Endometrial Cancer PDF

## CHAPTER 74 ### Endometrial Cancer ### Kaled M. Alektiar ### ANATOMY The uterus is a hollow, muscular organ located in the true pelvis between the bladder and the rectum. The average adult uterus is about 8 cm long, 5 cm wide, and 2.5 cm thick. It is divided into the fundus, body (corpus), and...

## CHAPTER 74 ### Endometrial Cancer ### Kaled M. Alektiar ### ANATOMY The uterus is a hollow, muscular organ located in the true pelvis between the bladder and the rectum. The average adult uterus is about 8 cm long, 5 cm wide, and 2.5 cm thick. It is divided into the fundus, body (corpus), and cervix. The junction between the body and cervix is called the isthmus. The fundus is pierced at each cornu by the fallopian tubes. The uterine surface is partially covered by peritoneum. The uterine cavity is lined by endometrium, made up of columnar cells forming many tubular glands. The thickness of the endometrium varies during the menstrual cycle, but by the end of menstruation, it should be 2 to 3 mm in thickness. The wall of the uterus is composed of myometrium, consisting of smooth muscle fibers. The major supports of the uterus are the broad, round, uterosacral and cardinal ligaments. The major blood supply to the uterus is the uterine artery, which enters the uterus at the isthmus after it crosses over the ureter. The lymphatic drainage for the body of the uterus is mainly to the obturator and internal and external iliac lymph nodes. The lymphatics from the fundus accompany the ovarian artery and drain into the para-aortic lymph nodes. ### EPIDEMIOLOGY AND RISK FACTORS Endometrial cancer is the most common gynecologic cancer and the fourth most frequently diagnosed cancer in women in the United States. According to 2018 cancer statistics, the estimated number of newly diagnosed cases is 63,230, with a probability of 1 in every 35 women (2.8%) developing it during her lifetime. Although it is a cancer that affects predominantly postmenopausal women, 14% are diagnosed in premenopausal women, with 5% being younger than 40 years. The expected number of deaths from endometrial cancer in 2018 is 11,350, making it the sixth leading cause of death from cancer in women. Recent estimates on the death rate from endometrial cancer seemed to indicate that the rate is on the rise, by about 2% per year. The incidence of endometrial cancer is higher in more developed areas of the world (5.5%) compared to less developed countries (4.2%), indicating a possible influence of environmental factors on the incidence of this disease. The exact etiology of endometrial cancer remains unknown, but several risk factors have been associated with it, chiefly unopposed estrogen. It is well established that endometrial cancer risk is increased among women who have high circulating levels of bioavailable estrogens and low levels of progesterone, so that the mitogenic effect of estrogens is insufficiently counterbalanced by the opposing effect of progesterone. The source of unopposed estrogen could be endogenous or exogenous. Regarding endogenous estrogen, in a nested case-control study of 93,676 postmenopausal women, parent estrogens (estrone and estradiol) were positively related to endometrial cancer risk, with the highest risk observed for unconjugated estradiol (OR 5th vs. 1st quintile = 6.19; 95% confidence interval [CI], 2.95 to 13.03, Ptrend = 0.0001). The association with unconjugated estradiol was stronger for type I than type II tumors (Phet = 0.01). Lifetime cumulative number of menstrual cycles, that is, menstruation span, is associated with increased risk of developing endometrial cancer. This is due to the fact that endometrial cell proliferation increases during the follicular phase, which is the longest in the menstrual cycle. Thus, early age at menarche (estimated relative risk [RR], 1.5 to 2) and late age at menopause (RR, 2 to 3), examples of increased menstruation span, are risk factors for endometrial cancer. Nulliparity (RR, 3) is also associated with increased risk of endometrial cancer due in part to anovulatory menstrual cycles. Obesity is a significant risk factor for endometrial cancer, with estimation that 38.4% of endometrial cancer worldwide could be attributed to high body mass index (BMI). The increase in endometrial cancer risk is mainly through changes in endogenous hormone metabolism. After menopause, when ovarian production of both estrogen and progesterone ceases, the major source of estrogen is via peripheral conversion, mostly within adipose tissue, of androgens that continue being produced by the adrenal glands and ovaries. Thus, with obesity, there is an increase in the amount of bioavailable estrogens in the circulation and the endometrial tissue. Obesity may also influence endometrial cancer risk via chronic hyperinsulinemia, which appears to be a key factor for the development of ovarian hyperandrogenism, associated with anovulation and progesterone deficiency, especially for premenopausal women. Non-insulin-dependent diabetes mellitus and hypertension (RR, 1 to 3) also increases the risk of endometrial cancer. This is often believed to be secondary to obesity, but there are data showing that these risk factors could be independent of obesity. With regard to exogenous estrogen, it is well established that the use of estrogen-only hormone replacement therapy and sequential oral contraceptives greatly increases endometrial cancer risk, whereas combined preparations, that is, those that contain a progestogen as well as estrogen throughout the treatment period, have a protective effect (RR, 0.3 to 0.5). 10,11 The use of tamoxifen in patients with breast cancer has been associated with increased risk of endometrial cancer. The mechanism of action of tamoxifen is in competition with that of endogenous estrogen for estrogen receptors. In premenopausal women, tamoxifen has an antiestrogenic effect, but in postmenopausal women, it has a weak estrogenic effect because of the up-regulation of estrogen receptors. In a meta-analysis on adjuvant tamoxifen and endometrial cancer, for patients who were <55 years of age, there was little absolute risk compared to patients of 55 to 69 years of age, for whom the 15-year incidence was 3.8% in the tamoxifen group versus 1.1% in the control group (absolute increase 2.6% [standard error 0.6], 95% CI = 1.4 to 3.8), highlighting the influence of age and the length of its use on the risk of endometrial cancer from tamoxifen use. 12,13 Initial data seemed to indicate that the majority of endometrial cancers associated with tamoxifen use were of early stage with favorable features. 14 More recent data, however, show a change in the profile of these endometrial cancers, with a rise in the rate of serous, clear cell, carcinosarcoma, and sarcoma types. 15 Inherited genetic predisposition, especially in the setting of hereditary nonpolyposis colorectal cancer (HNPCC), probably accounts for <5% of all endometrial cancer cases. Mutations in one of the four mismatch repair (MMR) genes hMLH1, hMSH2, hMSH6, or hPMS2 have been identified in patients with Lynch syndrome. Although HNPCC is thought of primarily in terms of risk of developing colorectal cancer, it is important to note that lifetime cumulative risk of endometrial cancer for women with HNPCC is 40% to 60%, which equals or exceeds their risk of colorectal cancer. 16 There seems to be a high rate of lower uterine segment involvement (LUSI) in patients with HNPCC-associated endometrial cancer. 17 ### CLINICAL PRESENTATION AND NATURAL HISTORY The most common presentation for endometrial cancer is postmenopausal vaginal bleeding, which is reported by 80% to 90% of patients. The incidence of endometrial cancer in women presenting with postmenopausal bleeding is only 10% to 15%. This incidence, however, could range from 1% up to 25%, depending on patient age and the presence of other risk factors. In a report of a total of 3,548 women presenting with postmenopausal vaginal bleeding, 201 (6%) had a diagnosis of endometrial carcinoma. Use of a multiple logistic regression model showed that recurrent episodes of bleeding (odds ratio [OR], 3.64), a history of diabetes (OR, 1.48), older age (1.06), and high body mass index (OR, 1.07) increased the risk of endometrial malignancy when corrected for other characteristics. 18 Other patterns of presentations include vaginal discharge, abnormal Papanicolaou smear, or thickened endometrium on routine transvaginal ultrasound. For patients with advanced disease, they may present with urinary or rectal bleeding, constipation, pain, lower extremity lymphedema, abdominal distension due to ascites, and cough and/or hemoptysis. The International Federation of Gynecology and Obstetrics (FIGO) annual report showed that the 5-year survival rate for 8,110 patients with endometrial cancer treated between 1999 and 2001 was 80%. Such excellent outcome is a reflection of the fact that the majority of patients are diagnosed with early-stage disease. The tumor was limited to the corpus uteri in 71% of cases, involved the cervix in 12%, and extended beyond the uterus, but short of distant spread in 13%. For patients with disease limited to the endometrium or with <50% myometrial invasion, the 5-year survival rate was 91%. However, the rate dropped to 66% when disease extended to adnexa/serosa/positive peritoneal cytology, to 57% with regional lymph node involvement, to 25.5% with bladder or rectal involvement, and to 20% with distant spread. For clinically staged patients, the 5-year survival rate ranged from 67% for early-stage disease down to 15% for advanced disease. Mass screening for endometrial cancer in women at average risk or increased risk due to a history of unopposed estrogen therapy, tamoxifen therapy, late menopause, nulliparity, infertility or failure to ovulate, obesity, diabetes, or hypertension is not recommended. American Cancer Society (ACS) recommends that women at average and increased risk should be informed about risks and symptoms (in particular, unexpected bleeding and spotting) of endometrial cancer at the onset of menopause and should be strongly encouraged to immediately report these symptoms to their physician. However, screening has been recommended by the ACS for women who carry, or are related to carriers of, the HNPCC mutation, starting at age 35 years, including annual transvaginal ultrasound and endometrial biopsy. 20 Prophylactic hysterectomy and bilateral salpingo-oophorectomy (BSO) once childbearing is completed have been shown to effectively reduce the risk of endometrial cancer in patients with HNPCC and should be strongly considered. 21 ### DIAGNOSTIC WORKUP Endometrial tissue sampling remains the gold standard by which the diagnosis of endometrial cancer is established. This is achieved via biopsy or dilation and curettage (D&C). Endometrial biopsy, which can be easily performed in the office with a Pipelle or similar device, is the preferred approach. Its sensitivity in detecting endometrial cancer in postmenopausal women is 99.6% compared to 91% in premenopausal women. Its specificity is >98% for both groups. 22 If the patient is undergoing hysterectomy, routine D&C is not necessary after an office Pipelle sampling has documented malignancy. However, if symptoms persist, the office sampling is inadequate, or the patient is being considered for conservative fertility-sparing approaches, a D&C should be performed. In addition, D&C provides more reliable assessments of final pathologic findings in hysterectomy specimens, mainly with regard to tumor grade. 23 Given that the incidence of endometrial cancer in women with postmenopausal bleeding is only 10% to 15%, it is unclear how feasible it is to perform endometrial sampling on every patient. Transvaginal ultrasonography (TVU) may be considered as a useful tool to assess patient's vaginal bleeding. Normal endometrium looks thin and homogeneously hyperechoic, but it is thickened and heterogeneous, with hyperplasia, polyps, and cancer. 24 as shown in Figure 74.1. The consensus statement from the Society of Radiologists in Ultrasound defines an endometrial thickness of 5 mm or greater as being abnormal. 25 If the thickness of the endometrium is <5 mm, the risk of endometrial cancer is minimal; the false-negative rate is about 4%. If the TVU is abnormal but the biopsy is negative/nondiagnostic or the uterine cavity is inaccessible, then saline infusion sonography or hysteroscopy. 26,27 should be considered to help exclude intracavitary lesions, especially polyps that might contain cancer. In addition, these methods are also helpful in premenopausal women, for whom the accuracy of TVU is limited because the endometrial thickness fluctuates, depending on the level of female hormones. The potential downside to saline infusion or hysteroscopy is that there have been reports that the insufflation of the distending medium into the canal has been associated with an increase in positive peritoneal cytology, although the prognostic implications are unclear of such positive cytology "induced" by sampling. 28 Several imaging studies are available to define the extent of disease preoperatively. 29 Good-quality pelvic computed tomography (CT) scans obtained with oral and intravenous contrast can demonstrate the extent of the endometrial tumor. The endometrial carcinoma is a hypodense mass relative to the normal myometrium and may be seen as a diffuse, circumscribed vegetative or polypoidal mass within the uterine cavity. CT is helpful in assessing regional and distant metastasis. Magnetic resonance imaging (MRI) is considered the most accurate imaging study to assess tumor extension in endometrial cancer, especially myometrial invasion. 30,31 Dynamic contrast-enhanced (DCE) and diffusion-weighted (DW) MRI are equivalent in detecting deep myometrial invasion. 32 A clear junctional zone or preservation of a sharp delineation between the tumor and the myometrium implies disease limited to the endometrium. Disease characterized by disruption of the junctional zone, increased-signal-intensity tumor in the inner half of the myometrium with preservation of the outer myometrium, or both correlates with superficial myometrial invasion. If there is extension of the high-signal-intensity tumor into the outer myometrium with preservation of a peripheral rim of normal, intact myometrium, then that is considered deep myometrial invasion (Fig. 74.2). MRI also helps to delineate tumor extension into the cervix. The normal cervical stroma is hypointense on T2-weighted images and is replaced by intermediate-signal-intensity tumor in cases of invasion. 33 The reported sensitivity of MRI in detecting lymph node metastasis is on average 43.5% and the specificity is 95.9%. 31 Positron emission tomography (PET)/CT is also being used in endometrial cancer. 34 There seems to be little benefit in assessing the primary tumor extension. With regard to regional lymph node metastasis, the reported sensitivity is 72% and the specificity is 94%. The main advantage of PET-CT over other imaging modalities is its accuracy in detecting distant metastasis. 33 The FIGO staging for endometrial cancer is a surgical staging, and thus, preoperative imaging studies (except chest x-rays) are not part of the staging. Cancer antigen 125 (CA-125) serum levels could be elevated in patients with endometrial cancer. Kim et al. 35 in a review of 413 patients found that 23.9% of patients had >35 U/mL serum CA-125 levels. Hsieh et al. 36 found that preoperative levels of >40 U/mL correlated significantly with regional lymph node metastasis and suggested that such levels could be used as an indication for full-pelvic and para-aortic lymph-adenectomy at the time of surgical staging in the absence of metastatic disease. ### Pathologic Classification #### Endometrial Hyperplasia The diagnostic criterion for hyperplasia is an increase in the number and size of proliferating glands. The International Society of Gynecologic Pathologists standardized the sub-classification of endometrial hyperplasia. In simple hyperplasia, there is only glandular proliferation and enlargement with increased stromal cellularity. This rarely progresses to carcinoma (<1%). Complex hyperplasia is characterized by back-to-back proliferation of glands with intraluminal papillae, epithelial pseudostratification, and few mitotic figures. If there is no cytologic atypia, the risk of malignant degeneration is again quite low, on the order of 3%. Any proliferation demonstrating cytologic abnormalities (in cellular or nuclear morphology) is classified as atypical hyperplasia. Atypical hyperplasia has a much higher risk of progression to an invasive carcinoma-8% for simple atypical hyperplasia, increasing to 29% for complex hyperplasia associated with atypia. 37 The Gynecologic Oncology Group (GOG) conducted a prospective trial in which all patients with atypical hyperplasia of the uterus underwent an immediate hysterectomy. The rate of underlying concurrent carcinoma in the uterus was 42.6% in these patients. 38 The standard recommended treatment for atypical hyperplasia of the uterus is hysterectomy if childbearing is complete and the patient has no other contraindications to surgery. In patients who desire future fertility or have an absolute contraindication to surgery, progestational therapies may be used with caution. 39 #### Carcinoma of the Endometrium ##### Endometrioid Carcinoma Endometrioid adenocarcinoma is the most common endometrial carcinoma, constituting 75% to 80% of all cases (Table 74.1). The classic histologic appearance is that of marked glandular proliferation with back-to-back proliferation of glands and little intervening stroma (Fig. 74.3A). The name endometrioid is derived from resemblance to proliferative-phase endometrium. Architectural grading is determined by the amount of solid mass of tumor cells compared to well-defined glands. Grade 1 is an endometrioid cancer in which <5% of the tumor growth is in solid sheets. Grade 2 is an adenocarcinoma in which 6% to 50% of the tumor is composed of solid sheets of cells. Grade 3 occurs when >50% of the tumor is made up of solid sheets. Nuclear grading is determined by the nuclear shape, size, chromatin distribution, and size of the nucleoli. The grading is primarily driven by the architectural grading, but if there is marked nuclear atypia in an otherwise grade 2 architectural grading, it should be increased to grade 3. Within endometrioid adenocarcinoma, the subtypes are endometrioid carcinoma not otherwise specified (NOS), endometrioid carcinoma with squamous differentiation, villoglandular endometrioid carcinoma, secretory carcinoma, and a ciliated cell variant. 40 Most of the endometrioid adenocarcinomas are designated NOS. Foci of squamous differentiation are often found with endometrioid adenocarcinoma. The squamous component could be benign, with the designation of adenoacanthoma, or malignant, in which case it is called adenosquamous carcinoma. Such designations have not been very useful, however, because the degree of differentiation of the squamous component parallels that of the glandular architectural grading. Therefore, most gynecologic pathologists use the term adenocarcinoma with squamous differentiation. Other subtypes of endometrioid adenocarcinoma include the relatively common villoglandular carcinoma, which grows in a papillary fashion. The prognosis of this subtype is similar to that of low-grade endometrioid cancer, and it must not be confused with serous carcinoma because of its papillary features. Secretory carcinoma, which represents <2% of all endometrial carcinomas, is characterized by a very well-differentiated glandular pattern with much intracellular glycogen, thus resembling early secretory endometrium. Although the cells have clear cytoplasm, their histologic and cytologic features are different from those of clear cell carcinoma. Ciliated carcinoma is a very rare subtype, characterized by the presence of ciliated cells comprising >75% of the tumor specimen. It is usually associated with a history of prior estrogen use, and the prognosis is quite good, because most are well differentiated. ##### Mucinous Carcinoma This designation requires >50% of the tumor cells to be mucinous. These cells are carcinoembryonic antigen positive and are laden with mucin, which stains positively with mucicar-mine and periodic acid-Schiff stains but is diastase resistant. Because of the resemblance to endocervical adenocarcinoma, it is essential to exclude it by endocervical curettage. Mucinous carcinomas are usually well differentiated and have the same prognosis as ordinary endometrioid carcinomas. ##### Serous Carcinoma Serous carcinomas, also known as papillary serous cancers, resemble ovary cancer in terms of histology and to some extent in terms of behavior. The mere presence of papillary structure is not diagnostic because other histologic types may have papilla as well. However, the presence of marked cellular atypia in addition to papilla distinguishes serous carcinoma from others (Fig. 74.3B). Psammoma bodies are found in up to 33% of cases. The incidence of serous endometrial cancer is about 11.4% that of endometrial carcinomas. 41 This is an aggressive subtype, with a high propensity for early lymphatic and intraperitoneal dissemination, often despite little myometrial penetration. In the FIGO annual report, the 5-year survival rate was 52.6% compared to 83.2% for endometrioid carcinoma. 19 ##### Clear Cell Carcinoma Clear cell carcinoma of the endometrium resembles renal carcinoma, but its origin from mullerian structures is now well established. Unlike vaginal and cervical clear cell carcinoma, it is not related to intrauterine diethylstilbestrol exposure. The microscopic structure may vary from solid patterns to glandular differentiation (Fig. 74.3C). In the latter pattern, small cells resembling "hobnail" cells line spaces and glands. These are cells that extruded their cytoplasm, leaving bare nuclei that protrude into the glandular lumens. The rate of clear cell carcinoma is about 3.5% of endometrial carcinomas. 41 The prognosis of this cancer is in between that of endometrioid and serous cancer. 42 In the FIGO annual report, the 5-year survival rate was 62.5% compared to 83.2% for endometrioid carcinoma and 52.6% for serous carcinoma. 19 ##### Squamous Carcinoma This type of cancer is extremely rare, and the diagnosis has to be made after the exclusion of cervical origin. The 5-year survival rate based on the FOGO report is 68.9% overall, but the prognosis is poor for patients with extrauterine disease or distant spread. 19 ##### Undifferentiated Carcinoma The World Health Organization classification describes endometrial undifferentiated carcinomas as “malignant poorly differentiated endometrial carcinomas, lacking any evidence of differentiation" without any further characterization. 43 Undifferentiated carcinomas can also be associated with an endometrioid carcinoma component, and such tumors have been referred to as "dedifferentiated carcinomas," which is being recognized with increased frequency. Some of these tumors may belong to the spectrum of gynecologic neoplasms seen in the setting of microsatellite instability and possibly Lynch syndrome. 44 ##### Mixed Histology Mixed cell-type endometrial cancer composed of two or more pure types was observed in 4.5% of patients in GOG 210 study. 41 By convention, in order to be designated as mixed, the other cell-type component has to comprise at least 10% of the tumor. Except for mixed endometrioid and serous or clear cell carcinoma, the clinical significance of mixed cell type is questionable. ##### Simultaneous Tumors Occasionally identical tumor type, mainly endometrioid histology, can be discovered in the ovary and endometrium. Usually, the site of the largest tumor is assigned the primary origin, but at times, true primary endometrial and ovarian malignancies may coexist. 45 If the endometrial tumor is <5 cm in diameter, well differentiated, with no vascular invasion, limited to less than the middle one-third of the myometrium, and the ovarian lesions are bilateral, it is more likely that there are two concomitant primary tumors. Genetic profiling may represent a powerful tool in clinical practice for distinguishing between metastatic and dual primaries in patients with simultaneous ovarian/endometrial cancer and for predicting disease outcome. 46 ### Molecular Biology Several investigators pointed out that there are two distinct types of endometrial cancer. 47,48 In type I endometrial cancer, there is strong correlation with prior estrogen stimulation. The cancers in this category are often indolent in nature, with minimal myometrial invasion and low-grade histology. They affect premenopausal and perimenopausal women. Type II endometrial cancer often affects postmenopausal women with no prior history of estrogen stimulation. The histology of the tumors is often high grade, such as serous or clear cell cancers with deep invasion, and at a more advanced stage at the time of presentation. What is intriguing is the fact that at the molecular level, the existence of two distinct types of endometrial cancer seems to be validated. 49 The most frequently altered molecular pathway in type I endometrial carcinomas is the P13 K/PTEN/AKT pathway, which is dysregulated by oncogenic mutations, PTEN loss of function, and/or overexpression of upstream tyrosine kinase growth factor receptors, leading to uncontrolled cell proliferation and survival. On the other hand, the main pathway alterations in type II endometrial cancers involve the tumor suppressors p53. However, the findings from the Cancer Genome Atlas (TCGA) have revolutionized our understanding of endometrial cancer. 50 In that study, the genomic landscape of endometrioid and serous carcinoma histologies were evaluated (Fig. 74.4). Most endometrioid tumors had frequent mutations in PTEN, CTNNB1, PIK3CA, ARID1A, and KRAS, novel mutations in the SWI/SNF chromatin remodeling complex gene ARID5B, and few copy number alterations or TP53 mutations. Uterine serous tumors and about 25% of high-grade endometrioid tumors (serous-like) had frequent TP53 mutations and extensive copy number alterations, but few deoxyribonucleic acid (DNA) methylation changes, and low estrogen receptor/progesterone receptor levels. A subset of endometrioid tumors (about 10%) that was identified had a markedly increased mutation frequency and newly identified hotspot mutations in the exonuclease domain of POLE. Based on these results, endometrial cancers can be classified into four categories: POLE ultramutated, microsatellite instability hypermutated, copy number low, and copy number high. The somatic copy number alterations (SCNAS) analysis showed that most endometrioid tumors have few SCNAS, whereas most serous and serous-like tumors (endometrioid) exhibit extensive SCNAS. Genomic analysis of clear cell carcinoma of the uterus demonstrated that, akin to endometrioid carcinomas, there are four gnomically distinct groups: POLE, MMR-deficient tumors, copy number low, and copy number high. 51 ### STAGING Before 1988, the staging system for endometrial cancer was clinical. Stage I was tumor limited to the uterus, with IA designation if the length was ≤8 cm and IB if it was >8 cm. Stage II was for when cervix was involved, stage III when disease extension beyond uterus/cervix was limited to the true pelvis, and stage IV when it extended beyond the true pelvis or involved bladder or rectum (IVA) or distant spread (IVB). This system is applicable to the few patients who cannot have surgery and are treated with definitive radiation. Using the FOGO 1988 staging system, Creasman et al. reported a GOG 210 study on 5,855 patients with endometrial cancer who underwent hysterectomy/BSO and peritoneal cytology. 41 During the initial phase of the study of 3,715 patients, enrollment was unrestricted, but in the later phase, enrollment was restricted to patients (n = 2,151) with adverse features, such as non-endometrioid histologies, non-Caucasian race, and preoperative imaging suggestive of deep myometrial invasion, and such histologies were as follows: endometrioid (grade 1 was 37.8%, grade 2 was 26.3%, and grade 3 was 9.7%), serous 11.4%, clear cell 3.5%, and mixed 4.5%. The rate of positive peritoneal cytology was 8.9% and that of adnexal involvement was 8.6%. The breakdown by stage (FIGO 1988) was as follows: IA 24.8%, IB 38.4%, IC 11.2%, IIA 2.3%, IIB 4.4%, IIIA 4.6%, IIIB 0.2%, IIIC 9.8%, and IV 4.4% (Table 74.2). In 2009, the FIGO staging system was modified. 52 Patients who formerly were staged as IB, that is, <50% myometrial invasion, are now considered IA. Patients with >50% myometrial invasion are designated as stage IB. Endocervical glandular involvement no longer affects staging; only patients with cervical stromal invasion are considered stage II. Having positive peritoneal cytology no longer affects staging. Parametrial extension is now considered IIIB. Patients with stage IIIC are now subdivided into IIIC1 if pelvic nodes are involved and IIIC2 if para-aortic nodes are involved (Table 74.3). The discriminating power of the new FIGO staging system is being debated. Page et al. 53 evaluated 10,839 cases from 1998 to 2006 using the Surveillance, Epidemiology, and End Results (SEER) Program. The analysis demonstrated the usefulness of two divisions rather than three for stage I in the new FIGO staging system. In contrast, a study from Memorial Sloan Kettering Cancer Center (MSKCC) of 1,307 patients with FIGO 1988 stage I disease showed that the revised system for stage I did not improve its predictive ability over the 1988 system. 54 ### Prognostic Factors Several clinicopathologic factors have been identified in patients with endometrial carcinoma to help predict the prognosis and individualize the treatment plan. At MSKCC, a nomogram was developed for predicting overall survival of women with endometrial cancer (n = 1,735) after primary therapy. 55 Use of five prognostic factors-age, grade, histologic type, number of lymph nodes removed, and FIGO 1988 surgical stage-predicted OS with high concordance probability. Postoperative Radiation Therapy in Endometrial Cancer (PORTEC) group also developed nomogram for predicting recurrence in FIGO stage I disease. 56 #### Age The influence of older age on worse outcome has been well established. The adverse impact of older age is often explained by pointing out that older patients tend to present with aggressive histology and more advanced disease and are generally treated less aggressively. What is intriguing, however, is that the strongest correlation between older age and poor outcome is seen in patients with otherwise favorable characteristics. Furthermore, the adverse impact of advanced age on outcome persists even when elderly patients are treated as aggressively as their younger counterparts. 57,58 #### Race The incidence of endometrial cancer is lower in African American than white women, yet the rate of high-risk features in this group is higher. In a GOG study, 24.3% of African Americans presented with stage III as opposed to 17.6% for white and the histology was serous in 24.4% as opposed to 11.2%, respectively. The higher recurrence rate could not be accounted for based on treatment received, indicating the need for better understanding of the biology of this disease. 59 #### Histologic Subtype According to the FIGO annual report, the 5-year survival rate was 83.2% for endometrioid adenocarcinoma, compared to 52.6% for serous cancer and 62.5% for clear cell cancer in 8,033 surgically staged patients. Patients with endometrioid histology have surgical stage III to IV disease only in 13.8% of patients, compared to 41.7% with serous and 33% with clear cell carcinoma, which could explain the worse outcome. However, the influence of histology was seen even in patients with surgical stage I disease (n = 5,285), for whom 5-year survival dropped from 90% for endometrioid histology to 79.9% with serous and 85.1% with clear cell carcinoma. 19 #### Grade Tumor grade is one of the most sensitive indicators of prognosis. Grade directly affects the depth of myometrial penetration and the frequency of lymph node involvement. In GOG 210 report by Cresman et al., 41 the rate of deep myometrial invasion was 15% for grade 1, 25% for grade 2, and 38% for grade 3. The rate of positive pelvic and para-aortic node based on depth of invasion and histology is shown in Table 74.4. In the FIGO annual report, 19 grade 3 was an independent predictor of poor survival on multivariate analysis within each stage-stages I (HR, 2.45), II (HR, 2.14), III (HR, 2.44), and IV (HR, 2.55). The recognition that about 25% of grade 3 endometrioid histology has copy number high mutations, that is, serous-like, further highlight the impact of genomic stratification on prognosis. 50 #### Myometrial Invasion Regardless of grade, only 1.7% of tumors limited to the endometrium had lymph nodal involvement, as compared with 29% pelvic and 14.5% para-aortic involvement with deep penetration. 41 Before the 1988 FIGO staging system, the depth of invasion had been reported as none or inner, middle, or outer one-third of the myometrium. The 1988 FIGO staging system subdivided myometrial invasion into none or inner or outer half. Under that staging system, for patients with <50% myometrial invasion, it seems that invasion to less than versus greater than one-third is not a significant predictor of outcome. 60 In the current 2009 FIGO staging system, depth of invasion in stage I is divided into two categories: A (no or <50% myometrial invasion) and B (>50% invasion). #### Lymphovascular Invasion In GOG 210 study, 41 the rate of lymphovascular invasion (LVI) was 22.7%. The presence of LVI increased the rate of positive pelvic node from 4.1% to 37.5%, and para-aortic node from 2.3% to 23.8%. LVI is also associated with higher rate of relapse in the vagina 61 and a poorer outcome especially if it was substantial. 62 The presence of LVI needs to be viewed in the context of other risk factors so that its mere presence does not trigger excessive therapy. 63 #### Lower Uterine Segment Involvement The presence of LUSI is associated with worse outcome. In a study of 481 surgically staged endometrioid endometrial cancers (FIGO stage I to II), LUSI was present in 223 cases (46.4%) and was associated with both decreased disease-free survival (P = .02) and overall survival (P = .01) in univariate analysis. 64 There seems to be a high rate of LUSI in patients with HNPCC-associated endometrial cancer. 65 #### Cervical Involvement In the 1988 FIGO staging system, cervical involvement was divided into IIA when limited to endocervical glandular involvement and IIB when it involves the cervical stroma. According to the FIGO report, the 5-year survival for stage IIA was very good (89.9% for grade 1 and 83.7% for grade 2). 19 In contrast, the corresponding figures for stage IIB were 81.2% and 76.9%, respectively. 19 This led to a change in the 2009 FIGO staging system, in which only cervical stromal invasion is considered stage II. Although the prognosis of the old stage IIA grades 1 and 2 approximated stage I rather than stage IIB, it is important to note that in the same FIGO annual report, patients with stage IIA grade 3 did not fare as well; their 5-year survival was 68.3%, which was worse than that for IC grade 3 (74.9%) and similar to that for IIB grade 3 (64.9%). #### Peritoneal Cytology In the 2009 FIGO staging, having positive peritoneal cytology is no longer considered stage IIIA. The reason for the change is due to lack of clear correlation between positive cytology and outcome for early-stage endometrial cancer. However, the true prognostic significance of positive peritoneal cytology on outcome cannot be devoid of the influence of surgical techniques or other prognostic factors. There is some suggestion of a higher rate of positive cytology for patients undergoing laparoscopic hysterectomy, because of manipulation of the uterine cavity. In a randomized trial trying to address this issue, the rate of positive cytology was 7.2% when manipulator was used compared to 1.8% when it was not, but that difference was not statistically significant (P = .147). In GOG 210 study, positive peritoneal cytology was found in 11.3% of patients undergoing surgical staging. This was associated with 31.8% pelvic lymph node involvement and 22.7% para-aortic node involvement. 41 Histology also impacts the rate of positive cytology: 7.7% for endometrioid histology compared to 20.2% for nonendometrioid histologies. 42 In patients with early-stage disease (low-grade endometrioid histology, minimal invasion), the influence of positive peritoneal cytology on outcome is not evident. 67 In contrast, for patients with stage III disease,