CARCINOMA OF THE UTERUS
This is the ninth most common malignancy in women with an incidence of 13 per 100,000 of the population in the UK. In the USA, approximately 4 % of women will develop uterine cancer in a lifetime. The most common histological type is adenocarcinoma, and adenomatous hyperplasia (endometrial precancer, endometrial intraepithelial neoplasia) may be the premalignant lesion. Of all endometrial adenocarcinomas, the endometrioid histology is the most common. Squamous cell carcinomas, leiomyosarcomas, and mixed mesodermal Tumours may occur but are rare.
Epidemiological studies have shown a slight increase in RR for endometrial cancer in women with a family history of this cancer, leading to the conclusion that about 1 % of endometrial cancers may be explained by genetic factors. Endometrial adenocarcinoma is a component cancer of Lynch syndrome (previously known as hereditary non-polyposis colorectal cancer syndrome) and of Cowden syndrome. In one large French study that attempted to control for ascertainment bias, the risk to age 70 for endometrial carcinoma among MLH1 mutation carriers was 54 % (95 % CI 20–80 %), for MSH2 it was 21 % (8–77 %), and 16 % (8–32 %) for MSH6. While the point estimates are of definite value, the confidence intervals are too broad to be useful in the clinic. In contrast, a recent review of 113 families with MSH6 mutations gave a much higher estimate of a 44 % risk of endometrial cancer in mutation carriers to 80 years age (95 % CI = 30–58 %); and for any cancer associated with Lynch syndrome, and 47 % (95 % CI = 32–66 %) for men and 40 % (95 % CI = 32–52 %) and 65 % (95 % CI = 53–78 %) for women.
Compared with incidence for the general population, female mutation carriers had a 26-fold increased incidence of endometrial cancer (HR = 25.5, 95 % CI = 16.8–38.7) and a sixfold increased incidence of other cancers associated with Lynch syndrome (HR = 6.0, 95 % CI = 3.4–10.7) (Baglietto et al 2010). This demonstrates some of the issues when comparing studies that focus on cancer-dense pedigrees, as often seen in the family cancer clinic, with those that are population-based or that adjust for ascertainment bias in various ways.
In the French study, the risk of endometrial cancer by age 40 years for all three genes was two percent or lower, indicating that intensive early screening is probably not justified. In an international collaborative study, the 10-year cumulative risk of endometrial cancer for carriers of mismatch repair gene mutations (grouped together) who had not previously had cancer was approximately 10 % (95 % CI 3.5–26 %) (Win et al. 2012). In contrast, the same group reported that the 10-year cumulative risk of endometrial carcinoma was 23.4 % (95 % CI: 15–36 %) for women with mismatch repair gene mutations and a previous diagnosis of colorectal cancer. Roughly one- quarter of women diagnosed with a Lynch syndrome-associated colorectal cancer will develop endometrial cancer within 10 years of their diagnosis (Obermair et al. 2010). These findings should be taken into account when considering screening and preventive surgery options. Notably, there was no evidence that women with MSH2 mutations were at higher risk of endometrial cancer than were female MLH1 carriers, as previously suggested (Vasen et al. 2001). A retrospective study showed that prophylactic surgery is effective prevention for endometrial and ovarian cancer in MMR gene mutation carriers (Schmeler et al. 2006), but prospective studies have not been conducted. The risk of ovarian cancer was 3 % by age 50 in the French study (Bonadona et al. 2011) and was 3 % 10 years after the identification of a MMR mutation in the Cancer Family Registry study (Win et al. 2012). Since the risk for MLH1 and MSH2 carriers in the French study increased rapidly after age 50 to reach 20–25 % by age 70, a strong case for peri- or postmenopausal hysterectomy with bilateral salpingo-oophorectomy can be made for MMR mutation gene carriers (NB fallopian tube cancer has been reported in Lynch syndrome patients) (Palma et al. 2008).
In terms of identifying Lynch syndrome in women with endometrial cancer, it has been pointed out that the difficulty in identifying MMR gene mutation carriers on clinical or morphological grounds justifies the use of immunohistochemistry for the four MMR proteins in all incident cases of endometrial cancers (Clarke and Cooper 2012). Nevertheless, it is clear that germline mutations would be found in a very small proportion of all such women tested.
Endometrioid endometrial carcinomas occur in women with Cowden syndrome, and a recent study estimated the lifetime risk for endometrial cancer to be 28 % (Tan et al. 2012), similar to the risk seen in MSH2 mutation carriers. If confirmed, this would suggest preventive hysterectomy and enhanced surveillance might be indicated in PTEN mutation carriers. It is considered a major criterion for the clinical diagnosis of Cowden syndrome Clinical surveillance for uterine malignancies in individuals at risk for endometrial cancers should be considered for all at-risk individuals. Indeed, the US-based National Comprehensive Cancer Network (NCCN) practice guidelines recommend annual uterine surveillance by blind repel biopsies of the endometrium from the age of 30 years for women with Lynch syndrome and from the age of 35–40 years for women with Cowden syndrome. After menopause, surveillance would change to annual endometrial (transabdominal or transvaginal) ultrasound with biopsy of suspicious lesions. These recommendations are similar to those put forward in 2006 by a group of European experts (Vasen et al. 2007), although since the value of surveillance is still unknown, the recommendation is that this should be offered to MMR mutation carriers from 35 to 40 years of age, preferably as part of a clinical trial (Vasen et al. 2013). Depending on their age, women who carry MMR gene mutations and have colorectal neoplasia should consider the option of concomitant prophylactic hysterectomy when they undergo bowel surgery for neoplasia.