO + wedge RSO + wedge LSO + RPN sampling LSO + wedge RSO + wedge
IC IA IC IA IA IC IC IA IC IC
IC(2) (–) IC(b) (–) (–) IC(b) IC(b) (–) IC(b) IC(b)
DOD NED NED NED NED NED NED NED NED NED
36.8 68.5 21.7 75.9 95.4 153.2 24.3 29.9 33.9 29.2
CAP PP TC N.D. PP EP DC TC TC TC
Brain, pelvic wall (–) (–) Second cancer (–) (–) (–) (–) (–) (−)
No No No Yes No No Yes Yes No Yes
Fertility
G2P2
G1P1 G1P1 G2P0
Clinical staging was defined according to the International Federation of Gynecology and Obstetrics (FIGO, 1985) criteria without considering the pathologic findings of the lymph nodes, using the macroscopic description during the surgical procedure and histological analysis of specimens removed during initial or restaging surgery (if the initial procedure was incomplete). IC(b), patients with intraoperative capsule rupture and negative peritoneal cytology; IC (2), those with positive malignant cells in the ascites. LSO, left salpingo-oophorectomy; RSO, right salpingo-oophorectomy; OM, omentectomy; wedge, wedge resection of the contralateral ovary; PLA, pelvic lymphadenectomy; RPN, retroperitoneal lymph node; DOD, died of the disease; NED, no evidence of the disease; CAP, cisplatin + adriamycin + cyclophosphamide; PP, cisplatin + carboplatin; EP, etoposide + cisplatin; DC, docetaxel + carboplatin; TC, paclitaxel + carboplatin; N.D., not done.
Clear-cell carcinoma of the ovary (CCC) is a distinctive subtype of EOC which was strictly defined by the World Health Organization (WHO) as a lesion characterized by clear-cell growth in solid/tubular or glandular patterns as well as hobnail cells lining tubules and cysts [8]. CCC is more likely to be diagnosed at an earlier stage, bilateral occurrence is rare, and it is frequently associated with endometriosis, hypercalcemia, and thromboembolic complications [9–12]. According to the highly malignant potential of CCC due to its comparative resistance to platinum-based chemotherapy [13], FSS has tended to be avoided as a rule, despite its frequent diagnosis at an earlier stage. Between 1988 and 2005, a total of 10 patients treated with FSS by the Tokai Ovarian Tumor Study Group and diagnosed with pure-type CCC under a central pathological review system were picked up after searching the medical records. In the present study, we retrospectively analyzed these patients to clarify the clinical outcome of CCC patients who would usually undergo radical surgery. Cases In the current study, FSS was carried out only when we could not obtain informed consent for our recommended surgical procedure from CCC patients who strongly desired to preserve fertility. As shown in Table 1, the mean age was 35.9 years (range: 32–39 years). The median follow-up time was 35.4 months (range: 21.7–153.2 months). All patients were nulliparous and received unilateral salpingo-oophorectomy. Two patients received laparoscopic cystectomy as an initial surgery prior to
secondary salpingo-oophorectomy. During initial or restaging surgery, all patients underwent salpingo-oophorectomy on the side of the ovarian tumor with at least peritoneal staging including cytology of peritoneal washing or ascites, careful palpation and inspection throughout the peritoneal cavity, and multiple peritoneal biopsies. Retroperitoneal lymphadenectomy (Case No. 5 and 8), wedge resection of the remaining ovary, omentectomy, and appendectomy were optional (Table 1). Five patients underwent a routine wedge resection of the contralateral ovary (normal in all cases). None were re-classified at a higher stage following the histological analysis of lymph nodes. The FIGO stage (International Federation of Gynecology and Obstetrics) was IA in 4 patients and IC in 6. In addition, patients with Stage IC were classified into four subtypes according to their pathological characteristics: IC(b) for patients with intraoperative capsule rupture and negative cytology, IC(a) for those with a tumor on the ovarian surface or preoperative capsule rupture, and IC(1) or IC(2) for those with positive malignant cells in the positive peritoneal washing or ascites, respectively. As a result, 5 patients were at stage IC(b), and one patient was at IC(2). In our current series, there were no patients with IC(a) and IC(1). Nine patients (90.0%) received adjuvant chemotherapy: four underwent adjuvant cisplatin-based combination chemotherapy, and five received taxan/platinum-based chemotherapy. One patient rejected additional treatment. One patient was diagnosed during pregnancy (at 18 gestational weeks), and underwent right salpingo-oophorectomy and omentectomy. No additional therapy was given to this patient based on her wishes (case no.4).
Table 2 Clinical outcomes and fertility results in CCC patients treated conservatively in the literature Reference
Patients (n)
Age
FIGO stage
Prognosis
Adjuvant chemotherapy
Recurrence
Pregnancy
Schilder et al. [16] Morice et al. [2] Eitan et al. [17] Current report
5 1 1 10
N.D. 33 30 32–39
IA–IC IA IA 4, IA; 6, IC
NED AWD NED 9, NED; 1, DOD
Yes Yes Yes 9, Yes; 1, No
None RLN, liver None 1, distant; 9, none
N.D. No Yes Yes (4/10)
RLN, retroperitoneal lymph node; DOD, died of the disease; NED, no evidence of the disease; AWD, alive with the disease; N.D., not precisely documented.
H. Kajiyama et al. / Gynecologic Oncology 111 (2008) 523–526
After the childbirth, she became pregnant again, and delivered 25.9 months after the initial treatment. However, she developed a stage IA adenocarcinoma of the uterine cervix 34.0 months after initial FSS and was treated with total abdominal hysterectomy, contralateral salpingo-oophorectomy, and then 3 cycles of taxan/platinum chemotherapy. Since the histological types of the primary and secondary tumors were different, she was thought to have another malignancy rather than recurrence. She is currently alive with no evidence of disease 75.6 months after the initial treatment. Nine patients were alive without evidence of recurrence 21.7–153.2 months (median: 33.9 months) after the initial surgery. One patient with stage IC(2) showed recurrence in the brain and abdominal wall 20.3 months after the initial surgery, and died of the disease at a follow-up time of 36.8 months. However, excluding this case, all patients were alive without evidence of disease. Following treatment, five pregnancies were observed in four patients (40.0%). These patients showed two full-term pregnancies, one premature delivery at 35 gestational weeks, and 2 spontaneous abortions. There were no congenital anomalies reported in any of the babies. Conclusions In general, patients with CCC have a poorer prognosis compared with those with other pathological types of EOC [14,15]. Ordinary, standard surgery for stage I-CCC includes intact tumor removal, total abdominal hysterectomy and bilateral salpingo-oophorectomy, omentectomy, lymph-node sampling, peritoneal and diaphragmatic sampling, and multiple washing for cytology. Although CCC generally affects older women, it can also be observed in women of childbearing age, frequently associated with a clinical history of endometriosis. Needless to say, preservation of the reproductive function is a crucial consideration at this age, however FSS has rarely been chosen in almost all juvenile patients with CCC, even if it is at an earlier stage, owing to its assembly poorer clinical outcome. Indeed, it is plausible that the potential risks may be an increase in the probability of recurrence and death if we adopt this surgical procedure. Nevertheless, if we could carry out FSS without compromising the curability of selected CCC cases, this would be an ideal therapeutic choice. In the current study, we reported the clinical courses of 10 stage I-CCC patients treated with FSS: 4 stage IA, 6 stage IC. While only the stage IC(2) patient experienced a recurrence in the distant organs and died of disease, the other 9 patients showed no evidence of disease. Four patients became pregnant, and 3 of them achieved successful childbearing. Indeed, there was the limitation of the small number of patients for retrospective analysis and the possibility of a selection bias. However, FSS may not worsen the prognosis of these patients despite the use of chemotherapy in almost all cases. Very few previous reports have demonstrated the role of FSS in early-stage CCC. Table 2 summarizes the CCC patients treated with conservative surgery in the literature [2,16,17]. All of them are similar to case reports. Especially, Schilder et al.
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reported 52 patients with stage I EOC, including 5 stage IA/IC CCC cases, who were treated with unilateral salpingooophorectomy. They observed no CCC relapses, while 5/47 (10.6%) patients with other histological types of EOC such as serous, mucinous, and endometrioid types developed tumor recurrence 8–78 months after initial surgery [16]. Of all the 17 CCC patients treated with FSS listed in Table 2, including our current cases, only 2 showed a relapse (11.8%) without any involvement of the preserved ovary or uterus. Therefore, a question arises as to whether recurrence could have been avoided in these two cases, if radical surgery had been performed in the initial operation. In particular, regarding the indication of FSS for Stage IC(2) patients, it appears that the existence of tumor cells in ascites has the potential risk of disseminating the tumor throughout the peritoneal cavity or to distant organs. We should keep in mind that the abovementioned risk is quite different from the risk that accompanies FSS. Nevertheless, since our case (No.1) actually developed tumor recurrence despite at a distant site, it would be better to exclude Stage IC(2) CCC patients from candidates for FSS due to the lack of sufficient evidence at present. Taken together, confined to these analyses, we may conclude that CCC patients with at least stage IA and IC(b) treated with FSS have an acceptable prognosis, although there was the limitation of indirect aggregation. In the present examination, adjuvant chemotherapy was conducted in 9 patients (90.0%). ICON 1-Action combined analysis showed that patients with early-stage EOC have a better prognosis when they receive platinum-based chemotherapy after surgery [18]. Indeed, it is widely accepted that CCC is resistant to a variety of chemotherapeutic agents, including platinum or taxane compounds. However, we think that it would be better to perform adjuvant chemotherapy in all CCC patients undergoing FSS because of its possible efficacy. In summary, although there is no established criterion for FSS in CCC patients at present, it seems that, in selected patients, it may be an option in young women presenting with early-stage CCC. However, this is based on a very small number of investigations, and further studies should be conducted with a larger-scale, prospective clinical trial in the future. Conflict of interest statement The authors declare that they have no conflicts of interest to disclose.
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