Prognostic factors in endometrial carcinoma - Wiley Online Library

J. Obstet. Gynaecol. Res. Vol. 34, No. 5: 776–783, October 2008

doi:10.1111/j.1447-0756.2008.00796.x

Prognostic factors in endometrial carcinoma Peter Uharcˇek Department of Obstetrics and Gynecology, Faculty Hospital Nitra, Slovakia

Abstract Endometrial carcinoma is the most common malignancy of the female genital tract in industrialized countries, and occurs predominantly after the menopause. Although most endometrial carcinomas are detected at low stage, there is still a significant mortality from the disease. In postmenopausal women, prolonged life expectancy, changes in reproductive behavior and prevalence of overweight and obesity, as well as hormone replacement therapy use, may partially account for the observed increases of incidence rates in some countries. In order to improve treatment and follow-up of endometrial carcinoma patients, the importance of various prognostic factors has been extensively studied. The identification of high-risk groups would make it possible to avoid unnecessary adjuvant treatment among patients with a good prognosis. Over the past few decades, several studies have demonstrated the prognostic importance of different parameters including lymph node status, histological type of carcinoma (serous carcinoma and clear cell carcinomas are poor prognostic types), histological grade, stage of disease, depth of myometrial invasion, lymphovascular space involvement and cervical involvement. Other factors currently being investigated are estrogen and progesterone receptor status, p53 status, flow cytometric analysis for ploidy and S-phase fraction, and oncogenes such as HER-2/neu (c-erbB-2). Key words: clinicopathological factors, endometrial carcinoma, prognosis.

Introduction Endometrial cancer comprises about 4% of all cancers in women globally and occurs predominantly after the menopause. Some of the highest incidence rates worldwide are found within European populations.1 According to the statistics reported by the National Cancer Registry of Slovak Republic, 669 endometrial cancer cases were newly diagnosed in 2000 and endometrial cancer was the most common malignancy of the female genitals with the incidence estimated at 25 in 100 000 women each year.2 In gynecologic oncology, valid prognostic factors are necessary to define biologically similar subgroups for analysis of therapeutic efficacy. During the past two decades many studies to evaluate the prognostic

parameters of endometrial cancer have been performed. These factors are important in tailoring proper adjuvant therapy consisting of modalities such as radiation, chemotherapy and hormonal therapy. Identification of high-risk endometrial cancer cases and referral of moderate- and high-risk patients to physicians with expertise in treating advanced or recurrent disease appear justified. In 1988 the Federation of Gynecology and Obstetrics (FIGO) changed the clinical staging of endometrial carcinoma to the surgically based system.3 The change was based on the prospective surgical staging studies conducted by the Gynecologic Oncology Group (GOG), which demonstrated that prognosis is related to the presence or absence of histopathologically determined uterine and extrauterine risk factors.4–6 The information

Received: October 11 2007. Accepted: January 1 2008. Reprint request to: Dr Peter Uharcˇek, Department of Obstetrics & Gynecology, Faculty Hospital, Špitálska 6, 949 01 Nitra, Slovakia. Email: [email protected]

776

© 2008 The Author Journal compilation © 2008 Japan Society of Obstetrics and Gynecology

Prognostic factors in endometrial cancer

acquired through surgical staging is more accurate compared to that acquired by imaging techniques. Uterine factors include histological type, histological grade, depth of myometrial invasion, lymphovascular invasion, cervical involvement, DNA-ploidy, oncogenes, tumor suppressor genes and hormone receptors. Extrauterine factors include positive peritoneal cytology, adnexal involvement, pelvic and para-aortic lymph node metastasis and peritoneal metastasis. During the past two decades, efforts have focused on attempting to identify cytokinetic or molecular factors that correlate with the malignant potential of endometrial cancer. Approximately 5% of endometrial cancer cases are considered familial.7 Many of these cases are associated with hereditary non-polyposis colorectal cancer (HNPCC), an autosomaldominant inherited cancer with germ-line abnormalities in one of DNA-mismatch repair genes with resultant microsatellite instability (MSI). Females with HNPCC have a 10-fold increased lifetime risk of endometrial cancer compared with that of the general population. The lifetime risk of endometrial cancer is 30–61% for HNPCC carriers.8 Hereditary endometrial cancer is more likely to occur at a younger age and is characterized by high FIGO stage and grade, cribriform growth pattern, mucinous differentiation and necrosis.9

Prognostic Parameters Age Younger patients with uterine endometrial carcinoma tend to have a better prognosis than older women. Younger patients usually have history of estrogen- or hormone-related disorders, such as ovarian dysfunction, chronic anovulation, infertility, obesity and polycystic ovary syndrome.10 Older endometrial cancer (age >63 years) patients have a significantly decreased overall survival, causespecific survival and greater risk of recurrence following postoperative irradiation independent of other prognostic factors.11 Poor prognosis in older patients has been related to a higher incidence of grade 3 tumors or unfavorable histologic subtypes. Independent prognostic influence of age has been reported in some studies,12,13 but no consensus has been reached in confirming its significance.14 Parity Obesity, nulliparity and late menopause are classically associated with endometrial carcinoma. If a patient is

nulliparous and obese and reaches menopause at age 52 or later, she appears to have a five-fold increase in the risk of developing endometrial cancer.15 Reduced 5-year survival of 57% among nulliparous women in comparison with 81% for patients with one or more deliveries has been reported,16 but there are no other studies to support this data.

Histological type Endometrial cancer has been described as consisting of two groups.17,18 The first group (type 1, approximately 80%) is characterized by well-differentiated tumors that present with localized disease. These patients usually have a favorable outcome; stage-1 disease carries a 5-year survival rate of 86%.19 The development of type 1 endometrial cancer is predominantly related to excess estrogen exposure. Risk factors include obesity, nulliparity, late menopause, diabetes mellitus, unopposed estrogen therapy, tamoxifen therapy and use of sequential oral contraception. Excess estrogen from any of these sources produces continued stimulation of the endometrial lining, which can result in endometrial hyperplasia and, potentially, endometrial cancer. Obesity has the highest associated risk ratio and is associated with excess estrogen exposure, even in postmenopausal women. The ovaries in postmenopausal women, together with the adrenal gland, continue to produce androstenedione. The aromatase enzyme found in adipose cells converts this androgen to estrone 5 and, over time, this relatively weak estrogen can stimulate chronic endometrial proliferation, and occasionally malignant change.19 In contrast, the second group (type 2, about 20%) is characterized by more aggressive tumors, early invading myometrium and vascular spaces, with associated advanced-stage disease and higher tumor grade nonendometrioid histology; and it carries a high mortality rate. Predominant histologic types are serous and clear cell carcinoma. Type 2 tumors are usually not associated with estrogen stimulation or hyperplasia. These patients are generally more slender than their type-1 counterparts, and their tumors are believed to be influenced by nonestrogenic factors.16 Adenocarcinoma with squamous differentiation (about 25% of endometrial cancers) is a variant of endometrioid carcinoma and the grade of the glandular component is a prognostic indicator for these tumors.20 Villoglandular adenocarcinomas represent another variant of endometrioid adenocarcinoma with no significant difference in behavior.21 Mucinous


777

P. Uharcˇek

carcinomas are usually low-grade and minimally invasive, and have a good prognosis.22

Histologic grade Histological grade is strongly associated with prognosis, stage, lymph-node metastasis and myometrial invasion. Nonendometrioid carcinomas are considered high-grade tumors and thus need not be graded. Grade is one of the prognostic factors applied in clinical decisions regarding treatment. The most frequently used grading criteria are the ones of FIGO23 and the World Health Organization,24 which include both architectural and nuclear features. Five-year survival rates of 94% in patients with grade 1 tumors, 84% in those with grade 2 tumors and 72% in those with grade 3 tumors has been reported.25 Boronow et al. reported 5-year survival 81% in stage I, grade 1 patients, and 50% in stage I, grade 3 patients.4 Some modifications to the FIGO grading system have been proposed. Lax et al. proposed a binary architectural grading system based on presence >50% solid growth, a diffusely infiltrative growth pattern and tumor cell necrosis. This system stratifies patients into three prognostic groups: (1) patients with low-stage (IA–IB) and low-grade (100% 5-year survival); (2) higher stage (IC, II–V) and lowgrade tumors, or high-grade tumors confined to endometrium (IB–IC) with 5-year survival 67–76%; and (3) advanced stage and high-grade tumors with 5-year survival of 26%.26

Myometrial invasion The 1988 FIGO staging system divided patients with stage I endometrial carcinoma into three categories: (i) stage IA includes patients with no myometrial invasion; (ii) stage IB includes patients with invasion of less than one-half of the myometrium; and (iii) stage IC includes patients with invasion of greater than one-half of the myometrium. Several other methods have been effectively used to measure myometrial invasion, including division of myometrial thickness by thirds, depth of tumor invasion (in mm), and distance between the tumor and the uterine serosa (in mm). This creates some difficulties in correlating these prognostic factors with the current staging system. Myometrial invasion is an independent predictor of outcome.5,6,13 Deep myometrial invasion is associated with a poor survival rate. In GOG Study 33, recurrence developed in only 1% of patients with no myometrial invasion. Fifteen of 196 patients (7.7%) had invasion of the inner one-third of the myometrium, eight of 55 patients (14.5%) had invasion of the middle-third of the

778

myometrium, and six of 40 patients (15%) had invasion of the outer-third of the myometrium.6 A study of more than 400 patients with clinical stage I endometrioid carcinoma revealed that the 5-year survival was 94% when the tumor was confined to the endometrium, 91% when the tumor involved the inner-third of the myometrium, 84% when the tumor extended into the middle-third of the myometrium, and 59% when the tumor infiltrated the outer-third of the myometrium.25

Vascular invasion The presence of metastases in the lymphatic or vascular spaces of the uterus, lymphovascular space involvement (LVSI) is an important prognostic factor for relapse of disease and poor survival, and it is independent of histological grade or depth of myometrial invasion.6,27–29 LVSI has also been shown to be an important prognostic factor for pelvic lymph node metastases in patients with endometrial cancer. The presence of LVSI significantly increases the rate of pelvic lymph node metastases compared with cancers without LVSI for all FIGO grades and depths of myometrial invasion.5,27,28,30 In the group of 609 patients,31 relapses occurred more frequently in patients with LVSI (48/ 123, 39%) compared to patients without LVSI (68/357, 19%). Lower uterine segment, cervical involvement Endometrial carcinoma of the lower uterine segment when compared to carcinoma of the uterine corpus has been found to be associated with a lower median age, higher histologic grade, less favorable histologies and deeper myometrial invasion.32 The accepted criteria for stage II disease are: endocervical epithelial involvement (stage IIA) and cervical stromal involvement (stage IIB). Patients with stage IIA tumors have similar survival with patients in stage IIB when treated surgically and with adjuvant radiotherapy.33,34 The estimated 5-year overall survival of 92.1% and disease-free survival of 89.9%, was reported in the study of Eltabbakh and Moore.33 Cervical stromal invasion was found to be an independent predictor of distant failure.35 Adnexal involvement, serosal invasion Stage IIIa endometrial cancer is a heterogeneous substage that includes one or more of the following conditions: adnexal involvement, uterine serosal invasion and positive results of peritoneal cytology. Isolated adnexal involvement has been reported to be a



favorable occurrence of extrauterine disease.36 Patients with isolated adnexal spread have a reported 5-year disease-free survival ranging from 71% to 86%.37 Serosal invasion is associated with poor prognosis, with a high percentage of distant failures.38 The number of extrauterine disease sites has been shown to be correlated with disease recurrence in surgically staged endometrial carcinoma. Greven et al. noted 5-year disease free survival rates of 68, 56 and 0% in pathologic stage III patients with one, two, and three or more sites of extrauterine disease.36

Peritoneal Cytology The purpose of taking peritoneal washings is to identify microscopic disease, and peritoneal cytology is assumed to add information on the spread of occult peritoneal disease. The prognostic significance of positive peritoneal cytology in endometrial carcinoma has led to the incorporation of peritoneal cytology into the current FIGO staging system. Although cytology was shown to be prognostically relevant in patients with clinical stage II and III disease, conflicting data exist about its significance in patients who have been clinical stage I but were classified as surgical stage III solely and exclusively on the basis of positive peritoneal cytology. Although some studies report good correlation of peritoneal cytology with prognosis, other studies do not. It has been suggested that studies before 1990 merely reported peritoneal washings to be significantly associated with outcome.39,40 More recent studies report different results for the prognostic value of positive peritoneal cytology in endometrial cancer.41–43

Lymph Node Metastasis Lymph node spread represents the most common site of extrauterine disease in endometrial cancer. Reports from both FIGO44 and the United States National Cancer Institute database45 show that 5-year survival for patients with stage I and II disease ranges from 80% to 91%, and that patients with nodal metastases have a survival of only 44–52%. The implications of finding and treating extrauterine nodal disease cannot be considered alone, but in the context of the presence or absence of other sites of disease. Patients of stage III disease with only positive cytology or only adnexal or serosal disease have 5-year survivals of 73% to 88% when treated with adjuvant pelvic radiation alone without formal staging.28,36 The

5-year disease-free survival for those with nodal involvement only treated with adjuvant irradiation is 68%, in contradiction to the 5-year disease free survival of only 25% (P < 0.01) where nodal disease is accompanied by peritoneal, serosal, adnexal or vaginal metastases. The patterns of failure for the two groups are different. Distant metastases predominate in the group with nodal plus other sites of disease, whereas this is unlikely with nodal involvement only. Peritoneal failure is unlikely unless at least two risk factors are present including nonendometrioid cell type, positive cytology, positive nodes and cervical involvement.46 Data from GOG in a series of surgically staged endometrial cancers demonstrated the relationship between FIGO grade and depth of myometrial invasion on the risk of retroperitoneal lymph-node metastases.5 The absolute number of positive nodes and lymphnode ratio are significant independent prognostic factors for survival. Increasing absolute number of positive nodes and lymph-node ratio are associated with a poorer survival in women with node-positive uterine cancers.47

Steroid Hormone Receptors Steroid hormones, especially estrogen, play an important role in the pathogenesis of endometrial cancer. The presence and quantity of steroid receptors have been correlated with stage, histological grade and survival in several studies, and several authors have reported that receptor status constitutes an independent prognostic factor.48–50 On the basis of these data, the United States National Cancer Institute recommended that steroid receptors should be included whenever possible in the evaluation of stage I and II patients.50 However, in some studies, authors have suggested that expression of steroid receptors does not constitute an independent prognostic factor for endometrial cancer.51,52 Because hormonal therapy with progestagens is widely used for treatment in cases of recurrent and advanced endometrial cancer, assessment of hormonereceptor concentration is providing guidance on prognosis and management of adjuvant treatment.

DNA Ploidy DNA ploidy have been found to be significantly correlated with established prognostic factors.53–55 Approximately one-third of endometrioid carcinomas have aneuploid DNA content. Diploid tumors are usually


779

P. Uharcˇek

low grade with limited myometrial invasion. DNA ploidy correlates with reduced survival. The strong association of ploidy with extrauterine disease has been identified. For stage I tumors disease-free survival was significantly better for diploid tumors.53,56 DNAaneuploidy (DNA index >1.3) is one of the most important independent molecular biological prognostic factors.57

Angiogenesis Angiogenesis is a critical factor for the growth and spread of malignant tumors. Various studies have shown that high intratumor microvessel density in endometrial cancer is associated with advanced stage, increased risk of recurrent disease and with poor prognosis.58,59 A progressive increase in microvessel density from benign endometrium through atypical complex hyperplasia to invasive carcinoma has been reported.58

Tumor Cell Proliferation Proliferation and proliferative capacity of tumor cells are basic features of growing tumor tissue. Proliferative activity is quantified by several methods; S-phase fraction, mitotic count and immunohistochemically detected markers of proliferation are the most used. Estimation of S-phase fraction by flow cytometry has been of prognostic significance in a number of studies.57,60,61 The risk of death was significantly higher in patients S-phase values greater than 20%.61 The nuclear Ki-67 antigen is present in all stages of the cell cycle except G0, and development of antibodies against Ki-67 allows the detection of proliferating cells. Ki-67 expression correlates with histological grade, depth of myometrial invasion and risk of recurrence. Endometrioid carcinomas with low Ki-67 proliferation index have a favorable prognosis.62

Oncogenes Overexpression of the c-erb-B2 (HER2/neu) oncogene occurs in about 20% to 40% of endometrial carcinomas and has been associated with other adverse prognostic factors, including advanced stage, higher grade and worse overall survival.63,64 Serous tumors with HER2/ neu over-expression have been shown to have decreased overall survival.65 However, other studies have found that HER-2/neu expression was not associated with clinicopathologic factors and prognosis in endometrial carcinoma.66–68

780

Overexpression of the p53 tumor suppressor gene is associated with lower rates of survival, particularly in serous carcinomas, in which it is correlated with other strong prognostic factors, such as advanced stage.67 Positive staining of p53 was significantly correlated with increased stage, lymph node metastases and nonendometrioid histology.69 p53 is strong predictor of recurrence-free survival, disease-related survival and also predictor of metastatic disease.70 The tumor-suppressor gene PTEN (phosphatase and tensin homolog) is mutated in 30% to 60% of endometrial carcinomas. PTEN-positive staining is a significant prognostic indicator of favorable outcome.69,71

MSI MSI has been reported in 75% of endometrial cancer cases associated with HNPCC, and also in 25% to 45% of sporadic endometrial carcinomas. Affected individuals in HNPCC families carry germline mutations in the DNA repair genes MLH1 and MSH2. Gene mutations are generally not found in sporadic endometrial cancer but, instead, mismatch repair genes are inactivated or silenced by a process of gene promoter hypermethylation particularly involving the MLH1 gene.72 The MSI-high phenotype in an endometrioid-type adenocarcinoma was characterized by high histologic grade, lymphovascular invasion, deep myometrial invasion and high clinical stage.73,74 Some investigators have found the MSI-high tumors to be associated with earlier tumor stage and not to be associated with prognosis.74,75

Cell Adhesion Molecules Epithelial cadherin (E-cadherin) is a member of the cadherin family of cell adhesion molecules. E-cadherin is needed to keep neighboring cells attached. Impaired function of this cadherin might lead to invasive potential of malignant epithelial tumors. Decreased Ecadherin expression is an independent prognostic factor for disease progression and mortality in pathological stage I–III endometrial cancer.76 Beta-catenin plays a critical role in the maintenance of epithelial cell–cell adhesion and normal tissue architecture as part of the E-cadherin/beta-catenin complex. Combined E-cadherin, alfa-catenin and beta-catenin expression was shown to be an independent prognostic factor for survival. Positive staining for all three factors identified a subset of patients with favorable outcomes.77



Conclusion Poor histologic differentiation, deep myometrial invasion, nonendometrioid histologic subtype, lymphovascular invasion, lymph node status, cervical involvement, and the presence and extent of extrauterine disease have been described as significant histopathologic predictors of distant recurrence. Knowledge of prognostic factors may enable physicians to find the best appropriate treatment for the prevention of recurrence. Patients at risk for aggressive or advanced disease could be referred to centers and clinicians with special expertise in managing advanced or recurrent endometrial carcinoma.

References 1. Bray F, Silva I, Moller H, Weiderpass E. Endometrial cancer incidence trends in Europe: Underlying determinants and prospects for prevention. Cancer Epidemiol Biomarkers Prev 2005; 14: 1132–1142. 2. Redecha M, Nižnˇanská Z, Korbel’ M. Výskyt zhubných nádorov tela maternice na Slovensku v rokoch 1990–2000. Gynekol Prax 2004; 2: 194–199. 3. Shepherd JH. Revised FIGO staging for gynaecological cancer. Br J Obstet Gynaec 1989; 96: 889–892. 4. Boronow RC, Morrow CP, Creasman WT. Surgical staging in endometrial cancer: Clinical-pathologic findings of a prospective study. Obstet Gynecol 1984; 63: 825–832. 5. Creasman WT, Morrow CP, Bundy BN et al. Surgical pathologic spread patterns of endometrial cancer (a GOG study). Cancer 1987; 60: 2035–2041. 6. Morrow CP, Bundy BN, Kurman RJ et al. Relationship between surgical-pathologic risk factors and outcome in clinical stage I and II carcinoma of the endometrium: A Gynecologic Oncology Group study. Gynecol Oncol 1991; 40: 55–65. 7. Gruber SB, Thompson WD. A population-based study of endometrial cancer and familial risk in younger women. Cancer Epidemiol Biomarkers Prev 1996; 5: 411–417. 8. Dunlop MG, Farrington SM, Carothers AD et al. Cancer risk associated with germline DNA mismatch repair gene mutations. Hum Mol Genet 1997; 6: 105–110. 9. Parc YR, Halling KC, Burgart LJ et al. Microsatellite instability and hMLH1/hMSH2 expression in young endometrial carcinoma patients: Associations with family history and histopathology. Int J Cancer 2000; 86: 60–66. 10. Ota T, Yoshida M, Kimura M, Kinoshita K. Clinicopathologic study of uterine endometrial carcinoma in young women aged 40 years and younger. Int J Gynecol Cancer 2005; 15: 657–662. 11. Jolly S, Vargas CE, Kumar T et al. The impact of age on longterm outcome in patients with endometrial cancer treated with postoperative radiation. Gynecol Oncol 2006; 103: 87–93. 12. Yamazawa K, Seki K, Matsui H, Kihara M, Sekiya S. Prognostic factors in young women with endometrial carcinoma: A report of 20 cases and review of literature. Int J Gynecol Cancer 2000; 10: 212–222.

13. Abeler VM, Kjørstad KE. Endometrial adenocarcinoma in Norway. A study of a total population. Cancer 1991; 67: 3093– 3103. 14. Britton LC, Wilson TO, Gaffey TA, Lieber MM, Wieand HS, Podratz KC. Flow cytometric DNA analysis of stage I endometrial carcinoma. Gynecol Oncol 1989; 34: 317–322. 15. Creasman WT. Adenocarcinoma of the uterus. In: DiSaia PJ, Creasman WT (eds). Clinical Gynecologic Oncology, 7th edn. Philadelphia, PA: Mosby Elsevier, 2007; 147–184. 16. Salvesen HB, Akslen LA, Albrektsen G, Iversen OE. Poorer survival of nulliparous women with endometrial carcinoma. Cancer 1998; 82: 1328–1333. 17. Deligdisch L, Holinka CF. Endometrial carcinoma: Two diseases? Cancer Detect Prev 1987; 10: 237–246. 18. Bokhman JV. Two pathogenic types of endometrial carcinoma. Gynecol Oncol 1983; 15: 10–17. 19. Gates EJ, Hirschfield L, Matthews RP, Yap OWS. Body mass index as a prognostic factor in endometrioid adenocarcinoma of the endometrium. J Natl Med Assoc 2006; 98: 1814–1822. 20. Abeler VM, Kjørstad KE. Endometrial adenocarcinoma with squamous differentiation. Cancer 1992; 69: 488–495. 21. Zaino RJ, Kurman RJ, Brunetto VL et al. Villoglandular adenocarcinoma of the endometrium: A clinicopathological study of 61 cases. A Gynecologic Oncology Group study. Am J Surg Pathol 1998; 22: 1379–1385. 22. Ross JC, Eifel PJ, Cox RS et al. Primary mucinous adenocarcinoma of the endometrium: A clinicopathological histochemical study. Am J Surg Pathol 1983; 7: 715–729. 23. International Federation of Gynecology and obstetrics (FIGO): Announcements. FIGO stages: 1998 revision. Gynecol Oncol 1999; 35: 125–127. 24. Silverberg et al. Epithelial tumors of the uterine corpus and related lesions. In: Tavassoli FA, Devilee P (eds). WHO Classification of Tumours, Pathology and Genetics, Tumours of the Breast and Female Genital Tract. Geneva: WHO Press, 2003; 221–232. 25. Zaino RJ, Kurman RJ, Herbold D et al. The significance of squamous differentiation in endometrial carcinoma. Cancer 1991; 68: 2293–2302. 26. Lax SF, Kurman RJ, Pizer ES, Wu L, Ronnett BM. A binary architectural grading system for uterine endoemetrial endometrioid carcinoma has superior reproducibility compared with FIGO grading and identifies subsets of advancedstage tumors with favorable and unfavorable prognosis. Am J Surg Pathol 2000; 24: 1201–1208. 27. Mariani A, Webb MJ, Keeney GL, Aletti G, Podratz KC. Endometrial cancer: Predictors of peritoneal failure. Gynecol Oncol 2003; 89: 236–242. 28. Mariani A, Webb MJ, Keeney GL, Aletti G, Podratz KC. Assessment of prognostic factors in stage IIIA endometrial cancer. Gynecol Oncol 2002; 86: 38–44. 29. Mariani A, Webb MJ, Keeney GL, Aletti G, Podratz KC. Predictors of lymphatic failure in endometrial cancer. Gynecol Oncol 2002; 84: 437–442. 30. Cohn DE, Horowitz NS, Mutch DG, Kim SM, Manolitsas T, Fowler JM. Should the presence of lymphvascular space involvement be used to assign patients to adjuvant therapy following hysterectomy for unstaged endometrial cancer? Gynecol Oncol 2002; 87: 243–246. 31. Briët JM, Hollema H, Reesink N et al. Lymphvascular space involvement: An independent prognostic factor in endometrial cancer. Gynecol Oncol 2005; 96: 799–804.


781

P. Uharcˇek

32. Hachisuga T, Fukuda K, Iwasaka T, Hirakawa T, Kawarabayashi T, Tsuneyoshi M. Carcinoma of the lower uterine segment. Int J Gynecol Pathol 1989; 8: 26–53. 33. Eltabbakh GH, Moore AD. Survival of women with surgical stage II endometrial cancer. Gynecol Oncol 1999; 74: 80–85. 34. Jordan LB, Al-Nafussi A. Clinicopathological study of the pattern and significance of cervical involvement in cases of endometrial adenocarcinoma. Int J Gynecol Cancer 2002; 12: 42–48. 35. Mariani A, Sebo TJ, Webb MJ et al. Molecular and histopathologic predictors of distant failure in endometrial cancer. Cancer Detect Prev 2003; 27: 434–441. 36. Greven KM, Curran WJ Jr, Whittington R et al. Analysis of failure patterns in stage III endometrial carcinoma and therapeutic implications. Int J Radiat Oncol Biol Phys 1989; 17: 35–39. 37. Connell PP, Rotmensch J, Waggoner S, Mundt AJ. The significance of adnexal involvement in endometrial carcinoma. Gynecol Oncol 1999; 74: 74–79. 38. Ashman JB, Connell PP, Yamada D, Rotmensch J, Waggoner SE, Mundt AJ. Outcome of endometrial carcinoma patients with involvement of the uterine serosa. Gynecol Oncol 2001; 82: 338–343. 39. Mazurka JL, Krepart GV, Lotocki RJ. Prognostic significance of positive peritoneal cytology in endometrial carcinoma. Am J Obstet Gynecol 1988; 158: 303–306. 40. Turner DA, Gershenson DM, Atkinson N, Sneige N, Wharton AT. The prognostic significance of peritoneal cytology for stage I endometrial cancer. Obstet Gynecol 1989; 74: 775– 780. 41. Aoki Y, Kase H, Watanabe M, Sato T, Kurata H, Tanaka K. Stage III endometrial cancer: Analysis of prognostic factors and failure patterns after adjuvant chemotherapy. Gynecol Oncol 2001; 83: 1–5. 42. Hirai Y, Takeshima N, Kato T, Hasumi K. Malignant potential of positive peritoneal cytology in endometrial cancer. Obstet Gynecol 2001; 97: 725–728. 43. Obermair A, Geramou M, Tripcony L, Nicklin JL, Perrin L, Crandon AJ. Peritoneal cytology: Impact on disease-free survival in clinical stage I endometrioid adenocarcinoma of the uterus. Cancer Lett 2001; 164: 105–110. 44. Creasman WT, Odicino F, Maisonneuve P et al. Carcinoma of the corpus uteri. Int J Gynaecol Obstet 2003; 83 (Suppl 1): 79–118. 45. Partridge EE, Shingleton HM, Menck HR. The National Cancer Data Base report on endometrial cancer. J Surg Oncol 1996; 61: 111–123. 46. Mariani A, Webb MJ, Keeney GL et al. Stage IIIC endometrioid corpus cancer includes distinct subgroups. Gynecol Oncol 2002; 87: 112–117. 47. Chan JK, Kapp DS, Cheung MK et al. The impact of the absolute number and ratio of positive lymph nodes on survival of endometrioid uterine cancer patients. Br J Cancer 2007; 97: 605–611. 48. Geisinger KR, Marshall RB, Kute TE, Homesley HD. Correlation of female sex steroid hormone receptors with histologic and ultrastructural differentiation in adenocarcinoma of the endometrium. Cancer 1986; 58: 1506–1517. 49. Kadar N, Malfetano JH, Homesley HD. Steroid receptor concentrations in endometrial carcinoma: Effect on survival in surgically staged patients. Gynecol Oncol 1993; 50: 281–286.

782

50. Jeon YT, Park IA, Kim YB et al. Steroid receptor expressions in endometrial cancer: Clinical significance and epidemiological implication. Cancer Lett 2006; 239: 198–204. 51. Iversen OE, Utaaker E, Skaarland E. DNA ploidy and steroid receptors as predictors of disease course in patients with endometrial carcinoma. Acta Obstet Gynecol Scand 1988; 67: 531–537. 52. Sivridis E, Giatromanolaki A, Koukourakis M, Anastasiadis P. Endometrial carcinoma: Association of steroid hormone receptor expression with low angiogenesis and bcl-2 expression. Virchows Arch 2001; 438: 470–477. 53. Zaino RJ, Davis AT, Ohlsson-Wilhelm BM et al. DNA content is an independent prognostic indicator in endometrial adenocarcinoma. A Gynecologic Oncology Group study. Int J Gynecol Pathol 1998; 17: 312–319. 54. Larson DM, Berg R, Shaw G et al. Prognostic significance of DNA ploidy in endometrial cancer. Gynecol Oncol 1999; 74: 356–360. 55. Lundgren C, Auer G, Frankendal B et al. Nuclear DNA content, proliferative activity, and p53 expression related to clinical and histopathologic features in endometrial carcinoma. Int J Gynecol Cancer 2002; 12: 110–118. 56. Nordstrom B, Strang P, Lindgren A et al. Carcinoma of the endometrium: Do the nuclear grade and DNA ploidy provide more prognostic information than do the FIGO and WHO classifications? Int J Gynecol Pathol 1996; 15: 191–201. 57. Wimberger P, Hillemanns P, Kapsner T, Hepp H, Kimmig R. Evaluation of prognostic factors following flow-cytometric DNA analysis after cytokeratin labelling: II. Cervical and endometrial cancer. Anal Cell Pathol 2002; 24: 147–158. 58. Abulafia O, Triest WE, Sherer DM, Hansen CC, Ghezzi F. Angiogenesis in endometrial hyperplasia and stage I endometrial carcinoma. Obstet Gynecol 1995; 86: 479–485. 59. Kirschner CV, Alanis-Amezcua JM, Martin VG et al. Angiogenesis factor in endometrial carcinoma: A new prognostic indicator? Am J Obstet Gynecol 1996; 174: 1879–1882. 60. Salvesen HB, Iversen OE, Akslen LA. Identification of highrisk patients by assessment of nuclear Ki-67 expression in a prospective study of endometrial carcinomas. Clin Cancer Res 1998; 4: 2779–2785. 61. Kaleli S, Kösebay D, Bese T et al. A strong prognostic variable in endometrial carcinoma: Flow cytometric S-phase fraction. Cancer 1997; 79: 944–951. 62. Stefansson IM, Salvesen HB, Immervoll H, Akslen LA. Prognostic impact of histological grade and vascular invasion compared with tumour cell proliferation in endometrial carcinoma of endometrioid type. Histopathology 2004; 44: 472– 479. 63. Rolitsky CD, Theil KS, McGaughy VR et al. HER-2/neu amplification and overexpression in endometrial carcinoma. Int J Gynaecol Pathol 1999; 18: 138–143. 64. Reinartz JJ, George E, Lindgren BR et al. Expression of p53, transforming growth factor receptor, and c-erb B2 in endometrial carcinoma and correlation with survival and known predictors of survival. Hum Pathol 1994; 25: 1075–1083. 65. Slomovitz BM, Broaddus RR, Burke TW et al. Her-2/neu overexpression and amplification in uterine papillary serous carcinoma. J Clin Oncol 2004; 22: 3126–3132. 66. Backe J, Gassel AM, Krebs S et al. Immunohistochemically detected HER-2/neu expression and prognosis in endometrial carcinoma. Arch Gynecol Obstet 1997; 259: 189–195.



67. Coronado PJ, Vidart JA, López-Asenjo JA et al. p53 overexpression predicts endometrial carcinoma recurrence better than HER-2/neu overexpression. Eur J Obstet Gynecol Reprod Biol 2001; 98: 103–108. 68. Heffner HM, Freedman AN, Asirwatham JE et al. Prognostic significance of p53, PCNA, and HER-2/neu in endometrial carcinoma. Eur J Gynaecol Oncol 1999; 20: 8–12. 69. Athanassiadou P, Athanassiades P, Grapsa D et al. The prognostic value of PTEN, p53, and beta-catenin in endometrial carcinoma: A prospective immunocytochemical study. Int J Gynecol Cancer 2007; 17: 697–704. 70. Mariani A, Sebo TJ, Katzmann JA et al. Pretreatment assessment of prognostic indicators in endometrial cancer. Am J Obstet Gynecol 2000; 182: 1535–1544. 71. Inaba F, Kawamata H, Teramoto T, Fukasawa I, Inaba N, Fujimori T. PTEN and p53 abnormalities are indicative and predictive factors for endometrial carcinoma. Oncol Rep 2005; 13: 17–24. 72. An HJ, Kim KI, Kim JY et al. Microsatellite instability in endometrioid type endometrial adenocarcinoma is associated

73.

74.

75.

76.

77.

with poor prognostic indicators. Am J Surg Pathol 2007; 31: 846–853. Caduff RF, Johnston CM, Svoboda-Newman SM et al. Clinical and pathological significance of microsatellite instability in sporadic endometrial carcinoma. Am J Pathol 1996; 148: 1671– 1678. Basil JB, Goodfellow PJ, Rader JS et al. Clinical significance of microsatellite instability in endometrial carcinoma. Cancer 2000; 89: 1758–1764. MacDonald ND, Salvesen HB, Ryan A et al. Frequency and prognostic impact of microsatellite instability in a large populationbased study of endometrial carcinomas. Cancer Res 2000; 15: 1750–1752. Mell LK, Meyer JJ, Tretiakova M et al. Prognostic significance of E-cadherin protein expression in pathological stage I-III endometrial cancer. Clin Cancer Res 2004; 10: 5546–5553. Scholten AN, Aliredjo R, Creutzberg CL, Smit VT. Combined E-cadherin, alpha-catenin, and beta-catenin expression is a favorable prognostic factor in endometrial carcinoma. Int J Gynecol Cancer 2006; 16: 1379–1385.


783