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Young patients with endometrial cancer: How many could be eligible for fertility-sparing treatment?
Gynecologic Oncology 114 (2009) 448–451
Contents lists available at ScienceDirect
Gynecologic Oncology j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / y g y n o
Young patients with endometrial cancer: How many could be eligible for fertility-sparing treatment? Isabelle Navarria a,⁎, Massimo Usel b, Elisabetta Rapiti b, Isabelle Neyroud-Caspar b, Marie-Françoise Pelte c, Christine Bouchardy b, Patrick Petignat a a b c
Department of Obstetrics and Gynecology, Surgical Gynecologic Oncology Unit, Geneva University Hospitals, 1211 Geneva 14, Switzerland Geneva Cancer Registry, Institute for Social and Preventive Medicine, Geneva University, Geneva, Switzerland Department of Clinical Pathology, Geneva University Hospitals, Geneva, Switzerland
a r t i c l e
i n f o
Article history: Received 25 March 2009 Available online 27 June 2009 Keywords: Endometrial carcinoma Fertility Young patient
a b s t r a c t Objectives. To assess the characteristics of young women with endometrial carcinoma, and evaluate those potentially eligible for conservative therapy. Methods. We identified women diagnosed with endometrial cancer between 1970 and 2005 at the population-based Geneva Cancer Registry (n = 1365). We classified patients into two age groups (≤45 and N 45 years old). Differences in demographic, tumor, diagnostic and treatment characteristics were tested with chi square. Kaplan–Meier analysis was used to calculate survival from endometrial cancer and the log-rank test to analyze differences in survival between the two groups. Results. The young group comprised 44 (3.2%) women and the old group 1321 (96.8%) women. Synchronous ovarian malignancies were found in six patients (14%) in the young group, compared with 23 (2%) in the old group (P b 0.001). Tumor stage was also different between the two groups, principally because of more stage II among the young (P = 0.012). Histological tumor type, grade and specific endometrial cancer 5-year survival did not significantly differ between the two groups. According to final histopathologic evaluation, eight patients from the young group had FIGO stage IA, grade I disease, i.e. may have been eligible for fertility-sparing treatment, corresponding to an incidence rate of 0.3/100,000. Conclusion. No significant difference regarding tumor characteristics and survival between young and older patients was observed, except stage of disease and rate of synchronous ovarian malignancy. Conservative approach is a meaningful quality of life goal for patients with cancer, but only suitable for a limited number of patients. © 2009 Elsevier Inc. All rights reserved.
Introduction Endometrial carcinoma (EC) is the most common gynecologic malignancy in women with a world-standardized incidence in Switzerland of 18.6/100,000 [1]. In Switzerland EC occurs typically in postmenopausal women with a mean age of 67.7 years [2]. Approximately 20% of women will be diagnosed before menopause, and 5% of them will develop the disease before the age of 40 years [3]. The occurrence of EC at a young age has been associated with prolonged unopposed estrogen exposure, for instance in women suffering from hormone-related disorders, obesity, infertility or polycystic ovary syndrome (PCOS) [4–6]. EC in patients aged less than 45 years may have a more favorable prognosis than in older patients with more frequent well-differentiated tumor and limited myometrial invasion [7–9]. Therefore, many attempts have been made to treat these women conservatively with medical fertility-sparing therapy using progestin. Several publications ⁎ Corresponding author. Fax: +41 22 382 41 86. E-mail address: [email protected] (I. Navarria). 0090-8258/$ – see front matter © 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.ygyno.2009.05.038
based on small numbers of patients have reported encouraging results [10–14]. However, conservative treatment entails the risk of progression. Recently, adverse outcomes in conservatively managed patients have been reported [15]. Also, several studies have pointed out that EC among young patients is not more indolent than in older and presents a higher risk of synchronous malignancies [16–18]. The aims of our study were to compare tumor characteristics and prognosis between women with EC aged 45 years old or less and older women, and estimate how many patients may potentially be eligible for fertility preservation at the time of diagnosis. Materials and methods We used information from the population-based Geneva Cancer Registry to identify all patients with a diagnosis of EC in the canton of Geneva (approximately 435,000 inhabitants) from 1970 to 2005. Patient information is derived from numerous sources: all university and private pathology laboratories, hospitals, private clinics, and private practitioners, and is considered exhaustive, as attested by the low percentage (b2%) of patient cases recorded from death certificates only [19].
I. Navarria et al. / Gynecologic Oncology 114 (2009) 448–451 Table 1 Characteristics of younger women (45 years old or less) with endometrial cancer (n = 44). Variables Median age years (standard deviation) Weight kg (range) BMI (range) Menarche (years) Parity Nulliparous 1P 2P 3P Clinical presentation Abnormal bleeding Abdominal pain Routine control Unknown Method of diagnosis Endometrial biopsy and/or curettage Intraoperative or postoperative detection Material visible through cervical orifice Hysteroscopy Unknown Radiological exam MRI Others (CAT or/and ultrasound)
39.8 (± 4.2) 67.7 (44–119)⁎ 29.2 (19–41)⁎⁎ 13.3 25 (57%) 10 (23%) 7 (16%) 2 (4%) 36 (82%) 4 (9%) 1 (2%) 3 (7%) 32 (73%) 4 (9%) 1 (2%) 3 (7%) 4 (9%) 6 (14%) 4 (7%)
⁎ Data were available for 19 patients. ⁎⁎ Data were available for 14 patients.
Recorded patient information comprises sociodemographic data, diagnostic circumstances and modalities, pathological tumor features, treatment provided during the first 6 months after diagnosis, survival status, cause of death, and second cancer occurrence. In addition to passive follow-up (routine examination of death certificates and hospital records), active follow-up is performed yearly by linking the files of the Cantonal Population Office with the Geneva Cancer Registry database, using personal ID numbers. Between January 1970 and December 2005 we identified 1618 patients with uterine cancer. We excluded patients with uterine sarcomas (n = 128), EC discovered at the time of death (n = 22), and patients with previous or synchronous invasive cancers (except synchronous ovarian cancer) or previous in situ gynecological cancers (n = 103). The study finally included 1365 patients. Two age groups were defined: ≤45 years old (“young group”) and N45 years old (“old group”). For the young group only, additional data such as BMI, parity, symptoms leading to diagnosis, methods of diagnosis, past gynecological history, depth of myometrial invasion, and type of surgery were collected in medical files. Adjuvant treatment was classified as radiotherapy (brachytherapy and/or external radiotherapy) and/or chemotherapy. Histological tumor types were classified into type I (endometrioid) and type II (papillary serous and clear cell carcinomas) EC. Tumor stages were classified according to the 1988 International Federation of Gynecology and Obstetrics (FIGO) staging system. Synchronous ovarian cancers were reported when the pathologic findings favored the criteria codified by Scully et al. [20]. In two cases pathologic specimens were revised to confirm classification and discriminate between ovarian metastasis and ovarian synchronous malignancies. We considered that women might benefit from fertility-sparing treatment if they had type I EC, FIGO stage IA, grade 1. Patients presenting with grade 2 or 3 and/or having myometrial invasion were excluded from conservative management because of the high risk of extrauterine spread of the disease and low response to endocrine therapy. To test differences by stage, tumor grade, histological type and synchronous malignancies among young and old women we used the chi square test in case of categorical variables. Using Kaplan–Meier
449
analysis we calculated disease-specific 5-year survival rates and compared them using the log-rank test. Data were analyzed using SPSS 15 software (SPSS Inc., Chicago, IL, USA) and differences were considered statistically significant if the P value was b0.05. Results A total of 1365 patients were included in the analysis. The young group comprised 44 patients (3.2%), and the old group 1321 patients (96.8%). For the young group, mean age at diagnosis was 39.8 (±standard deviation (SD) 4.2) years and for the old group 67.3 (±SD10.7) years. Incidence of EC was similar in the two groups during the study period. The clinical characteristics of the young group are presented in Table 1. BMI was available for 14 patients and revealed a mean BMI of 29.2 kg/m2 (range 19–41). The following characteristics were noted: 25 (57%) patients were nulliparous, 6 (14%) reported a history of infertility and 4 (9%) had a diagnosis of polycystic ovary syndrome (PCOS). Family history was available for 29 (66%) patients. One patient had a family history consistent with hereditary non-polyposis colon cancer (HNPCC). Abnormal vaginal bleeding was the most common symptom leading to diagnosis (82% of the patients). Diagnosis was confirmed with curettage and/or endometrial biopsy in 32 (73%) patients; 4 (9%) cases were diagnosed in patients having surgery for a presumed benign disease (Table 1). Almost all patients in the young group underwent surgery; most of them (73%) had a hysterectomy and bilateral salpingo-oophorectomy ± lymphadenectomy (Table 2). However, hysterectomy with preservation of one or both ovaries was performed in 25% of these patients. Nearly half of patients in both groups received adjuvant radiotherapy (48% vs. 47%, respectively). No patients had received a fertility-sparing approach. Table 3 reports the tumor characteristics of the two groups. In the young group, nine (20.5%) patients had FIGO IA disease (no myometrial invasion), and 18 (41%) patients had less than 50% myometrial invasion (FIGO IB). Stage distribution was not similar between the two groups, with young women presenting more often with stage II than older women (stage I 69% vs. 76%; stage II 18% vs. 6%; stage III–IV 13% vs. 18%, respectively; P = 0.012). Young patients tended more often to have low grade tumor (71% vs. 57%) compared to the old group, but the difference was not statistically significant (P = 0.24). However, there are missing data, particularly in the old group, probably because 12% of these patients did not undergo surgical staging. More synchronous ovarian malignancies were reported in the young group (14% vs. 2%, P b 0.001). Five percent of patient having 40 years old or less had a coexistent ovarian cancer compared to 23% for those aged between 41 and 45 years old (P = 0.19). In total, six patients (aged ≤45 years old) had a synchronous ovarian cancer, in Table 2 Treatment modalities for young vs. old women with endometrial cancer. Variables
Young (n = 44)
Type of surgical treatment Hysterectomy and BSO (± lymphadenectomy) 32 (73%) Hysterectomy with uni or bilateral ovarian preservation 11 (25%) Surgical treatment (without other precision concerning the type of surgery) No surgical treatment 1 (2%) Adjuvant treatment Radiotherapy 21 (48%) Chemotherapy 1 (2%) Radio- and chemotherapy 1 (2%) Unknown 9 (20%)
Old (n = 1321)
1166 (88%) 155 (12%) 623 (47%) 11 (0.8%) 25 (2%)
Patients were divided into young and old groups (≤ 45 years old or N45 years old, respectively).
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I. Navarria et al. / Gynecologic Oncology 114 (2009) 448–451
Table 3 Endometrial carcinoma characteristics in young vs. old group. Variables Histological type Endometrioid (type I) Sero-papillary or clear cells (type II) Grade Well differentiated Moderately differentiated Poorly differentiated Total Unknown Stage I II III + IV Total Unknown Synchronous ovarian malignancies
Young (n = 44)
Old (n = 1321)
40 (91%) 4 (9%)
1211 (92%) 110 (8%)
0.857
25 (71%) 7 (20%) 3 (9%) 35 (80%) 9 (20%)
511 (57%) 245 (28%) 136 (15%) 892 (68%) 429 (32%)
0.240
809 (76%) 65 (6%) 99 (18%) 1062 (80%) 259 (20%) 23 (2%)
0.012
27 7 5 39 5 6
(69%) (18%) (13%) (89%) (11%) (14%)
P value
b 0.001
Patients were divided into young and old groups (≤ 45 years or N 45 years old, respectively). For statistical purposes missing cases were excluded for P value calculation and stages III and IV were regrouped.
five it was discovered during surgery and for one it was discovered after final pathology analysis (occult cancer). One patient with stage FIGO IA synchronous ovarian malignancy died 11 years after primary surgery because of peritoneal recurrence and one died of another cause. In addition, one patient, who underwent hysterectomy without salpingo-oophorectomy, developed one year after surgery a bilateral ovarian tumor considered to be EC metastatic disease. Median follow-up was 7.4 years. Five-year disease-specific survival was 70% (95% confidence intervals [CI]: 43–97) for the young group and 62% (95% CI: 58–66) in the old group (log-rank test: P = 0.054). Among the young patients, eight (18%) had stage IA and grade 1 disease corresponding to the criteria for putative conservative therapy. Mean age was of 38.3 years (range 34–42) with the following age repartition: two patients aged 34–35 years, three patients aged 36–40 years, and three patients aged 41–42 years. Their mean BMI was 33 kg/m2. Of these patients, three were nulliparous, one was diagnosed with PCOS, and one followed for infertility problems. The 5year survival rate of these patients with stage IA, grade I EC was 100% (median follow-up was 11.7 years). The annual incidence of women with EC aged 20 to 45 years eligible for conservative therapy is 0.3/ 100,000 women. Discussion Standard therapy for EC stage I is surgical staging including total hysterectomy, bilateral salpingo-oophorectomy peritoneal cytology with or without retroperitoneal lymph node dissection. Young patients with EC have generally a good prognosis and tend to have disorders related to exposure of excessive estrogen levels. They develop well-differentiated type I EC that can regress with the use of progestin therapy. A fertility-sparing therapy may be proposed in a well-selected group of women who strongly wish to preserve their fertility. Our aims were to provide data to individualize treatments and to improve the planning and safety of a conservative approach. Furthermore, we aimed to determine in a population-based population the incidence of patients potentially eligible for conservative therapy. In the last years, a substantial proportion of women with welldifferentiated EC have been treated successfully with progestative agents, in the range of 60% to 75% with subsequent successful pregnancy [10–13,21]. Majority of patients were treated with either medroxyprogesterone acetate or megestrol acetate. Dosage and duration of treatment varied among the different studies. In rare cases tamoxifen was added to progestative treatment to promote
induction of progesterone receptor. IUD containing progesterone was also used for some patients during or after systemic progestative treatment [12]. However, despite the achievements of these studies on fertility-sparing treatments, there are no definite treatment guidelines or any evidence-based recommendations and many questions still remain unanswered regarding the selection of patients. Our study is based on final pathologic criteria which are the “gold standard” for the evaluation of grade and endometrial invasion. Preoperative assessment of the histological grade, using endometrial biopsy or curettage has only moderate ability to predict final pathology. Tumor grade at diagnosis matches the tumor grade determined after hysterectomy in 58% of the patients diagnosed with endometrial biopsy, and 77% of the patients diagnosed with dilation and curettage [22]. Depth of myometrial invasion can be estimated with surrogate staging techniques, such as those using MRI. However, MRI has limited sensitivity to differentiate between stage IA and stage IB disease [23]. Therefore it is important, throughout the processes of counseling patients, to inform them about the limited value of the pre-operative exams. In our series, true stage IA, grade I after final pathological analysis was reported in only eight cases. The occurrence of such cases remains quite rare even in young patients. We noticed a difference in the repartition of the stages between the two groups, essentially because more stage II were reported in the young group. Yamazawa et al. also showed statistically significant differences in the distribution of stages between the same two groups (P = 0.009) [24]. In their study, young patients presented more often with early stages which is related to a better disease-free survival for the young group (P = 0.03). However, in other studies there were no differences regarding repartition of the stages [16–18]. With regard to the other main pathological features (histological type and grade) and the 5-year disease-specific survival, no differences were reported in other studies [17,18]. We found 14% of our cohort of women aged 45 years old or younger with EC who had synchronous ovarian malignancy. This is within the range reported by other investigators [4,16,17,25]. Walsh et al. reported that 25% of patients with EC aged 45 years or younger had synchronous ovarian malignancies [25]. Evans-Metcalf et al. found that 11% of patients in the same age group had synchronous ovarian malignancies, compared with only 2% of older patients [17]. Finally, two of 14 patients reported by Randall and Kurman had coexistent ovarian carcinoma found 3 and 6 months after progestin treatment [21]. In general, this phenomenon of synchronously arising malignancies of the female genital tract appears to be more common in young than in older women. Based on our own and published data we would recommend a cautious approach to ovarian preservation in young patients with EC. The high incidence of coexisting malignancy in the ovaries and the young age at diagnosis suggest an increased susceptibility of the reproductive organs to carcinogenic transformation [25]. Our data and the literature review indicate that surgical exploration could be helpful to verify the absence of suspicious macroscopic lesions on the ovaries. Investigators have proposed the use of laparoscopy to rule out adnexal pathology before embarking on conservative hormonal treatment [26]. However, even intraoperative assessment of ovarian pathology is fallible, and two of our patients with benign-appearing ovaries at the time of surgery were found to have tumor in the adnexae on final pathologic examination. The presence of occult malignancy found in grossly normal-appearing ovaries in this population of young women has already been reported by other authors [4,16,17,25]. In the young group, 35 (79%) of the 44 patients were either nulliparous or had one child at the time of surgery. This is below the reported Swiss average of 1.4 children per woman [27]. Published series have also reported that most patients diagnosed with EC were nulliparous and frequently infertile or subfertile probably with underlying hormonal disorders [4,5,17,18,21]. The best candidates for
I. Navarria et al. / Gynecologic Oncology 114 (2009) 448–451
progestin therapy are women who have a relative hyperestrogenic state, which is thought to cause the malignancy. On the other hand, if the reason for the development of EC is secondary to a defect in mismatch repair genes or other tumor suppressor genes, there is no data to suggest that medical treatment (progesterone) will treat the cancer [28]. Therefore, women with Lynch syndrome/hereditary nonpolyposis colorectal cancer (HNPCC) are probably not eligible for a conservative management with preservation of fertility. In these patients, consideration should also be given to removing the ovaries due to their 9–12% risk of ovarian cancer [29]. The principal limitation of our study is its retrospective nature. In addition, it is based on final pathologic criteria which do not allow us to apply eligibility criteria used in practice (evaluation of myometrial invasion and grade), nor does it take into account the patient's desire to have children. Indeed, some patients would not chose fertility-sparing treatment given the lack of data on oncologic safety. Therefore it is impossible to determine retrospectively exactly what percentage of patients would benefit from conservative treatment, and this study is probably an overestimation of patient eligibility. Nevertheless, this study demonstrates that only a limited number of women undergoing surgical treatment did meet the pathologic criteria for a conservative approach. The strength of our study is that it is a population-based analysis, and the methodology employed here provides a useful tool to address current questions surrounding the prevalence and characteristics of a population as it avoids potential selection bias. Moreover, most of the previous studies have been performed with American and Australian patients and few data are available in a European population. In conclusion, cure is undoubtedly the most important end point of cancer treatment. The prognosis of well-differentiated EC without myometrial invasion is excellent, with survival rates of nearly 100% at 5 years. Fertility-sparing treatments are successfully used; however, these treatments can be offered only to a limited number of patients. Conflict of interest statement The authors declare that there are no conflicts of interest.
References [1] www.rgt.ch. [2] NICER. National Institute for Cancer Epidemiology and Registration, U.o.Z.R.c.d.t. [3] Creasman WT, et al. Carcinoma of the corpus uteri. J Epidemiol Biostat 2001;6(1): 47–86. [4] Soliman PT, et al. Risk factors for young premenopausal women with endometrial cancer. Obstet Gynecol 2005;105(3):575–80. [5] Schmeler KM, et al. Endometrial cancer in young, normal-weight women. Gynecol Oncol 2005;99(2):388–92.
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[6] Ota T, et al. Clinicopathologic study of uterine endometrial carcinoma in young women aged 40 years and younger. Int J Gynecol Cancer 2005;15 (4):657–62. [7] Silverberg SG, Makowski EL, Roche WD. Endometrial carcinoma in women under 40 years of age: comparison of cases in oral contraceptive users and non-users. Cancer 1977;39(2):592–8. [8] Crissman JD, et al. Endometrial carcinoma in women 40 years of age or younger. Obstet Gynecol 1981;57(6):699–704. [9] Gallup DG, Stock RJ. Adenocarcinoma of the endometrium in women 40 years of age or younger. Obstet Gynecol 1984;64(3):417–20. [10] Kaku T, et al. Conservative therapy for adenocarcinoma and atypical endometrial hyperplasia of the endometrium in young women: central pathologic review and treatment outcome. Cancer Lett 2001;167(1):39–48. [11] Wang CB, et al. Fertility-preserving treatment in young patients with endometrial adenocarcinoma. Cancer 2002;94(8):2192–8. [12] Gotlieb WH, et al. Outcome of fertility-sparing treatment with progestins in young patients with endometrial cancer. Obstet Gynecol 2003;102(4):718–25. [13] Ramirez PT, et al. Hormonal therapy for the management of grade 1 endometrial adenocarcinoma: a literature review. Gynecol Oncol 2004;95(1):133–8. [14] Ushijima K, et al. Multicenter phase II study of fertility-sparing treatment with medroxyprogesterone acetate for endometrial carcinoma and atypical hyperplasia in young women. J Clin Oncol 2007;25(19):2798–803. [15] Huang SY, et al. Ovarian metastasis in a nulliparous woman with endometrial adenocarcinoma failing conservative hormonal treatment. Gynecol Oncol 2005;97 (2):652–5. [16] Gitsch G, et al. Endometrial cancer in premenopausal women 45 years and younger. Obstet Gynecol 1995;85(4):504–8. [17] Evans-Metcalf ER, et al. Profile of women 45 years of age and younger with endometrial cancer. Obstetrics & Gynecology 1998;91(3):349–54. [18] Tran BN, et al. Characteristics and outcome of endometrial carcinoma patients age 45 years and younger. Am J Clin Oncol 2000;23(5):476–80. [19] Bouchardy C. Switzerland, Geneva. in Parkin DM, Whelan SL, Ferlay J, Teppo L, Thomas DB, editors. Cancer incidence in five continents, Vol. VIII. Lyon: International Agency for Research on Cancer; 2002. IARC Scientific Publications no 155:448–9. [20] Scully R, Young R, Clement P. Tumors of the ovary, maldeveloped gonads, fallopian tube, and broad ligament, Atlas of tumor pathology Bethesda. Washington Armed Forces Institute of Pathology; 1998. [21] Randall TC, Kurman RJ. Progestin treatment of atypical hyperplasia and welldifferentiated carcinoma of the endometrium in women under age 40. Obstet Gynecol 1997;90(3):434–40. [22] Larson DM, et al. Comparison of D&C and office endometrial biopsy in predicting final histopathologic grade in endometrial cancer. Obstetrics & Gynecology 1995;86(1):38–42. [23] Nakao Y, et al. MR imaging in endometrial carcinoma as a diagnostic tool for the absence of myometrial invasion. Gynecol Oncol 2006;102(2):343–7. [24] Yamazawa K, et al. Prognostic factors in young women with endometrial carcinoma: a report of 20 cases and review of literature. Int J Gynecol Cancer 2000;10(3):212–22. [25] Walsh C, et al. Coexisting ovarian malignancy in young women with endometrial cancer. Obstet Gynecol 2005;106(4):693–9. [26] Morice P, et al. A need for laparoscopic evaluation of patients with endometrial carcinoma selected for conservative treatment. Gynecol Oncol 2005;96(1):245–8. [27] www.bfs.admin.ch. [28] Goodman A. Endometrial cancer with concurrent ovarian malignancy: assessing the risks. Obstet Gynecol 2005;106(4):680–1. [29] Aarnio M, et al. Lifetime risk of different cancers in hereditary non-polyposis colorectal cancer (HNPCC) syndrome. Int J Cancer 1995;64:430.
Contents lists available at ScienceDirect
Gynecologic Oncology j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / y g y n o
Young patients with endometrial cancer: How many could be eligible for fertility-sparing treatment? Isabelle Navarria a,⁎, Massimo Usel b, Elisabetta Rapiti b, Isabelle Neyroud-Caspar b, Marie-Françoise Pelte c, Christine Bouchardy b, Patrick Petignat a a b c
Department of Obstetrics and Gynecology, Surgical Gynecologic Oncology Unit, Geneva University Hospitals, 1211 Geneva 14, Switzerland Geneva Cancer Registry, Institute for Social and Preventive Medicine, Geneva University, Geneva, Switzerland Department of Clinical Pathology, Geneva University Hospitals, Geneva, Switzerland
a r t i c l e
i n f o
Article history: Received 25 March 2009 Available online 27 June 2009 Keywords: Endometrial carcinoma Fertility Young patient
a b s t r a c t Objectives. To assess the characteristics of young women with endometrial carcinoma, and evaluate those potentially eligible for conservative therapy. Methods. We identified women diagnosed with endometrial cancer between 1970 and 2005 at the population-based Geneva Cancer Registry (n = 1365). We classified patients into two age groups (≤45 and N 45 years old). Differences in demographic, tumor, diagnostic and treatment characteristics were tested with chi square. Kaplan–Meier analysis was used to calculate survival from endometrial cancer and the log-rank test to analyze differences in survival between the two groups. Results. The young group comprised 44 (3.2%) women and the old group 1321 (96.8%) women. Synchronous ovarian malignancies were found in six patients (14%) in the young group, compared with 23 (2%) in the old group (P b 0.001). Tumor stage was also different between the two groups, principally because of more stage II among the young (P = 0.012). Histological tumor type, grade and specific endometrial cancer 5-year survival did not significantly differ between the two groups. According to final histopathologic evaluation, eight patients from the young group had FIGO stage IA, grade I disease, i.e. may have been eligible for fertility-sparing treatment, corresponding to an incidence rate of 0.3/100,000. Conclusion. No significant difference regarding tumor characteristics and survival between young and older patients was observed, except stage of disease and rate of synchronous ovarian malignancy. Conservative approach is a meaningful quality of life goal for patients with cancer, but only suitable for a limited number of patients. © 2009 Elsevier Inc. All rights reserved.
Introduction Endometrial carcinoma (EC) is the most common gynecologic malignancy in women with a world-standardized incidence in Switzerland of 18.6/100,000 [1]. In Switzerland EC occurs typically in postmenopausal women with a mean age of 67.7 years [2]. Approximately 20% of women will be diagnosed before menopause, and 5% of them will develop the disease before the age of 40 years [3]. The occurrence of EC at a young age has been associated with prolonged unopposed estrogen exposure, for instance in women suffering from hormone-related disorders, obesity, infertility or polycystic ovary syndrome (PCOS) [4–6]. EC in patients aged less than 45 years may have a more favorable prognosis than in older patients with more frequent well-differentiated tumor and limited myometrial invasion [7–9]. Therefore, many attempts have been made to treat these women conservatively with medical fertility-sparing therapy using progestin. Several publications ⁎ Corresponding author. Fax: +41 22 382 41 86. E-mail address: [email protected] (I. Navarria). 0090-8258/$ – see front matter © 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.ygyno.2009.05.038
based on small numbers of patients have reported encouraging results [10–14]. However, conservative treatment entails the risk of progression. Recently, adverse outcomes in conservatively managed patients have been reported [15]. Also, several studies have pointed out that EC among young patients is not more indolent than in older and presents a higher risk of synchronous malignancies [16–18]. The aims of our study were to compare tumor characteristics and prognosis between women with EC aged 45 years old or less and older women, and estimate how many patients may potentially be eligible for fertility preservation at the time of diagnosis. Materials and methods We used information from the population-based Geneva Cancer Registry to identify all patients with a diagnosis of EC in the canton of Geneva (approximately 435,000 inhabitants) from 1970 to 2005. Patient information is derived from numerous sources: all university and private pathology laboratories, hospitals, private clinics, and private practitioners, and is considered exhaustive, as attested by the low percentage (b2%) of patient cases recorded from death certificates only [19].
I. Navarria et al. / Gynecologic Oncology 114 (2009) 448–451 Table 1 Characteristics of younger women (45 years old or less) with endometrial cancer (n = 44). Variables Median age years (standard deviation) Weight kg (range) BMI (range) Menarche (years) Parity Nulliparous 1P 2P 3P Clinical presentation Abnormal bleeding Abdominal pain Routine control Unknown Method of diagnosis Endometrial biopsy and/or curettage Intraoperative or postoperative detection Material visible through cervical orifice Hysteroscopy Unknown Radiological exam MRI Others (CAT or/and ultrasound)
39.8 (± 4.2) 67.7 (44–119)⁎ 29.2 (19–41)⁎⁎ 13.3 25 (57%) 10 (23%) 7 (16%) 2 (4%) 36 (82%) 4 (9%) 1 (2%) 3 (7%) 32 (73%) 4 (9%) 1 (2%) 3 (7%) 4 (9%) 6 (14%) 4 (7%)
⁎ Data were available for 19 patients. ⁎⁎ Data were available for 14 patients.
Recorded patient information comprises sociodemographic data, diagnostic circumstances and modalities, pathological tumor features, treatment provided during the first 6 months after diagnosis, survival status, cause of death, and second cancer occurrence. In addition to passive follow-up (routine examination of death certificates and hospital records), active follow-up is performed yearly by linking the files of the Cantonal Population Office with the Geneva Cancer Registry database, using personal ID numbers. Between January 1970 and December 2005 we identified 1618 patients with uterine cancer. We excluded patients with uterine sarcomas (n = 128), EC discovered at the time of death (n = 22), and patients with previous or synchronous invasive cancers (except synchronous ovarian cancer) or previous in situ gynecological cancers (n = 103). The study finally included 1365 patients. Two age groups were defined: ≤45 years old (“young group”) and N45 years old (“old group”). For the young group only, additional data such as BMI, parity, symptoms leading to diagnosis, methods of diagnosis, past gynecological history, depth of myometrial invasion, and type of surgery were collected in medical files. Adjuvant treatment was classified as radiotherapy (brachytherapy and/or external radiotherapy) and/or chemotherapy. Histological tumor types were classified into type I (endometrioid) and type II (papillary serous and clear cell carcinomas) EC. Tumor stages were classified according to the 1988 International Federation of Gynecology and Obstetrics (FIGO) staging system. Synchronous ovarian cancers were reported when the pathologic findings favored the criteria codified by Scully et al. [20]. In two cases pathologic specimens were revised to confirm classification and discriminate between ovarian metastasis and ovarian synchronous malignancies. We considered that women might benefit from fertility-sparing treatment if they had type I EC, FIGO stage IA, grade 1. Patients presenting with grade 2 or 3 and/or having myometrial invasion were excluded from conservative management because of the high risk of extrauterine spread of the disease and low response to endocrine therapy. To test differences by stage, tumor grade, histological type and synchronous malignancies among young and old women we used the chi square test in case of categorical variables. Using Kaplan–Meier
449
analysis we calculated disease-specific 5-year survival rates and compared them using the log-rank test. Data were analyzed using SPSS 15 software (SPSS Inc., Chicago, IL, USA) and differences were considered statistically significant if the P value was b0.05. Results A total of 1365 patients were included in the analysis. The young group comprised 44 patients (3.2%), and the old group 1321 patients (96.8%). For the young group, mean age at diagnosis was 39.8 (±standard deviation (SD) 4.2) years and for the old group 67.3 (±SD10.7) years. Incidence of EC was similar in the two groups during the study period. The clinical characteristics of the young group are presented in Table 1. BMI was available for 14 patients and revealed a mean BMI of 29.2 kg/m2 (range 19–41). The following characteristics were noted: 25 (57%) patients were nulliparous, 6 (14%) reported a history of infertility and 4 (9%) had a diagnosis of polycystic ovary syndrome (PCOS). Family history was available for 29 (66%) patients. One patient had a family history consistent with hereditary non-polyposis colon cancer (HNPCC). Abnormal vaginal bleeding was the most common symptom leading to diagnosis (82% of the patients). Diagnosis was confirmed with curettage and/or endometrial biopsy in 32 (73%) patients; 4 (9%) cases were diagnosed in patients having surgery for a presumed benign disease (Table 1). Almost all patients in the young group underwent surgery; most of them (73%) had a hysterectomy and bilateral salpingo-oophorectomy ± lymphadenectomy (Table 2). However, hysterectomy with preservation of one or both ovaries was performed in 25% of these patients. Nearly half of patients in both groups received adjuvant radiotherapy (48% vs. 47%, respectively). No patients had received a fertility-sparing approach. Table 3 reports the tumor characteristics of the two groups. In the young group, nine (20.5%) patients had FIGO IA disease (no myometrial invasion), and 18 (41%) patients had less than 50% myometrial invasion (FIGO IB). Stage distribution was not similar between the two groups, with young women presenting more often with stage II than older women (stage I 69% vs. 76%; stage II 18% vs. 6%; stage III–IV 13% vs. 18%, respectively; P = 0.012). Young patients tended more often to have low grade tumor (71% vs. 57%) compared to the old group, but the difference was not statistically significant (P = 0.24). However, there are missing data, particularly in the old group, probably because 12% of these patients did not undergo surgical staging. More synchronous ovarian malignancies were reported in the young group (14% vs. 2%, P b 0.001). Five percent of patient having 40 years old or less had a coexistent ovarian cancer compared to 23% for those aged between 41 and 45 years old (P = 0.19). In total, six patients (aged ≤45 years old) had a synchronous ovarian cancer, in Table 2 Treatment modalities for young vs. old women with endometrial cancer. Variables
Young (n = 44)
Type of surgical treatment Hysterectomy and BSO (± lymphadenectomy) 32 (73%) Hysterectomy with uni or bilateral ovarian preservation 11 (25%) Surgical treatment (without other precision concerning the type of surgery) No surgical treatment 1 (2%) Adjuvant treatment Radiotherapy 21 (48%) Chemotherapy 1 (2%) Radio- and chemotherapy 1 (2%) Unknown 9 (20%)
Old (n = 1321)
1166 (88%) 155 (12%) 623 (47%) 11 (0.8%) 25 (2%)
Patients were divided into young and old groups (≤ 45 years old or N45 years old, respectively).
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Table 3 Endometrial carcinoma characteristics in young vs. old group. Variables Histological type Endometrioid (type I) Sero-papillary or clear cells (type II) Grade Well differentiated Moderately differentiated Poorly differentiated Total Unknown Stage I II III + IV Total Unknown Synchronous ovarian malignancies
Young (n = 44)
Old (n = 1321)
40 (91%) 4 (9%)
1211 (92%) 110 (8%)
0.857
25 (71%) 7 (20%) 3 (9%) 35 (80%) 9 (20%)
511 (57%) 245 (28%) 136 (15%) 892 (68%) 429 (32%)
0.240
809 (76%) 65 (6%) 99 (18%) 1062 (80%) 259 (20%) 23 (2%)
0.012
27 7 5 39 5 6
(69%) (18%) (13%) (89%) (11%) (14%)
P value
b 0.001
Patients were divided into young and old groups (≤ 45 years or N 45 years old, respectively). For statistical purposes missing cases were excluded for P value calculation and stages III and IV were regrouped.
five it was discovered during surgery and for one it was discovered after final pathology analysis (occult cancer). One patient with stage FIGO IA synchronous ovarian malignancy died 11 years after primary surgery because of peritoneal recurrence and one died of another cause. In addition, one patient, who underwent hysterectomy without salpingo-oophorectomy, developed one year after surgery a bilateral ovarian tumor considered to be EC metastatic disease. Median follow-up was 7.4 years. Five-year disease-specific survival was 70% (95% confidence intervals [CI]: 43–97) for the young group and 62% (95% CI: 58–66) in the old group (log-rank test: P = 0.054). Among the young patients, eight (18%) had stage IA and grade 1 disease corresponding to the criteria for putative conservative therapy. Mean age was of 38.3 years (range 34–42) with the following age repartition: two patients aged 34–35 years, three patients aged 36–40 years, and three patients aged 41–42 years. Their mean BMI was 33 kg/m2. Of these patients, three were nulliparous, one was diagnosed with PCOS, and one followed for infertility problems. The 5year survival rate of these patients with stage IA, grade I EC was 100% (median follow-up was 11.7 years). The annual incidence of women with EC aged 20 to 45 years eligible for conservative therapy is 0.3/ 100,000 women. Discussion Standard therapy for EC stage I is surgical staging including total hysterectomy, bilateral salpingo-oophorectomy peritoneal cytology with or without retroperitoneal lymph node dissection. Young patients with EC have generally a good prognosis and tend to have disorders related to exposure of excessive estrogen levels. They develop well-differentiated type I EC that can regress with the use of progestin therapy. A fertility-sparing therapy may be proposed in a well-selected group of women who strongly wish to preserve their fertility. Our aims were to provide data to individualize treatments and to improve the planning and safety of a conservative approach. Furthermore, we aimed to determine in a population-based population the incidence of patients potentially eligible for conservative therapy. In the last years, a substantial proportion of women with welldifferentiated EC have been treated successfully with progestative agents, in the range of 60% to 75% with subsequent successful pregnancy [10–13,21]. Majority of patients were treated with either medroxyprogesterone acetate or megestrol acetate. Dosage and duration of treatment varied among the different studies. In rare cases tamoxifen was added to progestative treatment to promote
induction of progesterone receptor. IUD containing progesterone was also used for some patients during or after systemic progestative treatment [12]. However, despite the achievements of these studies on fertility-sparing treatments, there are no definite treatment guidelines or any evidence-based recommendations and many questions still remain unanswered regarding the selection of patients. Our study is based on final pathologic criteria which are the “gold standard” for the evaluation of grade and endometrial invasion. Preoperative assessment of the histological grade, using endometrial biopsy or curettage has only moderate ability to predict final pathology. Tumor grade at diagnosis matches the tumor grade determined after hysterectomy in 58% of the patients diagnosed with endometrial biopsy, and 77% of the patients diagnosed with dilation and curettage [22]. Depth of myometrial invasion can be estimated with surrogate staging techniques, such as those using MRI. However, MRI has limited sensitivity to differentiate between stage IA and stage IB disease [23]. Therefore it is important, throughout the processes of counseling patients, to inform them about the limited value of the pre-operative exams. In our series, true stage IA, grade I after final pathological analysis was reported in only eight cases. The occurrence of such cases remains quite rare even in young patients. We noticed a difference in the repartition of the stages between the two groups, essentially because more stage II were reported in the young group. Yamazawa et al. also showed statistically significant differences in the distribution of stages between the same two groups (P = 0.009) [24]. In their study, young patients presented more often with early stages which is related to a better disease-free survival for the young group (P = 0.03). However, in other studies there were no differences regarding repartition of the stages [16–18]. With regard to the other main pathological features (histological type and grade) and the 5-year disease-specific survival, no differences were reported in other studies [17,18]. We found 14% of our cohort of women aged 45 years old or younger with EC who had synchronous ovarian malignancy. This is within the range reported by other investigators [4,16,17,25]. Walsh et al. reported that 25% of patients with EC aged 45 years or younger had synchronous ovarian malignancies [25]. Evans-Metcalf et al. found that 11% of patients in the same age group had synchronous ovarian malignancies, compared with only 2% of older patients [17]. Finally, two of 14 patients reported by Randall and Kurman had coexistent ovarian carcinoma found 3 and 6 months after progestin treatment [21]. In general, this phenomenon of synchronously arising malignancies of the female genital tract appears to be more common in young than in older women. Based on our own and published data we would recommend a cautious approach to ovarian preservation in young patients with EC. The high incidence of coexisting malignancy in the ovaries and the young age at diagnosis suggest an increased susceptibility of the reproductive organs to carcinogenic transformation [25]. Our data and the literature review indicate that surgical exploration could be helpful to verify the absence of suspicious macroscopic lesions on the ovaries. Investigators have proposed the use of laparoscopy to rule out adnexal pathology before embarking on conservative hormonal treatment [26]. However, even intraoperative assessment of ovarian pathology is fallible, and two of our patients with benign-appearing ovaries at the time of surgery were found to have tumor in the adnexae on final pathologic examination. The presence of occult malignancy found in grossly normal-appearing ovaries in this population of young women has already been reported by other authors [4,16,17,25]. In the young group, 35 (79%) of the 44 patients were either nulliparous or had one child at the time of surgery. This is below the reported Swiss average of 1.4 children per woman [27]. Published series have also reported that most patients diagnosed with EC were nulliparous and frequently infertile or subfertile probably with underlying hormonal disorders [4,5,17,18,21]. The best candidates for
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progestin therapy are women who have a relative hyperestrogenic state, which is thought to cause the malignancy. On the other hand, if the reason for the development of EC is secondary to a defect in mismatch repair genes or other tumor suppressor genes, there is no data to suggest that medical treatment (progesterone) will treat the cancer [28]. Therefore, women with Lynch syndrome/hereditary nonpolyposis colorectal cancer (HNPCC) are probably not eligible for a conservative management with preservation of fertility. In these patients, consideration should also be given to removing the ovaries due to their 9–12% risk of ovarian cancer [29]. The principal limitation of our study is its retrospective nature. In addition, it is based on final pathologic criteria which do not allow us to apply eligibility criteria used in practice (evaluation of myometrial invasion and grade), nor does it take into account the patient's desire to have children. Indeed, some patients would not chose fertility-sparing treatment given the lack of data on oncologic safety. Therefore it is impossible to determine retrospectively exactly what percentage of patients would benefit from conservative treatment, and this study is probably an overestimation of patient eligibility. Nevertheless, this study demonstrates that only a limited number of women undergoing surgical treatment did meet the pathologic criteria for a conservative approach. The strength of our study is that it is a population-based analysis, and the methodology employed here provides a useful tool to address current questions surrounding the prevalence and characteristics of a population as it avoids potential selection bias. Moreover, most of the previous studies have been performed with American and Australian patients and few data are available in a European population. In conclusion, cure is undoubtedly the most important end point of cancer treatment. The prognosis of well-differentiated EC without myometrial invasion is excellent, with survival rates of nearly 100% at 5 years. Fertility-sparing treatments are successfully used; however, these treatments can be offered only to a limited number of patients. Conflict of interest statement The authors declare that there are no conflicts of interest.
References [1] www.rgt.ch. [2] NICER. National Institute for Cancer Epidemiology and Registration, U.o.Z.R.c.d.t. [3] Creasman WT, et al. Carcinoma of the corpus uteri. J Epidemiol Biostat 2001;6(1): 47–86. [4] Soliman PT, et al. Risk factors for young premenopausal women with endometrial cancer. Obstet Gynecol 2005;105(3):575–80. [5] Schmeler KM, et al. Endometrial cancer in young, normal-weight women. Gynecol Oncol 2005;99(2):388–92.
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[6] Ota T, et al. Clinicopathologic study of uterine endometrial carcinoma in young women aged 40 years and younger. Int J Gynecol Cancer 2005;15 (4):657–62. [7] Silverberg SG, Makowski EL, Roche WD. Endometrial carcinoma in women under 40 years of age: comparison of cases in oral contraceptive users and non-users. Cancer 1977;39(2):592–8. [8] Crissman JD, et al. Endometrial carcinoma in women 40 years of age or younger. Obstet Gynecol 1981;57(6):699–704. [9] Gallup DG, Stock RJ. Adenocarcinoma of the endometrium in women 40 years of age or younger. Obstet Gynecol 1984;64(3):417–20. [10] Kaku T, et al. Conservative therapy for adenocarcinoma and atypical endometrial hyperplasia of the endometrium in young women: central pathologic review and treatment outcome. Cancer Lett 2001;167(1):39–48. [11] Wang CB, et al. Fertility-preserving treatment in young patients with endometrial adenocarcinoma. Cancer 2002;94(8):2192–8. [12] Gotlieb WH, et al. Outcome of fertility-sparing treatment with progestins in young patients with endometrial cancer. Obstet Gynecol 2003;102(4):718–25. [13] Ramirez PT, et al. Hormonal therapy for the management of grade 1 endometrial adenocarcinoma: a literature review. Gynecol Oncol 2004;95(1):133–8. [14] Ushijima K, et al. Multicenter phase II study of fertility-sparing treatment with medroxyprogesterone acetate for endometrial carcinoma and atypical hyperplasia in young women. J Clin Oncol 2007;25(19):2798–803. [15] Huang SY, et al. Ovarian metastasis in a nulliparous woman with endometrial adenocarcinoma failing conservative hormonal treatment. Gynecol Oncol 2005;97 (2):652–5. [16] Gitsch G, et al. Endometrial cancer in premenopausal women 45 years and younger. Obstet Gynecol 1995;85(4):504–8. [17] Evans-Metcalf ER, et al. Profile of women 45 years of age and younger with endometrial cancer. Obstetrics & Gynecology 1998;91(3):349–54. [18] Tran BN, et al. Characteristics and outcome of endometrial carcinoma patients age 45 years and younger. Am J Clin Oncol 2000;23(5):476–80. [19] Bouchardy C. Switzerland, Geneva. in Parkin DM, Whelan SL, Ferlay J, Teppo L, Thomas DB, editors. Cancer incidence in five continents, Vol. VIII. Lyon: International Agency for Research on Cancer; 2002. IARC Scientific Publications no 155:448–9. [20] Scully R, Young R, Clement P. Tumors of the ovary, maldeveloped gonads, fallopian tube, and broad ligament, Atlas of tumor pathology Bethesda. Washington Armed Forces Institute of Pathology; 1998. [21] Randall TC, Kurman RJ. Progestin treatment of atypical hyperplasia and welldifferentiated carcinoma of the endometrium in women under age 40. Obstet Gynecol 1997;90(3):434–40. [22] Larson DM, et al. Comparison of D&C and office endometrial biopsy in predicting final histopathologic grade in endometrial cancer. Obstetrics & Gynecology 1995;86(1):38–42. [23] Nakao Y, et al. MR imaging in endometrial carcinoma as a diagnostic tool for the absence of myometrial invasion. Gynecol Oncol 2006;102(2):343–7. [24] Yamazawa K, et al. Prognostic factors in young women with endometrial carcinoma: a report of 20 cases and review of literature. Int J Gynecol Cancer 2000;10(3):212–22. [25] Walsh C, et al. Coexisting ovarian malignancy in young women with endometrial cancer. Obstet Gynecol 2005;106(4):693–9. [26] Morice P, et al. A need for laparoscopic evaluation of patients with endometrial carcinoma selected for conservative treatment. Gynecol Oncol 2005;96(1):245–8. [27] www.bfs.admin.ch. [28] Goodman A. Endometrial cancer with concurrent ovarian malignancy: assessing the risks. Obstet Gynecol 2005;106(4):680–1. [29] Aarnio M, et al. Lifetime risk of different cancers in hereditary non-polyposis colorectal cancer (HNPCC) syndrome. Int J Cancer 1995;64:430.