Neutrophil-to-lymphocyte ratio is associated with sensitivity to platinum-based chemotherapy and prognosis in patients with advanced serous ovarian carcinoma.

The role of the neutrophil-to-lymphocyte ratio (NLR) in predicting sensitivity to chemotherapy and prognosis has attracted great interest in several types of cancer. In the present study, the correlation between pre-chemotherapy NLR and sensitivity to platinum-based chemotherapy and prognosis in patients with advanced serous ovarian carcinoma was examined by retrospectively reviewing the medical records of 50 patients with stage III-IV serous ovarian carcinoma from 2005 to 2012. Patients were divided into high-NLR (32 patients) and low-NLR (18 patients) groups according to a cutoff value of 2.47. This cutoff was calculated using a receiver operating characteristic (ROC) curve that demonstrated 84% specificity and 60% sensitivity. Patient characteristics, sensitivity to platinum-based chemotherapy and prognosis were subsequently compared. The results revealed no significant difference in patient characteristics between the two groups. In the low-NLR group, 14 of 18 patients (77.8%) were sensitive to platinum-based chemotherapy, whereas 11 of 32 were sensitive in the high-NLR group (34.4%) (P=0.007). Overall and disease-free survival (DFS) were significantly longer in the low-NLR than in the high-NLR group (P=0.013 and P=0.043, respectively). The current results suggested that pre-chemotherapeutical NLR may serve as a biomarker of sensitivity to platinum-based chemotherapy and prognosis in patients with advanced serous ovarian carcinoma.

Comparison of MR imaging features of uterine neuroendocrine carcinoma and uterine malignant lymphoma.

PURPOSE: We retrospectively investigated the characteristic magnetic resonance (MR) imaging findings of uterine neuroendocrine carcinoma (UNEC) compared to those of uterine malignant lymphoma (UML). METHODS: Nine consecutive female patients with UNEC and 5 female patients with UML participated in this study. MR imaging features were evaluated retrospectively. RESULTS: On MR imaging, seven of 9 UNEC lesions and no UML lesions showed an exophytic growth pattern. All 9 UNEC lesions and no UML lesions showed a growth pattern along the surface of the endocervix or endometrium. Only 1 UNEC lesion and all 5 UML lesions showed diffuse enlargement of the uterus. No UNEC lesions and all 5 UML lesions showed a multinodular shape. These findings showed significant differences between lesions. Findings for margin, endophytic growth pattern, signal intensity, and homogeneity on T2-weighted and T1-weighted imaging did not differ significantly between lesion types. Apparent diffusion coefficient was significantly lower for UML lesions than for UNEC lesions, but was quite low for both types. Local invasion to surrounding tissues was more frequent in UML lesions than in UNEC lesions. There was no significant difference in the frequency of lymphadenopathy between two entities. CONCLUSIONS: UNEC lesions tended to show an exophytic growth pattern and growth along the surface of the endocervix or endometrium, even when diffuse enlargement of the uterus was present, while all UML lesions showed a multinodular shape and diffuse enlargement of the uterus without thickening of the cervical epithelium and endometrium.

Age-related differences in prognosis and prognostic factors among patients with epithelial ovarian cancer.

Approximately 40% of all patients with ovarian cancer in Japan are aged ≥65 years. The aim of the present study was to evaluate the differences in prognosis and prognostic factors between elderly and younger patients with epithelial ovarian cancer. A total of 114 patients with International Federation of Gynecology and Obstetrics (FIGO) stage I-IV ovarian cancer who were initiated on primary treatment at the Osaka City University Hospital (Osaka, Japan) were included in this study. Patient characteristics, treatment outcome and prognosis were compared between elderly (aged ≥65 years) and younger patients, and the prognostic factors associated with overall survival were evaluated by univariate and multivariate analyses. The most common histological type in younger patients was clear cell carcinoma (33.8%) vs. serous carcinoma in elderly patients (44.1%), with a significant difference in the distribution of histological type (P=0.006). Complete resection was achieved in 56.2% of younger patients compared with 32.4% of elderly patients (P=0.03). The rates of standard primary treatment were comparable (56.7% of younger vs. 50.0% of elderly patients). Overall and disease-free survival did not differ significantly between the two groups. Multivariate analyses identified FIGO stage and standard primary therapy as prognostic factors in younger patients and performance status in elderly patients. Age was not an independent significant prognostic factor among patients with ovarian cancer. Therefore, performance status, rather than age, should be considered when selecting the optimal treatment for elderly patients based on objective assessment.

A retrospective clinical analysis of 5 cases of vaginal melanoma.

Vaginal melanoma is a rare tumor, accounting for <1% of all melanomas and ~1-5% of all vaginal malignant tumors. The prognosis of vaginal melanoma is extremely poor, as it is often resistant to chemotherapy and radiotherapy, and metastases may develop in the early stages of the disease. The present study investigated 5 patients with vaginal melanoma treated at the Department of Gynecology of Osaka City University Hospital (Osaka, Japan) between October, 2000 and April, 2014. All the cases presented with abnormal genital bleeding as the main complaint. Notably, in 3 of the 5 cases the tumors appeared as non-pigmented polyps. Local resection was performed as the primary treatment in all 5 cases. After surgery, dermal injection of interferon ß (feron maintenance therapy) was performed in 3 cases, and dacarbazine, nimustine, vincristine and interferon ß (DAVFeron therapy) was administered in 1 case as adjuvant therapy. All 5 cases recurred within 1 year. The site of recurrence varied, and included the vaginal wall, liver, brain and lung. The median overall survival was 419 days and the median progression-free survival 177 days. In this cohort, all the cases presented with abnormal genital bleeding as the main complaint. Therefore, malignant melanoma of the vagina must be considered along with other gynecological malignancies in patients with abnormal genital bleeding. In this study, over half of the cases had a non-pigmented polypoid lesion of the vagina. Therefore, malignant melanoma of the vagina must be considered when a polypoid lesion is identified on the vaginal wall.

Pharmacokinetic analyses of carboplatin in a patient with cancer of the fallopian tubes undergoing hemodialysis: A case report.

Opportunities for patients undergoing hemodialysis to receive chemotherapy are increasing. A combination of paclitaxel and carboplatin (TC) is first-line chemotherapy in patients with Müllerian cancer. However, the optimal dose and time interval between the end of carboplatin administration and initiation of hemodialysis remains to be elucidated. TC was administered to a patient with fallopian tube cancer undergoing hemodialysis. The paclitaxel regimen was determined to be 135 mg/m2 (total of 210 mg) over 3 h. After paclitaxel administration, 125 mg of carboplatin was administered over 1 h to achieve a target area under the concentration-time curve (AUC) of 5.0 mg•min/ml using the Calvert formula. The time interval between the end of carboplatin administration and hemodialysis initiation was 1 h at the first cycle, 16 h at the second cycle and 20 h at the third cycle, and the AUC obtained was 2.86, 4.16 and 6.0 mg•min/ml, respectively. The desired AUC of free platinum was demonstrated and only mild side effects were observed at the third cycle. Therefore, hemodialysis was initiated 20 h after completion of carboplatin infusion at cycles 4-6. The total chemotherapy planned was completed without severe adverse events. Measurement of the concentration of free platinum subsequent to administration is useful for determination of the optimal dose of carboplatin and time interval following administration to obtain an adequate AUC. The present study suggests that carboplatin can be administered to a patient undergoing hemodialysis, and that an adequate interval between the end of carboplatin administration and hemodialysis initiation may be ~20 h.

Serum Sialyl-Tn (STN) as a Tumor Marker in Patients with Endometrial Cancer.

There are no potential tumor markers validated for prognosis of endometrial cancer. However, sialyl Tn (STN) is a carbohydrate antigen that is associated with the production of mucin, which reportedly plays important roles in carcinogenesis. Although STN expression in endometrial cancer has been investigated, its prognostic value remains controversial and no studies have investigated serum STN levels in large case series. In this study, we investigated diagnostic and prognostic applications of serum STN for endometrial cancer. Between January 2006 and December 2012, serum STN levels were examined prospectively in patients with endometrial cancer. A total of 146 patients (stage I, 98; stage II, 15; stage III, 17; stage IV, 16) were treated for endometrial cancer. The median age was 60 years (28-83). Subsequently 29 patients (19.9%) relapsed at the time of the last follow-up and the median follow-up time was 44 months (1-83). Elevated serum STN levels were identified in 36 patients (24.7%) and were associated with histological grade (p = 0.02) and lymph node metastasis (p = 0.006). Elevated serum STN levels were not related to histological types, clinical stages, myometrial invasions, distant metastases, age, menopausal status, body mass index, or relapse. Among the 36 patients with elevated serum STN levels, 33 (91.7%) achieved remission and serum STN levels returned to the normal range. Seven patients (21.2%) with elevated serum STN levels at baseline relapsed and their serum STN levels were again elevated. Serum STN levels are a potential prognostic indicator for endometrial cancer.

Chemotherapy-induced neutropenia and febrile neutropenia in patients with gynecologic malignancy.

Chemotherapy-induced neutropenia is a common complication in cancer treatment. In this study, we investigated chemotherapy-induced neutropenia that was recently detected in all patients with gynecologic malignancy. Between January 2009 and December 2011, we examined cases of chemotherapy-induced neutropenia reported in our hospital. We analyzed the incidence and clinical features of chemotherapy-induced neutropenia and febrile neutropenia in patients with gynecologic malignancy. During the study period, we administered over 1614 infusions (29 regimens) to 291 patients. The median age of the patients was 60 years (range 24-84 years). Chemotherapy-induced neutropenia occurred in 147 (50.5%) patients over 378 (23.4%) chemotherapy cycles. Febrile neutropenia occurred in 20 (6.9%) patients over 25 (1.5%) cycles. The mean duration of neutropenia and fever was 3.6 days (range 1-12 days) and 3.4 days (range 1-9 days), respectively. The source of fever was unexplained by examination or cultures in 14 (56.0%) cycles. There were two cases of neutropenia-related death. Chemotherapy-induced neutropenia was associated with older age (over 70 years) (P<0.0001), less than five previous chemotherapy cycles (P=0.02), disseminated disease (P=0.03), platinum-based regimens (P<0.0001), taxane-containing regimens (P<0.0001), and combined therapy (P<0.0001). Febrile neutropenia was associated with poor performance status (P<0.0001), no previous chemotherapy (P<0.05), disseminated disease (P<0.0001), and distant metastatic disease (P=0.03). Neither chemotherapy-induced neutropenia nor febrile neutropenia was associated with bone marrow metastases or previous radiotherapy. By identifying risk factors for febrile neutropenia, such as performance status, no previous chemotherapy, disseminated disease, and distant metastatic disease, the safe management of chemotherapy-induced neutropenia may be possible in patients with gynecologic malignancy.

Complete recovery from paraneoplastic anti-NMDAR encephalitis associated with a small ovarian teratoma following a laparoscopic salpingo-oophorectomy: A case report.

Anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis is a severe but treatment-responsive disorder, initially identified in young women with an ovarian teratoma. Symptoms include mood, behavior and personality irregularities that resemble acute psychosis. The present study reports the rare case of a patient with anti-NMDAR encephalitis and severe neurological symptoms, that exhibited a rapid recovery following a laparoscopic salpingo-oophorectomy. The 39-year-old woman was admitted to the Department of Obstetrics and Gynecology, Osaka City University Graduate School of Medicine (Osaka, Japan) with a 5-day history of fever and stomach ache. One week later, the patient developed hallucinations and emotional lability. Initially, a diagnosis of limbic or herpes encephalitis was considered; thus, the patient was administered acyclovir and received steroid pulse therapy. However, the patient subsequently developed apnea, and in response, a tracheal intubation, mechanical ventilation and plasmapheresis were performed. Anti-NMDAR encephalitis was subsequently considered as a diagnosis and mediastinal and pelvic computed tomography (CT) examinations were conducted to detect for the presence of a teratoma. A 24×24-mm cystic lesion was identified in the pelvis from an abdominal CT scan and the lesion appeared to be an ovarian teratoma. In addition, serum and cerebrospinal fluid samples were collected, and were found to test positive for anti-NMDAR antibodies. A laparoscopic salpingo-oophorectomy was performed, which resulted in rapid improvement of the patients mental symptoms, followed by a complete recovery.

Minimal deviation mucinous adenocarcinoma of the uterine cervix that proved difficult to differentiate from endometrial cancer: A case report.

Minimal deviation adenocarcinoma (MDA), also known as adenoma malignum of the uterine cervix, accounts for only ~1% of uterine cervical adenocarcinomas. Adenoma malignum of the uterine cervix was initially described by Gusserow in 1870. Using magnetic resonance imaging (MRI), MDA appears as multilocular lesions with solid components that extend from the endocervical glands to the deep cervical stroma. Cytological evaluation and biopsies have low detection rates, therefore, it is difficult to diagnose MDA accurately prior to treatment. The current study describes a rare case of MDA that was difficult to differentiate from endometrial adenocarcinoma of the corpus uteri preoperatively, as the endometrial biopsy results suggested a well-differentiated endometrioid adenocarcinoma and MRI did not show typical images for MDA. A total abdominal hysterectomy with bilateral salpingo-oophorectomy was performed under the diagnosis of endometrial cancer, and the mass was subsequently diagnosed as MDA of the uterine cervix by pathological examination of the hysterectomy specimen. Postoperatively, although two types of adjuvant chemotherapy were performed, the remaining tumor continued to grow, causing obstruction of the bilateral ureters and leading to bilateral hydronephrosis. The patient is currently alive with the disease 10 months following the surgery.

Comparison of outcomes between squamous cell carcinoma and adenocarcinoma in patients with surgically treated stage I-II cervical cancer.

To improve our understanding of cervical adenocarcinoma (AD) and evaluate the clinical and pathological variables affecting its prognosis, we retrospectively reviewed the medical records of 455 patients with cervical cancer [International Federation of Gynecology and Obstetrics stage I/II; 91 cases with AD and 364 with squamous cell carcinoma (SCC)] who underwent surgery at our hospital between January, 1995 and August, 2012 and compared the characteristics and prognoses between AD and SCC cases, including age, clinical stage, histological type, lymph node metastasis, lymphovascular space invasion (LVSI), cervical stromal invasion, parametrial invasion, vaginal invasion, corpus invasion, ovarian metastasis and tumor diameter. We used Cox regression analysis to determine independent prognostic factors. AD was found to have a significantly poorer prognosis in all the patients (P=0.001), stage I patients (P=0.001) and stage IB patients (P<0.05). The prognosis did not differ in patients who did not require postoperative treatment; however, patients who received postoperative treatment exhibited a significantly poorer prognosis (P<0.05). Patients with AD who received postoperative irradiation alone had a significantly poorer prognosis (P<0.05). The multivariate analysis identified LVSI (P=0.008), stromal invasion (P=0.024) and ovarian metastasis (P=0.032) as independent predictors of shorter survival. AD was associated with a worse prognosis compared to SCC in patients with stage IB disease, particularly in those who required postoperative treatment. Such patients may benefit from individualized postoperative treatments that differ from those applied for SCC.

Comparison of osteopontin expression in endometrioid endometrial cancer and ovarian endometrioid cancer.

This study compared the DNA, RNA, and protein levels of osteopontin (OPN) in endometrioid endometrial cancer (EEC) and ovarian endometrioid cancer (OEC). In total, 63 cancer cases (EEC: 33, OEC: 30) were included. Of these, 47 (EEC: 26, OEC: 21) were examined by quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) and 48 (EEC: 25, OEC: 23) were examined by quantitative PCR. OPN expression was detected in 15 (50.0%) of 30 EECs and in 14 (50.0%) of 28 OECs. There was no significant difference in the percentage of positive cytoplasmic OPN staining between the EECs and OECs (12.8 vs 10.4; p = 0.6811). The correlation between relative mRNA and protein expression levels was significant in both the EECs and OECs; however, the correlation between relative DNA and mRNA levels was not significant. There was no significant difference in OPN expression between the EECs and OECs.

PTEN expression in clear cell adenocarcinoma of the ovary.

OBJECTIVES: In this study, we analyzed the PTEN expression in a large collection of clear cell adenocarcinomas of the ovary. Furthermore, we analyzed the expression of cyclin D1 and p27, and investigated the correlation among all these variables. METHODS: Totally, 40 clear cell adenocarcinomas were included in this study. The protein expression of PTEN, cyclin D1 and p27 was investigated by immunohistochemistry. RESULTS: Of 40 clear cell adenocarcinomas, 15 (37.5%) lost all PTEN immunoreactivity. There was no significant correlation between PTEN expression and clinical stage. Cyclin D1 expression and loss of p27 expression were detected in 16/40 (40.0%) and 14/40 (35.0%) clear cell adenocarcinoma cases. There was no significant correlation between PTEN expression and cyclin D1 or p27 protein expression. CONCLUSIONS: Loss of PTEN expression is relatively common and both cyclin D1 and p27 expressions are not related with PTEN inactivation in clear cell adenocarcinoma of the ovary.

Identification of overexpression and amplification of ABCF2 in clear cell ovarian adenocarcinomas by cDNA microarray analyses.

PURPOSE: Patients with ovarian clear cell adenocarcinoma generally have a poor response to combination chemotherapy and have overall poorer prognosis than patients with other histologic types of ovarian cancer. Genetic changes in this group of cancer have not been thoroughly explored. Identification of these changes may provide us new therapeutic targets to treat this disease. EXPERIMENTAL DESIGN: Genomic and expression array analyses were applied on 30 clear cell ovarian cancer cases and 19 serous cases using a 10,816-element cDNA microarray platform. Further validation and clinical correlation studies were done on differentially expressed genes that are related to chemoresistance. RESULTS: Based on array analyses, 12 genes showed a significant increase in DNA and mRNA copy number and 5 genes showed a significant decrease in DNA and RNA copy number in clear cell tumors compared with those in the serous type. One of the genes was ABCF2, which belongs to the ATP-binding cassette gene superfamily and has been shown to amplify in other tumor types. Validation studies were done using real-time quantitative PCR and immunohistochemistry. The results showed significantly higher ABCF2 DNA and mRNA copy number and protein levels in clear cell cases compared with those in serous cases. Furthermore, in 20 clear cell cases with chemo-response data available, ABCF2 cytoplasmic staining was significantly higher in nonresponders than that in the responders (60.0% versus 28.5%; P = 0.0002). CONCLUSIONS: These data suggest that ABCF2 protein may be a prognostic marker for ovarian clear cell ovarian adenocarcinoma.

Cyclin E amplification and overexpression in clear cell adenocarcinoma of the ovary.

OBJECTIVE: The purpose of this study is to compare DNA, mRNA and protein levels of the cyclin E between clear cell (CC) and serous (SC) ovarian carcinomas, and evaluate the relationship between cyclin E and p53 status. METHOD: We examined the DNA, mRNA and protein levels of cyclin E and the protein level of p53 in 44 CCs and 39 SCs using microdissected tissues. RESULTS: Relative cyclin E mRNA expression was significantly higher in CC (3.62, 95% CI, 2.24-4.99) than in SC (1.75, 95% CI, 1.05-2.45; p = 0.0098). The percentage of positive nuclear staining of cyclin E was significantly higher in CC (48.3, 95% CI, 40.4-56.1) than SC (25.3, 95% CI, 17.4-33.3; p = 0.0001). The mRNA and protein expression of cyclin E was significantly correlated (r = 0.66, p < 0.0001). However, the correlation between relative DNA copy number and relative mRNA expression was not significant (r = -0.063; p = 0.66). Percentage of positive nuclear staining of cyclin E was significantly higher in p53 positive cases (51.8, 95% CI, 40.0-63.5) than p53 negative cases (36.2, 95% CI, 28.2-44.2; p = 0.028). CONCLUSIONS: Cyclin E expression is significantly higher in CC than in SC. Cyclin E expression is significantly related with p53 positivity.

Relationship between HPV typing and the status of G2 cell cycle regulators in cervical neoplasia.

We examined human papillomavirus (HPV) typing and the status of ATM, chk2, CDC25C, cdc2 and cyclinB1 in cervical intraepithelial neoplasia (CIN) and invasive cancer (IC). A total of 93 samples [normal: 10; CIN: 34 (CINI:9, CINII:12, CINIII:13); IC: 49 (stage I:10, stage II:21, stage III:15, stage IV:3)] were included in this study. HPV status was evaluated by the PCR non-radioactive HPV detection system. We analyzed ATM, chk2, CDC25C, cdc2 and cyclinB1 protein expression by immunohistochemistry. HPV DNA was detected in 73.5% of 34 CINs and 89.8% of 49 ICs. Detection of HPV subtypes 16 and 18 was more frequent in ICs (46.9%) than in CINs (23.5%) (p=0.0387). Abnormal expression of ATM, chk2, CDC25C, cdc2 and cyclinB1 were 2.9%, 32.4%, 2.9% 20.6% and 0% in CINs and 8.2%, 30.6%, 10.2%, 46.9% and 12.2% in ICs. The alteration of cdc2 was higher in ICs than in CINs (p=0.0198). Altered expression of cdc2 was higher in HPV16 and 18 cases (69.6%) than in other cases (26.9%) (p=0.0042). However, the relationship between HPV typing and ATM, chk2, CDC25C and cyclinB1 expression was not significant. Cdc2 is implicated in cervical carcinogenesis and may be related to p53 inactivation by HPV.

Alteration of cell cycle regulators correlates with survival in epithelial ovarian cancer patients.

The p16-cyclinD1/CDK4-pRb pathway (RB pathway) and p14ARF-MDM2-p53 pathway (p53 pathway) work at the G1-S checkpoint, and the ATM-chk2-CDC25-cyclinB1/cdk1 pathway works at the G2-M checkpoint. The disruption of these pathways is thought to be related to the prognosis of human cancer. In this study, we analyzed the status of these pathways in 107 epithelial ovarian cancer (EOC) patients by immunohistochemistry and evaluated the relationship of these results with chemotherapy response and the prognosis. Altered RB, p53, and G2 pathways were detected in 50.5% (54/107), 51.4% (55/107), and 33.6% (36/107) of cases, respectively. The overall survival (OS) of 77.3% for patients with a normal RB pathway was significantly higher than the OS of 50.0% for patients with an altered RB pathway (by Kaplan-Meier analysis, P = 0.0021). The OS of 66.2% for patients with a normal G2 pathway was significantly higher than the OS of 58.3% for patients with an altered G2 pathway (P = 0.0416). However, the status of the p53 pathway was not related to OS. By univariate and multivariate analyses, advanced stage, high histological grade, altered RB pathway, and altered G2 pathway were significant predictors of poor OS. However, there was no significant relationship between pathway status and chemotherapy response. The status of the RB pathway and of the G2 pathway were independent prognostic factors of EOC.

Relationship between HPV typing and abnormality of G1 cell cycle regulators in cervical neoplasm.

OBJECTIVE: In tumorigenesis, loss of function of the G1 pathway (p16-CDK4/cyclinD1-pRB pathway (RB pathway) and p14-MDM2-p53 pathway (p53 pathway)) is a theoretically essential event. The simultaneous analysis of all components of the RB and p53 pathway may be able to explain cervical tumorigenesis. However, there are no reports in which all components of the G1 pathway and HPV typing were examined simultaneously in cervical cancer. METHODS: We examined HPV typing and the status of the G1 pathways simultaneously by PCR-SSCP, multiplex PCR, methylation-specific PCR, and immunohistochemical techniques in cervical neoplasia. A total of 105 samples (normal, 10; cervical intraepithelial neoplasm (CIN), 42; invasive cancer (IC), 53) were included. RESULTS: Abnormality of the RB pathway tended to be more frequent in ICs (60.4%) than in CINs (31.0%) (P = 0.069). The primary target was p16 (CIN, 14.3%; IC, 43.4%; P = 0.032). Abnormality of the p53 pathway was detected in ICs (56.6%) and in CINs (40.5%) (P = 0.1494). In particular, strong expression of MDM2 was higher in ICs (32.1%) than in CINs (7.1%) (P = 0.0045). Abnormalities of the RB and p53 pathways were higher in low-risk and negative HPV than in high-risk HPV (81.3% vs 51.4%, P = 0.0657; 81.3% vs 45.9%, P = 0.0328). Seven HPV-negative cases had abnormalities in the RB or p53 pathways. CONCLUSION: In conclusion, abnormality of the G1 pathway may be one of the important mechanisms for carcinogenesis of low-risk and negative HPV cases.

Alteration of G2 cell cycle regulators occurs during carcinogenesis of the endometrium.

OBJECTIVES: In this study, we examined the alteration of the G2 pathway in endometrial hyperplasia (EH) and endometrioid-type endometrial cancer (EC), and analyzed the relationship between the G2 pathway status and the p53 pathway status. METHODS: A total of 103 cases (proliferative phase of the endometrium: 20, EH: 22, and endometrioid-type EC: 61 (I: 39, II: 5, III: 15, recurrence: 2)) were included in this study. We examined the ATM, chk2, CDC25C, cdc2, and cyclin B1 protein expression by immunohistochemistry. In 55 cases (EH: 15; EC: 40), we analyzed CHK2 mutations by RT-PCR-SSCP. RESULTS: There were no CHK2 mutations in endometrial disease. Elevated or reduced expression rates of ATM, chk2, CDC25C, cdc2 and cyclin B1 were 4.5% (1/22), 0%, 0%, 0% and 4.5% (1/22) in EH and 3.3% (2/61), 4.9% (3/61), 13.1% (8/61), 9.8% (6/61) and 9.8% (6/61) in EC. Alteration of the G2 pathway was higher in EC (32.8%; 20/61) than in EH (9.1%; 2/22; p = 0.047). The G2 pathway was significantly higher in the altered p53 pathway group (48.4%; 15/31) than in the normal p53 pathway group (16.7%; 5/30) in EC (p = 0.0134). The altered p53 pathway tended to be related with the cdc2/cyclin B1 status (p = 0.0529). CONCLUSIONS: Alteration of the G2 pathway is thought to occur during carcinogenesis of the endometrium.

Relationship between p53 pathway and estrogen receptor status in endometrioid-type endometrial cancer.

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.