Original Article Gynecol Obstet Invest 2014;77:104–110 DOI: 10.1159/000357819
Received: April 15, 2013 Accepted after revision: November 18, 2013 Published online: February 5, 2014
Clinical Characteristics of Patients in Japan with Ovarian Cancer Presumably Arising from Ovarian Endometrioma Fuminori Taniguchi a Tasuku Harada a Hiroshi Kobayashi b Kunihiko Hayashi c Mikio Momoeda d Naoki Terakawa a a
Department of Obstetrics and Gynecology, Tottori University Faculty of Medicine, Yonago, and b Department of Obstetrics and Gynecology, Nara Medical University, Kashihara, c Department of Laboratory Science and Environment Health Sciences, Gunma University School of Health Sciences, Maebashi, and d Department of Women’s General Medicine, St. Luke General Hospital, Tokyo, Japan
Key Words Malignant transformation · Ovarian endometrioma · Cystectomy · Mural nodule
Abstract Objective: To investigate the clinical features of patients in Japan with malignant transformation of ovarian endometrioma. Patients: Thirty-three patients diagnosed with ovarian cancer presumably arising from endometrioma were recruited retrospectively. These patients had been followed for at least 2 years after the ovarian endometrioma diagnosis, then continued to be followed after they had been found to have malignant transformation. Results: The average age of the patients was 47.7 ± 9.3 years; 75.7% were premenopausal at the time of diagnosis of ovarian cancer. Among the 33 patients, ovarian cancer developed in the ipsilateral ovary of 6 patients with endometrioma after cystectomy. Twenty-eight patients were diagnosed with stage I ovarian cancer, and major histotypes were clear cell in 23 cases and endometrioid in 8. Before surgery for cancer, mural nodules within the endometriomas were detected in 32 patients, and 1 patient had a small 3-mm nodule. In 30 patients, the diameter of the tumor doubled in size 6 months prior to the diagnosis of ma-
© 2014 S. Karger AG, Basel 0378–7346/14/0772–0104$39.50/0 E-Mail [email protected] www.karger.com/goi
lignant transformation. The diameter of the endometrioma and the preoperative CA125 value did not significantly correlate. Conclusions: To detect malignant transformation of ovarian endometrioma early and precisely, the clinician should determine the existence of a mural nodule and assess the rapid growth of the endometrioma. © 2014 S. Karger AG, Basel
Introduction
Endometriosis, which occurs in approximately 10% of women of reproductive age, is defined as the presence of endometrial tissue outside the uterus [1]. Although endometriosis originates as a benign disease, epidemiological studies consistently show that endometriosis is associated with an increased risk of ovarian cancer, the most fatal malignancy of the female reproductive system. The exact rate of malignant transformation of endometriosis is not known because endometriotic lesions, such as the endometrioma, are not always resected and confirmed by pathological diagnosis. However, the evidence that endometriosis represents an important site of origin of epithelial ovarian cancer (EOC), especially clear cell and endoFuminori Taniguchi, MD, PhD Department of Obstetrics and Gynecology Tottori University Faculty of Medicine 36-1 Nishicho, Yonago 683-8504 (Japan) E-Mail tani4327 @ med.tottori-u.ac.jp
metrioid subtypes, is well known [2–4]. Endometriosisassociated EOC tends to be found in the earlier clinical stage. The clinician should therefore be aware of the increased risk of specific subtypes of ovarian cancer in women with endometriosis. Ovarian cancer incidence and mortality rates have increased in recent decades. In Japanese women, approximately 8,000 new cases of EOC are diagnosed each year, and the latest population-based cancer registry shows that the incidence rate of EOC is 8.1 per 100,000 women [5]. The cell origin of ovarian cancer has long been debated. EOC is generally accepted to arise from the ovarian surface epithelium, and it has been argued that the ovarian surface epithelium undergoes ‘metaplasia’ to account for this transformation. Recently, however, Kuhn et al. [6] proposed a new theory of ovarian carcinogenesis suggesting that the fallopian tube epithelium implants on the ovary give rise to both high-grade and low-grade serous carcinomas, and that endometrial tissue becomes implanted on the ovary and produces endometriosis, which can then undergo malignant transformation into endometrioid and clear cell carcinoma (CCC). Crum et al. [7] also described high-grade and serous carcinomas that actually arise from the fimbria of the fallopian tube. According to a cohort study in Japan, approximately 0.72% of patients with endometriosis subsequently developed ovarian cancer. The authors also reported that patients older than 45 with a large endometrioma had a higher incidence of malignant transformation. They further defined premenopausal women with an endometrioma 9 cm or more in diameter as the high-risk group and recommended extensive treatment, including surgical resection [3]. In another retrospective cohort study of 12,193 infertile women, 13 of 45 women with ovarian cancers had been treated for infertility associated with endometriosis. A 2.7-fold higher risk of ovarian cancer among patients with endometriosis compared with those without endometriosis was observed [8]. Recently, a meta-analysis to evaluate the association between endometriosis and histological subtypes of ovarian cancer was conducted. It showed that a history of endometriosis is associated with an increased risk of ovarian cancer, especially among clear cell, invasive low-grade serous and endometrioid subtypes [9]. The detailed characteristics and behavior of malignant transformation of endometriosis are intriguing and still poorly understood. The aim of this study was to investigate the clinical features of patients with ovarian cancer probably arising from ovarian endometrioma. Ovarian Cancer Presumably Arising from Ovarian Endometrioma
Patients and Methods The Institutional Review Board of the Tottori University Faculty of Medicine approved this project. The data were obtained retrospectively from 15 Japanese hospitals. Thirty-three patients diagnosed from 2008 to 2010 with ovarian cancer derived from endometriomas, as confirmed by each hospital’s gynecological pathologist, were enrolled in this study. Gynecologists and radiologists followed these patients for more than 2 years for benign ovarian endometrioma using vaginal ultrasonography (USG) and/or magnetic resonance imaging (MRI). When the diameter of the endometriotic cyst increased 2-fold within 6 months, we considered that rapid development. We also considered the mural nodule to be within the solid part of the endometrioma, using USG and/or MRI. Pathologists confirmed the coexistence of endometriosis and ovarian cancer, although not all data had been examined exhaustively to determine whether they met Sampson’s [10] and Scott’s [11] criteria for ovarian cancer associated with endometriosis. The pathological finding of benign endometriosis contiguous with malignant tissue was confirmed in 60.6% (20 of the 33 patients). No contiguous lesion was found in 15.2% of specimens (5 patients), and that finding was unclear in 24.2% of specimens (8 patients). Nineteen patients received hormonal treatment [GnRH agonist, oral contraceptive, antiestrogenic drug (danazol), and progestin (dienogest)] for endometriosis. These patients were followed for at least 2 years after the diagnosis of endometrioma. After being diagnosed with ovarian cancer, all patients underwent primary debulking surgery and were followed every 1–6 months. All clinical and pathological data were analyzed retrospectively. Statistical Analysis Data are shown as means ± standard deviation. Spearman’s rank correlation coefficient was calculated between the maximum diameter of endometrioma and the value of presurgical CA125. A p value of less than 0.05 was regarded as statistically significant.
Results
The clinical characteristics of the 33 patients with malignant transformation of ovarian endometrioma are summarized in table 1. Ages ranged from 31 to 74 years (47.7 ± 9.3 years), and 25 patients (75.7% of all patients) were premenopausal at the time of diagnosis of ovarian cancer and the debulking surgery. The mean body mass index of patients was 21.3 ± 9.3. Twenty-two patients (69.7%) had regular menstrual cycles, and only 9 patients (27.2%) needed medication for dysmenorrhea. The numbers of past pregnancies and deliveries were 1.3 ± 1.3 and 1.0 ± 1.1, respectively. Fifteen patients (45.4%) had never experienced childbirth. The mean largest diameter of ovarian endometrioma was 8.1 ± 3.2 cm (range: 2.0–20.0 cm), and the preoperative CA125 value was 110.8 ± 156.4 U/ml (range: 10.0–642.0 U/ml). These parameters did not significantly correlate (r = 0.359, p = 0.165). Gynecol Obstet Invest 2014;77:104–110 DOI: 10.1159/000357819
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Table 1. Clinical data for 33 patients with malignant transformation of ovarian endometrioma (numbers with percentages in parentheses) Patients
Age 60 years Body mass index 25 Number of past pregnancies 0 1 2 3 or more Parity (number of births) 0 1 2 3 or more Necessity of medication for dysmenorrhea Yes No Latent period between diagnosis of endometrioma and that of ovarian cancer 15 years Maximum diameter of tumor at diagnosis of malignant transformation 10 cm Preoperative CA125 value 100 U/ml FIGO classification Ia Ic IIc IIIc IV Histological subtypes Clear cell Endometrioid Carcinosarcoma Serous borderline tumor
106
5 (15) 17 (52) 9 (27) 2 (6) 12 (36) 17 (52) 4 (12) 13 (39) 7 (21) 6 (18) 7 (21) 15 (45) 8 (24) 6 (18) 4 (12) 9 (27) 24 (73) 3 (9) 8 (24) 12 (36) 9 (27) 1 (3) 2 (6) 12 (36) 11 (33) 8 (24) 17 (52) 6 (18) 10 (30) 5 (15) 23 (70) 2 (6) 2 (6) 1 (3) 23 (70) 8 (24) 1 (3) 1 (3)
Gynecol Obstet Invest 2014;77:104–110 DOI: 10.1159/000357819
At the time of surgery, the mean maximum diameter of cancer tissue was 9.5 ± 4.3 cm (range: 3.5–25.0 cm). Before surgery for ovarian cancer, mural nodules within endometriomas were detected by USG and/or MRI in 32 patients, i.e. all except for 1 case of endometrioma containing a small 3-mm nodule. As shown in table 1, two cases transformed from less than 4-cm endometriomas with a small mural nodule (3 and 17 mm in diameter). All ovarian cancers developed from the ipsilateral endometrioma with no tendency in laterality. Only 1 patient was identified with bilateral ovarian cancer (i.e. CCC). According to the Federation of Gynecology and Obstetrics classification of ovarian cancer, the postoperative stage of the 33 patients was diagnosed as Ia in 5 cases (15.2%), Ic in 23 cases (69.6%), IIc in 2 cases (6.1%), IIIc in 2 cases (6.1%), and IV in 1 case (3.0%). All patients were alive at the end of this survey in 2012. The histotype was clear cell in 23 cases (69.7%), endometrioid in 8 cases (24.2%), carcinosarcoma in 1 case (3.0%), and serous borderline tumor in 1 case (3.0%). Other cancer types (breast and lung cancer), which were not metastatic, occurred in 2 patients. The average latent period from the diagnosis of endometrioma to that of malignant transformation was 8.3 ± 4.6 years (range: 2–17 years). No patient reported a family history of ovarian cancer. Eleven patients younger than 45 years who developed ovarian cancer had a shorter latent period (5.6 ± 7.0 years) compared with those over the age of 45. The latent period was shorter still (4.2 ± 3.1 years) in 5 patients younger than 40 years. Under the age of 45, an estrogen-rich condition and other corresponding factors may contribute to malignant transformation of endometrioma. In table 2, 19 patients diagnosed with ovarian cancer after conservative surgery (i.e. cystectomy, aspiration of cyst fluid or electrocautery of the cyst wall) and/or hormonal treatment for endometriomas are shown. The average age of the patients when the endometriotic cyst was first identified was 38.6 ± 9.2 years. Surgery was performed only when the patient had severe pain and/or the cyst was over 6 cm in diameter. In 6 patients, cancer occurred in the ovary on the same side as a prior cystectomy performed 1–13 years before. The average latent period from the end of treatment for endometrioma to the diagnosis of malignant transformation was 4.5 ± 4.1 years (range: 3 months to 13 years). After aspiration or electrocautery of the endometrioma, ovarian cancers arose in 2 cases. Malignant transformation occurred in 16 patients previously treated with hormonal preparations (5 patients also underwent conservative surgery). The other 14 patients did not receive any treatments before surgery for ovarian cancer. Taniguchi /Harada /Kobayashi /Hayashi / Momoeda /Terakawa
Table 2. Nineteen patients with malignant transformation of endometrioma after conservative surgery and/or hormonal treatment
No.
Age, years
Treatment
Period from the last treatment
After surgery (with or without hormonal treatment) 1 41 Cystectomy 2 48 Cystectomy 3 31 Cystectomy + GnRHa 3 months 4 44 Cystectomy + GnRHa 3 months 5 45 Cystectomy + GnRHa 6 months twice 6 46 GnRHa 2 months + cystectomy + OC 5 months 7 35 Aspiration 8 50 Electrocautery + GnRHa 6 months × 3 times
3 years after surgery 13 years after surgery 1 year 6 months (9 years after surgery) 4 months (12 years after surgery) 3 years 3 months (9 years after surgery) 4 months (1 year after surgery) 1 year 6 months 8 months (17 years after surgery)
After hormonal treatment 9 46 10 48 11 57 12 47 13 59 14 42 15 52 16 53 17 52 18 31 19 43
3 years 6 months 2 years 9 months 6 years 6 months 12 years 13 years 8 years 6 months 2 years 10 months 5 years 2 years 7 months 1 years 2 months 3 months
GnRHa 4 months GnRHa 6 months GnRHa 6 months GnRHa 6 months GnRHa 1 month + DA 6 months GnRHa 6 months + DA 12 months GnRHa 6 months × 3 times GnRHa 6 months × 4 times GnRHa 6 months twice + OC 2 months DNG 12 months DNG 20 months
GnRHa = GnRH agonist; OC = oral contraceptive; DA = danazol; DNG = dienogest.
In the present study, we provide evidence regarding malignant transformation of endometriosis in Japanese women. The noteworthy finding is that ovarian cancer developed in the ipsilateral ovary of 6 of the 33 patients after cystectomy for endometrioma. Epidemiological, histopathological and molecular data suggest that endometriosis does have malignant potential. A stressful microenvironment within the endometrioma, such as hypoxia, poor nutrition or altered immune status, may lead to cancer development. A high iron concentration in the endometrioma is also presumably involved in cancer development [12]. Although there is a multifactorial pathophysiology of carcinogenesis, one of the causes of malignant transformation may be a stressful change of the microenvironment, such as high levels of estrogen and cytokines (interleukin-1, interleukin-6, interleukin-8, tumor necrosis factor-α, and tumor necrosis factor-β) in endometriotic tissues [13–15], and the influence of inflammation accompanying surgery. Sampson [10] first suggested a relationship between endometriosis and ovarian cancer and proposed criteria
for ovarian cancers arising from endometriosis. These criteria include: (1) coexistence of carcinoma and endometriosis in the same ovary; (2) a similar histological relationship, and (3) exclusion of another primary site. Later, Scott [11] redefined the criteria to include more stringent ones, which require the morphological demonstration of benign endometriosis contiguous with malignant tissue. Although a small subset of ovarian cancers fulfill these stringent criteria, the pathological evidence of malignant transformation and the precise incidence of this phenomenon are still difficult to ascertain. Indeed, cases with all the above criteria have rarely been found due to sampling technique and possible destruction of benign tissue by tumor invasion. Atypical endometriosis has been shown to occur in 60–80% of endometriosisassociated ovarian cancer [2, 15]. In this study, the histological findings of atypical endometriosis were seen in approximately 60% of the patients. Results of studies that investigated the synchronous presence of ovarian cancer and endometriosis have consistently shown an increased occurrence of endometriosis in women with endometrioid carcinoma and CCC relative to the other subtypes [16, 17]. In particular, CCC,
Ovarian Cancer Presumably Arising from Ovarian Endometrioma
Gynecol Obstet Invest 2014;77:104–110 DOI: 10.1159/000357819
Discussion
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which accounts for approximately 70% of the 33 patients in this study, is recognized in the World Health Organization classification of ovarian tumors as a distinct histological entity, and its clinical behavior differs from that of other EOCs. CCC accounts for about 4–12% of EOC cases in the USA and, for unknown reasons, more than 20% of those in Japan. Japanese women may exhibit a higher proportion of malignant transformation of endometriosis compared with the US population. CCC of the ovary is generally considered a slow-growing tumor. Several reports have shown that CCC is frequently diagnosed at an early stage, especially at stage Ic. Of the 23 cases of CCC histotype in the present study, 21 patients were diagnosed with stage I. The percentage of patients with stage I was higher in patients with CCC than in those with serous adenocarcinoma, and among those patients, stage Ic was observed in 32.2–38.8% in CCC and in 7.1–9.4% in serous adenocarcinoma [18–20]. Recently, Kawaguchi et al. [21] summarized the clinicopathological features of 18 patients with ovarian cancer associated with endometriosis in the Kinki district of Japan. According to their retrospective study, the values of mean age, body mass index, the number of childbirths, and the mean largest diameters of tumors at presentation of malignant transformation (45.2 years, 20.9 ± 0.6, 1.0 ± 0.2, and 8.5 cm) were similar to our current data. In addition, the ratios of histotypes and clinical stage of their data were consistent with ours. Although the average interval from the initial diagnosis of endometrioma to the malignant transformation was 8.3 ± 4.6 years in our study, in theirs it was 4.5 years (range: 1–16 years). We noted that 10 patients older than 45 had shorter latency intervals (mean: 1.0 year, range: 1–3) than those younger than 45 (mean: 8.4 years, range: 3–16) [21]. As shown in table 1, more than 70% of the 33 patients were diagnosed with malignant transformation within 10 years of followup of their endometriomas. As we described in the Results section, the patients younger than 45 years had a shorter latent period (5.6 ± 7.0 years) until malignant transformation compared with those over the age of 45. In addition, the latent period was shorter still (4.2 ± 3.1 years) in 5 patients younger than 40 years. Moreover, mural nodes inside endometriomas were detected in all cases. These data suggest that clinicians should carefully observe the acute growth and mural nodes of endometriomas, especially in patients younger than 45 years. With regard to the age of patients and the latent period until malignant transformation, there was a discrepancy between the study of Kawaguchi et al. [21] and our own. Resolving this issue only by these two 108
Gynecol Obstet Invest 2014;77:104–110 DOI: 10.1159/000357819
studies is difficult because the number of patients in both studies was insufficient. Our data and theirs showed that ovarian endometrioma might be regarded as a potentially preneoplastic lesion, particularly in pre- and perimenopausal women. This issue should be an area of future exploration for the management of endometriosis. In the current study, the postoperative Federation of Gynecology and Obstetrics stage of nearly 85% of the patients was stage I (Ia: 15.2% and Ic: 69.6%), and the maximum diameter of the endometrioma in 30 patients (90.9%) increased more than 2-fold in 6 months when the malignant transformation was diagnosed. Even when the endometrioma is small, examining for the presence of mural nodules is crucial to diagnosing malignant transformation. Except for 1 patient with a small 3-mm mural nodule that exhibited rapid growth, the existence of mural nodules before surgery for ovarian cancer was recognized in 32 cases. We therefore have to pay attention to the rapid growth of the endometrioma and the existence of mural nodules. Kawaguchi et al. [21] also showed that the levels of CA125 were elevated in 56% of patients with malignant transformation. In the present study, 45.5% of the 33 patients exhibited a more than 2-fold elevation of the CA125 value; however, in 42.4% of the patients, the CA125 value was under 35 U/ml after the malignant transformation, suggesting that the CA125 value is not a critical marker in diagnosing malignant transformation of endometriosis. Only 8 patients (approx. 24.2% of the patients), including 6 patients who had had cystectomy for endometrioma, were surgically diagnosed with benign tumors prior to the malignant transformation (table 2). The current data suggest that cystectomy for endometrioma cannot prevent postoperative ovarian cancer. As for the surgical procedure for endometrioma, Dan and Limin [22] showed the results of a meta-analysis that cystectomy provided better outcomes than fenestration/coagulation or laser ablation regarding the recurrence of symptoms and endometrioma. In the 16 patients in whom cancer emerged after hormonal treatment, shown in table 2, ovarian cancer was not found during medical treatment. These findings suggest that surgical or medical treatment has no effect on the possibility of malignant transformation. It should be considered as an important limitation of the conclusions of this study. In addition, we could not exclude completely that some patients had early cancers since the beginning of the follow-up with USG or MRI. However, in these patients, we could not detect any findings that showed the doubtful sign of neoplastic occurrence during the follow-up periods. Perez-Medina et al. Taniguchi /Harada /Kobayashi /Hayashi / Momoeda /Terakawa
[23] reported the efficacy of 3-dimensional power Doppler angiography for the prediction of malignancy in ovarian tissues. This may be a useful method to detect the malignant change of endometrioma. Recently, Melin et al. [24] reported that one-sided oophorectomy as well as radical extirpation of all visible endometrioses has a strong protective effect against later development of EOC. Based on their data and ours, we recommend salpingo-oophorectomy for patients older than 40 years who do not desire pregnancy and present with symptomatic endometrioma. In summary, to detect malignant transformation of ovarian endometrioma early and precisely, the clinician should ascertain the existence of a mural nodule and assess the rapid growth of the endometrioma. To verify the findings of previous investigations and our own studies and to clarify the biological plausibility of this association, large-scale studies are needed.
– Hiroyuki Ochi, Hiroyuki Yoshikawa, Tsukuba University Hospital; – Takahiro Suzuki, Shun-ichiro Izumi, Mikio Mikami, Tokai University Hospital; – Toshifumi Takahashi, Hirohisa Kurachi, Yamagata University Hospital; – Akira Fujishita, Daisuke Nakayama, Saiseikai Nagasaki Hospital; – Ken-ichi Makino, Yukihiro Terada, Akita University Hospital; – Naoki Yoshino, Osamu Iwanari, Shimane Prefectural Central Hospital; – Kenjiro Date, Chie Koide, Hideki Teramoto, Hiroshima General Hospital of West Japan Railway Company; – Yuichiro Takeuchi, Ayako Miyamoto, Masakuni Takahashi, Mihara Red Cross Hospital; – Mikio Takehara, Masahide Ohmichi, Osaka Medical College Hospital; – Seiji Isonishi, Kanae Sasaki, Jikei Daisan Hospital; – Hideaki Sawai, Hyogo Medical College Hospital; – Masahiko Maegawa, Tokushima Prefectural Central Hospital; – Chisato Kiuchi, Kiuchi Ladies Clinic; – Michiko Nonaka, Tottori University Hospital. This study was supported by KAKENHI to N.T. (No. 20249066; Japan Society for the Promotion of Science Grants-in-Aid).
Acknowledgment We thank the staff in the following hospitals and clinics for providing patient information and generous support for our work: – Kaori Koga, Yoko Urata, Miwako Nagai, Gentaro Izumi, Shiro Kozuma, Tokyo University Hospital;
Disclosure Statement The authors declare that they have no conflicts of interest.
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Taniguchi /Harada /Kobayashi /Hayashi / Momoeda /Terakawa
Copyright: S. Karger AG, Basel 2014. Reproduced with the permission of S. Karger AG, Basel. Further reproduction or distribution (electronic or otherwise) is prohibited without permission from the copyright holder.
Received: April 15, 2013 Accepted after revision: November 18, 2013 Published online: February 5, 2014
Clinical Characteristics of Patients in Japan with Ovarian Cancer Presumably Arising from Ovarian Endometrioma Fuminori Taniguchi a Tasuku Harada a Hiroshi Kobayashi b Kunihiko Hayashi c Mikio Momoeda d Naoki Terakawa a a
Department of Obstetrics and Gynecology, Tottori University Faculty of Medicine, Yonago, and b Department of Obstetrics and Gynecology, Nara Medical University, Kashihara, c Department of Laboratory Science and Environment Health Sciences, Gunma University School of Health Sciences, Maebashi, and d Department of Women’s General Medicine, St. Luke General Hospital, Tokyo, Japan
Key Words Malignant transformation · Ovarian endometrioma · Cystectomy · Mural nodule
Abstract Objective: To investigate the clinical features of patients in Japan with malignant transformation of ovarian endometrioma. Patients: Thirty-three patients diagnosed with ovarian cancer presumably arising from endometrioma were recruited retrospectively. These patients had been followed for at least 2 years after the ovarian endometrioma diagnosis, then continued to be followed after they had been found to have malignant transformation. Results: The average age of the patients was 47.7 ± 9.3 years; 75.7% were premenopausal at the time of diagnosis of ovarian cancer. Among the 33 patients, ovarian cancer developed in the ipsilateral ovary of 6 patients with endometrioma after cystectomy. Twenty-eight patients were diagnosed with stage I ovarian cancer, and major histotypes were clear cell in 23 cases and endometrioid in 8. Before surgery for cancer, mural nodules within the endometriomas were detected in 32 patients, and 1 patient had a small 3-mm nodule. In 30 patients, the diameter of the tumor doubled in size 6 months prior to the diagnosis of ma-
© 2014 S. Karger AG, Basel 0378–7346/14/0772–0104$39.50/0 E-Mail [email protected] www.karger.com/goi
lignant transformation. The diameter of the endometrioma and the preoperative CA125 value did not significantly correlate. Conclusions: To detect malignant transformation of ovarian endometrioma early and precisely, the clinician should determine the existence of a mural nodule and assess the rapid growth of the endometrioma. © 2014 S. Karger AG, Basel
Introduction
Endometriosis, which occurs in approximately 10% of women of reproductive age, is defined as the presence of endometrial tissue outside the uterus [1]. Although endometriosis originates as a benign disease, epidemiological studies consistently show that endometriosis is associated with an increased risk of ovarian cancer, the most fatal malignancy of the female reproductive system. The exact rate of malignant transformation of endometriosis is not known because endometriotic lesions, such as the endometrioma, are not always resected and confirmed by pathological diagnosis. However, the evidence that endometriosis represents an important site of origin of epithelial ovarian cancer (EOC), especially clear cell and endoFuminori Taniguchi, MD, PhD Department of Obstetrics and Gynecology Tottori University Faculty of Medicine 36-1 Nishicho, Yonago 683-8504 (Japan) E-Mail tani4327 @ med.tottori-u.ac.jp
metrioid subtypes, is well known [2–4]. Endometriosisassociated EOC tends to be found in the earlier clinical stage. The clinician should therefore be aware of the increased risk of specific subtypes of ovarian cancer in women with endometriosis. Ovarian cancer incidence and mortality rates have increased in recent decades. In Japanese women, approximately 8,000 new cases of EOC are diagnosed each year, and the latest population-based cancer registry shows that the incidence rate of EOC is 8.1 per 100,000 women [5]. The cell origin of ovarian cancer has long been debated. EOC is generally accepted to arise from the ovarian surface epithelium, and it has been argued that the ovarian surface epithelium undergoes ‘metaplasia’ to account for this transformation. Recently, however, Kuhn et al. [6] proposed a new theory of ovarian carcinogenesis suggesting that the fallopian tube epithelium implants on the ovary give rise to both high-grade and low-grade serous carcinomas, and that endometrial tissue becomes implanted on the ovary and produces endometriosis, which can then undergo malignant transformation into endometrioid and clear cell carcinoma (CCC). Crum et al. [7] also described high-grade and serous carcinomas that actually arise from the fimbria of the fallopian tube. According to a cohort study in Japan, approximately 0.72% of patients with endometriosis subsequently developed ovarian cancer. The authors also reported that patients older than 45 with a large endometrioma had a higher incidence of malignant transformation. They further defined premenopausal women with an endometrioma 9 cm or more in diameter as the high-risk group and recommended extensive treatment, including surgical resection [3]. In another retrospective cohort study of 12,193 infertile women, 13 of 45 women with ovarian cancers had been treated for infertility associated with endometriosis. A 2.7-fold higher risk of ovarian cancer among patients with endometriosis compared with those without endometriosis was observed [8]. Recently, a meta-analysis to evaluate the association between endometriosis and histological subtypes of ovarian cancer was conducted. It showed that a history of endometriosis is associated with an increased risk of ovarian cancer, especially among clear cell, invasive low-grade serous and endometrioid subtypes [9]. The detailed characteristics and behavior of malignant transformation of endometriosis are intriguing and still poorly understood. The aim of this study was to investigate the clinical features of patients with ovarian cancer probably arising from ovarian endometrioma. Ovarian Cancer Presumably Arising from Ovarian Endometrioma
Patients and Methods The Institutional Review Board of the Tottori University Faculty of Medicine approved this project. The data were obtained retrospectively from 15 Japanese hospitals. Thirty-three patients diagnosed from 2008 to 2010 with ovarian cancer derived from endometriomas, as confirmed by each hospital’s gynecological pathologist, were enrolled in this study. Gynecologists and radiologists followed these patients for more than 2 years for benign ovarian endometrioma using vaginal ultrasonography (USG) and/or magnetic resonance imaging (MRI). When the diameter of the endometriotic cyst increased 2-fold within 6 months, we considered that rapid development. We also considered the mural nodule to be within the solid part of the endometrioma, using USG and/or MRI. Pathologists confirmed the coexistence of endometriosis and ovarian cancer, although not all data had been examined exhaustively to determine whether they met Sampson’s [10] and Scott’s [11] criteria for ovarian cancer associated with endometriosis. The pathological finding of benign endometriosis contiguous with malignant tissue was confirmed in 60.6% (20 of the 33 patients). No contiguous lesion was found in 15.2% of specimens (5 patients), and that finding was unclear in 24.2% of specimens (8 patients). Nineteen patients received hormonal treatment [GnRH agonist, oral contraceptive, antiestrogenic drug (danazol), and progestin (dienogest)] for endometriosis. These patients were followed for at least 2 years after the diagnosis of endometrioma. After being diagnosed with ovarian cancer, all patients underwent primary debulking surgery and were followed every 1–6 months. All clinical and pathological data were analyzed retrospectively. Statistical Analysis Data are shown as means ± standard deviation. Spearman’s rank correlation coefficient was calculated between the maximum diameter of endometrioma and the value of presurgical CA125. A p value of less than 0.05 was regarded as statistically significant.
Results
The clinical characteristics of the 33 patients with malignant transformation of ovarian endometrioma are summarized in table 1. Ages ranged from 31 to 74 years (47.7 ± 9.3 years), and 25 patients (75.7% of all patients) were premenopausal at the time of diagnosis of ovarian cancer and the debulking surgery. The mean body mass index of patients was 21.3 ± 9.3. Twenty-two patients (69.7%) had regular menstrual cycles, and only 9 patients (27.2%) needed medication for dysmenorrhea. The numbers of past pregnancies and deliveries were 1.3 ± 1.3 and 1.0 ± 1.1, respectively. Fifteen patients (45.4%) had never experienced childbirth. The mean largest diameter of ovarian endometrioma was 8.1 ± 3.2 cm (range: 2.0–20.0 cm), and the preoperative CA125 value was 110.8 ± 156.4 U/ml (range: 10.0–642.0 U/ml). These parameters did not significantly correlate (r = 0.359, p = 0.165). Gynecol Obstet Invest 2014;77:104–110 DOI: 10.1159/000357819
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Table 1. Clinical data for 33 patients with malignant transformation of ovarian endometrioma (numbers with percentages in parentheses) Patients
Age 60 years Body mass index 25 Number of past pregnancies 0 1 2 3 or more Parity (number of births) 0 1 2 3 or more Necessity of medication for dysmenorrhea Yes No Latent period between diagnosis of endometrioma and that of ovarian cancer 15 years Maximum diameter of tumor at diagnosis of malignant transformation 10 cm Preoperative CA125 value 100 U/ml FIGO classification Ia Ic IIc IIIc IV Histological subtypes Clear cell Endometrioid Carcinosarcoma Serous borderline tumor
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5 (15) 17 (52) 9 (27) 2 (6) 12 (36) 17 (52) 4 (12) 13 (39) 7 (21) 6 (18) 7 (21) 15 (45) 8 (24) 6 (18) 4 (12) 9 (27) 24 (73) 3 (9) 8 (24) 12 (36) 9 (27) 1 (3) 2 (6) 12 (36) 11 (33) 8 (24) 17 (52) 6 (18) 10 (30) 5 (15) 23 (70) 2 (6) 2 (6) 1 (3) 23 (70) 8 (24) 1 (3) 1 (3)
Gynecol Obstet Invest 2014;77:104–110 DOI: 10.1159/000357819
At the time of surgery, the mean maximum diameter of cancer tissue was 9.5 ± 4.3 cm (range: 3.5–25.0 cm). Before surgery for ovarian cancer, mural nodules within endometriomas were detected by USG and/or MRI in 32 patients, i.e. all except for 1 case of endometrioma containing a small 3-mm nodule. As shown in table 1, two cases transformed from less than 4-cm endometriomas with a small mural nodule (3 and 17 mm in diameter). All ovarian cancers developed from the ipsilateral endometrioma with no tendency in laterality. Only 1 patient was identified with bilateral ovarian cancer (i.e. CCC). According to the Federation of Gynecology and Obstetrics classification of ovarian cancer, the postoperative stage of the 33 patients was diagnosed as Ia in 5 cases (15.2%), Ic in 23 cases (69.6%), IIc in 2 cases (6.1%), IIIc in 2 cases (6.1%), and IV in 1 case (3.0%). All patients were alive at the end of this survey in 2012. The histotype was clear cell in 23 cases (69.7%), endometrioid in 8 cases (24.2%), carcinosarcoma in 1 case (3.0%), and serous borderline tumor in 1 case (3.0%). Other cancer types (breast and lung cancer), which were not metastatic, occurred in 2 patients. The average latent period from the diagnosis of endometrioma to that of malignant transformation was 8.3 ± 4.6 years (range: 2–17 years). No patient reported a family history of ovarian cancer. Eleven patients younger than 45 years who developed ovarian cancer had a shorter latent period (5.6 ± 7.0 years) compared with those over the age of 45. The latent period was shorter still (4.2 ± 3.1 years) in 5 patients younger than 40 years. Under the age of 45, an estrogen-rich condition and other corresponding factors may contribute to malignant transformation of endometrioma. In table 2, 19 patients diagnosed with ovarian cancer after conservative surgery (i.e. cystectomy, aspiration of cyst fluid or electrocautery of the cyst wall) and/or hormonal treatment for endometriomas are shown. The average age of the patients when the endometriotic cyst was first identified was 38.6 ± 9.2 years. Surgery was performed only when the patient had severe pain and/or the cyst was over 6 cm in diameter. In 6 patients, cancer occurred in the ovary on the same side as a prior cystectomy performed 1–13 years before. The average latent period from the end of treatment for endometrioma to the diagnosis of malignant transformation was 4.5 ± 4.1 years (range: 3 months to 13 years). After aspiration or electrocautery of the endometrioma, ovarian cancers arose in 2 cases. Malignant transformation occurred in 16 patients previously treated with hormonal preparations (5 patients also underwent conservative surgery). The other 14 patients did not receive any treatments before surgery for ovarian cancer. Taniguchi /Harada /Kobayashi /Hayashi / Momoeda /Terakawa
Table 2. Nineteen patients with malignant transformation of endometrioma after conservative surgery and/or hormonal treatment
No.
Age, years
Treatment
Period from the last treatment
After surgery (with or without hormonal treatment) 1 41 Cystectomy 2 48 Cystectomy 3 31 Cystectomy + GnRHa 3 months 4 44 Cystectomy + GnRHa 3 months 5 45 Cystectomy + GnRHa 6 months twice 6 46 GnRHa 2 months + cystectomy + OC 5 months 7 35 Aspiration 8 50 Electrocautery + GnRHa 6 months × 3 times
3 years after surgery 13 years after surgery 1 year 6 months (9 years after surgery) 4 months (12 years after surgery) 3 years 3 months (9 years after surgery) 4 months (1 year after surgery) 1 year 6 months 8 months (17 years after surgery)
After hormonal treatment 9 46 10 48 11 57 12 47 13 59 14 42 15 52 16 53 17 52 18 31 19 43
3 years 6 months 2 years 9 months 6 years 6 months 12 years 13 years 8 years 6 months 2 years 10 months 5 years 2 years 7 months 1 years 2 months 3 months
GnRHa 4 months GnRHa 6 months GnRHa 6 months GnRHa 6 months GnRHa 1 month + DA 6 months GnRHa 6 months + DA 12 months GnRHa 6 months × 3 times GnRHa 6 months × 4 times GnRHa 6 months twice + OC 2 months DNG 12 months DNG 20 months
GnRHa = GnRH agonist; OC = oral contraceptive; DA = danazol; DNG = dienogest.
In the present study, we provide evidence regarding malignant transformation of endometriosis in Japanese women. The noteworthy finding is that ovarian cancer developed in the ipsilateral ovary of 6 of the 33 patients after cystectomy for endometrioma. Epidemiological, histopathological and molecular data suggest that endometriosis does have malignant potential. A stressful microenvironment within the endometrioma, such as hypoxia, poor nutrition or altered immune status, may lead to cancer development. A high iron concentration in the endometrioma is also presumably involved in cancer development [12]. Although there is a multifactorial pathophysiology of carcinogenesis, one of the causes of malignant transformation may be a stressful change of the microenvironment, such as high levels of estrogen and cytokines (interleukin-1, interleukin-6, interleukin-8, tumor necrosis factor-α, and tumor necrosis factor-β) in endometriotic tissues [13–15], and the influence of inflammation accompanying surgery. Sampson [10] first suggested a relationship between endometriosis and ovarian cancer and proposed criteria
for ovarian cancers arising from endometriosis. These criteria include: (1) coexistence of carcinoma and endometriosis in the same ovary; (2) a similar histological relationship, and (3) exclusion of another primary site. Later, Scott [11] redefined the criteria to include more stringent ones, which require the morphological demonstration of benign endometriosis contiguous with malignant tissue. Although a small subset of ovarian cancers fulfill these stringent criteria, the pathological evidence of malignant transformation and the precise incidence of this phenomenon are still difficult to ascertain. Indeed, cases with all the above criteria have rarely been found due to sampling technique and possible destruction of benign tissue by tumor invasion. Atypical endometriosis has been shown to occur in 60–80% of endometriosisassociated ovarian cancer [2, 15]. In this study, the histological findings of atypical endometriosis were seen in approximately 60% of the patients. Results of studies that investigated the synchronous presence of ovarian cancer and endometriosis have consistently shown an increased occurrence of endometriosis in women with endometrioid carcinoma and CCC relative to the other subtypes [16, 17]. In particular, CCC,
Ovarian Cancer Presumably Arising from Ovarian Endometrioma
Gynecol Obstet Invest 2014;77:104–110 DOI: 10.1159/000357819
Discussion
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which accounts for approximately 70% of the 33 patients in this study, is recognized in the World Health Organization classification of ovarian tumors as a distinct histological entity, and its clinical behavior differs from that of other EOCs. CCC accounts for about 4–12% of EOC cases in the USA and, for unknown reasons, more than 20% of those in Japan. Japanese women may exhibit a higher proportion of malignant transformation of endometriosis compared with the US population. CCC of the ovary is generally considered a slow-growing tumor. Several reports have shown that CCC is frequently diagnosed at an early stage, especially at stage Ic. Of the 23 cases of CCC histotype in the present study, 21 patients were diagnosed with stage I. The percentage of patients with stage I was higher in patients with CCC than in those with serous adenocarcinoma, and among those patients, stage Ic was observed in 32.2–38.8% in CCC and in 7.1–9.4% in serous adenocarcinoma [18–20]. Recently, Kawaguchi et al. [21] summarized the clinicopathological features of 18 patients with ovarian cancer associated with endometriosis in the Kinki district of Japan. According to their retrospective study, the values of mean age, body mass index, the number of childbirths, and the mean largest diameters of tumors at presentation of malignant transformation (45.2 years, 20.9 ± 0.6, 1.0 ± 0.2, and 8.5 cm) were similar to our current data. In addition, the ratios of histotypes and clinical stage of their data were consistent with ours. Although the average interval from the initial diagnosis of endometrioma to the malignant transformation was 8.3 ± 4.6 years in our study, in theirs it was 4.5 years (range: 1–16 years). We noted that 10 patients older than 45 had shorter latency intervals (mean: 1.0 year, range: 1–3) than those younger than 45 (mean: 8.4 years, range: 3–16) [21]. As shown in table 1, more than 70% of the 33 patients were diagnosed with malignant transformation within 10 years of followup of their endometriomas. As we described in the Results section, the patients younger than 45 years had a shorter latent period (5.6 ± 7.0 years) until malignant transformation compared with those over the age of 45. In addition, the latent period was shorter still (4.2 ± 3.1 years) in 5 patients younger than 40 years. Moreover, mural nodes inside endometriomas were detected in all cases. These data suggest that clinicians should carefully observe the acute growth and mural nodes of endometriomas, especially in patients younger than 45 years. With regard to the age of patients and the latent period until malignant transformation, there was a discrepancy between the study of Kawaguchi et al. [21] and our own. Resolving this issue only by these two 108
Gynecol Obstet Invest 2014;77:104–110 DOI: 10.1159/000357819
studies is difficult because the number of patients in both studies was insufficient. Our data and theirs showed that ovarian endometrioma might be regarded as a potentially preneoplastic lesion, particularly in pre- and perimenopausal women. This issue should be an area of future exploration for the management of endometriosis. In the current study, the postoperative Federation of Gynecology and Obstetrics stage of nearly 85% of the patients was stage I (Ia: 15.2% and Ic: 69.6%), and the maximum diameter of the endometrioma in 30 patients (90.9%) increased more than 2-fold in 6 months when the malignant transformation was diagnosed. Even when the endometrioma is small, examining for the presence of mural nodules is crucial to diagnosing malignant transformation. Except for 1 patient with a small 3-mm mural nodule that exhibited rapid growth, the existence of mural nodules before surgery for ovarian cancer was recognized in 32 cases. We therefore have to pay attention to the rapid growth of the endometrioma and the existence of mural nodules. Kawaguchi et al. [21] also showed that the levels of CA125 were elevated in 56% of patients with malignant transformation. In the present study, 45.5% of the 33 patients exhibited a more than 2-fold elevation of the CA125 value; however, in 42.4% of the patients, the CA125 value was under 35 U/ml after the malignant transformation, suggesting that the CA125 value is not a critical marker in diagnosing malignant transformation of endometriosis. Only 8 patients (approx. 24.2% of the patients), including 6 patients who had had cystectomy for endometrioma, were surgically diagnosed with benign tumors prior to the malignant transformation (table 2). The current data suggest that cystectomy for endometrioma cannot prevent postoperative ovarian cancer. As for the surgical procedure for endometrioma, Dan and Limin [22] showed the results of a meta-analysis that cystectomy provided better outcomes than fenestration/coagulation or laser ablation regarding the recurrence of symptoms and endometrioma. In the 16 patients in whom cancer emerged after hormonal treatment, shown in table 2, ovarian cancer was not found during medical treatment. These findings suggest that surgical or medical treatment has no effect on the possibility of malignant transformation. It should be considered as an important limitation of the conclusions of this study. In addition, we could not exclude completely that some patients had early cancers since the beginning of the follow-up with USG or MRI. However, in these patients, we could not detect any findings that showed the doubtful sign of neoplastic occurrence during the follow-up periods. Perez-Medina et al. Taniguchi /Harada /Kobayashi /Hayashi / Momoeda /Terakawa
[23] reported the efficacy of 3-dimensional power Doppler angiography for the prediction of malignancy in ovarian tissues. This may be a useful method to detect the malignant change of endometrioma. Recently, Melin et al. [24] reported that one-sided oophorectomy as well as radical extirpation of all visible endometrioses has a strong protective effect against later development of EOC. Based on their data and ours, we recommend salpingo-oophorectomy for patients older than 40 years who do not desire pregnancy and present with symptomatic endometrioma. In summary, to detect malignant transformation of ovarian endometrioma early and precisely, the clinician should ascertain the existence of a mural nodule and assess the rapid growth of the endometrioma. To verify the findings of previous investigations and our own studies and to clarify the biological plausibility of this association, large-scale studies are needed.
– Hiroyuki Ochi, Hiroyuki Yoshikawa, Tsukuba University Hospital; – Takahiro Suzuki, Shun-ichiro Izumi, Mikio Mikami, Tokai University Hospital; – Toshifumi Takahashi, Hirohisa Kurachi, Yamagata University Hospital; – Akira Fujishita, Daisuke Nakayama, Saiseikai Nagasaki Hospital; – Ken-ichi Makino, Yukihiro Terada, Akita University Hospital; – Naoki Yoshino, Osamu Iwanari, Shimane Prefectural Central Hospital; – Kenjiro Date, Chie Koide, Hideki Teramoto, Hiroshima General Hospital of West Japan Railway Company; – Yuichiro Takeuchi, Ayako Miyamoto, Masakuni Takahashi, Mihara Red Cross Hospital; – Mikio Takehara, Masahide Ohmichi, Osaka Medical College Hospital; – Seiji Isonishi, Kanae Sasaki, Jikei Daisan Hospital; – Hideaki Sawai, Hyogo Medical College Hospital; – Masahiko Maegawa, Tokushima Prefectural Central Hospital; – Chisato Kiuchi, Kiuchi Ladies Clinic; – Michiko Nonaka, Tottori University Hospital. This study was supported by KAKENHI to N.T. (No. 20249066; Japan Society for the Promotion of Science Grants-in-Aid).
Acknowledgment We thank the staff in the following hospitals and clinics for providing patient information and generous support for our work: – Kaori Koga, Yoko Urata, Miwako Nagai, Gentaro Izumi, Shiro Kozuma, Tokyo University Hospital;
Disclosure Statement The authors declare that they have no conflicts of interest.
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