National Cancer Institute®
Last Modified: July 1, 2002
UI - 12050510
AU - Chang SS; Cole E; Smith JA Jr; Cookson MS
TI - Pathological findings of gynecologic organs obtained at female radical cystectomy.
SO - J Urol 2002 Jul;168(1):147-9
AD - Department of Urologic Surgery, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
PURPOSE: Historically anterior pelvic exenteration has been the recommended treatment for invasive urothelial carcinoma in women undergoing radical cystectomy. We evaluated the pathological features of reproductive organs removed during exenteration to determine the incidence of malignant pathology in these organs and the need for removal. MATERIALS AND METHODS: We reviewed the records of all patients Of these 382 patients, we identified 68 females who underwent radical cystectomy for urothelial carcinoma. We reviewed preoperative, operative and pathological findings, including bladder, lymph nodes, uterine and adnexal pathology, in these female patients. RESULTS: Median patient age was 64 years (range 35 to 86). Gynecologic organs were present in 40 of the 68 surgical specimens (59%). The reasons for absent gynecologic pathology were previous hysterectomy in 26 cases and the preservation of organs during orthotopic urinary diversion creation in 2. Malignancy was identified in 3 specimens, including invasive urothelial carcinoma in 2 (5%). In these 2 cases invasion was clearly identified intraoperatively. Low grade stromal sarcoma of the uterus was present in 1 specimen (2%). CONCLUSIONS: In the absence of clinical suspicion radical hysterectomy at cystectomy rarely improves cancer control. Furthermore, secondary malignancies are rare. The functional impact of preserving gynecologic organs is a subject of ongoing study.
UI - 11854177
AU - Zhou XP; Kuismanen S; Nystrom-Lahti M; Peltomaki P; Eng C
TI - Distinct PTEN mutational spectra in hereditary non-polyposis colon cancer syndrome-related endometrial carcinomas compared to sporadic microsatellite unstable tumors.
SO - Hum Mol Genet 2002 Feb 15;11(4):445-50
AD - Clinical Cancer Genetics Program and Human Cancer Genetics Program, Comprehensive Cancer Center and Division of Human Genetics, Department of Internal Medicine, The Ohio State University, Columbus, OH 43210, USA.
Germline PTEN mutations cause Cowden syndrome (CS) and Bannayan-Riley-Ruvalcaba syndrome (BRR), two hamartoma-tumor syndromes with an increased risk of breast, thyroid and endometrial cancers. Somatic genetic and epigenetic inactivation of PTEN is involved in as high as 93% of sporadic endometrial carcinomas (EC), irrespective of microsatellite status, and can occur in the earliest precancers. EC is the most frequent extra-colonic cancer in patients with hereditary non-polyposis colon cancer syndrome (HNPCC), characterized by germline mutations in the mismatch repair (MMR) genes and by microsatellite instability (MSI) in component tumors. To determine whether PTEN is involved in the pathogenesis of EC arising in HNPCC cases, and whether PTEN inactivation precedes MMR deficiency, we obtained 41 ECs from 29 MLH1 or MSH2 mutation positive HNPCC families and subjected them to PTEN expression and mutation analysis. Immunohistochemical analysis revealed 68% (28/41) of the HNPCC-related ECs with absent or weak PTEN expression. The remaining 27% (11/41) of tumors had normal expression and 5% (2/41) with mixed populations showing weak/absent as well as normal expression. Mutation analysis of 20 aberrant PTEN-expressing tumors revealed that 17 (85%) harbored 18 somatic PTEN mutations. All mutations were frameshift, 10 (56%) of which involved the 6(A) tracts in exon 7 or 8. These results suggest that PTEN plays a significant pathogenic role in both HNPCC and sporadic endometrial carcinogenesis, unlike the scenarios for colorectal cancer. Furthermore, we have shown that somatic PTEN mutation, especially frameshift, is a consequence of profound MMR deficiency in HNPCC-related ECs. In contrast, among 60 previously reported MSI+ sporadic ECs with 70 somatic mutations in PTEN, 39 (56%) were frameshift, of which only eight (21%) were affecting the 6(A) tracts in exon 7 or 8 (P = 0.01), suggesting that PTEN mutations may precede MMR deficiency.
UI - 11986334
AU - Mutter GL
TI - Diagnosis of premalignant endometrial disease.
SO - J Clin Pathol 2002 May;55(5):326-31
AD - Department of Pathology, Harvard Medical School, Brigham and Women's Hospital, Boston, MA 02115, USA. firstname.lastname@example.org
Modern molecular methods for precancer diagnosis have expanded the range of detectable disease to a preclinical level and provided material for histopathological correlation. The precancer scenario begins with sporadic acquisition of rare PTEN mutation bearing glands, which are morphologically unremarkable, and progresses to discrete foci of cytologically altered glands, readily visible on routinely stained sections. Clinical outcome studies of women with endometrial lesions have established threshold diagnostic features that confer increased cancer risk. This class of high risk lesions has been designated endometrial intraepithelial neoplasia (EIN). EIN is diagnosed by presence of cytological demarcation, crowded gland architecture, minimum size of 1mm, and careful exclusion of mimics. Most EIN lesions have been diagnosed as atypical endometrial hyperplasias in the World Health Organisation system. Specialised molecular and morphometric analyses have been extremely useful in redefining clinically relevant premalignant endometrial disease, but translation to improved patient care requires the informed participation of pathologists.
UI - 12019154
AU - Parekh TV; Gama P; Wen X; Demopoulos R; Munger JS; Carcangiu ML; Reiss
TI - M; Gold LI Transforming growth factor beta signaling is disabled early in human endometrial carcinogenesis concomitant with loss of growth inhibition.
SO - Cancer Res 2002 May 15;62(10):2778-90
AD - Department of Pathology, Kaplan Comprehensive Cancer Center, New York University School of Medicine, 550 First Avenue, New York, NY 10016, USA.
Transforming growth factor beta (TGF-beta), a potent ubiquitous endogenous inhibitor of epithelial cell growth, is secreted as a latent molecule (LTGF-beta)requiring activation for function. TGF-beta signals through the type I(TbetaRI) and type II (TbetaRII) receptors, which cooperate to phosphorylate/activate Smad2/3, the transcriptional regulators of genes that induce cell cycle arrest. That carcinomas grow in vivo suggests that they are refractory to TGF-beta. However, this has been difficult to prove because of an inability to analyze the functional status of TGF-beta in vivo as well as lack of close physiological paradigms for carcinoma cells in vitro. The current studies demonstrate that whereas primary cultures of endometrial epithelial cells derived from normal proliferative endometrium (PE; n = 10) were dose-dependently and maximally growth inhibited by 55% +/- 5.3% with 10 pM TGF-beta1, endometrial epithelial cells derived from endometrial carcinomas (ECAs; n = 10) were unresponsive (P < or = 0.0066). To determine the mechanism of TGF-beta resistance in ECAs, we analyzed the TGF-beta signaling pathway in vivo by immunohistochemistry using specific antibodies to TbetaRI and TbetaRII, Smads, and to the phosphorylated form of Smad2 (Smad2P), an indicator of cells responding to bioactive TGF-beta. Smad2P was expressed in all of the normal endometria (n = 25), and was localized to the cytoplasm and nucleus in PE, and only nuclear in the secretory endometrium. In marked contrast, Smad2P immunostaining was weak or undetectable in ECA (n = 22; P < or = 0.001) and reduced in glandular hyperplasia (n = 25) compared with normal endometrium. However, total Smad2 and Smad7 (which inhibits Smad2 activation) levels were identical in ECA and normal tissue. Consistent with loss of downstream signaling, both TbetaRI (n = 19) and TbetaRII (n = 22) protein expression were significantly reduced in ECA compared with PE (n = 11; P < or = 0.05). By in situ hybridization, the mRNA levels of TbetaRI and TbetaRII were decreased in the carcinoma cells compared with normal PE glands, suggesting that receptor down-regulation occurs at the transcriptional level. Furthermore, a somatic frameshift mutation in the polyadenine tract at the 5' end of the TbetaR-II gene was detected in two of six cases examined. Finally, the ability of explants of ECA to activate endogenous LTGF-beta was deficient compared with normal tissue (23.5% versus 7.4%). Therefore, our results suggest that loss of Smad2 signaling in ECA may be because of down-regulation of TbetaRI and TbetaRII, and/or decreased activation of LTGF-beta. Because disruption of TGF-beta signaling occurred independent of grade or degree of invasion and was evident in premalignant hyperplasia, we conclude that inactivation of TGF-beta signaling leading to escape from normal growth control occurs at an early stage in endometrial carcinogenesis, thereby defining novel molecular targets for cancer prevention.
UI - 11824891
AU - Brock S; Ellison D; Frankel J; Davis C; Illidge T
TI - Anti-Yo antibody-positive cerebellar degeneration associated with endometrial carcinoma: case report and review of the literature.
SO - Clin Oncol (R Coll Radiol) 2001;13(6):476-9
AD - Wessex Cancer Centre, Southampton, UK.
Paraneoplastic cerebellar degeneration (PCD) is a rare, severely debilitating disease, often with a rapid onset and progression, which predate the diagnosis of malignancy. Despite characteristic features, diagnosis is commonly difficult and successful therapy, which relies on early instigation of treatment, is rare. Here we present a patient in whom anti-Yo antibody-positive PCD was associated with endometrial carcinoma and an extensive review of the literature outlining the clinical features, pathogenesis and treatment of PCD.
UI - 12055672
AU - Maeda K; Tsuda H; Hashiguchi Y; Yamamoto K; Inoue T; Ishiko O; Ogita S
TI - Relationship between p53 pathway and estrogen receptor status in endometrioid-type endometrial cancer.
SO - Hum Pathol 2002 Apr;33(4):386-91
AD - Department of Obstetrics and Gynecology, Osaka City University Graduate School of Medicine, Japan.
We analyzed the mechanism of estrogen receptor (ER) loss and status of the p53 pathway in 64 cases of endometrial cancer. 26.6% (17 of 64) of endometrial cancers lost ER. Methylation of the ER CpG island was significantly related to ER status (P = 0.0074). However, the methylation site of the ER CpG island differed between breast and endometrial cancers. The abnormal expression rate of p14ARF, MDM2, p53, and the p53 pathway were 7.8% (5 of 64), 32.8% (21 of 64), 25.0% (16 of 64) and 53.1% (34 of 64), respectively. There was no significant difference in the overexpression of MDM2 between p53-positive cases (43.8%: 7 of 16) and p53-negative cases (29.2%; 14 of 48) (P = 0.3595). Abnormal p53 was higher in grade 3 tumors (55.6%; 5 of 9) than in grade 1 and 2 tumors (20.0%; 11 of 55) (P = 0.0364). The abnormality of the p53 pathway was higher in grade 3 tumors (88.9%; 8 of 9) than in grade 1 and 2 tumors (47.3%; 26 of 55) (P = 0.0294). However, there was no significant difference in abnormal p53 pathway between ER-negative and ER-positive cases. In endometrial cancer, ER CpG island methylation was the important mechanism of ER loss. However, there was no significant relationship between the p53 pathway and ER status. Copyright 2002, Elsevier Science (USA). All rights reserved.
UI - 11891178
AU - Zysman MA; Chapman WB; Bapat B
TI - Considerations when analyzing the methylation status of PTEN tumor suppressor gene.
SO - Am J Pathol 2002 Mar;160(3):795-800
AD - Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada.
Epigenetic mechanisms of gene silencing, including promoter hypermethylation of tumor suppressor genes, have been shown to contribute to tumorigenesis. PTEN is an important tumor suppressor implicated in the pathogenesis of a number of familial and sporadic cancers. Germline mutations of PTEN predispose to dominantly inherited hamartomatous disorders Cowden syndrome and Bannayan-Zonana syndrome. Somatic PTEN mutations commonly occur in endometrial, breast, prostate, and thyroid tumors. Several investigators have speculated on PTEN promoter hypermethylation as a possible mechanism of PTEN inactivation but data supporting such observations is not forthcoming. The genomic sequence of PTEN is 98% identical to a highly conserved processed PTEN pseudogene (psiPTEN) and this sequence identity extends 841 base pairs into the promoter region. This high degree of homology has made analysis of the methylation status of the PTEN promoter quite challenging. We have investigated the methylation profiles of the promoter region of PTEN in endometrial, breast, and colon cancer cell lines, as well as in a panel of primary endometrial tumors using a combination of methylation-specific polymerase chain reaction, methylation-sensitive restriction analysis, and bisulfite sequencing. Our results show that the pseudogene, and not PTEN, is predominantly methylated in cell lines and tumors. Without careful consideration of the critical nucleotide differences between the two sequences, results obtained from PTEN analysis may not necessarily represent the methylation status of PTEN.
UI - 12057899
AU - Kuismanen SA; Moisio AL; Schweizer P; Truninger K; Salovaara R; Arola J;
TI - Butzow R; Jiricny J; Nystrom-Lahti M; Peltomaki P Endometrial and colorectal tumors from patients with hereditary nonpolyposis colon cancer display different patterns of microsatellite instability.
SO - Am J Pathol 2002 Jun;160(6):1953-8
AD - Department of Medical Genetics, University of Helsinki, Helsinki, Finland.
The colorectum and uterine endometrium are the two most commonly affected organs in hereditary nonpolyposis colon cancer (HNPCC), but the genetic basis of organ selection is poorly understood. As tumorigenesis in HNPCC is driven by deficient DNA mismatch repair (MMR), we compared its typical consequence, instability at microsatellite sequences, in colorectal and endometrial cancers from patients with identical predisposing mutations in the MMR genes MLH1 or MSH2. Analysis of non-coding (BAT25, BAT26, and BAT40) and coding mononucleotide repeats (MSH6, MSH3, MLH3, BAX, IGF2R, TGF beta RII, and PTEN), as well as MLH1- and MSH2-linked dinucleotide repeats (D3S1611 and CA7) revealed significant differences, both quantitative and qualitative, between the two tumor types. Whereas colorectal cancers displayed a predominant pattern consisting of instability at the BAT loci (in 89% of tumors), TGF beta RII (73%), dinucleotide repeats (70%), MSH3 (43%), and BAX (30%), no such single pattern was discernible in endometrial cancers. Instead, the pattern was more heterogeneous and involved a lower proportion of unstable markers per tumor (mean 0.27 for endometrial cancers versus 0.45 for colorectal cancers, P < 0.001) and shorter allelic shifts for BAT markers (average 5.1 bp for unstable endometrial cancers versus 9.3 bp for colorectal cancers, P < 0.001). Among the individual putative "target" loci, PTEN instability was associated with endometrial cancers and TGF beta RII instability with colon cancers. The different instability profiles in endometrial and colorectal cancers despite identical genetic predisposition underlines organ-specific differences that may be important determinants of the HNPCC tumor spectrum.
UI - 12066951
AU - Nieto JJ; Gornall R; Toms E; Clarkson S; Hogston P; Woolas RP
TI - Influence of omental biopsy on adjuvant treatment field in clinical Stage I endometrial carcinoma.
SO - BJOG 2002 May;109(5):576-8
AD - Department of Gynaecological Oncology, St Mary's Hospital, Portsmouth, UK.
In this study to assess the role of omental biopsy in the diagnosis of extrapelvic disease, data from 100 consecutive women with clinical Stage I endometrial cancer undergoing primary surgical treatment in our institution were analysed: 80 women had an omental biopsy, 20 did not, and six had adenocarcinoma in the omentum. No obvious morbidity attributable to this rapid and easily performed surgical procedure was recorded. We conclude that visual inspection and palpation of the omentum at the time of abdominal surgery for endometrial carcinoma is worthwhile and advisable. In addition, adopting a protocol of histological assessment upstaged a further two cases of this series. These data suggest that this technique might influence the prescription of adjuvant pelvic radiation in approximately one in 10 women currently considered for such therapy, as disease can be easily documented as having extended beyond the conventional radiotherapy field.
UI - 11549999
AU - Wiesenfeld U; Cova M; De Lazslo P; Tinelli A; Mangino F; Grimaldi E;
TI - Guaschino S [Magnetic resonance (MR) in endometrial carcinoma preoperative evaluation]
SO - Minerva Ginecol 2001 Oct;53(5):341-6
AD - Clinica Ginecologica ed Ostetrica, IRCCS Burlo Garofolo, Universita degli Studi, Trieste, Italy. email@example.com
BACKGROUND: Myometrial invasion of endometrial carcinoma is an important prognostic factor because the degree of myometrial invasion is correlated with the rate of lymphnode metastases and of recurrences. The aim of the study was a preoperative evaluation of endometrial carcinoma by Magnetic Resonance (MR). METHODS: The authors present a prospective study performed on 54 cases of endometrial carcinoma collected at the Department of Gynecology and Obstetrics of the University of Trieste (Italy). All the patients were considered as Stage I after hysteroscopy and endocervical curettage. Prior to surgery all the patients underwent MR at the Department of Radiology of the University of Trieste (Italy) in order to evaluate the depth of myometrial invasion. The surgical procedure included total abdominal hysterectomy, bilateral salpingo-oophorectomy and pelvic and lomboaortic lymphadenectomy in high risk cases. Statistical evaluation was performed by Fischer's exact test. RESULTS: Statistically significant positive correlation was found (p<0.001) between MR staging and surgical staging. The sensitivity reported in our series for distinguishing between superficial disease (Stage IA and IB) and deep myometrial invasion (Stage IC) was 92%. CONCLUSIONS: Preoperative MR is helpful in selecting patients at high risk of nodal involvement and it is suggested that, although MR is considered an expensive examination, its use should be always considered before surgical treatment of patients with high surgical risk.
UI - 11833867
AU - Perez-Medina T; Bajo J; Huertas MA; Rubio A
TI - Predicting atypia inside endometrial polyps.
SO - J Ultrasound Med 2002 Feb;21(2):125-8
AD - Department of Obstetrics and Gynecology, Santa Cristina University Hospital, Madrid, Spain.
OBJECTIVE: To evaluate the efficacy of color Doppler exploration for assessing atypia inside endometrial polyps. METHODS: A prospective study was conducted in a tertiary university hospital. Eight hundred six patients with endometrial polyps were studied with color Doppler sonography, and the resistive index inside the polyp stalk was obtained. The patients were then referred for hysteroscopic resection, and pathologic analysis was performed. RESULTS: Thirty-five polyps with sonographic indications of atypia were pathologically confirmed. Sonographic indications of atypia inside 16 polyps were not confirmed. Three nonquestionable endometrial polyps had atypia inside them. CONCLUSIONS: Low Doppler resistance is highly predictive of atypia inside endometrial polyps.
UI - 12065875
AU - Fujimoto J; Sakaguchi H; Aoki I; Toyoki H; Tamaya T
TI - Clinical implications of the expression of estrogen receptor-alpha and -beta in primary and metastatic lesions of uterine endometrial cancers.
SO - Oncology 2002;62(3):269-77
AD - Department of Obstetrics and Gynecology, Gifu University School of Medicine, Japan.
Novel human estrogen receptor (ER)-beta was identified in cDNA libraries from human testes. ER-beta specifically expresses in the testis, ovary, thymus, spleen, osteoblasts, fetus and uterine endometrium. ER-beta might not conserve the same physiological functions as does ER-alpha. Therefore, expressions of ER-alpha and ER-beta mRNAs in primary and metastatic lesions of uterine endometrial cancers were investigated. The levels of ER-beta mRNA were significantly lower than those of ER-alpha mRNA in uterine endometrial cancers and in normal uterine endometria. The ratio of ER-beta to ER-alpha mRNA in most primary uterine endometrial cancers was similar to that in normal uterine endometria (<0.4% of ER-beta mRNA to ER-alpha mRNA). On the other hand, in 14 of the 20 lymph node metastasis-positive cases of uterine endometrial cancers, the ratio in the metastatic lesion was significantly higher than that in the primary lesion of the corresponding case, and patient prognosis in these cases was extremely poor. Therefore, it is suggested that the intact synchronized expression of ER-beta interacting with ER-alpha might be disrupted, especially in most metastases of uterine endometrial cancers, leading to poor patient prognosis related to estrogen refractoriness. Copyright 2002 S. Karger AG, Basel
UI - 12115520
AU - Mizumoto H; Saito T; Ashihara K; Nishimura M; Tanaka R; Kudo R
TI - Acceleration of invasive activity via matrix metalloproteinases by transfection of the estrogen receptor-alpha gene in endometrial carcinoma cells.
SO - Int J Cancer 2002 Aug 1;100(4):401-6
AD - Department of Obstetrics and Gynecology, Sapporo Medical University School of Medicine, Sapporo, Japan.
It is well known that the functions of reproductive organs are regulated by sex steroids and their receptors and it is hypothesized that the progression of neoplasms that originate from the reproductive organs is influenced by them. However, the correlation between sex steroids and tumor progression, especially tumor invasion, is not well known in endometrial carcinoma. In our study, we focused on the influence of estrogen and its receptor in invasion and matrix metalloproteinases (MMPs), which are known to be important in tumor invasion, as well as on endometrial carcinoma cells. The growth of Ishikawa cells, to which an estrogen receptor-alpha expressing vector was transfected, was accelerated by 17 beta-estradiol as was the acceleration of the expression of cyclin D1. By invasion assay, in conditions with 17 beta-estradiol, the invasiveness of Ishikawa cells was enhanced. Furthermore, according to the accelerated invasiveness, the expression of MMP-1, -7 and -9 and Ets-1 was enhanced. These results suggest that activation of ER-alpha by estrogen results in tumor progression by stimulating cell growth and invasiveness via acceleration of the expression of MMPs. Copyright 2002 Wiley-Liss, Inc.
UI - 11813987
AU - Song M; Santanam N
TI - Increased myeloperoxidase and lipid peroxide-modified protein in gynecological malignancies.
SO - Antioxid Redox Signal 2001 Dec;3(6):1139-46
AD - Department of Gynecology and Obstetrics, Emory University, School of Medicine, Atlanta, GA 30322, USA.
Oxidative stress has been implicated in several diseases, including cancer. Oxidants induce oncogenes and their products associated with cell growth. Even though epidemiological studies implicate oxidants in promoting cancer, there is still a lack of in vivo evidence for the same. In this study, we measured the levels of myeloperoxidase (MPO), an enzyme associated with oxidation and autoantibodies to lipid peroxide-modified protein (LOOH-RSA), in the plasma of subjects with gynecological cancers. The gynecological cancer subjects (n = 201) had higher plasma MPO and LOOH-RSA levels compared with control subjects (n = 60). Immunohistochemical analysis of tissues revealed that immunostaining for MPO and LOOH-RSA was higher in cancer tissues compared with controls. The staining was specific to cell types and not ubiquitously present. Neutrophils, monocytes/macrophages, and natural killer cells have been proposed to play a role in cancer promotion and progression. This study proposes a role for oxidative stress and especially MPO in cancer.
UI - 11965713
AU - Ivanov S; Ivanov S; Kurlov T; Milev A; Kulander S; Ivanov V
TI - [Primary hormone treatment of early endometrial cancer]
SO - Akush Ginekol (Sofiia) 1999;38(1):20-3
Six cases of primary treated endometrial cancer are included in this research work. Five of these women ended with tumour regression and 2 with pregnancies and deliveries of children. All of the women are still alive without having disease with mean follow-up period of 36.5 months (from 16 to 80 months). We consider that this is very promising method of treatment to offer y conservative treatment with high level of survival and possibility for having y child. Diagnostic and therapeutic data for the patients who are with early endometrial cancer and wish to have y child are analyised in this study. Four of the women were treated with GnRh-analogs-Zoladex and 2 with progestins-high doses.
UI - 12092593
AU - Demopoulos RI; Mesia AF; Mittal K; Vamvakas E
TI - Immunohistochemical comparison of uterine papillary serous and papillary endometrioid carcinoma: clues to pathogenesis.
SO - Int J Gynecol Pathol 1999 Jul;18(3):233-7
AD - Department of Pathology, New York University Medical Center, New York, 10016, USA.
Twenty-four predominantly papillary carcinomas of the endometrium, 10 serous and 14 endometrioid, were compared using a variety of immunohistochemical antibodies, including p53, estrogen and progesterone receptors, carcinoembryonic antigen, and E-cadherin. These were selected to attempt to find clues to explain the disparate behavior of these two tumor subtypes. We found that 6 of 8 (75%) serous carcinomas had a p53 reactivity score of 300, whereas 90% of endometrioid tumors had a p53 reactivity score of less than 20 (p = 0.0008). Combined estrogen and progesterone hormone reactivity was positive in 13 (100%) of endometrioid lesions compared with 4 of 8 (50%) of serous lesions (p = 0.0117). The significantly greater p53 expression and its significantly diminished hormone receptor expression indicate that papillary serous carcinomas belong to the type II group of endometrial carcinomas that occur in a background of atrophic endometrium, are high grade, present with high stage disease, and have a poor prognosis. In contrast, papillary endometrioid carcinomas, which belong to type I carcinomas, often arise in a background of estrogen-stimulated endometrial hyperplasia, are usually well-differentiated, and have a good prognosis. Early p53 mutations in papillary serous carcinoma as well as in endometrial intraepithelial serous carcinoma may partially explain their proclivity for early intra-abdominal dissemination. Carcinoembryonic antigen expression was similar in both groups and therefore is not useful to characterize possible differences in the cell of origin. The reactivity scores for E-cadherin were also similar in the two tumor subtypes, thus not supporting the hypothesis that decreased cell to cell adhesion molecules might contribute to early dissemination of serous lesions.
UI - 12051868
AU - Singer CF; Kronsteiner N; Marton E; Walter I; Kubista M; Czerwenka K;
TI - Schreiber M; Tschugguel W; Wieser F; Kubista E Interleukin-1 system and sex steroid receptor gene expression in human endometrial cancer.
SO - Gynecol Oncol 2002 Jun;85(3):423-30
AD - Division of Special Gynecology, Department of Pathology, Division of Endocrinology, University of Vienna Medical Center, Waehringer Guertel 18-20, Vienna, Austria. Christian.Singer@univie.ac.at
OBJECTIVES: The interleukin-1 system is known to play a pivotal role in human physiology and reproduction. In the cycling endometrium, interleukin-1alpha activity is controlled by sex steroids and is confined to the perimenstrual phase, where it is involved in the events leading to tissue lysis and menstruation. Since local tissue degradation is also a feature of malignant tumors, our goal was to analyze the gene expression of interleukin-1alpha and other interleukin-1 family members and compare it with estrogen receptor alpha, estrogen receptor beta, and progesterone receptor mRNA expression in 27 endometrial carcinomas and 13 normal endometria. METHODS: Endometrial tumor tissues were obtained during hysterectomy for endometrial cancer, and normal endometrium was sampled in women undergoing surgical procedures for nonendometrial pathologies. Gene expression was analyzed by reverse transcription polymerase chain reaction. Protein expression was detected and localized by immunohistochemical staining. RESULTS: A strong gene expression of interleukin-1 type I receptor, estrogen recptor alpha, and progesterone receptor was detected in all tumor tissues and in the majority of benign endometrial tissues. However, in contrast to nonmalignant endometria, variable amounts of interleukin-1beta and interleukin-1 receptor antagonist mRNA were also detected in most of the tumor samples. Gene expression of interleukin-1alpha and estrogen receptor beta was considerably less frequent, with interleukin-1alpha being absent in all peri- and postmenopausal endometria and in all but one of the well-differentiated tumors. With decreasing differentiation interleukin-1alpha gene expression became more frequent. In these cases, interleukin-1alpha protein was detected predominantly in epithelial tumor cells of lower-grade tumors. CONCLUSION: We have demonstrated the presence of the interleukin-1 system in endometrial malignancies, and found a negative correlation between interleukin-1alpha and tumor differentiation. We hypothesize that the nonphysiological expression of interleukin-1alpha in less differentiated tumors might contribute to their invasiveness and malignant behavior.
UI - 12051878
AU - Vorgias G; Hintipas E; Katsoulis M; Kalinoglou N; Dertimas B; Akrivos T
TI - Intraoperative gross examination of myometrial invasion and cervical infiltration in patients with endometrial cancer: decision-making accuracy.
SO - Gynecol Oncol 2002 Jun;85(3):483-6
AD - Department of Gynaecology, Piraeus, Greece. firstname.lastname@example.org
OBJECTIVES: We sought to determine the accuracy of gross evaluation of the depth of myometrial invasion and the involvement of the cervix, and its value in determining the need for extensive surgery in patients with endometrial carcinoma. METHODS: The intraoperative records of 256 patients operated for endometrial cancer were used to compare the gross evaluations with the final microscopic histopathological findings. In the theater, the uterus was opened and inspected after its removal. The depth of myometrial invasion was noted as less or greater than 50% using a full-thickness incision through the tumor, while cervical involvement was noted as positive or negative, based on extension of the tumor below the internal cervical os. Standard statistical calculations were used to determine accuracy, sensitivity, specificity, positive and negative predictive values, and false-positive and false-negative rates of the method. RESULTS: Regarding the depth of myometrial invasion, gross evaluation could accurately predict the final result in 88.2% of patients. Sensitivity, specificity, positive, and negative predictive values were 83.7, 90.6, 82.8, and 91.1%, respectively. False-positive results were noted in 9.4% of cases and false-negative in 16.3%. Analysis of the characteristics of the false-negative patients showed that they had aggressive variant tumors, tumors of advanced grade, and tumors that more frequently had developed from an atrophic endometrium. With respect to cervical involvement, gross evaluation had an overall accuracy of 98.5%, 0% false-positive rate, 11.5% false-negative rate, 88.5% sensitivity, 100% specificity, 100% positive predictive value, and 98.3% negative predictive value. CONCLUSION: Our data suggest that visual gross examination of the uterus provides safe and reliable estimates of both myometrial invasion and cervical infiltration. So, the surgeon can rely on the procedure to decide the need for further operative manipulations.
UI - 12085172
AU - Crawford SC; De Caestecker L; Gillis CR; Hole D; Davis JA; Penney G;
TI - Siddiqui NA Staging quality is related to the survival of women with endometrial cancer: a Scottish population based study. Deficient surgical staging and omission of adjuvant radiotherapy is associated with poorer survival of women diagnosed with endometrial cancer in Scotland during 1996 and 1997.
SO - Br J Cancer 2002 Jun 17;86(12):1837-42
AD - Department of Gynaecological Oncology, Stobhill Hospital Glasgow G21 3UW, UK. email@example.com
The association between treatment variation and survival of women with endometrial cancer was investigated. A retrospective cohort based upon the complete Scottish population registered on in-patient and day-case hospital discharge data (Scottish Morbidity Record-1) and cancer registration (Scottish Morbidity Record-6) coded C54 and C55 in ICD10, hundred and three patients who underwent surgical treatment out of 781 patients that were diagnosed with endometrial cancer in Scotland during 1996 and 1997. The overall quality of surgical staging was poor. The quality of staging was related to both the year that the surgeon passed the Member of the Royal College of Obstetricians and Gynaecologists examination and also to 'specialist' status but was not related to surgeon caseload. Two clinically important prognostic factors were found to be associated with survival; whether the International Federation of Obstetrics and Gynaecology stage was documented, RHR=2.0 (95% CI=1.3 to 3.1) and also to the use of adjuvant radiotherapy, RHR=2.2 (95% CI=1.5 to 3.5). The associations with survival were strongest in patients with advanced disease, International Federation of Obstetrics and Gynaecology stages 1C through to stage 3. Deficiencies in staging and variations in the use of adjuvant radiotherapy represent a possible source of avoidable mortality in patients with endometrial cancer. Consequently, there should be a greater emphasis on improving the overall quality of surgical staging in endometrial cancer. Copyright 2002 Cancer Research UK
UI - 12118561
AU - Chao CK; Grigsby PW; Perez CA; Mutch DG; Herzog T; Camel HM
TI - Medically inoperable stage I endometrial carcinoma: a few dilemmas in radiotherapeutic management.
SO - Int J Radiat Oncol Biol Phys 1996 Jan 1;34(1):27-31
AD - Radiation Oncology Center, Mallinckrodt Institute of Radiology, Washington University School of Medicine, St Louis, MO 63110, USA.
PURPOSE: The aggressiveness of radiation therapy for patients with medically inoperable endometrial carcinoma is controversial. Patients may die of their underlining medical disease before succumbing to cancer. We try to identify certain subgroup of patients who might benefit most from an aggressive approach and also investigate the impact of residual tumor present in dilatation and curettage (D&C) specimen obtained in second intracavitary implant (ICI). METHODS AND MATERIALS: From 1965 to 1990, 101 patients were treated for clinical clinical Stage I endometrial carcinoma with RT alone due to medical problems. Ages ranged from 39 to 94 years (median 71 years). There were 18 patients with clinical Stage IA and 83 with clinical Stage IB disease. Histology included 44 well-differentiated, 37 moderately differentiated, and 20 poorly differentiated tumors. Radiation therapy consisted of external beam only in 3 patients, ICI alone in 26, whole pelvis plus ICI in 10, and whole pelvis plus split field plus ICI in 62. A second D&C was performed on 26 patients at the time of the second ICI. Minimum follow-up was 2 years (median, 6.3 years). RESULTS: The 5-year actuarial disease-free survival (DFS) for the studied cohort is comparable to the expected survival of an age-matched population. Pelvic control was 100% for Stage IA and 88% for Stage IB with 5-year disease-free survivals of 80 and 84%, respectively. We also observed a greater disassociation of DFS and overall survial among patients older than 75 years (84 and 55%, respectively) than in younger patients (84 and 78%, respectively). This is mainly because older patients succumbed to their medical illness. Well-differentiated disease demonstrated the trend toward a better outcome than moderately or poorly differentiated lesions in Stage IB patients (p = 0.05), but not in Stage IA patients. Aggressive radiation therapy approach showed the trend toward a better result in Stage IB patients 75 years of age or younger. There were two failures among 19 patients with no tumor found in the D&C specimen at the time of second implant. In contrast, seven patients with residual tumor seen in the endometrial sample at the time of second implant remain disease free. CONCLUSIONS: Radiation therapy alone is an effective treatment modality for medically inoperable Stage I endometrial carcinoma. Disease-free survival can be translated into longer overall survival in the younger age group, but not in older patients. The latter tend to die of their underlining medical illness. Tumor differentiation influenced the prognosis of Stage IB disease. No tumor seen in the endometrial sampling at the time of second implant did not correlate with a better disease control, and the treatment plan should not be modified on such information.
UI - 10987271
AU - Piao Z; Fang W; Malkhosyan S; Kim H; Horii A; Perucho M; Huang S
TI - Frequent frameshift mutations of RIZ in sporadic gastrointestinal and endometrial carcinomas with microsatellite instability.
SO - Cancer Res 2000 Sep 1;60(17):4701-4
AD - The Burnham Institute, La Jolla, California 92037, USA.
Many lines of evidence suggest that the retinoblastoma protein interacting zinc finger gene RIZ is a strong candidate for the tumor suppressor locus on 1p36, a region commonly deleted in many human cancers with chromosomal instability. In addition, a role for RIZ in tumors of the microsatellite instability pathway is suggested by frequent frameshift mutations in hereditary non-polyposis colorectal carcinomas. Here we studied RIZ mutations in sporadic cancers with microsatellite instability. Frameshift mutations in the two coding polyadenosine tracks of RIZ were found in 19 (48%) of 40 gastric carcinomas, 6 (33%) of 18 endometrial carcinomas, 14 (26%) of 51 of colorectal carcinomas, and 7 (54%) of 13 cell lines. Eleven tumor tissues showed biallelic inactivation of RIZ. In contrast, no frameshift mutations were found in 70 microsatellite stable tumors. These results suggest an important role for RIZ in sporadic cancers with microsatellite instability.
UI - 12034345
AU - Mizumoto H; Saito T; Ashihara K; Nishimura M; Takehara M; Tanaka R; Ito
TI - E; Kudo R Expression of matrix metalloproteinases in ovarian endometriomas: immunohistochemical study and enzyme immunoassay.
SO - Life Sci 2002 Jun 7;71(3):259-73
AD - Department of Obstetrics and Gynecology, Sapporo Medical University School of Medicine, S-1, W-16, Chuo-ku, Sapporo 060-0061, Japan.
Like carcinoma, endometriosis has the unique characteristics, of invasion and metastasis, though pathologically, it is a benign tumor. However, the mechanism of destruction of the surrounding tissue in endometriosis is still unclear. In this study, the expression and localization of matrix metalloproteinases (MMP)-1, -2, -3, -7, -9 and tissue inhibitors of metalloproteinases-1 (TIMP-1) were evaluated by immunohistochemistry for 20 cases and the amounts of MMP-1, TIMP-1 and MMP-1/TIMP-1 complex in the fluid of endometrioma, were analyzed by ELISA and western blotting for 20 cases, which were analyzed by immunohistochemical study. MMP-1, -2 and -9 were detected strongly in both stromal and epithelial cells and MMP-7 in the epithelial cells in the menstrual period. MMP-3 was mainly expressed in macrophage containing hemosiderin but the change of expression was not clear. TIMP-1 was intensively detected in both stromal and epithelial cells in the menstrual period but the expression decreased in other stages of the menstrual cycle. ELISA for MMP-1 also showed results similar to immunohistochemistry, suggesting that it was released to the cyst in the menstrual period when it was released to the extracellular space from the cytoplasm. The expression of TIMP-1 was not clearly changed during the menstrual cycle. From these results, it was suggested that the destruction of the surrounding matrix by endometriosis might be caused by various MMPs, which are mainly produced in stromal cells.
UI - 12115503
AU - Whelan AJ; Babb S; Mutch DG; Rader J; Herzog TJ; Todd C; Ivanovich JL;
TI - Goodfellow PJ MSI in endometrial carcinoma: absence of MLH1 promoter methylation is associated with increased familial risk for cancers.
SO - Int J Cancer 2002 Jun 10;99(5):697-704
AD - Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, USA.
Loss of DNA mismatch repair occurs in a variety of malignancies and is associated with genome-wide instability of microsatellite repeats, a molecular phenotype referred to as microsatellite instability (MSI). MSI is a consistent feature of colorectal and endometrial tumors from patients with hereditary non-polyposis colorectal cancer (HNPCC). Sporadic colorectal and endometrial cancers that exhibit MSI frequently have methylation of the MLH1 promoter. We undertook a detailed family and medical history study to compare family cancer risk for women with MSI-positive and -negative endometrial cancers. The MLH1 promoter methylation status was determined for all cancers. Family histories were developed for 80 probands (40 with MSI-positive and 40 with MSI-negative tumors). The numbers of reported cancers in first- and second-degree relatives of the 2 groups were similar. There was a modest increase in familial cancer clustering for MSI-positive probands. When MSI-positive tumors were subclassified according to MLH1 promoter methylation, a clear association between methylation status and familial cancer risk was evident. Women with MSI-positive endometrial cancers in which the MLH1 promoter was unmethylated had a 7-fold relative risk (RR) of demonstrating familial clustering of cancers [RR 7.07 (95% confidence interval 2.29-21.81)]. The women with MSI-positive, MLH1-unmethylated tumors were significantly younger than the rest of the study population (56.1 years vs. 65.4, p < or = 0.01). Age of onset and tumor MSI not associated with MLH1 promoter methylation may point to women with a genetic susceptibility to malignancies. Copyright 2002 Wiley-Liss, Inc.
UI - 11866205
AU - Pervez S; Hitchcock A; Sinton TM; Mani A; Smith JL
TI - DNA ploidy and S-phase fraction analyses of hyperplastic, atypical and cancerous endometrium using flow cytometry from paraffin-embedded tissues.
SO - Pathol Res Pract 2002;198(1):13-7
AD - Department of Pathology, The Aga Khan University Hospital Karachi, Pakistan. firstname.lastname@example.org
Atypical hyperplasia of the endometrium is an entity that needs to be clearly distinguished from other florid hyperplastic states on the one hand and from well-differentiated adenocarcinomas on the other. This may at times be difficult on pure morphological grounds. In this study, DNA ploidy and S-phase fraction of hyperplastic, atypical and cancerous endometrium were evaluated using flow cytometry from paraffin-embedded tissues. In total, 72 cases (24 hyperplastic, 24 atypical and 24 adenocarcinomas) were selected. All hyperplastic endometria showed a diploid stemline, while 2/24 atypical hyperplasias showed aneuploid (Near-diploid) peaks. Both of these cases were severely atypical and one of these, on hysterectomy, showed early invasive carcinoma. There was no significant difference in mean S-phase fractions of hyperplastic vs. atypical endometria. DNA aneuploidy was significantly more common with much higher S-phase fractions in poorly and moderately differentiated carcinomas than in well-differentiated ones. It was concluded that aneuploid (near-diploid) peaks, if ever present in atypical hyperplasias, may indicate an aggressive disease/neoplastic transformation.
UI - 12062616
AU - Alektiar KM; McKee A; Venkatraman E; McKee B; Zelefsky MJ; Mychalczak
TI - BR; Hoskins WJ; Barakat RR Intravaginal high-dose-rate brachytherapy for Stage IB (FIGO Grade 1, 2) endometrial cancer.
SO - Int J Radiat Oncol Biol Phys 2002 Jul 1;53(3):707-13
AD - Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA. email@example.com
PURPOSE: To evaluate the outcome of patients with Stage IB Grades 1 and 2 endometrial cancer treated with adjuvant high-dose-rate intravaginal 1999, 233 patients with Stage IB FIGO Grades 1 and 2 were treated with postoperative adjuvant high-dose-rate intravaginal brachytherapy. The median dose was 21 Gy in 7 Gy/fraction given at 2-week intervals. The mean age was 60 years. All patients underwent simple hysterectomy. Comprehensive surgical staging, defined as pelvic washing and pelvic and paraaortic lymph nodes sampling, was done in 9% of patients. Patients with FIGO Grade 3, papillary serous cancer, or clear-cell cancer were excluded from this analysis. Complications were assessed in terms of late Radiation Therapy Oncology Group toxicity (Grade > or =3) of the gastrointestinal tract, genitourinary tract, and vagina. RESULTS: With a median follow-up of 57 months, the 5-year vaginal/pelvic control, disease-free survival, and overall survival rate was 96% (95% confidence interval [CI] 94-99%), 94% (95% CI 91-98%), and 94% (95% CI 91-98%), respectively. The influence on outcome of age, grade (1 vs. 2), depth of invasion (one-third or less or greater than one-third), capillary space-like invasion, lower uterine segment involvement, and comprehensive surgical staging was evaluated. None of these factors significantly affected the rate of vaginal/pelvic control. Only age > or =60 years influenced the outcome for disease-free and overall survival. The 5-year rate for both disease-free and overall survival was 90% (95% CI 84-97%) for patients > or =60 years old compared with 99% (95% CI 96-100%) for those <60 years (p = 0.03 and 0.005, respectively). Of 233 patients, 3 (1%) developed Grade 3 or greater complications, with a 5-year actuarial rate of 2% (95% CI 0-5%). Two patients developed Grade 3 genitourinary toxicity, and 1 Grade 4 vaginal toxicity. CONCLUSION: On the basis of this retrospective study, adjuvant postoperative high-dose-rate intravagin