**Hereditary Endometrial Carcinoma**

J. Salvador Saldivar

*Texas Tech University Health Sciences Center Department of Obstetrics & Gynecology, Division of Gynecology Oncology, El Paso, Texas USA* 

## **1. Introduction**

38 Cancer of the Uterine Endometrium – Advances and Controversies

Yu, J., Zhang, Y., McIlroy, J., Rordorf-Nikolic, T., Orr, GA. & Backer, JM. (1998b). Regulation

Zhang, D., Sliwkowski, MX., Mark, M., Frantz, G., Akita, R., Sun, Y., Hillan, K., Crowley, C.,

Zhang, X., Gureasko, J., Shen, K., Cole, PA. & Kuriyan, J. (2006). An allosteric mechanism for

Zhang, H., Berezov, A., Wang, Q., Zhang, G., Drebin, J., Murali, R. & Greene, MI. (2007).

Zhong, Z., Wen, Z. & Darnell, JE Jr. (1994). Stat3: a STAT family member activated by

Cancer 4:97-105.

94(18):9562-9567.

125(6):1137-1149.

Science 264(5155):95-98.

2058.

of the p85/p110 phosphatidylinositol 3 -kinase: stabilization and inhibition of the p110 catalytic subunit by the p85 regulatory subunit. Mol Cell Biol 18:1379-1387. Yu, H. & Jove, R. (2004). The STATs of cancer - new molecular targets come of age. Nat Rev

Brush, J. & Godowski, PJ. (1997). Neuregulin-3 (NRG3): a novel neural tissueenriched protein that binds and activates ErbB4. Proc Natl Acad Sci U S A

activation of the kinase domain of epidermal growth factor receptor. Cell

ErbB receptors: from oncogenes to targeted cancer therapies. J Clin Invest 117:2051-

tyrosine phosphorylation in response to epidermal growth factor and interleukin-6.

Cancer of the uterine endometrium is the most common gynecologic malignancy diagnosed in women of the United States. It is estimated that in 2011, there will be 46,470 new endometrial cancers and 8,120 deaths due to this malignancy (American Cancer Society, 2011). The lifetime risk of developing endometrial cancer is approximately 3% in the general population. In Western countries, lifestyle changes and environmental factors play an important role in the carcinogenesis of endometrial cancer; however, there exist a proportion of cases in which an inherited predisposition increases this risk. In this chapter, hereditary nonpolyposis colorectal cancer syndrome or more commonly, Lynch Syndrome, will be reviewed and its association with endometrial cancer detailed.

## **2. Lynch syndrome: Definition and clinical features**

Lynch syndrome (LS) or hereditary nonpolyposis colorectal cancer (HNPCC) is an autosomal-dominant hereditary cancer syndrome that predisposes carriers to multiple malignancies. It is caused by germline mutations in specific genes that participate in DNA mismatch repair (MMR), these include *MLH1, MSH2, MSH6, PMS2,* and most recently, *EPCAM* (Kupier et al., 2011; Lynch et al., 2003). As the name implies, colorectal cancer (CRC) traditionally has been perceived as the dominant malignancy with a lifetime risk of 43-48% for carriers, however, women with LS have an equal or greater lifetime risk of endometrial cancer (EC) (Stoffel et al., 2009). Further, in more than half of cases, women present with a gynecological cancer as their first or "sentinel" malignancy (Lu et al., 2005). For LS families, extracolonic cancers also include ovarian, stomach, upper urologic tract, small bowel, pancreas, hepato-biliary, brain (Turcot variant) and sebaceous adenomas/carcinomas (Muir-Torre variant) (Lynch et al., 2003). This predisposition for other cancers has led to the use of Lynch Syndrome instead of HNPCC. It is also important to distinguish between Lynch I, in which colon cancer is the only contracted cancer, from Lynch II, where there exists other extracolonic cancers in the familial syndrome. In addition, some authors have reported a Lynch III as an appropriate name for identifying individuals with constitutively compromised MMR associated with biallelic mutations as seen with the Turcot and Muir-Torre variants (Felton et al., 2007).

#### **2.1 Clinical characteristics**

Current population estimates are that approximately 1 in 300 to 1 in 500 people carry a LS mutation making it similar in prevalence to Hereditary Breast and Ovarian cancer syndrome (Antoniou et al., 2000). These MMR mutations are inherited in an autosomal dominant manner and first-degree relatives have a 50% chance of inheriting the LS-related cancers (Hampel et al., 2005). Women who inherit LS-associated germline mutations have a greatly increased risk of developing a gynecologic cancer. Further, among women with LS who develop two primary cancers, over 50% are diagnosed with a gynecologic cancer before colon cancer (Lu et al., 2005). The range of risk for EC in women with LS is 27-71% compared with 3% in the general population and this risk varies with the specific MMR gene(s) involved, which will be discussed below (Koornstra et al., 2009).

The suspicion of a LS mutation should be raised among women diagnosed with EC at younger ages. The mean age range of EC in women with LS is 46 to 54 years, compared to 60 years in sporadic EC (Boks et al., 2002; Hampel et al., 2006). In a study by Lu et al., of 100 women with EC under age 50, 9 (9%) were found to have identifiable mutations in the MMR genes *MLH1, MSH2* and *MSH6* (Lu et al., 2007). In another study that included 69 women with LS, EC was diagnosed under the age 40 in 18% of their cohort (Schmeler et al., 2006).

Currently, there is no evidence to suggest that LS-associated EC portends a better or worse prognosis in patients when compared to sporadic EC. In fact, the majority of LS endometrial cancers are diagnosed in early stages, and like their sporadic counterparts, carry a favorable prognosis (Boks et al., 2002; Vasen et al., 1994). A case-control study of 50 women with LSassociated EC matched to 100 controls with sporadic EC for age and stage, found similar 5 year cumulative survival rates, 88% vs. 82%, respectively (P=0.59) (Boks et al., 2002). In another series of 125 women with clinically defined HNPCC, the overall survival rate for patients diagnosed with EC was high, with only 12% of patients succumbing to their disease (Vasen et al., 1994). A large study comparing the pathological features of sporadic EC to that of 50 patients with LS found that 78% were diagnosed as stage I, 10% were stage II, and 12% were stage III/IV in the LS cohort. Deep myometrial involvement was noted in 26% of cases, while lymphvascular space involvement was seen in 24%. However, when the LS cases were compared to the sporadic EC cases, stage, myometrial invasion, and lymphvascular space involvement were not statistically significantly different (Broaddus et al., 2006).

#### **2.2 Histopathologic characteristics**

Like sporadic endometrial cancer, the majority of LS-associated histology is of the endometrioid variety. However, studies evaluating the histologies of endometrial tumors in patients with LS have reported a wide variety of non-endometrioid types, including papillary serous carcinoma, clear cell carcinoma, malignant mixed Mullerian and neuroendocrine tumors (Broaddus et al., 2006; Carcangiu et al., 2010). For example, a small study of six LS-related endometrial cancers found significantly more often, poorly differentiated (83% versus 27%), presence of a Crohn-like lymphoid reaction (100% versus 13%), lymphangio-invasive growth (67% versus 0%), and high number of tumor-infiltrating lymphocytes (100% versus 36%), when compared with sporadic ECs (van den Bos et al., 2004). As mentioned previously, there is no evidence of a significant survival advantage or disadvantage associated with LS-related endometrial cancer (Boks et al., 2002).

Conversely, tumor location appears to differ between sporadic and LS-associated endometrial cancer. Although the majority is commonly found in the uterine corpus,

Current population estimates are that approximately 1 in 300 to 1 in 500 people carry a LS mutation making it similar in prevalence to Hereditary Breast and Ovarian cancer syndrome (Antoniou et al., 2000). These MMR mutations are inherited in an autosomal dominant manner and first-degree relatives have a 50% chance of inheriting the LS-related cancers (Hampel et al., 2005). Women who inherit LS-associated germline mutations have a greatly increased risk of developing a gynecologic cancer. Further, among women with LS who develop two primary cancers, over 50% are diagnosed with a gynecologic cancer before colon cancer (Lu et al., 2005). The range of risk for EC in women with LS is 27-71% compared with 3% in the general population and this risk varies with the specific MMR

The suspicion of a LS mutation should be raised among women diagnosed with EC at younger ages. The mean age range of EC in women with LS is 46 to 54 years, compared to 60 years in sporadic EC (Boks et al., 2002; Hampel et al., 2006). In a study by Lu et al., of 100 women with EC under age 50, 9 (9%) were found to have identifiable mutations in the MMR genes *MLH1, MSH2* and *MSH6* (Lu et al., 2007). In another study that included 69 women with LS, EC was diagnosed under the age 40 in 18% of their cohort (Schmeler et al., 2006). Currently, there is no evidence to suggest that LS-associated EC portends a better or worse prognosis in patients when compared to sporadic EC. In fact, the majority of LS endometrial cancers are diagnosed in early stages, and like their sporadic counterparts, carry a favorable prognosis (Boks et al., 2002; Vasen et al., 1994). A case-control study of 50 women with LSassociated EC matched to 100 controls with sporadic EC for age and stage, found similar 5 year cumulative survival rates, 88% vs. 82%, respectively (P=0.59) (Boks et al., 2002). In another series of 125 women with clinically defined HNPCC, the overall survival rate for patients diagnosed with EC was high, with only 12% of patients succumbing to their disease (Vasen et al., 1994). A large study comparing the pathological features of sporadic EC to that of 50 patients with LS found that 78% were diagnosed as stage I, 10% were stage II, and 12% were stage III/IV in the LS cohort. Deep myometrial involvement was noted in 26% of cases, while lymphvascular space involvement was seen in 24%. However, when the LS cases were compared to the sporadic EC cases, stage, myometrial invasion, and lymphvascular space

gene(s) involved, which will be discussed below (Koornstra et al., 2009).

involvement were not statistically significantly different (Broaddus et al., 2006).

disadvantage associated with LS-related endometrial cancer (Boks et al., 2002).

Like sporadic endometrial cancer, the majority of LS-associated histology is of the endometrioid variety. However, studies evaluating the histologies of endometrial tumors in patients with LS have reported a wide variety of non-endometrioid types, including papillary serous carcinoma, clear cell carcinoma, malignant mixed Mullerian and neuroendocrine tumors (Broaddus et al., 2006; Carcangiu et al., 2010). For example, a small study of six LS-related endometrial cancers found significantly more often, poorly differentiated (83% versus 27%), presence of a Crohn-like lymphoid reaction (100% versus 13%), lymphangio-invasive growth (67% versus 0%), and high number of tumor-infiltrating lymphocytes (100% versus 36%), when compared with sporadic ECs (van den Bos et al., 2004). As mentioned previously, there is no evidence of a significant survival advantage or

Conversely, tumor location appears to differ between sporadic and LS-associated endometrial cancer. Although the majority is commonly found in the uterine corpus,

**2.2 Histopathologic characteristics** 

**2.1 Clinical characteristics** 

endometrial cancer in the lower uterine segment (LUS) appears to have a strong association with Lynch syndrome. One study that included over 1000 patients with EC, found the prevalence of LS in patients with LUS tumors (10 of 35 or 29%) to be much greater than that of the general EC patient population (Westin et al., 2008). On the basis of this finding, the authors recommend that LS should be considered in all women with LUS tumors.
