It is being recognized that, in LS, the risk of EC is equal to, or higher than the risk of CRC. Lifetime risk of LS-related EC is associated with age and a mutation of a specific MMR gene. Patients with MSH6 mutations are at higher risk (64–71%) for developing EC than those with MSH2 or MLH1 mutations (40–50%) [12, 13]. They are also at significantly higher risk of developing EC than CRC. It has long been thought that LS-related EC occurs at younger ages than in sporadic cases. In one study, the mean age at diagnosis for LS-related EC was 49 years compared to 60 years for EC in the general population . In an unselected cohort of endometrial cancers with age younger than 50 years, the incidence of LS was 9% . However, others  have found the mean age in a prospective unselected cohort to be 54 years. If an age cut-off of 50 years old had been selected instead for LS screening, 60% of patients would have been missed . In fact, others have described that 25% of LS patients do not fit standard screening criteria, such as the Amsterdam, Bethesda, and SGO criteria, where age is a prominent factor (cut-off age 50) .
It is interesting to note that LS-related EC sometimes is accompanied (synchronous, or metachronous) by LS-related ovarian cancer. In fact in LS, the lifetime risk for endometrial cancer is 40-60%, and for ovarian cancer, 9-12% . The latter is usually clear cell carcinoma and can present independently and less frequency [4, 20]. Compared to LS-related EC cases, LS-related ovarian cancer tends to have a higher MSH2 mutation rate and occurs in a younger age, average of 45 years old . For patients with LS-related EC, the risk of developing a second cancer is estimated at 25% in 10 years and 50% at 15 years following initial EC diagnosis [22, 23]. In LS, 50% of the time, endometrial cancers present first before the CRC diagnosis, if the diagnoses are not synchronous. Therefore, EC can serve as a ‘sentinel’ cancer for patients themselves and potentially for their family members. Optimally, this provides adequate time to screen for a second cancer leading to either prevention or earlier diagnosis and treatment.
Clinically, studies have revealed that patients with LS-related EC have unique features. Both Type 1 and Type 2 ECs are part of LS [24–26]. In the general population, non-endometrioid EC is typically diagnosed in older women with a mean age of 65 to 68 years [27, 28]. In LS, however, the mean age of diagnosis of these non-endometrioid tumors is 46.4 years, similar to the mean age of LS-related EC overall (46.8 years) . Patients with LS-related EC often have no evidence of estrogen overstimulation such as obesity, diabetes, exogenous estrogen usage, and polycystic ovarian syndrome. Patients may present irregular bleeding, but it is less likely to be found to have endometrial hyperplasia prior to EC diagnosis. LS-related EC is suspected when a patient is diagnosed with EC, but presents without risk factors known to be associated with EC. In addition, low body mass index, relatively young age, and positive family history LS or LS-related cancers should raise suspicion of LS-related EC [29, 30].
Pathologically, there is considerable literature on the presence or absence of distinctive microscopic features in LS-related EC. Historically, many studies correlated the morphologic features of MSI and MLH1 methylation status. In addition, there are many studies correlation LS-related EC to MMR gene mutation status. We summarize the overall pathologic features for LS-related EC as follows:
LS-related ECs tend to be more histologically diverse and can include endometrioid and non-endometrioid histotypes. Clear cell carcinoma, endometrial serous carcinoma, undifferentiated carcinoma, and carcinosarcoma all have been identified as non-endometrioid histology in LS-related ECs [24–26]. In contrast, sporadic ECs that have MSI due to MLH1 methylation are predominantly endometrioid, especially FIGO grades 2 and 3, with the percentage endometrioid histotype reaching 96% .
Microscopic features that have been associated with the presence of high level of MSI include poor differentiation, mucinous features, signet ring cell differentiation, mixed tumor histology, tumor cells growing in a medullary-type pattern, increased tumor-infiltrating lymphocytes, and a Crohn-like inflammatory infiltrate at the tumor invading front or periphery .
LS-related EC cases also have a tendency to involve low uterine segment (LUS). Westin et al. showed that a relatively high percentage (34%) of the LUS cancers had a high level of MSI. Among them, 29% of the LUS ECs were confirmed to be from women with LS . This percentage of LS-related EC with LUS location is extremely high when compared with the incidence of LUS involvement in non LS-related EC [25, 32, 33]. In addition, LS-related EC with LUS involvement is also more associated with hMSH2 mutations .
Although the published data for LS-related EC is limited, it is our opinion that these pathologic features are not sufficiently sensitive and specific to be used in the clinical setting as accurate predictors of the presence of LS. However, they do raise suspicion of LS. Therefore, appropriate tissue testing (described below) followed as appropriate with genetics counseling with germline DNA mutational analysis for suspected MMR genes are needed to confirm if LS is present.