Patients affected with Lynch syndrome develop colorectal cancer before the age of 50 years, and in around one-third of the patients, another HNPCC-related malignancy occurs within 10 years [13]. Individuals affected with Lynch syndrome have a 25–70 % lifetime risk of developing endometrial carcinoma [3]. Now, it is known that more than 50 % of the affected patients present with endometrial cancer as their sentinel cancer [5].

These patients usually do not have features of estrogen excess like obesity, diabetes mellitus, estrogen, tamoxifen use, or polycystic ovarian syndrome [14]. An association with low body mass index (BMI) has been suggested [15]. They can present with irregular menstrual bleeding but are less likely to be associated with endometrial hyperplasia. A clinical suspicion of Lynch syndrome should arise when a patient is presenting with endometrial cancer without the usual risk factors. A patient has 25 % chance of developing a second cancer in 10 years and 50 % chance at 15 years following the diagnosis of a Lynch syndrome-related endometrial carcinoma [14]. Therefore, a clinical suspicion and diagnosis will help in screening for other cancers and will also be beneficial for the patient and her family members.

Lynch syndrome is caused by germline mutations in the MMR genes MLH1, MSH 2, MSH 6, and PMS 2. Rarely patients can have deletions of the EPCAM gene upstream to the MSH2 gene causing Lynch syndrome [8]. The MMR genes provide stability to the DNA by correcting the mismatches that are produced during DNA replication. Any mutation in the MMR gene causes loss of function and microsatellite instability (MSI) leading to the formation of cancer [16]. MSI can also be caused by an epigenetic mechanism – hypermethylation of MLH1 promoter gene leading to gene silencing and MSI. This is seen in 20–25 % of patients with sporadic endometrial cancer [17]. Carcinogenesis in the presence of MSI appeared to be due to frame-shift mutations of microsatellite repeats within the coding regions of the genes. PTEN seems to be the candidate gene in endometrial carcinoma [18].

Frequency of mutations of MMR genes in Lynch syndrome-related endometrial carcinomas is 50–66 % for MSH2, 24–40 % for MLH1, 10–13 % for MSH 6, and less than 5 % for PMS2 [19, 20]. Even though MSH6 mutations are less frequent, they have an increased risk of endometrial cancer compared to individuals with MSH2 or MLH1 mutations [3].

It has been noted that endometrial cancers due to Lynch syndrome arise predominantly in the lower uterine segment. Overall 10–15 % of the lower uterine segment tumors are associated with Lynch syndrome [11, 21]. Both endometrioid and non-endometrioid tumors occur in Lynch syndrome. The non-endometrioid varieties include clear cell carcinoma, serous carcinoma of the endometrium, carcinosarcoma, and also undifferentiated tumors of the endometrium [22, 23]. In a study by Honoré et al. [24], it was found that MSI correlates with high tumor grades in endometrioid adenocarcinoma. The MSI-related beta-catenin mutations cause the upregulation of Cmyc which in turn stimulates CDK4, leading to the inactivation of the retinoblastoma suppressor gene, thus activating the CDK4/cyclin complex and sequestering the cell cycle inhibitors like p16, p21, and p27. This is the probable mechanism behind the high tumor grade in MSI [24]. Honoré et al. also state that the MSI-related endometrioid adenocarcinoma arises in a background of atrophic endometrium and is associated with more myometrial invasion, lymphovascular space invasion, and nodal metastases, which are adverse prognostic factors in carcinoma of the endometrium.

There are several histological features that are linked to MSI and MMR protein deficiency in endometrioid adenocarcinomas. Most prominent among them are the undifferentiated and de-differentiated tumor patterns [3]. Other features that are thought to be suggestive of MSI are prominent peritumoral lymphocytes, dense tumor infiltrating lymphocytes (TIL), and tumor heterogeneity [3]. The undifferentiated tumor pattern was initially described by Altrabulsi et al. [25] as solid sheets of medium-sized, monotonous epithelial cells with complete absence of glandular proliferation. The term de-differentiated carcinoma is used when an undifferentiated tumor pattern is associated with a focus of well to moderately differentiated endometrioid adenocarcinoma [26]. Tumor-infiltrating lymphocytes are considered as a marker of MMR protein deficiency and are seen in both genetic and sporadic conditions. More than 42 TIL per 10 high power fields has been proposed as more suggestive of Lynch syndrome [27]. Peritumoral lymphocytes are defined as readily appreciable aggregates of lymphocytes around the tumor at scanning magnification [28]. Tumor heterogeneity is defined as a tumor having two or more morphologically separate patterns, each constituting at least 10 % of the tumor with each component being juxtaposed and not intimately admixed [28].

Pelvic epithelial tumors, previously referred to as “ovarian tumors” found in association with Lynch syndrome, are well to moderately differentiated endometrioid carcinomas and clear cell carcinomas. Pelvic epithelial clear cell ovarian carcinoma in a younger patient has a strong association with Lynch syndrome [15, 29]. There are reports of synchronous endometrioid carcinomas of uterus and pelvic clear cell carcinoma ovary in women with MMR protein defects [15, 29].

In unselected endometrial cancer patients, 1.8–2.1 % MMR gene mutation rates have been found [10, 30]. These rates are similar to the MMR mutation rates found in colorectal carcinoma [31]. In patients below the age of 50 years affected by endometrial cancer, the rates of MMR gene mutations have been found to be as high as 9 % [32]. The identification of patients affected with these mutations is important as they have increased risk for synchronous and metachronous cancers. They themselves and their family members would benefit from surveillance methods to detect other related cancers and genetic counseling. Also there could be prognostic and therapeutic implications for the affected patients [27]. The Amsterdam criteria [6] and Bethesda guidelines [7] focus mainly on colorectal cancers. The SGO guidelines [9] focus on gynecologic cancers and give better screening results [12] but still underestimate these cancers.

Screening for Lynch syndrome in all patients of endometrial cancer has been advocated and also implemented by some centers [14]. But it is not practical to screen all patients with endometrial cancers for Lynch syndrome. Many criteria have been proposed based on the age, family history, and pathological factors for screening Lynch syndrome. Using 50 years as a cutoff age will cause underdetection, as many women (especially patients with MSH6 mutations) above the age of 50 years present with MMR protein-deficient endometrial cancer [33]. Using the tumor morphology – lower segment tumors, presence of TIL, peritumoral lymphocytes, and undifferentiated and dedifferentiated tumor patterns – has been suggested to increase the detection rates of endometrial cancer patients at risk of HNPCC [27].

Use of immunohistochemistry (IHC) to detect the four main MMR proteins is an easy procedure and can detect most mutations, at significant direct cost but potential high returns and value over the long run for both the patient and her family [34]. Kwon et al. compared various criteria for Lynch syndrome testing for women with endometrial cancer and found that IHC triage of women having endometrial cancer at any age having at least one first-degree relative with Lynch associated cancer is a cost-effective strategy for Lynch syndrome detection [34].

The definitive way to detect Lynch syndrome is mutational analysis of the MMR gene DNA. In view of the cost, it is suggested that mutational analysis be used only as a confirmatory test after screening with IHC, MSI analysis, and MLH1 methylation studies [3].

Modica et al. have reported a sensitivity of 91 % and a specificity of 83 % for IHC in detecting MSI phenotype in endometrial carcinoma when antibodies against all four MMR proteins were used [35]. As MLH1 dimerizes with PMS 2 and MSH2 dimerizes with MSH 6 in their functional state, mutations of MLH1 and MSH2 will lead to loss of PMS2 and MSH 6, respectively. Using antibodies only against MLH1 and MSH2 only provides 69 % sensitivity and 100 % specificity and can be used as an economical alternative to the four-antibody test [35]. IHC has the advantage being a simple and less expensive test and can direct the gene sequencing to one or more specific genes.

MSI analysis is by polymerase chain reaction (PCR) amplification of the National Cancer Institute reference loci (BAT25, BAT26, D2S123, D5S346, and D17S250) on tumor and normal tissue for each patient [36]. Tumor with no instability detected is termed as MSI stable, instability at one focus is termed MSI low, and instability at two loci is termed MSI high. MSH6 mutations may be MSI stable or MSI low, and if MSI is used as a screening test, some mutation carriers may not be detected [3].

All tumors showing inactivation of MLH1 by IHC or MSI analysis should be subjected MLH1 promoter methylation assay. This is because MLH1 inactivation can occur also due to an acquired mechanism – MLH1 promoter methylation resulting in loss of protein. Tumors showing MLH1 promoter methylation are likely to be associated with Lynch syndrome [3].

DNA MMR mutation test is the confirmatory test to establish the diagnosis of Lynch syndrome. This is usually performed when the abovementioned screening tests show a strong possibility of Lynch syndrome [3].

There is limited data on the efficacy of endometrial cancer screening in women with Lynch syndrome. Vasen et al. have recommended annual physical examination and transvaginal sonography along with endometrial biopsy from the age of 30 to 35 years [37]. NCCN still states that there is no clear evidence to support screening for endometrial cancer in Lynch syndrome [38]. This may stem from the fact that screening for endometrial cancer had not produced improved outcomes, as well as reports of interval carcinomas not detected by screening [39]. But Renkonen‐Sinisalo et al. showed that screening with endometrial biopsies in women affected with Lynch syndrome detected endometrial cancers at an early stage and there were more frequent detection of premalignant lesions which enabled prophylactic hysterectomy in the screened group. Compared with the unscreened group presenting with mutation-positive endometrial cancer, the surveillance group presented with a more favorable stage distribution and there were no deaths due to endometrial cancer [40].