What is the evidence based surgical approach for bilateral salpingo–oophorectomy in premenopausal women with low and high risk apparent early stage endometrial cancer

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What is the evidence based surgical approach for bilateral salpingo–oophorectomy in premenopausal women with low and high risk apparent early stage endometrial cancer?

Common belief has been that uterine cancer is a disease of oestrogen imbalance, given that the risk factors are:

  • Relative infertility
  • Obesity
  • Non-insulin-dependent diabetes mellitus

The accepted surgical management of endometrial cancer has been total hysterectomy, and bilateral salpingo-oophorectomy. So widespread is the belief that bilateral salpingo-oophorectomy is a necessary component of management, several published guidelines do not even reference its use.[1][2] Indeed, the major surgical discussion has been when, and on whom, to perform pelvic lymph node sampling.

The majority of women with uterine cancer will expect to have a good prognosis and the majority of women with uterine cancer are post-menopausal; thus, removal of the ovaries is not seen as a major concern.

However, 10% of women with endometrial cancer will be diagnosed premenopausally. For these women, premature surgical menopause will potentially seriously affect their quality of life. Thus, the merits of salpingo-oophorectomy as part of the routine surgical treatment must be carefully considered and evaluated.

Prognostic variables include stage, histological subtype and differentiation and depth of myometrial penetration. In their seminal paper, Creasman et al[3] studied 621 patients with clinical stage I endometrial cancer, looking at the surgico- pathological patterns of spread. Thirty-four patients (5%) had metastatic disease to one or both ovaries. For those with adnexal metastases, 32% had pelvic node metastases, compared with 8% positivity in those with no metastases. This study is a case collection from 43 institutions with 1180 patients enrolled, but only 621 were the subject of the paper. Although it would not be admissible as evidence by today’s standards, this historic paper sets the scene for further thought.[3]

The common belief has been that uterine cancer is a disease of oestrogen imbalance. This has applied predominantly to the endometrioid histology type, as it frequently arises in a background of atypical adenomatous hyperplasia.

There is no evidence that either serous papillary or clear cell carcinomas follow this pattern.

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Premenopausal women and routine salpingo-oophorectomy

In a premenopausal woman, there may be several scenarios to consider in the evaluation and recommendation of bilateral salpingo-oophorectomy.

  • Is there a risk of retaining ovaries with occult metastases?
  • Is there a risk of metachronous ovarian and endometrial cancer?
  • Is there a risk that continued oestrogen production might contribute to an increased recurrence rate?
  • Is there a risk of Lynch Syndrome?

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Risk of leaving occult metastases in situ

About 5% of endometrial cancers will have synchronous ovarian disease.[3][4] This may be either synchronous primaries, or metastatic disease from the endometrium to the ovary. However, the literature is sparse, conflicting, and based on retrospective case series.[5][6] Lee et al, performed a retrospective review at a single Korean institution and found a coexisting ovarian malignancy in 19 of 261 (7.3%) women with endometrial cancer.[5] Twelve cases were metastatic and seven were synchronous tumours. All patients had independent risk factors; for example, intraoperative extra-uterine disease, non-endometrioid histology, lymph node metastases and age >45 years. In women with no evidence of intraoperative disease, only 2 of 206 (0.97%) had ovarian disease and none were younger than 45 years of age. Their conclusion was that the risk of coexisting ovarian malignancy in women without predictable risk factors was minimal. This conclusion is consistent with the Creasman paper of 1987, which found a high correlation of ovarian metastases with positive nodal disease.

Conversely, Walsh et al conducted a retrospective chart review of 102 women between the ages of 24 and 45 who underwent hysterectomy for endometrial cancer and found that 26 patients (25%) had co-existing ovarian tumours.[6] Of these 26 cases, 23 were classified as synchronous primaries and three as metastases. The authors were not able to identify risk factors which predicted the presence of ovarian tumours. Indeed, 69% of tumours occurred in patients with grade 1 endometrial cancer and 58% in patients with less than 50% myometrial invasion. Information on the intra-operative appearance of the ovaries was available on 21 of the 26 patients with ovarian tumours. Only three of the patients (or 2.9% of the whole group) had what would be considered normal-appearing ovaries. The authors concluded that if ovaries were to be preserved at the time of hysterectomy in young women with endometrial cancer, careful assessment of the adnexa is warranted.

A population based study of 1618 women diagnosed with endometrial cancer between 1970 and 2005, identified 44 patients who were <45 years of age at the time of diagnosis.[7] Compared to the 1321 patients who were older than 45 years, the younger patients were more likely to have synchronous ovarian cancers (14% vs 2%). In the six younger patients with ovarian malignancies, five were evident at the time of surgery and only one at final pathological analysis. There was no difference in five year survival. Unfortunately, the study did not report on the presence or absence of adverse risk factors in patients with synchronous ovarian tumours.

Lee et al reviewed the Tumour Registers of 14 tertiary Korean referral hospitals to determine the outcomes of 175 patients with endometrial cancer, ranging in age from 25 to 57, who elected ovary-saving surgery. Ovary-preserving surgery was possible in 101 of the 175 women (57.7%). Median duration of follow-up was 55.0 months (range 6.2-180.0 months). Recurrence-free survival was 94.3%. Seven patients experienced a recurrence, all of whom had poor prognostic factors. None had had stage I disease. None were randomised and all were self-selected.[8]

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Risk of metachronous ovarian cancer in young women

Metachronous tumours are defined as those tumours which develop on multiple separate occasions. The literature in regard to development of ovarian cancer subsequent to primary diagnosis of endometrial cancer is sparse. Lee reported no metachronous tumours in 101 endometrial cancer patients who had ovarian preserving surgery and were followed for a median of 55 months. None of these studies made any reference to family history of Lynch Syndrome.[8]

Endometrioid cancers and risk of activation of quiescent endometrial cancer cells by endogenous oestrogen

Epidemiological studies do not support this hypothesis. Most studies are retrospective or small prospective, non-randomised studies. The only study that attempted to answer this question by randomising endometrial cancer patients to either estrogen replacement therapy or placebo, was unable to be completed.[9] It closed prematurely because of concerns regarding a decreased accrual rate as a result of the Women’s Health Initiative Study results and a lower than expected recurrence rate in patients on the trial.

The risks of castration in young women are not insignificant, with increase risk of cardiovascular disease, cognitive impairment, osteoporosis, vasomotor instability and even death.[10][11][12][13][14] A large population- based cohort study of 1091 women who underwent bilateral salpingo-oophorectomy for non-cancer indications were compared to a population bases referent sample of 2383 women. The authors found that early castration (before the age of 45 years) was associated with a higher mortality for women who did not receive oestrogen.[13] A further large study reported on a subset of 10,094 women enrolled in the Nurses’ Health Study, who had either oophorectomy or ovarian conservation and had never used oestrogen replacement therapy, and showed that oophorectomy before age 50, but not after age 50, was associated with a significantly increased risk of all cause mortality (HR 1.40, 95% CI 1.01-1.96).[14]

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Other histological types

There is a paucity of evidence to inform guidelines regarding extent of surgery for serous papillary and clear cell carcinomas, especially with regard to possible retention of ovaries in younger women, and none with credible level of evidence of hormone sensitivity.

Lynch Syndrome

Lynch syndrome (also known as HNPCC) is characterised by an autosomal dominant inheritance pattern, caused by a germline mutation in a mismatch repair gene. It denotes an increased risk of colorectal cancer, but gynaecological cancers are also over-represented.

Lifetime risk of endometrial cancer associated with the Lynch Syndrome varies according to the gene involved. In a recent large study of women with Lynch syndrome the risk of endometrial cancer was 54% (95% CI 20-80%), 21% (95% CI, 8%-77%), and 16% (95% CI, 8%-32%) for MLH1, MSH2 and MSH6 respectively, although estimates have varied.[15] The corresponding risks for ovarian cancer were 20% (95% CI, 1%-65%), 24% (95% CI, 3%-52%), and 1% (95% CI, 0%-3%)., but the number of MSH6 carriers was relatively small.

This increased future risk of ovarian/fallopian tube cancer warrants consideration of BSO at the time of therapeutic hysterectomy in women with early endometrial cancer either with Lynch syndrome or at-risk of Lynch Syndrome.

Conclusion

As seen from the scenarios above, there is no uniform answer to the dilemma of retention or removal of ovaries in premenopausal women with endometrial cancer.

A full discussion needs to take place, as to the risks and benefits of removal or retention of ovaries in premenopausal women who have no additional risk factors.

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Evidence summary and recommendations

Evidence summary Level References
The risk of a coexisting ovarian malignancy in young women (less than 45 years of age) with endometrial cancer is minimal (<3%), in patients who have clinically normal ovaries at the time of operation, endometrioid histology and are at low risk of lymph node metastases. III-3 [5], [7]
Survival does not appear to be affected in young patients in whom ovaries are left in situ. IV [8]
Premature menopause in young women results in an increased risk of cardiovascular disease, cognitive impairment, osteoporosis, vasomotor instability and death. III-2 [10], [11], [12], [13], [14]


Recommendation Grade
Consideration should be given to retaining ovaries in young women less than 45 years of age with endometrial cancer whose ovaries appear normal at operation and have no adverse risk factors.
C


Evidence summary Level References
A woman with Lynch Syndrome has up to 24% lifetime risk of developing ovarian cancer. III-3 [15]


Recommendation Grade
Patients with Lynch Syndrome should be counselled that their ovaries should be removed at the time of hysterectomy given the high lifetime risk of developing ovarian cancer.
C

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References

  1. Plataniotis G, Castiglione M, ESMO Guidelines Working Group. Endometrial cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2010 May;21 Suppl 5:v41-5 [Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/20555100].
  2. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology. Uterine Neoplasms Version 1.2011. 2010 Jan 1;National Comprehensive Cancer Network. [Abstract available at http://www.nccn.org/professionals/physician_gls/pdf/uterine.pdf].
  3. 3.0 3.1 3.2 Creasman WT, Morrow CP, Bundy BN, Homesley HD, Graham JE, Heller PB. Surgical pathologic spread patterns of endometrial cancer. A Gynecologic Oncology Group Study. Cancer 1987 Oct 15;60(8 Suppl):2035-41 [Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/3652025].
  4. Gemer O, Bergman M, Segal S. Ovarian metastasis in women with clinical stage I endometrial carcinoma. Acta Obstet Gynecol Scand 2004 Feb;83(2):208-10 [Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/14756742].
  5. 5.0 5.1 5.2 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. Gynecol Oncol 2007 Jan;104(1):52-7 [Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/16887175].
  6. 6.0 6.1 Walsh C, Holschneider C, Hoang Y, Tieu K, Karlan B, Cass I. Coexisting ovarian malignancy in young women with endometrial cancer. Obstet Gynecol 2005 Oct;106(4):693-9 [Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/16199623].
  7. 7.0 7.1 Navarria I, Usel M, Rapiti E, Neyroud-Caspar I, Pelte MF, Bouchardy C, et al. Young patients with endometrial cancer: how many could be eligible for fertility-sparing treatment?. Gynecol Oncol 2009 Sep;114(3):448-51 [Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/19560801].
  8. 8.0 8.1 8.2 Lee TS, Kim JW, Kim TJ, Cho CH, Ryu SY, Ryu HS, et al. Ovarian preservation during the surgical treatment of early stage endometrial cancer: a nation-wide study conducted by the Korean Gynecologic Oncology Group. Gynecol Oncol 2009 Oct;115(1):26-31 [Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/19635630].
  9. 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 Feb 1;24(4):587-92 [Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/16446331].
  10. 10.0 10.1 Rivera CM, Grossardt BR, Rhodes DJ, Brown RD Jr, Roger VL, Melton LJ 3rd, et al. Increased cardiovascular mortality after early bilateral oophorectomy. Menopause 2009;16(1):15-23 [Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/19034050].
  11. 12.0 12.1 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 Sep 11;69(11):1074-83 [Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/17761551].
  12. 13.0 13.1 13.2 Rocca WA, Grossardt BR, de Andrade M, Malkasian GD, Melton LJ 3rd. Survival patterns after oophorectomy in premenopausal women: a population-based cohort study. Lancet Oncol 2006 Oct;7(10):821-8 [Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/17012044].
  13. 14.0 14.1 14.2 Parker WH, Broder MS, Chang E, Feskanich D, Farquhar C, Liu Z, et al. Ovarian conservation at the time of hysterectomy and long-term health outcomes in the nurses' health study. Obstet Gynecol 2009 May;113(5):1027-37 [Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/19384117].
  14. 15.0 15.1 Bonadona V, Bonaïti B, Olschwang S, Grandjouan S, Huiart L, Longy M, et al. Cancer risks associated with germline mutations in MLH1, MSH2, and MSH6 genes in Lynch syndrome. JAMA 2011 Jun 8;305(22):2304-10 [Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/21642682].

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Supporting material

Initial literature search

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