Evaluation of the Safety of Ovarian Preservation at Early Stage of Endometrial Cancer in Premenopausal Women

Document Type : Original article

Authors

1 Department of Gynecologic Oncology, Tehran University of Medical Sciences, Tehran, Iran

2 Department of Gynecologic Oncology, Ahvaz University of Medical Sciences, Ahvaz, Iran

3 Department of Gynecologic Oncology, Shahid Beheshti University of Medical Sciences, Tehran, Iran

4 Valie-Asr Reproductive Health Research Center, (VRHRC), Tehran University of Medical Sciences, Tehran, Iran

Abstract

Abstract
Background: Endometrial cancer usually occurs at postmenopause stage of life but its incidence in younger patients is increasing in the last decades. The objective of the study was to evaluate the ovarian preservation in the early stage of endometrial cancer.
Methods: In this cross-sectional study, 174 patients with endometrial cancer who underwent Total Abdominal Hysterectomy (TAH) and Bilateral Salpingo-oophorectomy in 5 years were included.
Results: The results showed that 51.1% of the patients were at stage IA, 28.7% at stage IB, 6.9% at stage II, 11.5% at stage III and 1.7% at stage IV of endometrial cancer when they underwent surgery. One patient (1.12%) at stage IA of endometrial cancer, one patient (2%) at stage IB and one patient (8.3%) at stage II had micrometastasis in ovaries, and 8 patients (40%) at stage III and 2 patients (66.6%) at stage IV had micrometastasis and co-existing tumor.
Conclusion: In conclusion, findings revealed the high safety of ovarian preservation in endometrial cancer at earlier stages of the endometrial cancer with low risk of ovarian involvement.

Keywords


Abstract
Background: Endometrial cancer usually occurs at postmenopause stage of life but its incidence in younger patients is increasing in the last decades. The objective of the study was to evaluate the ovarian preservation in the early stage of endometrial cancer.
Methods: In this cross-sectional study, 174 patients with endometrial cancer who underwent Total Abdominal Hysterectomy (TAH) and Bilateral Salpingo-oophorectomy in 5 years were included.
Results: The results showed that 51.1% of the patients were at stage IA, 28.7% at stage IB, 6.9% at stage II, 11.5% at stage III and 1.7% at stage IV of endometrial cancer when they underwent surgery. One patient (1.12%) at stage IA of endometrial cancer, one patient (2%) at stage IB and one patient (8.3%) at stage II had micrometastasis in ovaries, and 8 patients (40%) at stage III and 2 patients (66.6%) at stage IV had micrometastasis and co-existing tumor.
Conclusion: In conclusion, findings revealed the high safety of ovarian preservation in endometrial cancer at earlier stages of the endometrial cancer with low risk of ovarian involvement.
Keywords: Endometrial neoplasms, Hysterectomy, Fertility preservation,
Salpingo-oophorectomy

Introduction
Cancer is one of the most important public health concerns, which is the second cause of death in many countries of the world following cardiovascular diseases (1), and the burden of cancer is increasing worldwide, especially in less developed countries, which have more populations (82% of the world’s population) (2).
Endometrial cancer is the most common cancer in the female genitourinary system by the mean age of 61 (3); however, 20-25% of patients are premenopausal and about 5% of patients are younger than 40 years old (4), and also 70% of endometrial cancers are localized (5).
Early diagnosis of endometrial cancer in younger females usually has a good prognosis and better survival because of earlier stage and lower grade in time of diagnosis and treatment (6). Endometrial cancer in younger age warns more about cancer associated with Lynch/Hereditary Non-Polyposis Colorectal Cancer (HNPCC) syndrome (7). The standard treatment of endometrial cancer is Total Abdominal Hysterectomy (TAH), Bilateral Salpingo-oophorectomy (BSO) and staging (8-10). Therefore, because of the possibility of endometrial cancer at younger age and lack of estrogen due to TAH-BSO surgery, conservative treatments to preserve fertility may be safe and do not increase the cancer related mortality (11). However, this study aimed to assess the ovarian involvement in patients with endometrial cancer who underwent TAH and BSO.

Materials and Methods
This cross-sectional study included 174 patients with endometrial cancer who underwent TAH and BSO from 2010 to 2015 in two hospitals, affiliated to Tehran University of Medical Sciences, Tehran, Iran.
In this study, all patients were analyzed in the mentioned period. All patients had documented pathology of endometrial cancer, confirmed by two pathologists. The staging system was from the cancer committee of the International Federation of Gynecology and Obstetrics (FIGO, 2019)(12).
Total para-aortic and pelvic dissection was performed for patients with the following criteria: (a) pelvic lymphadenopathy, (b) gross adnexal involvement, and (c) grade 2 or 3 lesions with outer one-third myometrial invasion (13,14).
Ultrasound and Magnetic Resonance Imaging (MRI) with and without contrast was performed before surgery and both ovaries and uterus were evaluated for pathology after surgery in all patients (15,16).
This study had been approved by the ethics committee of Tehran University of Medical Sciences. Moreover, all the ethical codes on human subjects were followed as well. Patients’ information was kept confidential and was reported as aggregated data. All the participants signed the informed consent form related to the study.
Quantitative variables were reported as mean (range) and qualitative variables as number (percentages). To examine the relationship between qualitative variables, likelihood-ratio Chi-square test was applied. Data was analyzed using Stata software, version 14 (Stata Corp, College Station, TX, USA). The P-value of less than 0.05 was considered statistically significant.

Results
The data of 174 patients were analyzed. The mean age of the patients was 44 years old (minimum 24 years and maximum 66 years). Half of the patients (50.6%) had a chief complaint of abnormal uterine bleeding. The mean parity of patients included 4 pregnancies, 3 live births, 1 abortion and all of the patients were Iranian.
As it is displayed in table 1, 13.8% of the patients had diabetes mellitus and 22.4% had hypertension. Eight percent were smokers, whereas 4% were confirmed cases of breast cancer before diagnosing endometrial cancer and they were treated by total mastectomy. The most pathologic sign detected in ultrasound before surgery was endometrial thickening in 36.7% of cases.
All patients had documented pathology for endometrioid adenocarcinoma of the endometrium.
As it is shown in table 2, 51.1% of the patients were at stage IA, 28.7% were at stage IB, 6.9% were at stage II, 11.5% were at stage III and 1.7% were at stage IV when they underwent surgery. In pathologic evaluation, 31.6% had myometrium invasion greater than 50%, 25.9% had para-aortic lymph node invasion and 32.7% had isthmus or cervical involvement.
The findings showed that one patient at stage IA (1.12%), one patient at stage IB (2%) and one patient (8.3%) at stage II of endometrial cancer had micrometastasis in ovaries, whereas 8 patients at stage III (40%) and 2 patients (66.6%) at stage IV had micrometastasis in ovaries with a co-existing tumor. Chi square test showed that there was a significant difference between disease stages and frequency of micrometastasis in ovaries (p<0.001) (Table 3).

Table 1. Frequency distribution of demographic and clinical variables in the study  

Variables

N(%)

Total

174

100%

Age (yr)

Mean (Range)

44(24-66)

Smoking status

Ever

Never

14(8%)

160(92%)

Chief complaint

Postmenopausal bleeding

Abnormal uterine bleeding

88(50.6%)

78(44.8%)

Diabetes mellitus

Yes

No

24(13.8%)

150(86.2%)

Hypertension

Hypertensive

Normotensive 

39(22.4%)

135(77.6%)

Breast cancer

Yes

No

7(4%)

167(96%)

 

Table 2. Tumor specific characteristics of patients in the study

Variables

N (%)

Stages of endometrial cancer

IA

IB

II

III

IV

89(51.5%)

50(28.7%)

12(6.9%)

20(11.5%)

3(1.7%)

Myometrium invasion greater than 50%

55(31.6%)

Para-aortic lymph node involvement

45(25.9%)

Isthmus or cervical involvement with cancer

57(32.7%)

     

 

Table 3. Frequency of endometrial cancer patients who had micrometastasis in ovaries

Stages

Micrometastasis in ovaries

p value

Yes

No

IA

IB

II

III

IV

1(1.12%)

1(1%)

1(8.3%)

8(40%)

2(66.6%)

88(98.88%)

49(99%)

11(93.7%)

12(60%)

1(33.4)

p<0.001,

likelihood-ratio Chi2(4)= 34.0568

 

 

 

Discussion
The standard treatment of endometrial cancer is TAH and BSO, and staging (8-10) but because estrogen deprivation imposes nearly lots of side effects on younger patients and decreases their quality of life, ovarian preservation in endometrial cancer, particularly in young patients at early stage of cancer may be beneficial (17).
BSO is considered somewhat safe; but it has some side effects in young patients including hot flushes, vaginal atrophy, increased cardiovascular disorder, osteoporosis and dementia (18-22).
There are two main risks in preserving ovaries in perimenopausal women. First, estrogen can stimulate microscopic foci of residual endometrial cancer, but in the study of Barakat et al (23), Hormone Replacement Therapy (HRT) with estrogen on 1236 women with history of endometrial cancer at early stages had no effect on mortality or recurrence of te cancer (absolute recurrence rate was 2.1% and the incidence of new malignancy was low). Second, the rate of coexisting ovarian tumors was reported to be 5% (24): however, in younger patients with an endometrial cancer, the risk of such tumors varies between 5-29% (24-26).
In a study by Walsh et al (25) on 102 patients at the age of 45 years or younger who underwent surgery for endometrial cancer, 25% had co-existing ovarian malignancies. In pathology report, 18 cases of co-existing ovarian malignancies out of 26 (69%) were detected in patients with grade 1 endometrial cancers, and 15 (58%) were detected in patients with inner myometrial invasion. In 15.7% of the patients, ovaries were preserved and all of them were at stage I. Also, 18.7% of these patients with preserved ovaries needed another operation in the next 50 months after the initial surgery due to adnexal abnormalities and because of the high rate of co-existing tumor (25%), younger patients were advised to undergo ovarian preservation.
In the present study, just 1.1% of cases at stage IA and 2% at stage IB had micrometastasis in their ovaries which shows the high safety of ovarian preservation at early stages. Similarly, in Wright et al’s study (27) on 3269 women aged 45 or younger at stage I of endometrial cancer, it was shown that ovarian preservation in young premenopausal women at stage I is safe and not associated with an increase in cancer-related mortality. However, the 5-year survival at stage IA in both patients with and without ovarian preservation was reported to be 98%. Our results suggested that there is a linear relationship between the stage of the disease and micrometastasis in ovaries, which also significantly increases with the stage progression of the cancer.
Predictor factors for ovarian involvement during surgery are morphology of the ovaries, grossly involved lymph node confirmed by frozen section during surgery and tumor spreading (28,29). In the present study, risk of micrometastasis regardless of normal appearance of ovaries was just 2%.
However, our study showed high safety of ovarian preservation at early stages in patients with low risk of ovarian involvement in endometrial cancer (cases younger than 45 years for whom cancer doesn’t invade serous membrane, with no family history of breast cancer or susceptibility to Lynch syndrome); however, the medical team should consult with the patients before surgery.
This study was conducted as a cross sectional one in two hospitals. Some similar studies with larger sample size in different ethnic groups and geographic areas with longer follow up should be conducted in order to be able to generalize the findings.

Conclusion
Findings show the high safety of ovarian preservation at earlier stages of endometrial cancer in patients with low risk of ovarian involvement (Cases younger than 45 years for whom cancer doesn’t invade serous membrane, with no family history of breast cancer or susceptibility to Lynch syndrome).

Conflict of Interest
All authors declare no competing interest.

1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin 2018;68(1):7-30. https://pubmed.ncbi.nlm.nih.gov/29313949/
2. TorreLA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. CA Cancer J Clin 2015;65(2):87-108. https://pubmed.ncbi.nlm.nih.gov/25651787/
3. Pellerin GP, Finan MA. Endometrial cancer in women 45 years of age or younger: a clinicopathological analysis. Am J Obstet Gynecol 2005;193(5):1640-4. https://pubmed.ncbi.nlm.nih.gov/16260203/
4. Jemal A, Siegel R, Ward E, Murray T, Xu J, Thun MJ. Cancer statistics, 2007. CA Cancer J Clin 2007;57(1):43-66. https://pubmed.ncbi.nlm.nih.gov/17237035/
5. Creasman WT, Odicino F, Maisonneuve P, Quinn MA, Beller U, Benedet JL, et al. Carcinoma of the corpus uteri. FIGO 26th Annual Report on the Results of Treatment in Gynecological Cancer. Int J Gynaecol Obstet 2006;95 Suppl 1:S105-43. https://pubmed.ncbi.nlm.nih.gov/17161155/
6. Bakour SH, Khan KS, Gupta JK. Controlled analysis of factors associated with insufficient sample on outpatient endometrial biopsy. BJOG 2000;107(10):1312-4. https://pubmed.ncbi.nlm.nih.gov/11028588/
7. Lynch HT, Lynch JF, Lynch PM, Attardet T. Hereditary colorectal cancer syndromes: molecular genetics, genetic counseling, diagnosis and management. Fam Cancer 2008;7(1):27-39.
8. Walker JL, Piedmonte MR, Spirtos NM, Eisenkop SM, Schlaerth JB, Mannel RS, et al. Laparoscopy compared with laparotomy for comprehensive surgical staging of uterine cancer: Gynecologic Oncology Group Study LAP2. J Clin Oncol 2009;27(32):5331-6. https://pubmed.ncbi.nlm.nih.gov/19805679/
9. Janda M, Gebski V, Brand A, Hogg R, Jobling TW, Land R, et al. Quality of life after total laparoscopic hysterectomy versus total abdominal hysterectomy for stage I endometrial cancer (LACE): a randomised trial. Lancet Oncol 2010;11(8):772-80. https://pubmed.ncbi.nlm.nih.gov/20638899/
10. Mourits MJ, Bijen CB, Arts HJ, ter Brugge HG, van der Sijde R, Paulsen L, et al. Safety of laparoscopy versus laparotomy in early-stage endometrial cancer: a randomised trial. Lancet Oncol 2010;11(8):763-71. https://pubmed.ncbi.nlm.nih.gov/20638901/
11. Wright JD, Buck AM, Shah M, Burke WM, Schiff PB, Herzog TJ. Safety of ovarian preservation in premenopausal women with endometrial cancer. J Clin Oncol 2009;27(8):1214-9. https://pubmed.ncbi.nlm.nih.gov/19171707/
12. Obstetrics, I.F.o.G.a. Staging of endometrial cancer. 2019  29 Oct. 2020].
13. Mariani A,  Dowdy SC, Cliby WA, Haddock MG, Keeney GL, Lesnick TG, et al. Efficacy of systematic lymphadenectomy and adjuvant radiotherapy in node-positive endometrial cancer patients. Gynecol Oncol 2006;101(2):200-8. https://pubmed.ncbi.nlm.nih.gov/16510174/
14. Nomura H,  Aoki D, Suzuki N, Susumu N, Suzuki A, Tamada Y, et al. Analysis of clinicopathologic factors predicting para‚Äźaortic lymph node metastasis in endometrial cancer. Int J Gynecol Cancer 2006;16(2):799-804. https://pubmed.ncbi.nlm.nih.gov/16681764/
15. Nagar H, Dobbs S, McClelland R, Price J, McCluggage M, Grey A. The diagnostic accuracy of magnetic resonance imaging in detecting cervical involvement in endometrial cancer. Gynecologic Oncology 2006;103(2):431-4.
16. Chung HH, Kang SB, Cho JY, Kim JW, Park NH, Song YS, et al. Accuracy of MR imaging for the prediction of myometrial invasion of endometrial carcinoma. Gynecol Oncol 2007;104(3):654-9. https://pubmed.ncbi.nlm.nih.gov/17095081
17. Orshan SA, Furniss KK, Forst C, Santoro N. The lived experience of premature ovarian failure. J Obstet Gynecol Neonatal Nurs 2001;30(2):202-8.
18. Atsma F,  Bartelink MEL, Grobbee DE, van der Schouw YT. Postmenopausal status and early menopause as independent risk factors for cardiovascular disease: a meta-analysis. Menopause 2006;13(2):265-79. https://pubmed.ncbi.nlm.nih.gov/16645540/
19. Rocca WA, Bower JH, Maraganore DM, Ahlskog JE, Grossardt BR, de Andrade M, et al. Increased risk of cognitive impairment or dementia in women who underwent oophorectomy before menopause. Neurology 2007;69(11):1074-83. https://pubmed.ncbi.nlm.nih.gov/17761551/
20. Jacobsen BK, Nilssen S, Heuch I, Kvåle G. Does age at natural menopause affect mortality from ischemic heart disease? J Clin Epidemiol 1997:50(4):475-9. https://pubmed.ncbi.nlm.nih.gov/9179106/
21. Cooper GS, Sandler DP. Age at natural menopause and mortality. Ann Epidemiol 1998;8(4):229-35. https://pubmed.ncbi.nlm.nih.gov/9590601/
22. Cummings SR, Browner WS, Bauer D, Stone K, Ensrud K, Jamal S, Ettinger B. Endogenous hormones and the risk of hip and vertebral fractures among older women. N Engl J Med 1998;339(11):733-8. https://pubmed.ncbi.nlm.nih.gov/9731089/
23. Barakat RR, Bundy BN, Spirtos NM, Bell J, Mannel RS, Gynecologic Oncology Group Study. Randomized double-blind trial of estrogen replacement therapy versus placebo in stage I or II endometrial cancer: a Gynecologic Oncology Group Study. J Clin Oncol 2006;24(4):587-92. https://pubmed.ncbi.nlm.nih.gov/16446331/
24. Shamshirsaz AA, Withiam-Leitch M, Odunsi K, Baker T, Frederick PJ, Shashikant L. Young patients with endometrial carcinoma selected for conservative treatment: a need for vigilance for synchronous ovarian carcinomas, case report and literature review. Gynecologic Oncology 2007;104(3):757-60.
25. Walsh C, Holschneider C, Hoang Y, Tieu K, Karlan B, Cass I. Coexisting ovarian malignancy in young women with endometrial cancer. Obstetrics & Gynecology 2005;106(4):693-9. https://europepmc.org/article/med/16199623
26. Lee TS, Jung JY, Kim JW, Park NH, Song YS, Kang SB, et al. Feasibility of ovarian preservation in patients with early stage endometrial carcinoma. Gynecologic Oncology 2007;104(1):52-7.
27. Wright JD, Buck AM, Shah M, Burke WM, Schiff PB, Herzog TJ. Safety of ovarian preservation in premenopausal women with endometrial cancer. J Clin Oncol 2009;27(8):1214-9. https://europepmc.org/article/med/19171707
28. Ugaki H, Kimura T, Miyatake T, Ueda Y, Yoshino K, Matsuzaki S, et al. Intraoperative frozen section assessment of myometrial invasion and histology of endometrial cancer using the revised FIGO staging system. Int J Gynecol Cancer 2011;21(7):1180-4. https://pubmed.ncbi.nlm.nih.gov/21795987/
29. Kumar S,  Medeiros F, Dowdy SC, Keeney GL, Bakkum-Gamez JN, Podratz KC, et al. A prospective assessment of the reliability of frozen section to direct intraoperative decision making in endometrial cancer. Gynecolo Oncol 2012;127(3):525-31. https://pubmed.ncbi.nlm.nih.gov/22940491/