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Synchronous primary cancers of the endometrium and ovary Y.-C. CHIANG, C.-A. CHEN, C.-Y. HUANG, C.-Y. HSIEH & W.-F. CHENG Department of Obstetrics and Gynecology, College of Medicine, National Taiwan University, Taipei, Taiwan Abstract. Chiang Y-C, Chen C-A, Huang C-Y, Hsieh C-Y, Cheng W-F. Synchronous primary cancers of the endometrium and ovary. Int J Gynecol Cancer 2008;18:159–164. Simultaneous detection of malignancy in the endom
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  Synchronous primary cancers of the endometriumand ovary Y.-C. CHIANG, C.-A. CHEN, C.-Y. HUANG, C.-Y. HSIEH & W.-F. CHENG Department of Obstetrics and Gynecology, College of Medicine, National Taiwan University, Taipei, Taiwan Abstract.  Chiang Y-C, Chen C-A, Huang C-Y, Hsieh C-Y, Cheng W-F. Synchronous primary cancers of theendometrium and ovary.  Int J Gynecol Cancer  2008; 18: 159–164. Simultaneous detection of malignancy in the endometrium and ovary represents an uncommon event. Theobjective of the study was to clarify the possible factors that influenced on the survival. From 1977 to 2005,totally 27 patients fulfilled the criteria and were included in the study. The medical records and the patho-logic reports were reviewed. The histologic determination was followed by the World Health OrganizationCommittee classification, and cancer stage was based on the staging system of the FIGO. The Kaplan–Meier survival analyses were generated and compared by the log-rank test. The incidence of synchronousprimary endometrial and ovarian cancers was 3.3% in patients with endometrial cancer and 2.7% in patientswith ovarian cancer. The mean survival in the group of similar histology ( n  ¼  15) was 63 months, and 48months in the group of dissimilar histology ( n  ¼  12) ( P   ¼  0.63). The mean survival in the group of earlystage ( n  ¼  21) was 68 months and 15 months in the group of advanced stage ( n  ¼  6) with statistic signifi-cance ( P   ¼  0.0003). However, the impact of adjuvant therapy on survival did not reach statistic significance( P   ¼  0.15 for chemotherapy;  P   ¼  0.69 for radiotherapy). We conclude that the majority of the patients be-longed to concordant endometrioid histology in endometrium and ovary, and it tends to be early stage andlow grade with favorable prognosis. The stage had more significant influence on the survival than the his-tology. Adjuvant therapy should be given especially in patients with advanced stage although the optimalmanagement remained to be determined. KEYWORDS : endometrial cancer, ovarian cancer, synchronous cancers. Simultaneous detection of malignancy in the endome-trium and ovary represent an uncommon event. Itoccurred in 5% of the patients with endometrial cancerand 10% of the patients with ovarian cancer (1) . It ispossible to encounter difficulty in definite diagnosis of simultaneously detected cancers in both endometriumand ovary, which could present one of the three con-ditions: primary endometrial cancer with ovarianmetastasis, primary ovarian cancer with endometrialmetastasis, or synchronous primary endometrial andovarian cancers. However, the differentiation is impor-tant because it would influence on cancer staging,management, and prognosis. Pathologic criteria to dis-tinguish synchronous primary cancers from metastaticlesions were proposed by Ulbright and Roth (2) first,and were revised in more detail by Scully  et al. (3) . Sev-eral authors described methods of molecular analysisin order to differentiate the dilemma of diagnosismore definitely, but there is no consensus about themost appropriate method now. Previous studiespointed out that the prognosis of synchronous pri-mary cancers of the endometrium and ovary is favor-able, especially for early stage and low grade (1,4) . Inthis retrospective study, we reviewed the records of the patients with synchronous primary endometrialand ovarian cancers in past three decades to study thecharacteristics and prognosis of the patients with thisunusual diagnosis. Materials and methods From the National Taiwan University Hospital CancerRegistry database, we retrospectively reviewed themedical records and pathologic reports during the Address correspondence and reprint requests to: Wen-Fang Cheng,MD, PhD, Department of Obstetrics and Gynecology, College of Medicine, National Taiwan University, No. 7, Chung-Shan SouthRoad, Taipei 10016, Taiwan. Email: wenfangcheng@yahoo.comdoi:10.1111/j.1525-1438.2007.00975.x #  2007, Copyright the Authors Journal compilation #  2007, IGCS and ESGO  Int J Gynecol Cancer  2008,  18,  159–164  period from 1977 to 2005. The pathologic specimenswere diagnosed by our pathologists with the patho-logical criteria proposed by Ulbright and Roth (2) andScully  et al. (3) . Totally 27 patients fulfilled the criteria,and they were included in the study. All of these 27patients received management and were followed upat our institution. The basic information including ini-tial presenting symptoms, age at diagnosis, parity,menstrual status, hormone use, medical comorbidities(such as diabetes mellitus or hypertension), and familyhistory of malignancy were collected from medical re-cords. The pathologic findings including histology,grade, invasion of myometrium, lymphovascular per-meation, involvement of lymph nodes, and extrapelvicextension were obtained from pathologic reports. Thehistologic determination followed the World HealthOrganization Committee classification, and cancerstage was based on the staging system of the FIGO.For analysis of possible prognostic factors to overallsurvival, the patients were assigned to subgroups based on the symptoms, the histology, the stage, andthe adjuvant therapy. The data were analyzed by Sta-tistical Package of Social Studies software (SPSS forWindows, version 10.0.7C, SPSS Inc., Chicago, IL). TheKaplan–Meier survival analyses were generated andcompared by the log-rank test. The probability valueof less than 0.05 was defined as statistical significance. Results Totally 844 patients had endometrial cancer and 1004patients had ovarian cancer in our institution duringthe period. Twenty-seven patients fulfilled the patho-logic criteria proposed by Ulbright and Roth (2) andScully  et al. (3) , and they were included in the study. Of these patients enrolled in our studies, the mean age atdiagnosis was 47 years (range: 31–59 years). The inci-dence of synchronous primary endometrial and ovar-ian cancers was 3.3% in patients with endometrialcancer and 2.7% in patients with ovarian cancer. Themean body mass index was 26.5 kg/m 2 (range: 20–33kg/m 2 ). Diabetes mellitus was noted in six patients(22%), and endometriosis was also noted in six pa-tients (22%). Nine patients were nulliparous (33%),and ten patients were menopausal (37%). None hadused hormone agent, such as hormone replacementtherapy or oral pills. The common presenting symp-toms were abnormal uterine bleeding (AUB) (41%),abdominal pain (22%), abdominal fullness (18%), ele-vated CA-125 level (7%), abdominal mass (4%), bodyweight loss (4%), and constipation (4%). The histologyof endometrial cancer consisted of clear cell carcinoma(4%) and endometrioid adenocarcinoma (96%), includ-ing grade 1 (64%), 2 (24%), and 3 (12%). The FIGOstage of the endometrial cancer consists of IA (48%),IB (40%), IIA (4%), IIB (4%), and IIIA (4%). The histol-ogy of ovarian cancer includes endometrioid (58%),clear cell (11%), mixed endometrioid and clear cell(11%), mixed mucinous and endometrioid (4%), se-rous adenocarcinoma (4%), malignant mixed mu¨lleriantumor (4%), Brenner tumor (4%), and granulosa celltumor (4%). The grade of histology included grade 1(62%), 2 (28%), 3 (10%). The FIGO stage of ovariancancer consists of IA (44%), IC (24%), IIA (4%), IIC(8%), IIIA (4%), and IIIC (16%) (Table 1). Fifteen pa-tients (56%) had similar histology in both primaries.However, dissimilar histology was noted in the other12 patients (44%). All of the patients received surgicalintervention (at least hysterectomy and bilateral sal-pingo-oophorectomy). Four patients did not receiveany postoperative adjuvant therapy. Seventeen pa-tients received platin-based adjuvant chemotherapy,and seven patients received adjuvant radiotherapypostoperatively. Two patients received both adjuvantchemotherapy and radiotherapy. Five patients hadrecurrence (18%), including abdomen (three patientswith the mean interval of 15 months), vagina (onepatient with the interval of 10 months), and necklymphadenopathy (one patient with the interval of 3months). One patient died of acute renal failure inpostoperational period, and another patient died of recurrence 8 months after initial treatment. The meanduration of follow-up was 59 months (range: 6–153months). The mean survival was 56 months. The five-year survival rate was about 85%. If dividing to twogroups upon initial presentation of AUB, there were11 patients in the AUB group and 16 patients in thenon-AUB group. The mean survival in the AUB groupwas 60 months, and 54 months in the non-AUB group. Table 1.  FIGO stage of the 27 patients with synchronousendometrial and ovarian cancersEndometrium OvaryStage I 88 (%) 68 (%)A 48 44B 40 0C 0 24Stage II 8 (%) 12 (%)A 4 4B 4 0C — 8Stage III 4 (%) 20 (%)A 4 4B 0 0C 0 16Stage IV 0% 0% 160  Y.-C. Chiang  et al. #  2007 IGCS and ESGO,  International Journal of Gynecological Cancer  18,  159–164  It did not reach statistic significance ( P ¼ 0.90). Classi-fied upon histology on each primary site of malig-nancy, the group of similar histology ( n  ¼  15) meantthe same histology of endometrium and ovary, anddifferent histology in the dissimilar group ( n  ¼  12).The mean survival in the group of similar histologywas 63 months, and 48 months in the group of dissim-ilar histology. It also did not reach statistic significance( P  ¼  0.63). Based upon FIGO stage, the group of advanced stage included stage III/IVendometrial ( n ¼ 1) or ovarian cancer ( n ¼ 5) and stage I/II endometrialor ovarian cancer in the group of early stage ( n  ¼  21).The mean survival in the group of early stage was 68months, and 15 months in the group of advancedstage. Statistic significance was noted ( P  ¼  0.0003,Fig. 1). However, the impact of adjuvant therapy onsurvival did not reach statistic significance ( P  ¼  0.15for chemotherapy, Fig. 2a;  P  ¼  0.69 for radiotherapy,Fig. 2b). The results of survival analysis based onthese factors were summarized in Table 2. Discussion Synchronous primary cancers of the endometrium andovary represent an uncommon event. According toprevious literature, coexistence of carcinoma in endo-metrium and ovary occurred in about 5% of the pa-tients with endometrial cancer and 10% of the patientsof ovarian cancer (1) . In our study, the incidence was3.3% of patients with endometrial cancer and 2.7% of patients with ovarian cancer. Our study was con-ducted in a single institution rather than multicenteranalysis, and we only included cases with confirmeddiagnosis of synchronous tumors and excluded otherconditions such as primary endometrial cancer withovarian metastasis or primary ovarian cancer withendometrial metastasis. It might explain why the inci-dence of synchronous endometrial and ovarian can-cers was lower in our series.Simultaneous detection of malignancy at endome-trium and ovary often challenges the clinicians andpathologists to make correct diagnosis and arrangeappropriate managements. It consists of one of the fol-lowing conditions: primary endometrial cancer withovarian metastasis, primary ovarian cancer with endo-metrial metastasis, or synchronous primary endome-trial and ovarian cancer. If the histology of both sites is Figure 1.  Survival analysis of 27 patients with synchronous endo-metrial and ovarian cancers in stage. Patients with advanced stageshowed significantly poorer overall survival than those with earlystage ( P ¼ 0.0003, log-rank test). Figure 2.  Survival analysis of 27 patients with synchronous endo-metrial and ovarian cancers with adjuvant chemotherapy or radio-therapy. a) Adjuvant chemotherapy. There was no statisticaldifference in the overall survival of patients with or without adju-vant chemotherapy ( P  ¼  0.15, log-rank test). b) Adjuvant radiother-apy. There was no statistical difference in the overall survival of patients with or without adjuvant radiotherapy, either ( P  ¼  0.69,log-rank test). Synchronous cancers with endometrial and ovarian cancers  161 #  2007 IGCS and ESGO,  International Journal of Gynecological Cancer  18,  159–164  dissimilar, the answer is straightforward. However,the problem occurs especially when the histology of  both sites are similar like the 15 patients in our series.According to cancer staging system, it may representmore advanced stage of single cancer, such as stageIIIA endometrial cancer or stage IIA ovarian cancer,in spite of synchronous primary double cancers.The majority of previous reports enrolled patientswith similar histology of malignancy at endometriumand ovary synchronously, especially endometrioidadenocarcinoma.The prognosis of these patients was more favorablethan stage II ovarian cancer or stage III endometrialcancer, and therefore, it seemed to represent anotherentity other than single cancer with metastasis.Ulbright and Roth (2) proposed pathologic criteria fordifferentiation in 1985, including either a multinodularovarian pattern (major criterion) or two or more of thefollowing minor criteria: small (less than 5 cm) ovary(ies), bilateral ovarian involvement, deep myometrialinvasion, vascular invasion, and tubal lumen involve-ment. Scully  et al. (3) further developed the pathologiccriteria in detail to more extensive degree. Severalmethods of molecular analysis had been developed toadd in differentiating synchronous primary tumorsfrom metastatic disease, such as DNA flow cy-tometry (5) , loss of heterozygosity on chromosome (6) ,X-chromosome inactivation (7) , PTEN/MMAC1 (8,9) , beta-catenin (10) , and microsatellite instability (11) . How-ever, the numbers of cases in these studies are small,and there is still no consensus about the most appro-priate method. To date, the majority of publishedstudies like our study depended mainly on morpho-logic pathologic criteria.The pathogenesis of synchronous endometrial andovarian cancer is unclear. The theory of ‘‘secondaryMu¨llerian system’’ proposed that the epithelia of cer-vix, uterus, fallopian tubes, ovaries, and peritonealsurface had shared molecular receptors responding tocarcinogenic stimulus leading to the development of multiple primary malignancies synchronously (12–15) .The hypothesis could provide explanation to synchro-nous malignancies of similar histology. It may not bethe case in synchronous cancers of dissimilar histol-ogy, and there should be another mechanism underly-ing the interesting phenomenon. Further studies areneeded to disclose the possible pathogenesis of syn-chronous endometrial and ovarian cancer.The mean age at diagnosis was 47.2 years in ourseries and comparable to previous reports (1,4) . It isyounger than that of ovarian or endometrial canceroccurring predominantly in women during 60 or 70years. In synchronous endometrial and ovarian prima-ries of endometrioid histology, the age at diagnosistended to be younger. In contrast, the age was older inpatients of dissimilar histology. In the study of Soliman et al. (4) , women with synchronous endometrioid/endometrioid tumors (50-year-old) were younger thanthose with synchronous endometrioid/serous tumors(63-year-old). They thought this difference could indi-cate different pathogenesis in these two groups of pa-tients. In our study, the mean age of diagnosis was 48years in the 15 patients of similar histology. Twelvepatients had dissimilar histology with the mean age of 46.3 years (range: 28–58 years) at diagnosis. It differedfrom previous literature and the exact cause wasunknown. Early presentation of AUB may contributeto the incidental simultaneous ovarian malignancy of dissimilar histology. In addition, limited case numberswith wide age range could also have influence on it.The most common presenting symptoms were AUB(41%), abdominal pain (22%), and abdominal fullness(18%) in our study. Endometrial cancer usually produ-ces early symptoms like AUB even when malignancyis still confined to the uterus. In contrast to vaguesymptoms of ovarian cancer and generally late detec-tion of disease, AUB usually causes these women toseek for help that results in detecting the disease ear-lier. In other words, the silent ovarian malignancy wasdiagnosed earlier due to the symptomatic endometrialmalignancy (15–18) . In our study, there were 11 patientspresenting with AUB. The mean survival in the AUBgroup was 60 months, and 54 months in the non-AUBgroup. The results supported the viewpoint as men-tioned above although it did not reach the statistic sig-nificance ( P  ¼  0.90). It also partially accounts forfavorable prognosis of these patients because of earlydetection and treatment. Table 2.  Survival analysis based on prognostic risk factorsMean survival (months)  P  valueInitial presentation AUB ( n ¼ 11):60 Non-AUB ( n ¼ 16):54 0.90Histology Similar ( n ¼ 15):63 Dissimilar ( n ¼ 12):48 0.63Stage Early ( n ¼ 21):68 Advanced ( n ¼ 6):15 0.0003Adjuvant therapy Chemotherapy ( n ¼ 17):47 No chemotherapy ( n ¼ 10):74 0.15Radiotherapy ( n ¼ 7):63 No radiotherapy ( n ¼ 20):55 0.69 162  Y.-C. Chiang  et al. #  2007 IGCS and ESGO,  International Journal of Gynecological Cancer  18,  159–164
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