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子宮頸部腺癌の取り扱い子宮頸部腺癌の化学療法術前Neoadjuvant化学療法(NAC療法)としてのPaclitaxel+CBDCA併用療法(TJ療法)の有用性について

石岡伸一, 寒河江悟, 杉村政樹, 江坂嘉昭, 斉藤豪

日本婦人科腫瘍学会雑誌 ( (公社)日本婦人科腫瘍学会 ) 23 ( 3 ) 422 - 426 2005.06

1989年以降に治療を行ったBulky腫瘍を有する臨床進行期IbからIIIbの子宮頸部腺癌で,術前paclitaxel+CBDCA併用療法(TJ療法)を施行した5例について,従来のPAM療法を施行した28例との間で臨床的比較検討を行い,術前化学療法(NAC療法)としてのTJ療法の有用性を検討した.PAM療法群はCDDP 70mg/m2,AclacinomycinA 15mg/m2,MitomycinC 10mg/m2を4週ごとに2〜3コース,TJ療法群はPTX 175mg/m2,CBDCAをACU6にて4週ごとに2〜3コース施行後に,根治手術を施行した.TJ療法後,5例中4例,80%で腫瘍サイズの減少(縮小率61〜89%)を認めた.また,画像診断上のTJ療法後の骨盤リンパ節および子宮傍組織浸潤の所見と実際の摘出物の所見はほぼ相関し,TJ療法のNAC療法としての良好な一次治療効果を示したものと考えられた.副作用の発現はGrade3の好中球減少の発現がやや多いものの,G-CSFの投与にてコントロール可能であった

子宮内膜癌症例における子宮頸部細胞診所見(子宮体部5, 第46回日本臨床細胞学会総会(春期大会))

鈴木孝浩, 伊東英樹, 田中綾一, 藤本尚, 野田雅也, 永井美帆, 斉藤豪

日本臨床細胞学会雑誌 ( 特定非営利活動法人日本臨床細胞学会 ) 44 ( 1 ) 2005.03

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Hypermethylation in promoter region of retinoic acid receptor-beta gene and immunohistochemical findings on retinoic acid receptors in carcinogenesis of endometrium

R Li, T Saito, R Tanaka, S Satohisa, K Adachi, M Horie, Y Akashi, R Kudo

CANCER LETTERS ( ELSEVIER IRELAND LTD ) 219 ( 1 ) 33 - 40 2005.02

In the present study, we analyzed the immunohistochemical findings for the RA receptor (RAR), retinoic X receptor (RXR) and hypermethylation of promoter-region CpG island methylation of RAR-beta2. Immunohistochemistry indicated that though RXR-alpha and -gamma were present in endometrial hyperplasia and cancer, other retinoid receptors were only weakly detected. The hypermethylation of RAR-beta2 was found in 75.0% of endometrial hyperplasia samples and 92.2% of carcinomas. No normal endometria had methylation. This evidence may point to one of the reasons why endometrial hyperplasia acquires high proliferative capacity without differentiation, and the hypermethylation of RAR-beta2 may occur in the early stage of endometrial carcinogenesis. (C) 2004 Elsevier Ireland Ltd. All rights reserved.

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Nerve-preserving techniques for radical hysterectomy

E Ito, T Saito

EJSO ( ELSEVIER SCI LTD ) 30 ( 10 ) 1137 - 1140 2004.12

Aims. Postoperative bladder dysfunction of varying severity is common after radical hysterectomy due to damage to the pelvic autonomic nerves during surgical resection. Pelvic autonomic nerve damage occurs at two main sites: the fibrous tissue at the lateral aspect of the uterosacral. ligament (FLUSL) and the posterior layer of the vesicouterine ligament (PLVUL). In this article, we classify the main sites of pelvic autonomic nerve damage based on previous reports and our own experience, outline the problems with current nerve-preserving techniques, and describe an improved nerve-preserving technique that we have developed. Results. We present urodynamic data for 25 patients who underwent radical hysterectomy using the nerve-preserving technique we described previously and preliminary results for four patients treated by the latest technique. To avoid pelvic autonomic nerve damage, injury to the FLUSL and PLVUL should be minimized. For the FLUSL, we have obtained relatively good Madder function with the cardinal ligament pull-through technique. However, a new method is needed for management of the PLVUL, since the only way to minimize nerve damage at this site currently is to limit the extent of PLVUL resection. (C) 2004 Elsevier Ltd. All rights reserved.

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Identification of SCN3B as a novel p53-inducible proapoptotic gene

K Adachi, M Toyota, Y Sasaki, T Yamashita, S Ishida, M Ohe-Toyota, R Maruyama, Y Hinoda, T Saito, K Imai, R Kudo, T Tokino

ONCOGENE ( NATURE PUBLISHING GROUP ) 23 ( 47 ) 7791 - 7798 2004.10

Tumor suppressor p53 is a transcription factor that induces growth arrest and/or apoptosis in response to cellular stress. To identify novel p53-inducible genes, we compared the expression of genes in normal mouse embryo fibroblasts (MEFs) to p53-null cells by cDNA representational difference analysis. We report here that expression of endogenous sodium channel subunit beta 3 (SCN3B) is upregulated in mouse embryonic fibroblasts by DNA damage in a p53-dependent manner. In addition, we found that SCN3B levels are upregulated in human cancer cell lines by DNA damaging agents, as well as by overexpression of p53, but not significantly by p63 or p73. Furthermore, we identified two putative p53-binding sites upstream of the first exon (RE1) and in the third intron (RE2). The p53 protein can directly interact with the putative p53-binding sites in vivo, as assessed by chromatin immunoprecipitation. A reporter gene assay revealed that these two p53-binding sites are functional response elements. The SCN3B protein appears to be localized to the endoplasmic reticulum (ER). Introduction of the SCN3B gene into T98G and Saos2 cells potently suppressed colony formation. Furthermore, we found that adenovirus-mediated transfer of SCN3B induced apoptosis when combined with anticancer agents. The results presented here suggest that SCN3B mediates a p53-dependent apoptotic pathway and may be a candidate for gene therapy combined with anticancer drugs.

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Cytology of vaginal and uterine sarcomas

E Ito, T Saito, T Suzuki, M Fujii, R Kudo

ACTA CYTOLOGICA ( SCI PRINTERS & PUBL INC ) 48 ( 5 ) 601 - 607 2004.09

OBJECTIVE: To retrospectively review, based on cytologic and histopathologic findings, the diagnoses of 13 patients with uterine sarcoma and 1 with vaginal sacoma. STUDY DESIGN: There were 8 cases of uterine carcinosarcoma (CS), 2 of leiomyosarcoma, 2 of endometrical stromal sarcoma (ESS), 1 of endocervical stromal sarcoma (ECSS) and 1 of malignant fibrous histiocytoma (MFH) of the vagina. The presence of sarcomatous components was retrospectively investigated by microscopic observation of preoperative specimens from the endocervical canal and endometrial cells. Characteristic features of sarcomatous cells were then investigated by cytodiagnostic micrometry of malignant cells. RESULTS: Of the 14 patients, 1 with low grade ESS and 1 with homologous CS were diagnosed as negative for sarcomatous components. One case of high grade ESS had been overlooked, as were 4 cases of CS. Thus, 7 cases (50%) were diagnosed as positive for sarcomatous cells by preoperative cytologic observation. Based. on these findings, 12 of the 14 cases (85.7%) were positive for sarcomatous elements on retrospective reexamination of the specimens. CONCLUSION: Careful attention should be paid to small sarcomatous cells since cases of ESS or ECSS with such cells show morphologic characteristics similar to those of stromatous cells. Furthermore, careful microscopic observation of an entire specimen is required to avoid misdiagnosis as carcinoma since it is easy to overlook sarcomatous elements in smears with carcinosarcoma if there are only a few sarcomatous cells.

Overexpressed progesterone receptor form B inhibit invasive activity suppressing matrix metalloproteinases in endometrial carcinoma cells

T Saito, H Mizumoto, R Tanaka, S Satohisa, K Adachi, M Horie, R Kudo

CANCER LETTERS ( ELSEVIER SCI IRELAND LTD ) 209 ( 2 ) 237 - 243 2004.06

In this study, we focused on the influence of progesterone and its receptor in invasion and MMPs on endometrial carcinoma cells. The growth of lshikawa cells, to which an progesterone receptor form B (PR-B) expressing vector was transfected, was inhibited by progesterone as was the inhibition of the expression of cyclin D1. By invasion assay, in conditions with progesterone, the invasiveness of Ishikawa cells was inhibited as well as the expression of (metalloproteinase) MMP-1, -2, -7 and -9 and Ets-1 decreased. These results suggest that activation of PR-B by progesterone results in tumor suppression by inhibiting cell growth and invasiveness via suppression of the expression of MMPs. (C) 2004 Elsevier Ltd. All rights reserved.

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【腟式手術の現状と今後の課題】腟式子宮全摘出術(TVH)の現状と今後の課題

石岡伸一, 寒河江悟, 寺澤勝彦, 杉村政樹, 江坂嘉昭, 斉藤豪, 伊東英樹, 工藤隆一

産婦人科手術 ( (株)メジカルビュー社 ) ( 15 ) 47 - 53 2004.06

Neoadjuvant chemotherapy with cisplatin, aclacinomycin A, and mitomycin C for cervical adenocarcinoma - a preliminary study

T Saito, M Takehara, R Lee, T Fujimoto, M Nishimura, R Tanaka, E Ito, K Adachi, R Kudo

INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER ( BLACKWELL PUBLISHING INC ) 14 ( 3 ) 483 - 490 2004.05

Between 1989 and 2002, 28 patients with locally advanced cervical adenocarcinoma (bulky IB-IIIB) were recruited for a pilot study aimed at evaluation of the effectiveness of neoadjuvant chemotherapy with cisplatin, aclacinomycin-A, and mitomycin-C (PAM), followed by radical surgery. This regimen was administrated intra-arterially or intravenously. In addition to patients treated with PAM, we retrospectively analyzed the prognoses of 26 patients in stage I and II, who had been treated between 1975 and 1981 with radical surgery with/without radiation therapy. Twenty-eight patients received PAM therapy as neoadjuvant chemotherapy, and 75.0% of the 16 intra-arterially infused patients showed a response, as did 66.7% of the 12 intravenously infused patients. There was a significant difference in the 5-year prognosis of stage II (PAM group, 72.9%; without-PAM group, 36.4%). The results suggest that, as the free space in the parametrium is widened by neoadjuvant chemotherapy with PAM, it is possible that the tumor could be completely resected by radical hysterectomy. Thus, neoadjuvant chemotherapy with PAM is expected to improve the survival rate of patients with advanced cervical adenocarcinoma by the preliminary study. However, the survival rates of stage II with lymph node metastasis in the without-PAM group seem low, and we must also consider that the various technologies to evaluate and treat the cervical adenocarcinomas, e.g. computed tomography, magnetic resonance imaging, and surgical equipments, had improved during 1989-2002 than was the scenario during 1975-1981, and these improvements contributed to better prognosis. A prospective-randomized study is needed to assess the value of this approach compared with standard management.

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Expression of uteroglobin in normal and carcinogenic endometrium and influence of hormone replacement therapy

R Tanaka, T Saito, N Shijubo, M Takehara, G Yamada, Kawabata, I, Y Itoh, R Kudo

INTERNATIONAL JOURNAL OF CANCER ( WILEY-LISS ) 109 ( 1 ) 43 - 48 2004.03

Uteroglobin, first reported in 1968 as a steroid secreted in rabbit uterine fluid during early pregnancy, is a progesterone-regulated and progesterone-binding protein. There is evidence that indicates that uteroglobin is inversely correlated to neoplastic growth but its role to endometrial carcinogenesis is not known. Therefore we analyzed the expression of uteroglobin in 13 normal endometrium, 19 hyperplasia and 21 endometrial carcinoma samples and the relation to estrogen receptor-alpha (ER-alpha) and progesterone receptor (PR) by immunohistochemistry and Western blotting. We also analyzed the expression of uteroglobin in 15 menopausal women who received hormone replacement therapy (HRT). The expression of uteroglobin was higher during the secretory phase than in the proliferative phase; however, it was detected in endometrial hyperplasia as weakly as in the proliferative phase and decreased according to the loss of differentiation in endometrial carcinoma. The results were basically in accord with those for PR; however, the expression of uteroglobin was weak, though PR was most detected in endometrial hyperplasia. In menopausal endometrium,the group treated with estrogen plus progesterone exhibited higher expression of uteroglobin than the group treated only with estrogen. The evidence suggests that uteroglobin expression is regulated by progesterone in the normal endometrium but that the regulation by PR is lost in endometrial hyperplasia and carcinoma according to acquirement of tumorigenesis and that estrogen plus progesterone therapy reduces the risk for endometrial carcinoma by restoring uteroglobin. (C) 2003 Wiley-Liss, Inc.

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Overexpression of estrogen receptor-alpha gene suppresses gap junctional intercellular communication in endometrial carcinoma cells

T Saito, R Tanaka, K Wataba, R Kudo, H Yamasaki

ONCOGENE ( NATURE PUBLISHING GROUP ) 23 ( 5 ) 1109 - 1116 2004.02

Stimulation of the endometrium by estrogens without the differentiating effect of progestins is the primary etiological factor associated with the development of endometrial hyperplasia and adenocarcinoma. However, the correlation between sex steroids and gap junctional intercellular communication (GJIC), which is considered to play an important role in the control of cell growth and differentiation, is not well known in endometrial carcinoma. In this study, we focused on the influence of estrogen and its receptor in connexin (Cx) expression and GJIC in endometrial carcinoma cells, established stable clone IK-ER1 overexpressing ER-alpha to transfect the expression vector and analysed them in various hormonal conditions. The growth of IK-ER1 was accelerated by 17beta-estradiol and the acceleration of the 5-bromo-25-deoxyuridine labeling index was observed. GJIC was assayed by scoring the number of dye-coupled cells after microinjecton of single cells with Lucifer-Yellow, and subcellular localization of Cx26 and Cx32 was analysed by immunocytochemistry. In the presence of estradiol, dye-coupled cells of IK-ER1 were significantly reduced compared to those without estradiol and the reduction was completely inhibited by adding ICI182.780, a pure antiestrogen substrate. Cxs were detected as only small spots by immunocytochemistry, and Western blotting showed that the expression was decreased. These results suggest that activation of ER-alpha by estrogen results in tumor progression by stimulating cell growth and suppressing GJIC via suppression of the expression of Cxs in endometrial carcinogenesis.

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Correlation between responsiveness of neoadjuvant chemotherapy and apoptosis-associated proteins for cervical adenocarcinoma

T Saito, M Takehara, R Tanaka, R Lee, M Horie, K Wataba, E Ito, R Kudo

GYNECOLOGIC ONCOLOGY ( ACADEMIC PRESS INC ELSEVIER SCIENCE ) 92 ( 1 ) 284 - 292 2004.01

Objective. Adenocarcinoma of the uterine cervix appears to be increasing in prevalence and it has been suggested that these tumors tend to be less sensitive to radiation therapy and to chemotherapy than squamous carcinomas. In the present study, 29 patients with locally advanced cervical adenocarcinoma (bulky IB-IVB) were treated with neoadjuvant chemotherapy (NAC) using cisplatin, aclacinomycin-A and mitomycin-C, followed by radical surgery or irradiation. Methods. To predict the prognosis and response to the chemotherapy, the expression of apoptosis associated-proteins, p53, p21WAF1/ CIP1, Bcl-2 and activated caspase-3 was evaluated for tumor samples by immunohistochemistry. Results. Of the analyzed clinicopathological factors, the overexpression of p53 was frequently observed in endocervical-type adenocarcinoma, nonresponders to chemotherapy and the grade 0 histologic effect of the chemotherapy. Positive staining of Bcl-2 was frequently observed in the early stage and had a better prognosis than for patients with the negative staining; however, there was no correlation between responders and nonresponders to chemotherapy. The expression of p21 WAF1/CIP1 and caspase-3 was not correlated to the clinicopathological factors. Conclusion. In this study, the overexpression of p53 was found to be a factor to predict the chemoresistance and positive expression of Bcl-2 indicated as a better prognostic value. For p21WAF1/CIP1 and caspase-3, further analysis is necessary. (C) 2003 Elsevier Inc. All rights reserved.

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[Metastasize mechanism of endometrial cancer]

Nippon Rinsho 62 269 - 72 2004

[A pilot study of combined chemotherapy with paclitaxel, doxorubicin and cisplatin for endometrial cancer]

Gan To Kagaku Ryoho 31 549 - 53 2004

The reproducibility of a binary tumor grading system for uterine endometrial endometrioid carcinoma, compared with FIGO system and nuclear grading

S Sagae, T Saito, M Satoh, T Ikeda, S Kimura, M Mori, N Sato, R Kudo

ONCOLOGY ( KARGER ) 67 ( 5-6 ) 344 - 350 2004

Objective: A binary grading system has been proposed to assess the amount of solid growth, the pattern of invasion, and the presence of necrosis, and thereby divide endometrial endometrioid carcinomas into low- and high-grade tumors. We analyzed this system for predicting the prognosis, with respect to inter- and intraobserver reproducibility and treatment modalities. Methods: A total of 200 endometrial carcinomas, based on hysterectomy specimens, were graded according to the binary grading system, for comparison against The International Federation of Gynecology and Obstetrics (FIGO) system and nuclear grading. Results: Both inter- and intraobserver agreement using the binary grading system (kappa = 0.57; percent agreement: 82% and kappa = 0.62; 84%) were superior compared with the FIGO system (0.50; 60% and 0.62; 73%) and the nuclear grading (0.23; 49% and 0.43; 65%). Patients with early-stage low- grade tumors had a 98% rate for 5-year survival (5YS). Patients with early-stage high-grade tumors, and those with advanced-stage low-grade tumors, had respectively 86% to 87% rates for 5YS. But patients with advanced-stage high-grade tumors had a 49% rate for 5YS. In binary low-grade early-stage tumors, the patient outcome was better with no adjuvant therapy and chemotherapy, compared with other therapies. Conclusion: A binary grading system was superior to others in permitting greater reproducibility and predicting the prognosis of endometrial cancer patients. Copyright (C) 2004 S. Karger AG, Basel.

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Changed expression of heat shock proteins in various pathological findings in placentas with intrauterine fetal growth restriction

Koya Wataba, Tsuyoshi Saito, Makoto Takeuchi, Masahiro Nakayama, Noriyuki Suehara, Ryuichi Kudo

Medical Electron Microscopy 37 ( 3 ) 170 - 176 2004

Heat shock proteins (HSPs) are activated in the cells of most organisms in response to sublethal heat shock and other stressors. It has been reported that HSP27, HSP60, HSP70, and HSP90 are expressed in normal human placenta, and it was thought that these HSPs play a role in the demonstration of cell viability and function. In this study, we performed an immunohistochemical (IHC) study of these HSPs for 27 placentas that had complicated intrauterine fetal growth restriction (IUGR) and compared the IHC findings with the pathological findings. To quantify HSP27, HSP60, HSP70, and HSP90, immunoreacted cells in the chorionic villi, syncytiotrophoblasts (ST), and cytotrophoblasts (CT) were counted. In thrombus, excessive syncytial knots, and avascular villi, the expression of HSPs was higher in the pathological sections compared to control in both ST and CT. In contrast, all HSPs decreased in both ST and CT around the infarction region. The data suggested that chorionic villi cells locally responded to some stresses, e.g., hypoxia and increase or decrease in the expression of HSPs. Although the villous cells around the infarction histologically appear viable, they may have received lethal damage, and as a result the expression of HSPs was decreased. These results are expected to improve our understanding of the pathological findings of IUGR in placentas, including the quality, damage, and function of the chorionic villi. © The Clinical Electron Microscopy Society of Japan 2004.

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Suppression of gap junctional intercellular communication via 5 ' CpG island methylation in promoter region of E-cadherin gene in endometrial cancer cells

M Nishimura, T Saito, H Yamasaki, R Kudo

CARCINOGENESIS ( OXFORD UNIV PRESS ) 24 ( 10 ) 1615 - 1623 2003.10

Previously, we demonstrated that connexins (Cxs) showed aberrant localization and expression in most endometrial hyperplasia and carcinoma samples, indicating that during endometrial carcinogenesis, loss of gap junctional intercellular communication (GJIC) may occur at relatively early stages. In the present study, we focused on the correlations between GJIC and the expression of the E-cadherin and its 5' CpG island methylation in endometrial cancer cells and tissues to investigate their roles in the carcinogenesis and tumor progression of endometrial cancer. In this study, three of the 10 cell lines investigated, Ishikawa, RL-952 and KLE, in which both Cxs and E-cadherin mRNA were expressed, exhibited GJIC by scrape-loading/dye transfer. On the other hand, the other seven cell lines, in which either or both Cxs and E-cadherin mRNA were negative or weakly expressed, did not show GJIC. HEC-50, HEC-1B and HEC-108, in which Cxs were positively expressed but E-cadherin was negatively expressed, showed cytoplasmic localization of Cxs by immunohistochemistry. All five lines, which showed the weak expression of E-cadherin, had E-cadherin 5' CpG island methylation. By immunohistochemistry of 56 endometrial carcinomas, 13 of 27 methylated samples showed weak expression of Cx26 and the other 14 showed diffuse localization in cytoplasm. On the other hand, of 29 unmethylated samples, two showed cell-cell localization, 25 weak expression and two diffuse localization. Furthermore, E-cadherin expression was revealed to be drastically down-regulated by E-cadherin antisense oligonucleotides that post-transcriptionally down-regulated E-cadherin expression and in the cell, the localization of Cxs were changed from the cell-cell borders to the cytoplasm, and GJIC also decreased. The results indicated that 5' CpG island methylation, which caused loss of E-cadherin expression, indirectly caused the suppression of GJIC by aberrant localization of Cxs in endometrial carcinoma cells.

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Three-dimensional coculture of endometrial cancer cells and fibroblasts in human placenta derived collagen sponges and expression matrix metalloproteinases in these cells

R Tanaka, T Saito, K Ashihara, M Nishimura, H Mizumoto, R Kudo

GYNECOLOGIC ONCOLOGY ( ACADEMIC PRESS INC ELSEVIER SCIENCE ) 90 ( 2 ) 297 - 304 2003.08

Objective. Collagen gel constitutes a valuable tool for the study of cell-matrix interactions; however, it is sometimes difficult to use the gel, in which tumor and stromal cells are cocultured, for immunohistochemistry, because it is easily broken during the process of fixation and embedding in paraffin, especially after long-term culture. Methods. To examine the interaction between endometrial cancer cells and fibroblasts in tumor invasion, we carried out three-dimensional (3-D) coculture of various endometrial cancer cell lines and fibroblasts in human placenta derived collagen sponges and analyzed the expression and localization of matrix metalloproteinases (NIMP) and plasminogen activators (PA) in these cells by immunohistochemistry. Results. After 4 weeks of culture on the collagen sponges, endometrial cancer cells composed stratiform or glandular structures on the layer of extracellular matrix, which was composed from fibloblasts and extracellular matrix. Compared to Ishikawa cells, which were rarely invasive, HEC-1A and HEC-1BE and cocultured fibroblasts showed high invasiveness and strong expression of some proteins. In cell line HEC-1BE, MMP-1, -7, and -9, MT1-MMP, tissue inhibitors of metalloprotemases 2, and uPA showed intensive staining in both cancer cells and fibroblasts by immunohistochemistry. HEC-1A cells and cocultured fibroblasts showed expression patterns similar to those of HEC-1BE. Conclusion. These results suggested that expression of MMPs and uPA was accelerated in fibroblasts surrounded by cancer cells. We believe that our 3-D coculture system has merit in that the interaction between cancer cells and stromal cells can be visually analyzed by immunohistochemistry and that experiments for a long period, at least 2 weeks, are possible. Furthermore, it is expected that some animal, e.g., nude mouse, experiments can be replaced by experiments using this culture system. (C) 2003 Elsevier Inc. All rights reserved.

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Treatment and prognosis of the invasive cervical cancer with pregnancy

TANAKA Ryoichi, SAITO Tsuyoshi, ITO Eiki, MIZUMOTO Hisanobu, NISHIMURA Makoto, KUDO Ryuichi

日本婦人科腫瘍学会雑誌 = The journal of the Japan Society of Gynecologic Oncology 21 ( 3 ) 245 - 250 2003.06

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Hypermethylation in promoter region of E-cadherin gene is associated with tumor dedifferention and myometrial invasion in endometrial carcinoma

T Saito, M Nishimura, H Yamasaki, R Kudo

CANCER ( JOHN WILEY & SONS INC ) 97 ( 4 ) 1002 - 1009 2003.02

BACKGROUND. Loss of E-cadherin expression is associated with aberrant 5' CpG island methylation in various tumors. METODS. The authors analyzed the methylation status and immunohistochemical expression of E-cadherin in 142 endometrial tissues, consisting of 21 normal endometria, 17 endometrial hyperplasias, and 104 endometrial carcinomas. RESULTS. All normal endometria and endometrial hyperplasias showed positive staining of E-cadherin, and methylation of the E-cadherin gene was not detected in any samples. In endometrial carcinoma, the positive ratio of methylation was higher and was associated with tumor dedifferention and myometrial invasion. In G1 endometrial adenocarcinomas, 66.7% showed positive staining and 33.3% showed heterogeneous staining. Methylation of the E-cadherin gene was detected in 15.6%. In G2 tumors, 19.0% showed positive staining, 69.0% showed heterogeneous staining and 11.9% showed negative staining. Methylation of the E-cadherin gene was found in 50.0%. In G3 tumors, 9.1% showed positive staining, 54.5% showed heterogeneous staining and 36.3% showed negative staining. Methylation of the E-cadherin gene was found in 81.8% of the tumors. Of the samples with no-myometrial invasion, 23.1% had methylation. In those with invasion in less than half of the myometrium, 28.6% did and in those with invasion of half or more of the myometrium, 55.6% had methylation. Of samples that did not have lymph node metastasis, 33.7% had methylation, whereas of samples that had lymph node metastasis, 60.0% had methylation. CONCLUSIONS. This is the first report to analyze methylation of the E-cadherin gene promoter of endometrial carcinoma and the evidence suggests that methylation of the E-cadherin gene occurs in association with the acquisition of invasive capacity.

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