- Open Access
Lynch syndrome related endometrial cancer: clinical significance beyond the endometrium
- Yiying Wang†1, 2, 3,
- Yue Wang†1, 2, 3,
- Jie Li2, 3, 4,
- Janiel Cragun2, 5,
- Kenneth Hatch2, 5,
- Setsuko K Chambers2, 5Email author and
- Wenxin Zheng2, 3, 4, 5Email author
© Wang et al.; licensee BioMed Central Ltd. 2013
- Received: 29 January 2013
- Accepted: 17 March 2013
- Published: 25 March 2013
Lynch syndrome (LS), an autosomal dominant inherited cancer susceptibility syndrome, also known as hereditary non-polyposis colon cancer (HNPCC), is caused by a germline mutation in one of several DNA mismatch repair (MMR) genes. LS is the most common presentation of hereditary colorectal cancer (CRC), accounting for about 2–5% of all CRC cases. More recently, it is found that a similar number of endometrial cancers is also due to one of the MMR gene mutations. There has been significant progress in LS-related CRC in terms of molecular pathogenesis, risks, genetic basis, and cancer prevention. In contrast, the advance about LS-related endometrial cancer (EC) is very much limited. In this commentary, we summarize the main clinicopathologic features of LS-related EC and propose universal screening for LS in individuals with endometrial cancer.
- Endometrial Cancer
- Lynch Syndrome
- BRAF Mutation
- Clear Cell Carcinoma
- Universal Screening
Lynch syndrome (LS), an autosomal dominant inherited cancer susceptibility syndrome, also known as hereditary non-polyposis colon cancer (HNPCC), is caused by a germline mutation in one of several DNA mismatch repair (MMR) genes: MLH1, MSH2, MSH6 or PMS2. LS is the most common presentation of hereditary colorectal cancer (CRC), accounting for about 2–5% of all CRC cases [1, 2]. There has been significant progress in LS-related CRC in terms of molecular pathogenesis, risks, genetic basis, and cancer prevention. Moreover, universal screening for LS in all individuals affected by CRC has been adopted by national working groups, with algorithms for cost-effective screening developed .
Recently, focus has shifted to LS-related endometrial cancer (EC) as women with LS have a 40-60% chance of presenting with EC as the first clinical manifestation . From a clinical perspective, confirmation that an EC is LS-related has the potential to influence early detection, screening, and prevention of other LS-associated cancers, more so than a diagnosis of LS related CRC. Many countries, including United States, have started screening patients with EC to identify those with LS, thereby leading to earlier screening for CRC. Earlier screening would aim to either prevent CRC or detect it in earlier stages . In that 50% of LS patients present with endometrial cancer first, diagnosis of LS at the time of diagnosis of the endometrial cancer, may prove to be a cost-effective approach, although currently untested. It may be more cost effective mainly because the mortality of CRC is much higher than that of EC. At this time, although several groups nationally are now focusing on LS-related ECs, research on LS-related EC is still evolving. The majority of physicians and health care providers are not aware of the clinicopathologic features of LS-related EC. Further, many are unclear as to how to make the diagnosis of LS-related EC from clinicopathologic perspective and how to best confirm the diagnosis of LS on a genetic level. In this commentary, we summarize the main clinicopathologic features of LS-related EC and propose universal screening for LS in individuals with endometrial cancer.
Tissue testing (immunohistochemistry for MMR proteins, MSI analysis, and MLH1 methylation analysis) has been used as a practical first step in the evaluation of individuals thought to be at risk for having LS. Practically, each of these tests can be performed using formalin-fixed, paraffin-embedded tissues and commercially available antibodies. In many institutions, MSI analysis is performed in parallel with immunohistochemistry for MLH1, MSH2, MSH6, and PMS2. It requires both tumor and normal non-tumor tissues. For endometrial cancer, adjacent benign endometrium and stromal cells in addition to normal cervix or ovarian tissues could be used as normal controls. For those tumors with MSI and loss of MLH1 by immunohistochemistry, a PCR-based assay to detect for hypermethylation of the MLH1 promoter is performed. If methylation is present, it is much more likely that the patient has a sporadic endometrial carcinoma rather than a LS-related EC. For CRC, BRAF mutation is also an explanation for loss of MLH1 protein expression. However, studies  of EC specimens show that BRAF mutation is very rare, thus BRAF mutation testing is not recommended in endometrial cancers when MLH1 loss is seen. The MLH1 and PMS2 proteins and the MSH2 and MSH6 proteins act as functional pairs, forming heterodimers . Mutation of MLH1 or methylation of MLH1 typically results in loss of immunhistochemical expression of both MLH1 and PMS2. Similarly, mutation of MSH2 usually results in immunohistochemical loss of both MSH2 and MSH6. However, mutation of MSH6 alone usually is associated with loss of MSH6 protein but retention of MSH2 by immunohistochemistry. Similarly, mutation of PMS2 is typically associated with loss of PMS2 protein but retained MLH1 immunohistochemical expression.
Nationally, universal screening for LS in endometrial cancer patients is being advocated, and implemented by several centers. Algorithms for such screening have been developed [16, 35]. In many centers, universal screening for CRC has already been implemented. The incidence in unselected populations of LS in EC patients is 2.3% , which approaches the 3% rate of LS in CRC patients. Usage of standard criteria such as the Amsterdam, Bethesda, or SGO criteria has led to underestimation of the true rate of EC in LS patients. Endometrial cancer is the most common gynecologic malignancy and is the sentinel event in LS 50% of the time.
Patients, particularly with pathologic diagnosis as endometrioid carcinoma, show no evidence of estrogen overstimulation such as low body mass index (no obesity), no history of polycystic ovarian syndrome, nor unopposed estrogen usage;
Patients with a synchronous endometrial and ovarian cancer, particularly clear cell carcinoma of the ovary;
Patients with a family history of apparent LS;
Patients with a personal history colon cancer;
Endometrioid carcinoma without hyperplastic endometrium in the background;
Heterogeneous cancer pathology such as one area with well differentiated carcinoma, but another area with different pathologic patterns such poor differentiation, mucinous features including signet ring cells, and medullary growth pattern;
Tumor-infiltrating lymphocytes or a Crohn-like inflammatory infiltrate invading either front or periphery;
Predominantly low uterine segment location after excluding cervical primary;
Well differentiated (FIGO grade 1) endometrioid carcinoma but with more than 50% myometrial invasion;
History of well differentiated endometrioid carcinoma with recurrence within 2 years after ruling out endometrial serous or clear cell carcinoma.
It is imperative that pathologists communicate with corresponding gynecologists prior to ordering the MMR protein immunohistochemical stains, if the institution is not prepared to implement universal screening for EC patients. Although the above clinicopathologic findings are neither specific nor sensitive, we think this may be a cost effective clinical method to identify patients at risk for LS prior to developing other LS related cancers. Based on the current understanding and clinical experience gained, we are advocating universal screening for patients who are 60 years or younger, and selective screening for those patients older than 60 years based on clinicopathologic findings (see screening algorithm above).
Our understanding of clinicopathologic features, pathogenesis, and the individual role of MMR gene mutation of LS-related ECs is continuing to evolve. Many studies including large scale clinical studies are needed to further characterize the above parameters in order to develop efficient surveillance systems and genetic tests in order to provide ideal diagnostic, therapeutic, and prevention modalities for the majority of LS-related cancers.
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