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Survival outcome in endometrial cancer patients according to hereditary predisposition
Taiwanese Journal of Obstetrics & Gynecology 54 (2015) 24e28
Contents lists available at ScienceDirect
Taiwanese Journal of Obstetrics & Gynecology journal homepage: www.tjog-online.com
Original Article
Survival outcome in endometrial cancer patients according to hereditary predisposition Heon Jong Yoo a, b, Myong Cheol Lim a, c, *, Yedong Son a, d, Sang-Soo Seo a, Sokbom Kang a, c, Sun Ho Kim a, Chong Woo Yoo a, Sang-Yoon Park a, c a
Center for Uterine Cancer, Research Institute and Hospital, National Cancer Center, Goyang-si, South Korea Department of Obstetrics and Gynecology, Chungnam National University Hospital, Daejeon, South Korea Gynecologic Cancer Branch, Research Institute and Hospital, National Cancer Center, Goyang-si, South Korea d Red Cross College of Nursing, Chung-Ang University, Seoul, South Korea b c
a r t i c l e i n f o
a b s t r a c t
Article history: Accepted 30 June 2014
Objective: A familial history of ovarian cancer/breast cancer is considered a significant prognostic factor for ovarian cancer. We investigated hereditary factors by examining the incidence of synchronous malignancy in patients with endometrial cancer, and assessed the prognostic role of heredity in endometrial cancer. Methods: We retrospectively evaluated patients with endometrial cancer who underwent surgery from January 2001 to April 2011. A hereditary background in this study was defined as double primary cancer, that is, endometrial cancer accompanied by colon, ovarian, or breast cancer suggestive of Lynch syndrome, hereditary breast ovarian cancer syndrome, or Cowden syndrome, respectively. Results: Among 282 patients with endometrial cancer in the study population, 20 patients (7.1%) had a hereditary predisposition: 10 patients (3.5%) had ovarian cancer, six patients (2.1%) had breast cancer, and four patients (1.4%) had colon cancer. Age and lower uterine segment involvement were not statistically different between the hereditary and nonhereditary groups. The majority of the women in the hereditary group presented with Stage I cancer; however, there were no significant differences in Stage I cancer between the hereditary group and the sporadic endometrial cancer group (85% and 77%, respectively, p ¼ 0.561). The median follow-up period was 60 months. A 5-year overall survival rate was not different between the two groups (95% and 95%, respectively, p ¼ 0.659). Among a subgroup of patients with Stage I endometrial cancer, the 5-year overall survival rate was lower in the endometrial cancer with a hereditary predisposition group compared with the sporadic endometrial cancer group (94% and 98%, respectively, p ¼ 0.027). Conclusion: Seven percent of the women with endometrial cancer in our study had other malignancies such as ovarian, colon, or breast cancer synchronously. Among a subgroup of patients with Stage I cancer in the endometrial cancer with a hereditary predisposition group, the 5-year overall survival rate was significantly lower (94%). This finding should be confirmed in a larger population. Copyright © 2014, Taiwan Association of Obstetrics & Gynecology. Published by Elsevier Taiwan LLC. All rights reserved.
Keywords: endometrial cancer hereditary predisposition survival outcome
Introduction The incidence of endometrial cancer has been increasing over the past decade in Korea [1e3]. Among the many risk factors for
* Corresponding author. Center for Uterine Cancer, Research Institute and Hospital, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang-si, Gyeonggi-do, 410-769, South Korea. E-mail address: [email protected] (M.C. Lim).
endometrial cancer, including obesity, diabetes, late menopause, unopposed estrogen therapy, and nulliparity [4], inherited factors have also been suggested as important risk factors [5]. The occurrence of synchronous cancers is relatively uncommon, but it is important to detect them in clinical practice because a diagnosis of synchronous malignancy in the later stages affects clinical management and prognosis. In particular, double primary cancer with endometrial cancer is strongly associated with hereditary factors; for example, colon cancer and endometrial cancer, suggestive of Lynch syndrome [5], ovarian cancer and endometrial
http://dx.doi.org/10.1016/j.tjog.2014.11.003 1028-4559/Copyright © 2014, Taiwan Association of Obstetrics & Gynecology. Published by Elsevier Taiwan LLC. All rights reserved.
H.J. Yoo et al. / Taiwanese Journal of Obstetrics & Gynecology 54 (2015) 24e28
cancer, suggestive of Lynch syndrome and/or hereditary breast ovarian cancer syndrome [6], and breast cancer and endometrial cancer, suggestive of Cowden syndrome [7]. A familial history of ovarian cancer/breast cancer is considered a strong prognostic factor for ovarian cancer, and this might be explained by BRCAness [8]. However, double primary cancer with endometrial cancer has not been well studied previously. Therefore, we investigated the prognostic role of heredity in endometrial cancer, a potentially autosomal dominant disease. Materials and methods A total of 282 patients were diagnosed with endometrial cancer by pathologic examination at the Department of Uterine Cancer at the National Cancer Center Korea between January 2000 and April 2011. This retrospective study was approved by the Institutional Review Board of the National Cancer Center (NCCNCS-12-597). A hereditary background in this study was defined as the existence of a primary cancer concurrent with endometrial cancer, that is, colon cancer and endometrial cancer, suggestive of Lynch syndrome, ovarian cancer and endometrial cancer, suggestive of Lynch syndrome and/or hereditary breast ovarian cancer syndrome, and breast cancer and endometrial cancer, suggestive of Cowden syndrome. The clinicopathological factors analyzed were age at the time of diagnosis, body mass index (BMI), parity, menstrual history, history of diabetes, tumor histology, tumor grade, the International Federation of Gynecology and Obstetrics stage, and involvement of the lower uterine segment. In the cases of synchronous cancers of the endometrium and ovary, all surgical specimens were examined by gynecologic pathologists, according to the criteria described by Scully et al [9]. The pathological criteria for synchronous primary cancers of the endometrium and ovary were as follows: (1) histological dissimilarity of tumors; (2) no or only superficial myometrial invasion of endometrial tumor; (3) no vascular space invasion of endometrial tumor; (4) atypical endometrial hyperplasia additionally present; (5) absence of other evidence of spread of endometrial tumor; (6) unilateral ovarian tumor (80e90% of cases); (7) ovarian tumors located mainly in the parenchyma; (8) no vascular space invasion, surface implants, or predominant hilar location in the ovary; (9) absence of other evidence of the spread of ovarian tumor; and (10) presence of ovarian endometriosis [9]. In the cases of synchronous cancers of the endometrium and breast or endometrium and colon, the records of the patients with a preexisting diagnosis of breast or colon cancer were examined to determine whether the endometrial cancer was a concurrent disease or a metastatic one. It has been reported that the risk of tamoxifen-related endometrial cancer increases proportionally with the duration of tamoxifen use irrespective of menopausal status [10]. In the current study, endometrial cancer patients who used tamoxifen for 5 or more years (odds ratio, 2.4; 95% confidence interval, 1.8e3.0) were excluded [10]. All oncological treatments were performed in accordance with institutional guidelines, which were based on the National Comprehensive Cancer Network (NCCN) guideline and the Health Insurance Review and Assessment Service (HIRA) in Korea. All patients underwent total hysterectomy and pelvic lymph node dissection, with or without para-aortic lymph node dissection. Adjuvant pelvic radiation after complete surgical staging was performed in patients with potential adverse risk factors such as age, grade, lymphovascular invasion, tumor size, lower uterine involvement, and outer-third myometrial invasion [11e13]. Adjuvant chemotherapy was performed in patients with Stage IVb disease or concurrent ovarian cancer. However, the endometrial patients with concurrent ovarian cancer, which was stage Ia or Ib
25
and Grade 1 tumor, were not performed adjuvant chemotherapy based on the NCCN guideline. We reviewed the medical records, such as the stages for each cancer, tumor markers, and imaging studies, to exclude the possibility of recurrence from colon or breast cancer. In this study, we excluded all patients who had uncertain recurrence from endometrial or colon/breast cancer. Chi-square test and t tests were used to evaluate differences in patient and tumor characteristics between the sporadic and hereditary endometrial cancer groups including age at diagnosis, menopause, BMI, parity, diabetes, stage, tumor grade, endometrial cancer histology, and lower uterine segment involvement. Endometrial cancer-specific survival was used for analysis. KaplaneMeier survival analyses were generated and compared by the log-rank test. A p value <0.05 was taken to be significant. All the analyses were performed using STATA 11.0 (STATACORP, College Station, TX, USA) and SPSS 21.0 (IBM-SPSS Inc., Chicago, IL, USA). Results The clinicopathological characteristics of endometrial cancer according to hereditary components are presented in Table 1. Among 282 patients with endometrial cancer in the study population, 20 patients (7.1%) had a hereditary predisposition: 10 patients (3.5%) had ovarian cancer, six patients (2.1%) had breast cancer, and four patients (1.4%) had colon cancer. The mean age of the total endometrial cancer patients at onset was 53.2 ± 12.1 years (range, 23e81 years). The mean age at diagnosis of endometrial cancer for the hereditary predisposition was not statistically different compared with the mean age at diagnosis for the sporadic endometrial cancer group (55 years and 53 years, respectively, p ¼ 0.791). The percentage of patients diagnosed at an age younger than 50 years in the hereditary endometrial cancer group was 40%, and there were no significant differences in this percentage between the sporadic endometrial cancer group and the endometrial cancer with a hereditary predisposition group (p ¼ 0.428). The BMI and incidence of diabetes were not significantly different between the sporadic endometrial cancer group and the endometrial cancer with a hereditary predisposition group (p ¼ 0.434 and p ¼ 0.149, respectively). As shown in Table 2, both cancers were detected simultaneously in the majority of the synchronous cases (55%). All ovarian cancers were found concurrently with endometrial cancer. However, only one colorectal cancer was diagnosed concurrently with endometrial cancer. Apart from the simultaneous cases, the interval between the first and second tumor was <2 years in four cases, <3 years in one case, and <5 years in one case, and >5 years in three cases. Among the six patients who had breast cancer, two patients had taken tamoxifen for 26 months and 16 months, respectively, before the diagnosis of endometrial cancer. The interval from the last dose of tamoxifen to the diagnosis of endometrial cancer was 46.1 months and 1 month, respectively. BMI of two patients who had taken tamoxifen was 26.7 and 21.8 and there was no familial history of cancers. The majority of the women in the hereditary predisposition group presented at Stage I. However, the proportion of patients who presented at Stage I was not statistically different between the group with a hereditary predisposition and the group with sporadic endometrial cancer (85% and 76%, respectively, p ¼ 0.561). Tumor grade and histological type were not significantly different between the two groups (p ¼ 0.804 and p ¼ 0.999, respectively). Lower uterine segment involvement, a factor suggestive of hereditary endometrial cancer, was not different between the group with endometrial cancer and a hereditary predisposition and the group with sporadic endometrial cancer (15% and 11%, p ¼ 0.471). The median follow-up period was 60 months (range, 1e102 months). There were three cases of recurrence (15%); all patients
26
H.J. Yoo et al. / Taiwanese Journal of Obstetrics & Gynecology 54 (2015) 24e28
Table 1 Clinicopathological characteristics of endometrial cancer with a hereditary component based on synchronous tumors. Endometrial cancer (N ¼ 282) N (%) Mean age (y) 53.2 Age 50 101 (36) >50 181 (64) Menarche (y) 15.6 Parity (N) 2.2 Menopause (y) 51 Menopause Yes 153 (57) No 117 (43) Diabetes Yes 25 (12) No 179 (88) Body mass index 25.2 Histologic type Endometrioid 248 (84) Nonendometrioid 33 (11) Grade G1 126 (45) G2 88 (30) G3 45 (15) Stage I 217 (77) II 17 (6) III 46 (16) IV 2 (1) Lower uterine segment involvement Yes 31 (11) No 251 (89)
Sporadic endometrial cancer (N ¼ 262) N (%)
Endometrial cancer with a hereditary component (N ¼ 20) N (%)
p
53.0
55.5
0.791
93 (36) 169 (64) 15.7 2.2 51
8 (40) 12 (60) 14.6 2.3 49
0.428 0.168 0.786 0.226
140 (56) 110 (44)
13 (65) 7 (35)
0.227
23 (12) 162 (88) 25.2
2 (10) 17 (90) 24.7
0.149 0.434
230 (88) 31 (12)
18 (90) 2 (10)
0.999
119 (50) 80 (33) 41 (17)
7 (37) 8 (42) 4 (21)
0.804
200 (77) 17 (6) 43 (16) 2 (1)
17 (85) 0 3 (15) 0
0.791
28 (11) 234 (89)
3 (15) 17 (75)
0.471
had multiple distant recurrences such as liver, lung, and supraclavicular lymph node metastasis. The concurrent tumors of recurrent patients were breast (n ¼ 1) and colon (n ¼ 2). Two patients with recurrence had Stage Ia endometrial cancer and another patient with recurrence had Stage IIIa endometrial cancer. All recurrent patients were treated with combination chemotherapy. The 5-year progression-free survival rate and the 5-year overall
Table 2 Characteristics of synchronous tumor. N Type of cancer Ovary Breast Colorectal Initially diagnosed cancer type Ovary Breast Colorectal Interval between first and second tumor simultaneous detection <1 y <2 y <3 y <5 y 5 y Synchronous ovarian cancer stage I III Synchronous breast cancer stage II III Unknown Synchronous colon cancer stage I III Unknown
10 6 4 6 3 11 11 0 4 1 1 3 7 3 2 3 1 1 1 2
survival rate of the total endometrial cancer patients were 85% and 95%, respectively. The 5-year progression-free survival rate was not significantly different between the endometrial cancer with a hereditary predisposition group and the sporadic endometrial cancer group (86% and 71%, respectively, p ¼ 0.271, Fig. 1). The 5-year overall survival rate was also not significantly different between the two groups (95% and 95%, respectively, p ¼ 0.659; Fig. 1). However, among a subgroup of Stage I endometrial cancer patients, the 5-year progression-free survival and 5-year overall survival rates were lower in the endometrial cancer with a hereditary predisposition group compared with the sporadic endometrial cancer group (73% vs. 93%, p ¼ 0.026 and 94% vs. 98%, p ¼ 0.027, respectively, Fig. 2). The median follow up of the two groups in Stage I was 36 months and 64 months, respectively. Discussion In this study, survival outcome was significantly lower in patients with Stage I endometrial cancer with a hereditary predisposition. This may indicate a different prognostic role of heredity in endometrial cancer compared with ovarian cancer [8,14,15]. Increased sensitivity to chemotherapy is one of the explanations provided for the better survival rate of ovarian cancer patients with a familial history of ovarian cancer/breast cancer [8]. Unlike ovarian cancer, most endometrial cancers are diagnosed in the early stages and adjuvant treatments are restrictively performed [16,17]. The exact reason for the lower survival outcome in patients with endometrial cancer with a hereditary predisposition was difficult to identify in this study because of the limited number of cases and study design. Surgical methodology should also be considered as a part of the survival difference [18], however, because the current study is not prospective this was not evaluated. Genetic testing was limited in the current study because of the medical environment regulated by the HIRA in Korea [19]. Therefore, a larger cohort study
H.J. Yoo et al. / Taiwanese Journal of Obstetrics & Gynecology 54 (2015) 24e28
27
Fig. 2. Overall survival and progression-free survival of Stage I endometrial cancer between the sporadic and hereditary predisposition groups. Fig. 1. Overall survival and progression-free survival of patients who have sporadic endometrial cancer and endometrial cancer with a hereditary predisposition.
with adequate genetic information corresponding to the hereditary predisposition is needed to confirm this new finding and to interpret the cause in near future. Obesity and diabetes are well-known risk factors for endometrial carcinoma. We have previously compared the BMI between the sporadic and hereditary nonpolyposis colorectal cancer (HNPCC)-related endometrial cancer groups and found that there was a difference in the proportion. Especially, among the nonobese patients, the proportion of normal weight was significantly higher in the HNPCC-related group than in the sporadic endometrial cancer group [20]. In this study, no significant difference was identified in BMI and diabetes between the hereditary group (according to the presence of synchronous malignancy) and the sporadic group. Wang et al [21] reported an association of diabetes with hereditary endometrial cancer; however, the prevalence of diabetes was not different between those with HNPCC and those without HNPCC. The results of our study are consistent with those of Wang and co-workers’ study. This finding should be more clearly revealed in a larger population. Endometrial cancer in the lower uterine segment is one of the markers of HNPCC [22e24]. The endometrium in the lower uterine
segment is less responsive to hormones [25]. In this study, the proportion of patients with lower uterine segment involvement was not statistically different between the two groups. Further studies are needed to confirm this result. We recognize that our study has certain limitations. First, with retrospective data collection in this study, selection bias and other confounders can be present. Second, we based hereditary predisposition on the presence of double primary cancer. However, the diagnosis of double primary cancer was based on pathological reports. Therefore, it is completely reproducible. This is also one of the strong merits of the study [26]. Third, we did not perform genetic testing to confirm a germline mutation. Even with these limitations, we investigated the proportion of patients with a hereditary predisposition and the prognostic role of hereditary predisposition (based on the presence of synchronous cancer) in endometrial cancer patients. In conclusion, we found that approximately 7% of the endometrial cancer patients had other malignancies such as ovarian, colon, or breast cancer synchronously. In addition, the recurrence rate and the overall survival rate were not significantly different between the sporadic group and the hereditary predisposition group. However, among a subgroup of Stage I endometrial cancer patients, the 5-year progression-free survival and 5-year overall
28
H.J. Yoo et al. / Taiwanese Journal of Obstetrics & Gynecology 54 (2015) 24e28
survival rates were lower in the endometrial cancer with a hereditary predisposition group. These results should be further verified by future studies using a larger study population. Conflicts of interest All contributing authors declare no conflicts of interest. References [1] Jung K-W, Won Y-J, Kong H-J, Oh C-M, Lee DH, Lee JS. Prediction of cancer incidence and mortality in Korea. Cancer Res Treat 2014;2014(46):124e30. [2] Jung K-W, Won Y-J, Kong H-J, Oh C-M, Lee DH, Lee JS. Cancer statistics in Korea: incidence, mortality, survival, and prevalence in 2011. Cancer Res Treat 2014;46:109e23. [3] Lim MC, Moon E-K, Shin A, Jung K-W, Won Y-J, Seo SS, et al. Incidence of cervical, endometrial, and ovarian cancer in Korea, 1999e2010. J Gynecol Oncol 2013;24:298e302. [4] Deligdisch L, Holinka CF. Endometrial carcinoma: two diseases? Cancer Detect Prev 1987;10:237e46. [5] Park JG, Vasen HF, Park YJ, Park KJ, Peltomaki P, de Leon MP, et al. Suspected HNPCC and Amsterdam criteria II: evaluation of mutation detection rate, an international collaborative study. Int J Colorectal Dis 2002;17:109e14. [6] Shulman LP. Hereditary breast and ovarian cancer (HBOC): clinical features and counseling for BRCA1 and BRCA2, Lynch syndrome, Cowden syndrome, and Li-Fraumeni syndrome. Obstet Gynecol Clin North Am 2010;37:109e33. [7] Erickson J, Lyon DE. Breast cancer in Cowden syndrome: manifestation of a familial cancer syndrome. Clin J Oncol Nurs 2010;14:33e5. [8] Tan DS, Rothermundt C, Thomas K, Bancroft E, Eeles R, Shanley S, et al. “BRCAness” syndrome in ovarian cancer: a case-control study describing the clinical features and outcome of patients with epithelial ovarian cancer associated with BRCA1 and BRCA2 mutations. J Clin Oncol 2008;26:5530e6. [9] Scully RE, Young RH, Clement PB. Tumors of the ovary, maldeveloped gonads, fallopian tube and broad ligament. Atlas of tumor pathology. Third Series, Bethesda, MD: Washington Armed Forces Institute of Pathology; 1998. [10] Swerdlow AJ, Jones ME. British tamoxifen second cancer study G. Tamoxifen treatment for breast cancer and risk of endometrial cancer: a case-control study. J Natl Cancer Inst 2005;97:375e84. [11] Keys HM, Roberts JA, Brunetto VL, Zaino RJ, Spirtos NM, Bloss JD, et al. A phase III trial of surgery with or without adjunctive external pelvic radiation therapy in intermediate risk endometrial adenocarcinoma: a gynecologic oncology group study. Gynecol Oncol 2004;92:744e51.
rl [12] Creutzberg CL, van Putten WL, Koper PC, Lybeert ML, Jobsen JJ, Wa amRodenhuis CC, et al. Surgery and postoperative radiotherapy versus surgery alone for patients with stage-1 endometrial carcinoma: multicentre randomised trial. PORTEC Study Group. Post operative radiation therapy in endometrial carcinoma. Lancet 2000;355:1404e11. [13] Koh W-J, Tran AB, Douglas JG, Stelzer KJ. Radiation therapy in endometrial cancer. Best Pract Res Clin Obstet Gynaecol 2001;15:417e32. [14] Zaino R, Whitney C, Brady MF, DeGeest K, Burger RA, Buller RE. Simultaneously detected endometrial and ovarian carcinomasda prospective clinicopathologic study of 74 cases: a gynecologic oncology group study. Gynecol Oncol 2001;83:355e62. [15] Soliman PT, Slomovitz BM, Broaddus RR, Sun CC, Oh JC, Eifel PJ, et al. Synchronous primary cancers of the endometrium and ovary: a single institution review of 84 cases. Gynecol Oncol 2004;94:456e62. [16] DeLeon MC, Ammakkanavar NR, Matei D. Adjuvant therapy for endometrial cancer. J Gynecol Oncol 2014;25:136e47. [17] Sonoda Y. Surgical treatment for apparent early stage endometrial cancer. Obstet Gynecol Sci 2014;57:1e10. [18] Todo Y, Sakuragi N. Methodological considerations in the analysis of the therapeutic significance of lymphadenectomy in endometrial cancer. Taiwan J Obstet Gynecol 2013;52:8e13. [19] Lim MC, Seo SS, Kang S, Seong MW, Lee BY, Park SY. Hereditary non-polyposis colorectal cancer/Lynch syndrome in Korean patients with endometrial cancer. Jpn J Clin Oncol 2010;40:1121e7. [20] Yoo HJ, Joo J, Seo SS, Kang S, Yoo CW, Park SY, et al. Correlation between body mass index and prevalence of hereditary nonpolyposis colorectal cancer in korean patients with endometrial cancer. Int J Gynecol Cancer 2012;22: 267e72. [21] Chang JW, Tsai HL, Wang HH, Yang LY. Clinicopathological features and prognosis of Chinese children with idiopathic nephrotic syndrome between different age groups. Eur J Pediatr 2009;168:1189e94. [22] Westin SN, Lacour RA, Urbauer DL, Luthra R, Bodurka DC, Lu KH, et al. Carcinoma of the lower uterine segment: a newly described association with Lynch syndrome. J Clin Oncol 2008;26:5965e71. [23] Hachisuga T, Kaku T, Enjoji M. Carcinoma of the lower uterine segment. Clinicopathologic analysis of 12 cases. Int J Gynecol Pathol 1989;8:26e35. [24] Hachisuga T, Fukuda K, Iwasaka T, Hirakawa T, Kawarabayashi T, Tsuneyoshi M. Endometrioid adenocarcinomas of the uterine corpus in women younger than 50 years of age can be divided into two distinct clinical and pathologic entities based on anatomic location. Cancer 2001;92:2578e84. [25] Sorvari TE, Laakso L. Histochemical investigation of epithelial mucosubstances in the uterine isthmus. Obstet Gynecol 1970;36:76e81. [26] Lim MC, Kang S, Seo SS, Kong SY, Lee BY, Lee SK, et al. BRCA1 and BRCA2 germline mutations in Korean ovarian cancer patients. J Cancer Res Clin Oncol 2009;135:1593e9.
Contents lists available at ScienceDirect
Taiwanese Journal of Obstetrics & Gynecology journal homepage: www.tjog-online.com
Original Article
Survival outcome in endometrial cancer patients according to hereditary predisposition Heon Jong Yoo a, b, Myong Cheol Lim a, c, *, Yedong Son a, d, Sang-Soo Seo a, Sokbom Kang a, c, Sun Ho Kim a, Chong Woo Yoo a, Sang-Yoon Park a, c a
Center for Uterine Cancer, Research Institute and Hospital, National Cancer Center, Goyang-si, South Korea Department of Obstetrics and Gynecology, Chungnam National University Hospital, Daejeon, South Korea Gynecologic Cancer Branch, Research Institute and Hospital, National Cancer Center, Goyang-si, South Korea d Red Cross College of Nursing, Chung-Ang University, Seoul, South Korea b c
a r t i c l e i n f o
a b s t r a c t
Article history: Accepted 30 June 2014
Objective: A familial history of ovarian cancer/breast cancer is considered a significant prognostic factor for ovarian cancer. We investigated hereditary factors by examining the incidence of synchronous malignancy in patients with endometrial cancer, and assessed the prognostic role of heredity in endometrial cancer. Methods: We retrospectively evaluated patients with endometrial cancer who underwent surgery from January 2001 to April 2011. A hereditary background in this study was defined as double primary cancer, that is, endometrial cancer accompanied by colon, ovarian, or breast cancer suggestive of Lynch syndrome, hereditary breast ovarian cancer syndrome, or Cowden syndrome, respectively. Results: Among 282 patients with endometrial cancer in the study population, 20 patients (7.1%) had a hereditary predisposition: 10 patients (3.5%) had ovarian cancer, six patients (2.1%) had breast cancer, and four patients (1.4%) had colon cancer. Age and lower uterine segment involvement were not statistically different between the hereditary and nonhereditary groups. The majority of the women in the hereditary group presented with Stage I cancer; however, there were no significant differences in Stage I cancer between the hereditary group and the sporadic endometrial cancer group (85% and 77%, respectively, p ¼ 0.561). The median follow-up period was 60 months. A 5-year overall survival rate was not different between the two groups (95% and 95%, respectively, p ¼ 0.659). Among a subgroup of patients with Stage I endometrial cancer, the 5-year overall survival rate was lower in the endometrial cancer with a hereditary predisposition group compared with the sporadic endometrial cancer group (94% and 98%, respectively, p ¼ 0.027). Conclusion: Seven percent of the women with endometrial cancer in our study had other malignancies such as ovarian, colon, or breast cancer synchronously. Among a subgroup of patients with Stage I cancer in the endometrial cancer with a hereditary predisposition group, the 5-year overall survival rate was significantly lower (94%). This finding should be confirmed in a larger population. Copyright © 2014, Taiwan Association of Obstetrics & Gynecology. Published by Elsevier Taiwan LLC. All rights reserved.
Keywords: endometrial cancer hereditary predisposition survival outcome
Introduction The incidence of endometrial cancer has been increasing over the past decade in Korea [1e3]. Among the many risk factors for
* Corresponding author. Center for Uterine Cancer, Research Institute and Hospital, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang-si, Gyeonggi-do, 410-769, South Korea. E-mail address: [email protected] (M.C. Lim).
endometrial cancer, including obesity, diabetes, late menopause, unopposed estrogen therapy, and nulliparity [4], inherited factors have also been suggested as important risk factors [5]. The occurrence of synchronous cancers is relatively uncommon, but it is important to detect them in clinical practice because a diagnosis of synchronous malignancy in the later stages affects clinical management and prognosis. In particular, double primary cancer with endometrial cancer is strongly associated with hereditary factors; for example, colon cancer and endometrial cancer, suggestive of Lynch syndrome [5], ovarian cancer and endometrial
http://dx.doi.org/10.1016/j.tjog.2014.11.003 1028-4559/Copyright © 2014, Taiwan Association of Obstetrics & Gynecology. Published by Elsevier Taiwan LLC. All rights reserved.
H.J. Yoo et al. / Taiwanese Journal of Obstetrics & Gynecology 54 (2015) 24e28
cancer, suggestive of Lynch syndrome and/or hereditary breast ovarian cancer syndrome [6], and breast cancer and endometrial cancer, suggestive of Cowden syndrome [7]. A familial history of ovarian cancer/breast cancer is considered a strong prognostic factor for ovarian cancer, and this might be explained by BRCAness [8]. However, double primary cancer with endometrial cancer has not been well studied previously. Therefore, we investigated the prognostic role of heredity in endometrial cancer, a potentially autosomal dominant disease. Materials and methods A total of 282 patients were diagnosed with endometrial cancer by pathologic examination at the Department of Uterine Cancer at the National Cancer Center Korea between January 2000 and April 2011. This retrospective study was approved by the Institutional Review Board of the National Cancer Center (NCCNCS-12-597). A hereditary background in this study was defined as the existence of a primary cancer concurrent with endometrial cancer, that is, colon cancer and endometrial cancer, suggestive of Lynch syndrome, ovarian cancer and endometrial cancer, suggestive of Lynch syndrome and/or hereditary breast ovarian cancer syndrome, and breast cancer and endometrial cancer, suggestive of Cowden syndrome. The clinicopathological factors analyzed were age at the time of diagnosis, body mass index (BMI), parity, menstrual history, history of diabetes, tumor histology, tumor grade, the International Federation of Gynecology and Obstetrics stage, and involvement of the lower uterine segment. In the cases of synchronous cancers of the endometrium and ovary, all surgical specimens were examined by gynecologic pathologists, according to the criteria described by Scully et al [9]. The pathological criteria for synchronous primary cancers of the endometrium and ovary were as follows: (1) histological dissimilarity of tumors; (2) no or only superficial myometrial invasion of endometrial tumor; (3) no vascular space invasion of endometrial tumor; (4) atypical endometrial hyperplasia additionally present; (5) absence of other evidence of spread of endometrial tumor; (6) unilateral ovarian tumor (80e90% of cases); (7) ovarian tumors located mainly in the parenchyma; (8) no vascular space invasion, surface implants, or predominant hilar location in the ovary; (9) absence of other evidence of the spread of ovarian tumor; and (10) presence of ovarian endometriosis [9]. In the cases of synchronous cancers of the endometrium and breast or endometrium and colon, the records of the patients with a preexisting diagnosis of breast or colon cancer were examined to determine whether the endometrial cancer was a concurrent disease or a metastatic one. It has been reported that the risk of tamoxifen-related endometrial cancer increases proportionally with the duration of tamoxifen use irrespective of menopausal status [10]. In the current study, endometrial cancer patients who used tamoxifen for 5 or more years (odds ratio, 2.4; 95% confidence interval, 1.8e3.0) were excluded [10]. All oncological treatments were performed in accordance with institutional guidelines, which were based on the National Comprehensive Cancer Network (NCCN) guideline and the Health Insurance Review and Assessment Service (HIRA) in Korea. All patients underwent total hysterectomy and pelvic lymph node dissection, with or without para-aortic lymph node dissection. Adjuvant pelvic radiation after complete surgical staging was performed in patients with potential adverse risk factors such as age, grade, lymphovascular invasion, tumor size, lower uterine involvement, and outer-third myometrial invasion [11e13]. Adjuvant chemotherapy was performed in patients with Stage IVb disease or concurrent ovarian cancer. However, the endometrial patients with concurrent ovarian cancer, which was stage Ia or Ib
25
and Grade 1 tumor, were not performed adjuvant chemotherapy based on the NCCN guideline. We reviewed the medical records, such as the stages for each cancer, tumor markers, and imaging studies, to exclude the possibility of recurrence from colon or breast cancer. In this study, we excluded all patients who had uncertain recurrence from endometrial or colon/breast cancer. Chi-square test and t tests were used to evaluate differences in patient and tumor characteristics between the sporadic and hereditary endometrial cancer groups including age at diagnosis, menopause, BMI, parity, diabetes, stage, tumor grade, endometrial cancer histology, and lower uterine segment involvement. Endometrial cancer-specific survival was used for analysis. KaplaneMeier survival analyses were generated and compared by the log-rank test. A p value <0.05 was taken to be significant. All the analyses were performed using STATA 11.0 (STATACORP, College Station, TX, USA) and SPSS 21.0 (IBM-SPSS Inc., Chicago, IL, USA). Results The clinicopathological characteristics of endometrial cancer according to hereditary components are presented in Table 1. Among 282 patients with endometrial cancer in the study population, 20 patients (7.1%) had a hereditary predisposition: 10 patients (3.5%) had ovarian cancer, six patients (2.1%) had breast cancer, and four patients (1.4%) had colon cancer. The mean age of the total endometrial cancer patients at onset was 53.2 ± 12.1 years (range, 23e81 years). The mean age at diagnosis of endometrial cancer for the hereditary predisposition was not statistically different compared with the mean age at diagnosis for the sporadic endometrial cancer group (55 years and 53 years, respectively, p ¼ 0.791). The percentage of patients diagnosed at an age younger than 50 years in the hereditary endometrial cancer group was 40%, and there were no significant differences in this percentage between the sporadic endometrial cancer group and the endometrial cancer with a hereditary predisposition group (p ¼ 0.428). The BMI and incidence of diabetes were not significantly different between the sporadic endometrial cancer group and the endometrial cancer with a hereditary predisposition group (p ¼ 0.434 and p ¼ 0.149, respectively). As shown in Table 2, both cancers were detected simultaneously in the majority of the synchronous cases (55%). All ovarian cancers were found concurrently with endometrial cancer. However, only one colorectal cancer was diagnosed concurrently with endometrial cancer. Apart from the simultaneous cases, the interval between the first and second tumor was <2 years in four cases, <3 years in one case, and <5 years in one case, and >5 years in three cases. Among the six patients who had breast cancer, two patients had taken tamoxifen for 26 months and 16 months, respectively, before the diagnosis of endometrial cancer. The interval from the last dose of tamoxifen to the diagnosis of endometrial cancer was 46.1 months and 1 month, respectively. BMI of two patients who had taken tamoxifen was 26.7 and 21.8 and there was no familial history of cancers. The majority of the women in the hereditary predisposition group presented at Stage I. However, the proportion of patients who presented at Stage I was not statistically different between the group with a hereditary predisposition and the group with sporadic endometrial cancer (85% and 76%, respectively, p ¼ 0.561). Tumor grade and histological type were not significantly different between the two groups (p ¼ 0.804 and p ¼ 0.999, respectively). Lower uterine segment involvement, a factor suggestive of hereditary endometrial cancer, was not different between the group with endometrial cancer and a hereditary predisposition and the group with sporadic endometrial cancer (15% and 11%, p ¼ 0.471). The median follow-up period was 60 months (range, 1e102 months). There were three cases of recurrence (15%); all patients
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Table 1 Clinicopathological characteristics of endometrial cancer with a hereditary component based on synchronous tumors. Endometrial cancer (N ¼ 282) N (%) Mean age (y) 53.2 Age 50 101 (36) >50 181 (64) Menarche (y) 15.6 Parity (N) 2.2 Menopause (y) 51 Menopause Yes 153 (57) No 117 (43) Diabetes Yes 25 (12) No 179 (88) Body mass index 25.2 Histologic type Endometrioid 248 (84) Nonendometrioid 33 (11) Grade G1 126 (45) G2 88 (30) G3 45 (15) Stage I 217 (77) II 17 (6) III 46 (16) IV 2 (1) Lower uterine segment involvement Yes 31 (11) No 251 (89)
Sporadic endometrial cancer (N ¼ 262) N (%)
Endometrial cancer with a hereditary component (N ¼ 20) N (%)
p
53.0
55.5
0.791
93 (36) 169 (64) 15.7 2.2 51
8 (40) 12 (60) 14.6 2.3 49
0.428 0.168 0.786 0.226
140 (56) 110 (44)
13 (65) 7 (35)
0.227
23 (12) 162 (88) 25.2
2 (10) 17 (90) 24.7
0.149 0.434
230 (88) 31 (12)
18 (90) 2 (10)
0.999
119 (50) 80 (33) 41 (17)
7 (37) 8 (42) 4 (21)
0.804
200 (77) 17 (6) 43 (16) 2 (1)
17 (85) 0 3 (15) 0
0.791
28 (11) 234 (89)
3 (15) 17 (75)
0.471
had multiple distant recurrences such as liver, lung, and supraclavicular lymph node metastasis. The concurrent tumors of recurrent patients were breast (n ¼ 1) and colon (n ¼ 2). Two patients with recurrence had Stage Ia endometrial cancer and another patient with recurrence had Stage IIIa endometrial cancer. All recurrent patients were treated with combination chemotherapy. The 5-year progression-free survival rate and the 5-year overall
Table 2 Characteristics of synchronous tumor. N Type of cancer Ovary Breast Colorectal Initially diagnosed cancer type Ovary Breast Colorectal Interval between first and second tumor simultaneous detection <1 y <2 y <3 y <5 y 5 y Synchronous ovarian cancer stage I III Synchronous breast cancer stage II III Unknown Synchronous colon cancer stage I III Unknown
10 6 4 6 3 11 11 0 4 1 1 3 7 3 2 3 1 1 1 2
survival rate of the total endometrial cancer patients were 85% and 95%, respectively. The 5-year progression-free survival rate was not significantly different between the endometrial cancer with a hereditary predisposition group and the sporadic endometrial cancer group (86% and 71%, respectively, p ¼ 0.271, Fig. 1). The 5-year overall survival rate was also not significantly different between the two groups (95% and 95%, respectively, p ¼ 0.659; Fig. 1). However, among a subgroup of Stage I endometrial cancer patients, the 5-year progression-free survival and 5-year overall survival rates were lower in the endometrial cancer with a hereditary predisposition group compared with the sporadic endometrial cancer group (73% vs. 93%, p ¼ 0.026 and 94% vs. 98%, p ¼ 0.027, respectively, Fig. 2). The median follow up of the two groups in Stage I was 36 months and 64 months, respectively. Discussion In this study, survival outcome was significantly lower in patients with Stage I endometrial cancer with a hereditary predisposition. This may indicate a different prognostic role of heredity in endometrial cancer compared with ovarian cancer [8,14,15]. Increased sensitivity to chemotherapy is one of the explanations provided for the better survival rate of ovarian cancer patients with a familial history of ovarian cancer/breast cancer [8]. Unlike ovarian cancer, most endometrial cancers are diagnosed in the early stages and adjuvant treatments are restrictively performed [16,17]. The exact reason for the lower survival outcome in patients with endometrial cancer with a hereditary predisposition was difficult to identify in this study because of the limited number of cases and study design. Surgical methodology should also be considered as a part of the survival difference [18], however, because the current study is not prospective this was not evaluated. Genetic testing was limited in the current study because of the medical environment regulated by the HIRA in Korea [19]. Therefore, a larger cohort study
H.J. Yoo et al. / Taiwanese Journal of Obstetrics & Gynecology 54 (2015) 24e28
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Fig. 2. Overall survival and progression-free survival of Stage I endometrial cancer between the sporadic and hereditary predisposition groups. Fig. 1. Overall survival and progression-free survival of patients who have sporadic endometrial cancer and endometrial cancer with a hereditary predisposition.
with adequate genetic information corresponding to the hereditary predisposition is needed to confirm this new finding and to interpret the cause in near future. Obesity and diabetes are well-known risk factors for endometrial carcinoma. We have previously compared the BMI between the sporadic and hereditary nonpolyposis colorectal cancer (HNPCC)-related endometrial cancer groups and found that there was a difference in the proportion. Especially, among the nonobese patients, the proportion of normal weight was significantly higher in the HNPCC-related group than in the sporadic endometrial cancer group [20]. In this study, no significant difference was identified in BMI and diabetes between the hereditary group (according to the presence of synchronous malignancy) and the sporadic group. Wang et al [21] reported an association of diabetes with hereditary endometrial cancer; however, the prevalence of diabetes was not different between those with HNPCC and those without HNPCC. The results of our study are consistent with those of Wang and co-workers’ study. This finding should be more clearly revealed in a larger population. Endometrial cancer in the lower uterine segment is one of the markers of HNPCC [22e24]. The endometrium in the lower uterine
segment is less responsive to hormones [25]. In this study, the proportion of patients with lower uterine segment involvement was not statistically different between the two groups. Further studies are needed to confirm this result. We recognize that our study has certain limitations. First, with retrospective data collection in this study, selection bias and other confounders can be present. Second, we based hereditary predisposition on the presence of double primary cancer. However, the diagnosis of double primary cancer was based on pathological reports. Therefore, it is completely reproducible. This is also one of the strong merits of the study [26]. Third, we did not perform genetic testing to confirm a germline mutation. Even with these limitations, we investigated the proportion of patients with a hereditary predisposition and the prognostic role of hereditary predisposition (based on the presence of synchronous cancer) in endometrial cancer patients. In conclusion, we found that approximately 7% of the endometrial cancer patients had other malignancies such as ovarian, colon, or breast cancer synchronously. In addition, the recurrence rate and the overall survival rate were not significantly different between the sporadic group and the hereditary predisposition group. However, among a subgroup of Stage I endometrial cancer patients, the 5-year progression-free survival and 5-year overall
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survival rates were lower in the endometrial cancer with a hereditary predisposition group. These results should be further verified by future studies using a larger study population. Conflicts of interest All contributing authors declare no conflicts of interest. References [1] Jung K-W, Won Y-J, Kong H-J, Oh C-M, Lee DH, Lee JS. Prediction of cancer incidence and mortality in Korea. Cancer Res Treat 2014;2014(46):124e30. [2] Jung K-W, Won Y-J, Kong H-J, Oh C-M, Lee DH, Lee JS. Cancer statistics in Korea: incidence, mortality, survival, and prevalence in 2011. Cancer Res Treat 2014;46:109e23. [3] Lim MC, Moon E-K, Shin A, Jung K-W, Won Y-J, Seo SS, et al. Incidence of cervical, endometrial, and ovarian cancer in Korea, 1999e2010. J Gynecol Oncol 2013;24:298e302. [4] Deligdisch L, Holinka CF. Endometrial carcinoma: two diseases? Cancer Detect Prev 1987;10:237e46. [5] Park JG, Vasen HF, Park YJ, Park KJ, Peltomaki P, de Leon MP, et al. Suspected HNPCC and Amsterdam criteria II: evaluation of mutation detection rate, an international collaborative study. Int J Colorectal Dis 2002;17:109e14. [6] Shulman LP. Hereditary breast and ovarian cancer (HBOC): clinical features and counseling for BRCA1 and BRCA2, Lynch syndrome, Cowden syndrome, and Li-Fraumeni syndrome. Obstet Gynecol Clin North Am 2010;37:109e33. [7] Erickson J, Lyon DE. Breast cancer in Cowden syndrome: manifestation of a familial cancer syndrome. Clin J Oncol Nurs 2010;14:33e5. [8] Tan DS, Rothermundt C, Thomas K, Bancroft E, Eeles R, Shanley S, et al. “BRCAness” syndrome in ovarian cancer: a case-control study describing the clinical features and outcome of patients with epithelial ovarian cancer associated with BRCA1 and BRCA2 mutations. J Clin Oncol 2008;26:5530e6. [9] Scully RE, Young RH, Clement PB. Tumors of the ovary, maldeveloped gonads, fallopian tube and broad ligament. Atlas of tumor pathology. Third Series, Bethesda, MD: Washington Armed Forces Institute of Pathology; 1998. [10] Swerdlow AJ, Jones ME. British tamoxifen second cancer study G. Tamoxifen treatment for breast cancer and risk of endometrial cancer: a case-control study. J Natl Cancer Inst 2005;97:375e84. [11] Keys HM, Roberts JA, Brunetto VL, Zaino RJ, Spirtos NM, Bloss JD, et al. A phase III trial of surgery with or without adjunctive external pelvic radiation therapy in intermediate risk endometrial adenocarcinoma: a gynecologic oncology group study. Gynecol Oncol 2004;92:744e51.
rl [12] Creutzberg CL, van Putten WL, Koper PC, Lybeert ML, Jobsen JJ, Wa amRodenhuis CC, et al. Surgery and postoperative radiotherapy versus surgery alone for patients with stage-1 endometrial carcinoma: multicentre randomised trial. PORTEC Study Group. Post operative radiation therapy in endometrial carcinoma. Lancet 2000;355:1404e11. [13] Koh W-J, Tran AB, Douglas JG, Stelzer KJ. Radiation therapy in endometrial cancer. Best Pract Res Clin Obstet Gynaecol 2001;15:417e32. [14] Zaino R, Whitney C, Brady MF, DeGeest K, Burger RA, Buller RE. Simultaneously detected endometrial and ovarian carcinomasda prospective clinicopathologic study of 74 cases: a gynecologic oncology group study. Gynecol Oncol 2001;83:355e62. [15] Soliman PT, Slomovitz BM, Broaddus RR, Sun CC, Oh JC, Eifel PJ, et al. Synchronous primary cancers of the endometrium and ovary: a single institution review of 84 cases. Gynecol Oncol 2004;94:456e62. [16] DeLeon MC, Ammakkanavar NR, Matei D. Adjuvant therapy for endometrial cancer. J Gynecol Oncol 2014;25:136e47. [17] Sonoda Y. Surgical treatment for apparent early stage endometrial cancer. Obstet Gynecol Sci 2014;57:1e10. [18] Todo Y, Sakuragi N. Methodological considerations in the analysis of the therapeutic significance of lymphadenectomy in endometrial cancer. Taiwan J Obstet Gynecol 2013;52:8e13. [19] Lim MC, Seo SS, Kang S, Seong MW, Lee BY, Park SY. Hereditary non-polyposis colorectal cancer/Lynch syndrome in Korean patients with endometrial cancer. Jpn J Clin Oncol 2010;40:1121e7. [20] Yoo HJ, Joo J, Seo SS, Kang S, Yoo CW, Park SY, et al. Correlation between body mass index and prevalence of hereditary nonpolyposis colorectal cancer in korean patients with endometrial cancer. Int J Gynecol Cancer 2012;22: 267e72. [21] Chang JW, Tsai HL, Wang HH, Yang LY. Clinicopathological features and prognosis of Chinese children with idiopathic nephrotic syndrome between different age groups. Eur J Pediatr 2009;168:1189e94. [22] Westin SN, Lacour RA, Urbauer DL, Luthra R, Bodurka DC, Lu KH, et al. Carcinoma of the lower uterine segment: a newly described association with Lynch syndrome. J Clin Oncol 2008;26:5965e71. [23] Hachisuga T, Kaku T, Enjoji M. Carcinoma of the lower uterine segment. Clinicopathologic analysis of 12 cases. Int J Gynecol Pathol 1989;8:26e35. [24] Hachisuga T, Fukuda K, Iwasaka T, Hirakawa T, Kawarabayashi T, Tsuneyoshi M. Endometrioid adenocarcinomas of the uterine corpus in women younger than 50 years of age can be divided into two distinct clinical and pathologic entities based on anatomic location. Cancer 2001;92:2578e84. [25] Sorvari TE, Laakso L. Histochemical investigation of epithelial mucosubstances in the uterine isthmus. Obstet Gynecol 1970;36:76e81. [26] Lim MC, Kang S, Seo SS, Kong SY, Lee BY, Lee SK, et al. BRCA1 and BRCA2 germline mutations in Korean ovarian cancer patients. J Cancer Res Clin Oncol 2009;135:1593e9.