2.1 Risk factors for endometrial cancer

The absolute risk of endometrial cancer in non-users of HRT who present with post-menopausal bleeding ranges from 5.7% to 11.5%.^5,6,7 Evidence level 2+,3

No evidence was identified which determined whether different patterns of PMB, such as one-off or more frequent bleeds, are more or less likely to be associated with endometrial cancer.

2.1.1 AGE

Scottish cancer registration data indicate the background incidence of endometrial cancer by age group for women in Scotland (see Table 1) . Note that these data represent the incidence for all women in the age group whereas the vast majority of women under 50, and a substantial proportion of those between 50 and 60 years, will not yet be post-menopausal. Therefore registration data cannot be used to estimate incidence of endometrial cancer in post-menopausal women under 60 years.

Furthermore, the data in Table 1 include all cases regardless of presentation, and so do not inform as to risk of endometrial cancer in women presenting with PMB. In a representative population of post-menopausal Swedish women it has been found that the incidence of bleeding decreases markedly with age.⁶ It was furthermore shown that the probability of endometrial cancer being present in the women with post-menopausal bleeding increased after 50 years of age, and increased further after 60, 65 and 80 years of age.

Table 1: Age specific rates of cancer of the body of the uterus in Scottish women (1986-95)⁸

Age Group (years)	Rates per 100,000 p.a.
<50	0.4
50 - 59	6.36
60 - 69	8.68
70 - 79	8.22
80+	7.28

2.1.2 HORMONE REPLACEMENT THERAPY (HRT)

Older HRT regimens that utilise unopposed oestrogen increase the relative risk of endometrial carcinoma by around six times after five years of use.⁹ Progestogens are added to HRT regimens to prevent endometrial hyperplasia and cancer: their inclusion reduces the relative risk of endometrial cancer to around 1.5.¹⁰ Protection is provided by either 10-12 days of cyclical progestogens or continuous combined regimens. Evidence level 1++

Sequential (or cyclical) combined regimens cause scheduled bleeding in most users. Continuous combined regimens are associated with a reduced relative risk of endometrial cancer⁹ but may cause unpredictable spotting or bleeding during initial use.^{11, 12} Evidence level 1+,4

The incidence of endometrial abnormalities in women receiving HRT may be higher in the general population than in clinical trial populations because the latter might be investigated before commencing HRT to exclude pre-existing problems. Data on incidence of endometrial cancer recorded from 1997 - 2000 at all CMR (continuous morbidity recording) practices in Scotland is available from the SIGN website. Bleeding in HRT users is less likely to be associated with endometrial carcinoma than bleeding in non-HRT users although benign pathology, such as polyps, may be present.¹³ Evidence level 2+

Clinicians should be aware of the background incidence of endometrial cancer among users and non-users of HRT and in those who present with post-menopausal bleeding.

A HRT should include a progestogen regime which is protective against the endometrial effects of unopposed oestrogen.

2.1.3 TAMOXIFEN

Women receiving tamoxifen in the treatment or prevention of breast cancer experience a three to sixfold greater incidence of endometrial cancer.^14,15,16,17 An increasing number of women are now receiving this therapy. Evidence level 1+

The risk of endometrial cancer rises with both the use of higher doses and increasing duration of tamoxifen use. Treatment beyond five years increases risk by at least fourfold.^{18, 19} Evidence level 2+

Furthermore, there is evidence from one case control study that endometrial cancers occurring in long-term users of tamoxifen have a poorer prognosis (due to less favourable histology and higher stage) than cancers occurring in other women.²⁰ Evidence level 2+

There has been some debate about how closely women on tamoxifen should be monitored for the development of endometrial cancer, including suggestions that this should take the form of periodic investigations in those with no history of PMB. However, evidence mainly from observational studies indicates that periodic investigations are unlikely to be cost-effective.^{21, 22} Therefore, PMB should remain as the primary trigger for investigation of women on tamoxifen. Evidence level 2+

Clinicians should be aware that post-menopausal women receiving tamoxifen therapy, particularly for longer than five years, are at increased risk of endometrial cancer.

2.1.4 OTHER RISK FACTORS

Hereditary non-polyposis colorectal cancer (HNPCC) is one of the commonest cancer family syndromes. Its inheritance is autosomal dominant. It is characterised by a familial aggregation of colorectal cancer in addition to extra-colonic cancers of which endometrial cancer is the commonest.

The estimated lifetime risk of developing endometrial cancer in women carrying these mutations is around 42% to 60%.^{23, 24} Importantly, in contrast to "sporadic" endometrial cancer, women from such affected families usually develop endometrial cancer pre-menopausally.²⁵ Evidence level 2+

See the SIGN guideline on Management of Colorectal Cancer which is under review in 2002.

The evidence on other risk factors is less robust but it suggests there are potential risk groups i.e. obese patients with diabetes; women with hypertension; a past history of hyper-oestrogenism (endogenous or exogenous).^{5, 26} Examples of the latter include women with early menarche and late menopause. However, current evidence is insufficient to quantify this risk as a guide to referral practice. Evidence level 2+,3