**2. Clinico-anatomopathological characteristics**

17 studies covering 10,572 women showed a prevalence of a malignancy within endometrial polyps in postmenopausal women about 5.42% compared to 1.70% in premenopausal women [Lee, 2010]. Endometrial neoplasia was identified in 214 of 3,946 women with endometrial polyps who were postmenopausal compared with 68 of 3,997 premenopausal women (relative risk 3.86). There were 4,967 women with symptomatic bleeding and 195 from them (4.15%) had neoplastic polyps compared with 85 of 3,941 (2.16%) without normal bleeding, according to the report (relative risk 1.97). Looking at the increased risks seen with postmenopausal status and abnormal bleeding, this did not seem to be additive. Polyp size did not appear to be associated with malignancy. Women with hereditary nonpolyposis colorectal cancer (HNPCC) syndrome have a markedly increased risk of endometrial cancer compared with women in the general population. Among women who are HNPCC mutation carriers, the estimated cumulative incidence of endometrial cancer ranges from 20% to 60% [Morrow, 1991; Goff, 1994]. In terms of histopathology, endometrial cancer can be considered as two types: type I, endometrioid, most commonly seen in 80-90% of cases and type II, and all other forms nonendometrioide serous. Endometrial carcinoma has three architectural degrees, depending on Solid to glandular component rate (for grade 1 is <5% and >50% for grade 3). That tipycally will be arised in younger obese women, hyper lipidemia, and signs of hyperestrogenism (exogenous or endogenous). Serous carcinomas are high-grade carcinomas. Comprising -1% of endometrial adenocarcinomas, the clear cell carcinomas are rare. There is an increasing of them in thinner, older women and show no hormonal risk factors. The endometrial carcinomas type I are commonly diagnosed at an early stage and have a favorable prognosis, often only surgically treated; recurrences are usually local (the most common site is pelvis) and curable very frequently with tumor-

Prevention and Therapeutic Strategies in Endometrial Cancer 443

Endometrial cancer is generally staged according to the International Federation of Gynecology and Obstetrics (FIGO) system. Since 1988, the FIGO system has recommended surgical staging with systematic pelvic and para-aortic lymphadenectomy. In May 2009, a new FIGO staging system was published, but most of studies are based on the old classification (Tables 1). Some centers use intraoperative frozen section analysis of the uterus based upon histological grade, type and depth of myometrial invasion and appears significantly better than MRI scanning in the assessment of myometrial invasion.

[Furukawa, 2010].

**Stage Involvement** 

IIIC 1 Positive pelvic nodes

**2.2 Risk assessment** 

**2.3 Surgical staging** 

Table 1. FIGO staging of endometrial cancer

**Stage I** Tumor confined to the corpus uteri IA No or less than half myometrial invasion

**Stage III** Local and/or regional spread of the tumor

IIIB Vaginal and/or parametrial involvement†

IB Invasion equal to or more than half of the myometrium

IIIC Metastases to pelvic and/or para-aortic lymph nodes†

IVA Tumor invasion of bladder and/or bowel mucosa

Stage I can be subdivided into three risk categories [Fiorelli, 2008]:

Intermediate risk: stage IA (G3) with endometrioid type stage IB (G1 and G2) with endometrioid type

High risk: stage IB (G3) with endometrioid type all stages with non-endometrioid type

Low risk: stage IA (G1 and G2) with endometrioid type

IIIA Tumor invades the serosa of the corpus uteri and/or adnexae†

IIIC 2 Positive para-aortic lymph nodes ± positive pelvic lymph nodes

**Stage IV** Tumor invades bladder and/or bowel mucosa, and/or distant metastases

IVB Distant metastases, including intra-abdominal metastases ± inguinal nodes \*Positive cytology should be reported separately without changing the stage [Pecorelli, 2009].

Multiple factors have been identified for relative high risk of recurrence in apparent earlystage disease: histological subtype, grade 3 histology, myometrial invasion ‡50%, lymphovascular space invasion (LVSI), lymph node metastases and tumor diameter >2 cm.

Full staging endometrial cancer can be performed surgically [Pecorelli, 2009]. In addition to data related to uterine tumor, surgical research can provide data about state and pelvic lymph lomboaortic by lymphadenectomy. Studies of women undergoing full pelvic

**Stage II** Tumor invades cervical stroma, but does not extend beyond the uterus

Endocervical glandular involvement alone should be considered as stage I

directed radiotherapy. The carcinomas type II from endometrial are present with metastatic disease at diagnosis and carry a poorer prognosis (Soslow 2007). Complex or simple hyperplasia could be associated with cellular atypia. We can subdivide them into mild atypia (nuclear enlargement and rounding with evenly dispersed chromatin) or moderate atypia (clumped chromatin, larger nuclear size, prominent nucleoli). There is a low likelihood of hyperplasia without atypia, either simple or complex (1%, 3%) of progressing to carcinoma. In contrast, atypical endometrial hyperplasia is believed to be the direct precursor to endometrioid carcinoma [Bokhman, 1983; Soslow, 1997]. An investigation by The Gynecologic Oncology Group found that from19% to 62% of endometrial biopsy. There is an association between endometrial hyperplasia and invasive endometrial cancer postoperative. (Merisio, 2005) Complex and simple hyperplasia can be treated with only progestative therapy, whereas hysterectomy is mandatory for patients with atypical hyperplasia. Atypical hyperplasia regresses after treatment with progestational therapy in 60% to 95% of patients [Randall, 1997].

In patients with atypical hyperplasia and the high risk of progression to endometrium carcinoma, hysterectomy is the standard treatment. For women who desire a fertility preserving therapy should be reserved progestative therapy for six months (Trimble, 2006).

The risk factors of endometrioid cancer are late menopause, continuous anovulation (e.g., polycystic ovarian syndrome), obesity and nulliparity. Additional risk factors may be related to estrogenic effects, a high-fat diet, tamoxifen use, early menarche. Endometrioid adenocarcinomas frequently show genetic instability, typically found in patients with hereditary nonpolyposis colon cancer and mutations (the b-catenin gene is more frequently mutated in carcinomas with squamous differentiation). Serous carcinomas are characterized by chromosomal instability and p53 mutations. Clear cell carcinomas have absent reactivity for estrogen and progesterone receptors and low immunoreactivity for p53. After an initial assessment, necessary treatment of the disease, this depends on its stage of development and disease risk (the risk of recurrence and metastasis).

#### **2.1 Assessment**

Assessment of myometrial invasion is to specify the page, the possible extension to the pelvic organs and distance and tumor grade. This evaluation consisted of noninvasive preoperative investigations (imaging) and invasive (biopsy curettage). CT scans have poor sensitivity and specificity in detecting the depth of myometrial invasion, cervical and parametrial involvement, and lymph node metastases [Zerbe, 2000]. MRI appears to be the best imaging modality for preoperative assessment of myoinvasion [Kinkel, 2009]. MRI presents an overall staging accuracy of 85% [Hricak, 1991]. In addition, whilst more accurate than CT, the limitations of MRI in detecting myometrial invasion must be considered [Kinkel, 1999]. In one institutional review of endometrial cancer, 30% of tumors were found to be at an advanced stage and 24% of women had high-grade tumors [Bandyopadhyay, 2008]. Another study of 301 women with stage I endometrial cancer reported that the negative predictive value of MRI for myometrial invasion was 49.2% [Suh, 2009]. The use of PET/ CT is reported in small prospective series to have a high negative predictive value for nodal metastases [Frumovitz, 2004; Signorelli, 2009; Picchio, 2010]. Park demonstrated that PET/CT had a sensitivity of 69.2%, specificity of 90.3%, positive predictive value of 42.9%, and negative predictive value of 96.6 % [Park, 2008].

directed radiotherapy. The carcinomas type II from endometrial are present with metastatic disease at diagnosis and carry a poorer prognosis (Soslow 2007). Complex or simple hyperplasia could be associated with cellular atypia. We can subdivide them into mild atypia (nuclear enlargement and rounding with evenly dispersed chromatin) or moderate atypia (clumped chromatin, larger nuclear size, prominent nucleoli). There is a low likelihood of hyperplasia without atypia, either simple or complex (1%, 3%) of progressing to carcinoma. In contrast, atypical endometrial hyperplasia is believed to be the direct precursor to endometrioid carcinoma [Bokhman, 1983; Soslow, 1997]. An investigation by The Gynecologic Oncology Group found that from19% to 62% of endometrial biopsy. There is an association between endometrial hyperplasia and invasive endometrial cancer postoperative. (Merisio, 2005) Complex and simple hyperplasia can be treated with only progestative therapy, whereas hysterectomy is mandatory for patients with atypical hyperplasia. Atypical hyperplasia regresses after treatment with progestational therapy in

In patients with atypical hyperplasia and the high risk of progression to endometrium carcinoma, hysterectomy is the standard treatment. For women who desire a fertility preserving therapy should be reserved progestative therapy for six months (Trimble, 2006). The risk factors of endometrioid cancer are late menopause, continuous anovulation (e.g., polycystic ovarian syndrome), obesity and nulliparity. Additional risk factors may be related to estrogenic effects, a high-fat diet, tamoxifen use, early menarche. Endometrioid adenocarcinomas frequently show genetic instability, typically found in patients with hereditary nonpolyposis colon cancer and mutations (the b-catenin gene is more frequently mutated in carcinomas with squamous differentiation). Serous carcinomas are characterized by chromosomal instability and p53 mutations. Clear cell carcinomas have absent reactivity for estrogen and progesterone receptors and low immunoreactivity for p53. After an initial assessment, necessary treatment of the disease, this depends on its stage of development

Assessment of myometrial invasion is to specify the page, the possible extension to the pelvic organs and distance and tumor grade. This evaluation consisted of noninvasive preoperative investigations (imaging) and invasive (biopsy curettage). CT scans have poor sensitivity and specificity in detecting the depth of myometrial invasion, cervical and parametrial involvement, and lymph node metastases [Zerbe, 2000]. MRI appears to be the best imaging modality for preoperative assessment of myoinvasion [Kinkel, 2009]. MRI presents an overall staging accuracy of 85% [Hricak, 1991]. In addition, whilst more accurate than CT, the limitations of MRI in detecting myometrial invasion must be considered [Kinkel, 1999]. In one institutional review of endometrial cancer, 30% of tumors were found to be at an advanced stage and 24% of women had high-grade tumors [Bandyopadhyay, 2008]. Another study of 301 women with stage I endometrial cancer reported that the negative predictive value of MRI for myometrial invasion was 49.2% [Suh, 2009]. The use of PET/ CT is reported in small prospective series to have a high negative predictive value for nodal metastases [Frumovitz, 2004; Signorelli, 2009; Picchio, 2010]. Park demonstrated that PET/CT had a sensitivity of 69.2%, specificity of 90.3%, positive predictive value of 42.9%,

60% to 95% of patients [Randall, 1997].

**2.1 Assessment** 

and disease risk (the risk of recurrence and metastasis).

and negative predictive value of 96.6 % [Park, 2008].

Endometrial cancer is generally staged according to the International Federation of Gynecology and Obstetrics (FIGO) system. Since 1988, the FIGO system has recommended surgical staging with systematic pelvic and para-aortic lymphadenectomy. In May 2009, a new FIGO staging system was published, but most of studies are based on the old classification (Tables 1). Some centers use intraoperative frozen section analysis of the uterus based upon histological grade, type and depth of myometrial invasion and appears significantly better than MRI scanning in the assessment of myometrial invasion. [Furukawa, 2010].


\*Positive cytology should be reported separately without changing the stage [Pecorelli, 2009].

Table 1. FIGO staging of endometrial cancer

### **2.2 Risk assessment**

Multiple factors have been identified for relative high risk of recurrence in apparent earlystage disease: histological subtype, grade 3 histology, myometrial invasion ‡50%, lymphovascular space invasion (LVSI), lymph node metastases and tumor diameter >2 cm.

Stage I can be subdivided into three risk categories [Fiorelli, 2008]:


#### **2.3 Surgical staging**

Full staging endometrial cancer can be performed surgically [Pecorelli, 2009]. In addition to data related to uterine tumor, surgical research can provide data about state and pelvic lymph lomboaortic by lymphadenectomy. Studies of women undergoing full pelvic

Prevention and Therapeutic Strategies in Endometrial Cancer 445

This protection occurs in women who have used oral contraceptives for at least 12 months, and continues for at least 10 years after oral contraceptive use. The protection is most

Edward Giovannucci, M.D., Sc.D., Professor of Nutrition and Epidemiology at the Harvard School of Public Health, said coffee is emerging as a protective agent in cancers that are linked to obesity, estrogen and insulin. Giovannucci, along with Youjin Je, a doctoral candidate in his lab, and colleagues observed cumulative coffee intake in relation to endometrial cancer in 67,470 women who enrolled in the Nurses' Health Study. During the course of 26 years of follow-up, researchers documented 672 cases of endometrial cancer. Drinking more than four cups of coffee per day was linked with a 25 percent reduced risk for endometrial cancer. Drinking between two and three cups per day was linked with a 7 percent reduced risk [Giovannucci, 2005]. A similar link was seen in decaffeinated coffee, where drinking more than two cups per day was linked with a 22 percent reduced risk for

Hormone and lifestyle factors explain up to 80% of risk for endometrial cancer. The investigators found that women who were normal weight and active had a reduction in risk of 73%, compared with inactive women who were overweight (BMI above 25 kg/m2). Women who were normal weight but inactive had a 55% lower risk for endometrial cancer than inactive women who were overweight. Women who were overweight but active had a

Aspirin has been shown in vitro to inhibit endometrial cancer cell growth through the

Other NSAIDs have also been shown to reduce endometrial cancer cell proliferation and

African-american women with advanced stage endometrial cancer have lower survival rates than white women with the disease even when both groups receive similar treatments,

One of the major challenges in endometrial cancer treatment remains the current inability to effectively prevent distant metastasis in women with deeply myoinvasive, high-grade or biologically aggressive tumors (e.g., serous and clear cell cancers). One potential target in serous tumors is HER2 [Konecny, 2009; Villella, 2006; Flemimg, 2003]. The monoclonal antibody trastuzumab binds to HER-2 and can reduce growth in cell lines that overexpress HER-2. Epidermal growth factor receptor (also known as c-erbB-1). One strategy to tackle tumor growth is to target angiogenesis,. The main factor controlling angiogenesis is VEGF. The most well known of these is bevacizumab, a monoclonal antibody against VEGF-A. A study of single-agent bevacizumab in women with recurrent endometrial cancer demonstrated a 15% response rate and a median progression-free survival of 4 months, although approximately 36% of women had a progression-free survival of 6 months

induction of apoptosis in a dose-dependent manner [Arango, 2001].

induce apoptosis in a dose- and time-dependent manner [Gao, 2004; Li, 2002].

according to a study published online September 25, 2006, in the journal Cancer .

notable for women who have never been pregnant.

endometrial cancer.

38% lower risk for endometrial cancer.

**4. Therapeutic strategies** 

[Konecny, 2009].

**4.1 Molecularly targeted treatments** 

lymphadenectomy report rates of occult pelvic lymph node disease ranging from 8 to 28% depending on grade and depth of myometrial invasion [Zivanovic, 2009; Lin, 2008]. Lymphadenectomy causes significant morbidity in approximately 11% of cases [Nunns, 2000]. Pelvic MRI and sentinel lymph node evaluation appear equally effective in detecting pelvic node metastases although the ability to detect the sentinel node varies significantly between studies [Selman, 2008]. Hirahatake reported that para-aortic lymph node metastases in 2.5% of stage IA, 8.5% of stage IB, and 15.7% of stage II endometrial cancers [Hirahatake, 1997]. Mariani and Tanaka reported a direct correlation between pelvic and para-aortic lymph node involvement [Mariani, 2004; Tanaka, 2006]. In a study of 291 endometrial cancer patients by Goudge 18% were upgraded postoperative [Goudge, 2004]. Ben-Shachar reported that tumor was upgraded in 19% of 181 patients with a preoperative grade 1 tumor [Ben-Shachar, 2005]. The results of surgical staging also led to adjuvant treatment in 12% of patients who were found to have extrauterine disease or other high-risk characteristics [Ben-Shachar, 2005].
