Two Distinct Tumorigenic Processes in Endometrial Endometrioid Adenocarcinoma.

Endometrial endometrioid adenocarcinoma (EEA) is conventionally considered to be a single pathologic entity that develops through a hyperplasia-carcinoma sequence under the influence of estrogen. Previously, another EEA subtype was described and proposed to arise directly from normal endometrium. These conventional and de novo subtypes are designated groups 1 and 2, respectively. To identify the molecular mechanisms of these distinct tumorigenic processes, we conducted comprehensive integrated analyses of genomic data with hormonal status for group 1 paired carcinoma and hyperplasia and group 2 carcinoma samples. Although group 1 carcinomas mostly exhibited genomically stable characteristics and the activation of estrogen signaling, group 2 EEAs showed enriched hypermutator and CpG island methylator phenotypes. Pairwise comparisons of hyperplasia and carcinoma, along with time-course analyses of the hyperplasia-carcinoma sequence, revealed the acquisition of driver mutations in the evolutionary process of hyperplasia but not in the transition from hyperplasia to carcinoma. The current study confirms the existence of two different histopathologic programs during EEA development that harbor distinct molecular bases and demonstrates the biological relevance of these differential tumorigenic processes.

Small endometrial carcinoma 10 mm or less in diameter: clinicopathologic and histogenetic study of 131 cases for early detection and treatment.

Natural history and clinicopathologic features of early endometrial carcinoma are not evident. Its knowledge is essential to make up strategies for prevention, early detection, and treatment of endometrial carcinoma. Especially it is important to know pathways of endometrial carcinogenesis and frequency of endometrial carcinomas arising from endometrial hyperplasia. Clinicopathologically 131 patients with endometrial carcinoma measuring ≤10 mm in diameter ("small endometrial carcinoma") were studied to get useful information for early diagnosis, treatment, and histogenesis. The entire endometrium of surgically removed uterus was step-cut and examined. The patients were, on average, 5 years younger than the controls whose carcinomas measure >10 mm (P < 0.0001). Of the 131 patients, 20% were asymptomatic although only 5% of the controls were asymptomatic (P < 0.0001). Seventy-six percent had the carcinomas located in the upper third section of the uterine corpus. Macroscopically 44% of the tumors were flat and 56% were elevated. Incidence of nodal and ovarian metastases were <1%. Forty percent of "small endometrial carcinomas" were associated with endometrial hyperplasia and 60% were not. It is logical to believe that there are two pathways of endometrial carcinogenesis: carcinomas occurring from hyperplasia (40%) and carcinomas occurring from normal endometrium (60%). As hyperplasia-carcinoma sequence is not a main route, we cannot probably prevent carcinomas only by treatment of hyperplasia. Effort must be focused on detecting early de novo carcinomas. As most "small endometrial carcinomas" arise in the upper third of the corpus, careful endometrial sampling there is important for early detection.

Postoperative adjuvant chemotherapy for node-positive cervical adenocarcinoma.

We examined the effectiveness of postoperative adjuvant chemotherapy for node-positive cervical adenocarcinoma. During the period from 1994 to 2002, 98 consecutive patients with clinical stage I and II cervical adenocarcinoma were treated surgically without having undergone any prior treatment. Surgical procedures included radical hysterectomy, bilateral salpingo-oophorectomy, and pelvic lymphadenectomy. Postoperatively, 21 patients were found to have lymph node metastasis, and all were treated with chemotherapy in the absence of radiotherapy. All patients were followed up for at least 5 years. Recurrence developed in 9 of the 21 patients, all 9 died of the disease. Six of the 9 recurrences were extrapelvic lesions. Five-year disease-free survival and overall survival were 57% and 67%, respectively. Recurrence was more common in patients with 6 or more positive nodes than in those with fewer than 3 positive nodes. These data suggest the potential role of postoperative chemotherapy for treatments of cervical adenocarcinoma. However, the effectiveness of chemotherapy alone in node-positive cervical adenocarcinoma was likely not as high as that in squamous cell carcinoma. Despite our use of postoperative chemotherapy in the absence of pelvic radiation, the disease recurred predominantly at distant sites.

Postoperative adjuvant chemotherapy in surgically staged grade 3 endometrial cancer.

BACKGROUND: The effectiveness of postoperative adjuvant chemotherapy for surgically staged grade 3 endometrial cancer was investigated. PATIENTS AND METHODS: Sixty-three consecutive patients with grade 3 endometrial cancer (49 with surgical stage I-II disease and 14 with stage III disease) were treated surgically. Postoperatively, 40 patients (63.5%) were treated with a chemotherapy regimen consisting of ifosfamide, epiadriamycin, and cisplatin scheduled for 3-5 cycles. No patient underwent radiotherapy. RESULTS: Recurrence developed in 8 out of the 63 patients, all within two years. Six of the 8 recurrences were found to be extrapelvic lesions. Recurrences occurred predominantly at distant sites in the absence of pelvic radiation. Estimated 5-year disease-free survival rates were 89.8% for patients with surgical stage I-II disease, 78.6% for those with surgical stage III disease, and 87.3% overall. CONCLUSION: The current study suggests the potential role of adjuvant chemotherapy alone in grade 3 endometrial cancer.

Treatment results of adjuvant chemotherapy after radical hysterectomy for intermediate- and high-risk stage IB-IIA cervical cancer.

OBJECTIVE: To determine the effectiveness of chemotherapy alone as postoperative adjuvant therapy for intermediate- and high-risk cervical cancer. METHODS: The study group comprised of 65 consecutive patients with stage IB or IIA squamous cell or adenosquamous cervical cancer who were initially treated with radical hysterectomy and pelvic lymphadenectomy between 1993 and 2002. Tumors were of intermediate-risk (stromal invasion > 50%, n = 30) or high-risk (positive surgical margin, parametrial invasion, and/or lymph node involvement, n = 35). In all cases, chemotherapy was administered adjuvantly: three courses of bleomycin, vincristine, mitomycin, and cisplatin for intermediate-risk cases and five courses for high-risk cases. Disease-free survival and complications of the combined therapy were investigated. RESULTS: Estimated 5-year disease-free survival was 93.3% for the 30 patients with intermediate-risk tumors (100% for those with squamous cell carcinoma and 71.4% for those with adenosquamous carcinoma) and 85.7% for the 35 patients with high-risk tumors (89.3% for those with squamous cell carcinoma and 71.4% for those with adenosquamous carcinoma). The incidence of locoregional recurrence was 3.3% in the intermediate-risk group and 8.6% in the high-risk group. Side effects of chemotherapy and complications of the combined therapy were within acceptable limits. No patient had severe bleomycin-related pulmonary toxicity. Only 1.5% of patients developed small bowel obstruction, which was cured by conservative therapy. CONCLUSIONS: The treatment results suggest the potential role of adjuvant chemotherapy alone for patients with cervical cancer.

Effectiveness of postoperative chemotherapy for para-aortic lymph node metastasis of endometrial cancer.

OBJECTIVE: To examine the effectiveness of postoperative chemotherapy for para-aortic lymph node (PAN) metastasis in patients with endometrial cancer. METHODS: Among 350 clinical stage I-II endometrial cancer patients who underwent systemic pelvic and para-aortic lymphadenectomy during the period 1995 through 2002, 26 patients were identified with PAN metastasis. Of these patients, nine had only one positive PAN and 17 had two or more positive PANs (mean 4.9, range 1-22). All patients were treated postoperatively with a single chemotherapy regimen consisting of ifosfamide, epiadriamycin, and cisplatin scheduled for 5 cycles. Median (range) follow-up for surviving patients was 85 (38-119) months. Treatment outcome, including disease-free survival relative to the number of positive PANs, was investigated. RESULTS: Among the 26 patients with PAN involvement, four developed recurrence. Three of the four patients had 10 or more positive PANs. Estimated 5-year disease-free survival rates were 89% for patients with one positive PAN, 82% for those with two or more positive PANs, and 85% for all patients. No significant difference was identified between the first two groups (P = 0.6543). CONCLUSIONS: Postoperative chemotherapy can yield a favorable outcome in endometrial cancer patients with PAN metastasis, even those with multiple positive nodes.

Lymph node metastasis in ovarian cancer: difference between serous and non-serous primary tumors.

OBJECTIVE: To investigate the lymph node sites most susceptible to involvement relative to primary tumor histology in ovarian cancer. METHODS: The locations of metastatic lymph nodes were investigated in 208 patients with primary ovarian cancer who underwent systemic lymphadenectomy covering both the pelvic and para-aortic regions. RESULTS: Lymph node metastasis was present in 12.8% (20/156) of patients with stage I (pT1M0), 48.6% (18/37) with stage II (pT2M0), and 60% (9/15) with stage III (pT3M0) disease, thus in 22.6% (47/208) of all study patients. Isolated para-aortic nodal involvement was present in 23.3% (14/60) of patients with serous tumor and 4.1% (6/148) of those with non-serous tumor (P = 0.00002). In an analysis of 35 positive nodes from 25 patients with up to 3 positive nodes, 86.4% (19/22) of metastatic lymph nodes from patients with serous tumor were found in the para-aortic region, with 14 positive nodes located above the inferior mesenteric artery (IMA) and 5 below it, whereas metastasis to para-aortic lymph nodes accounted for 53.8% (7/13) of metastatic lymph nodes from patients with non-serous tumor (P = 0.0334). CONCLUSIONS: The locations of metastatic lymph nodes in ovarian cancer depend upon the histologic type of the primary cancer. In cases of serous tumor, the para-aortic region, particularly above the IMA, is the prime site for the earliest lymph node metastasis. However, the likelihood of pelvic node involvement is almost equal to that of para-aortic node involvement in cases of non-serous tumor.

Putative gene loci associated with carcinogenesis and metastasis of endocervical adenocarcinomas of uterus determined by conventional and array-based CGH.

OBJECTIVES: This study aimed to estimate the gene loci associated with carcinogenesis of endocervical adenocarcinoma of uterus (EA) and metastasis. Study design Sixteen patients with EA were studied; 6 had nodal metastasis. DNA was extracted from EAs, and subjected to both conventional comparative genomic hybridization (CGH) and array-based CGH. Copy number abnormalities were compared between cases with and without nodal metastasis. RESULTS: In all EAs, high frequencies of copy number losses were detected in genes LRP1B (on 2q21.2), DAB2 (5p13), and DCC (18q21.3), as well as regions 3p, 16q, and 22q, and copy number amplifications in genes NRAS (1p13.2), TOP2A (17q21-q22), NCOA3(AIB1) (20q12), and ARSA (22q tel). Nodal metastasis was associated with high frequencies of copy number loss in genes PGRMC2 and LAMA3 and amplification in CDK6 and NCOA3(AIB1). CONCLUSION: This is the first report of gene copy number alterations spanning the whole genome in EA. These altered genes are speculated to be associated with EAs as a tumor suppressor and/or oncogene.

Phase II trial of 3-h infusion of paclitaxel in patients with adenocarcinoma of endometrium: Japanese Multicenter Study Group.

OBJECTIVE: We assessed the antineoplastic effect and adverse reactions of paclitaxel monotherapy with paclitaxel 210 mg/m(2) given every 3 weeks by 3-h infusion on patients with endometrial cancer given as a 3-h infusion. METHODS: This study was a multi-center, open-label phase II clinical trial of paclitaxel 210 mg/m(2) given every 3 weeks by 3-h infusion. Patients with advanced or recurrent endometrial cancer were enrolled. The primary endpoint for efficacy was tumor response rate. The secondary endpoints were duration of response and adverse drug reactions. RESULTS: Among 23 patients evaluated for efficacy, partial remission (PR) was achieved in 7, no change (NC) in 10, progressive disease (PD) in 5, and not estimable (NE) in 1. The overall response rate was 30.4% (7/23 cases). In seven PR cases, median duration of response was 130 days (100-245 days). Subjective or objective symptoms > or =grade 3 included febrile neutropenia and constipation in 8.7% (2/23 cases) each; and nausea, vomiting, fatigue, pain, urinary tract infection, lowered oxygen saturation, anorexia, arthralgia, myalgia, neuropathy, weight loss, dyspnea, and need for red cell transfusion in 4.3% (1/23) each. Laboratory test abnormalities > or =grade 3 included neutropenia (78.3%, 18/23), leucopenia (47.8%, 11/23), lowered hemoglobin (13.0%, 3/23), decreased potassium (8.7%, 2/23), and decreased sodium (4.3%, 1/23). All adverse reactions were successfully managed by prolonging treatment interval, dose reduction, interrupting administration, discontinuation, and administration of G-CSF. CONCLUSION: Three-hour intravenous infusion of paclitaxel 210 mg/m(2) is useful for endometrial cancer. Antineoplastic effect was achieved and adverse reactions were clinically manageable.

[Chemotherapy with combination of UFT and cisplatin against metastatic ovarian tumor originating from gastric cancer].

Krukenberg's tumor, an metastatic ovarian tumor originating from gastric cancer, is a disease with extremely poor prognosis, and it is rare for patients to survive for more than 2 years after the diagnosis. We encountered a patient in whom a long-term good prognosis could be obtained probably because of the effects of chemotherapy after the ovarian tumor extraction. This patient was treated by a combination of UFT and cisplatin. Enhancement of the antitumor effects by the concomitant use of 5-FU and cisplatin has been attracting attention, and the methods of administration of these drugs have been investigated by numerous researchers as FP therapy. It was characteristic to the treatment of our patient that 5-FU was administered in the form of oral UFT. We believe this was an important experience suggesting that this administration method is safe and effective, and even influences the long-term prognosis.

Conventional and array-based comparative genomic hybridization analyses of novel cell lines harboring HPV18 from glassy cell carcinoma of the uterine cervix.

We established 2 novel human cell lines (GCCOT-1, GCCRK) from glassy cell carcinoma. Both cell lines showed dual tendencies of glandular and squamous differentiation, and thus possess the characteristics resembling reserve cells, the putative origin of most carcinomas arising from the uterine cervix. HPV type 18 DNA including E6-E7, which is commonly found in cell types other than squamous cell carcinoma of uterine cervix, was detected in both cell lines. We analyzed gene copy number alterations of the 2 cell lines using conventional comparative genomic hybridization (CGH) coupled with array-based CGH. Among the putative oncogenes demonstrating copy number gain in both cell lines, FGR(SRC2) at 1p36.2-1 and LAMC2 at 1q25-31 have not been reported to show amplification in previous analyses of conventional cervical cell lines. These oncogenes are thus speculated to be directly associated with oncogenesis of glassy cell carcinoma. On the other hand, among the putative suppressor genes demonstrating copy number loss in both cell lines, the 9q region, ATM at 11q22.3, and CYLD at 16q12-13 have not been reported to show loss in conventional cervical cancer cell lines. These sites are speculated to be important as tumor suppressors directly associated with oncogenesis of glassy cell carcinoma. This study suggests for the first time that together with the presence of HPV type 18, alterations at the above sites are closely associated with oncogenesis of glassy cell carcinoma, a special type of carcinoma in the uterine cervix.

Clinicopathologic features of villoglandular papillary adenocarcinoma of the uterine cervix.

OBJECTIVES: The objectives of this study are to analyze the clinicopathologic features of villoglandular papillary adenocarcinoma (VGPA) of the uterine cervix and to discuss the management thereof. We examined 13 patients with VGPA. METHODS: Clinical profiles, including patient age, clinical stage, surgical procedure, and outcome, were recorded. Pathologically, macroscopic features, polypoid tumor size, horizontal spread and depth of endophytic tumor, nuclear atypicality, mitotic count, lymph capillary space invasion, and lymph node metastasis were investigated. RESULTS: The median age of 13 patients was 45 years, with 10 and 3 patients staged Ib and IIb, respectively. All the patients underwent hysterectomy and pelvic lymphadenectomy and are alive without recurrence. Macroscopically, the tumor showed a polypoid pattern in 8 patients and a flat pattern in the remaining 5 patients. Polypoid tumor size ranged between 4 x 2 and 20 x 15 mm. Horizontal spread and depth of endophytic tumor ranged between 8 and 30 mm and between 3 and 11 mm, respectively. The tumor in all the 13 patients except 1 showed moderate nuclear atypicality. The mean mitotic count was 43/10 high-power fields. Lymph capillary space invasion was present in 4 patients, 1 of whom also had bulky lymph node metastases. CONCLUSIONS: VGPA has been reported to rarely involve lymph capillary space invasion or lymph node metastasis, leading some surgeons to conduct less radical surgeries such as conization. Nevertheless, we encountered patients with these pathologic risk factors. Much caution should be exercised in managing patients with VGPA.

[Neurotoxicity of weekly TP (weekly paclitaxel + consecutive low-dose CDDP) therapy].

OBJECTIVES: To evaluate drug-induced neurotoxicity with combination consecutive low-dose CDDP (CLD-CDDP) and weekly paclitaxel in comparison with TJ therapy. Neurotoxicity was judged according to accumulative scores on questionnaires. SUBJECTS AND METHODS: Weekly TP therapy (CDDP: 10 mg/m2, days 1-7, paclitaxel: 60-80 mg/m2, days 1, 8, 15) and TJ therapy (paclitaxel: 170-180 mg/m2, 3 hours, carboplatin AUC 4-5) were given to 24 subjects in 57 courses and 19 subjects in 30 courses as previously reported, respectively. RESULTS: 1. Significant differences were found in numbness accumulative scores (p = 0.011) between weekly TP and TJ therapy, but not in pain accumulative scores (p = 0.926) between weekly TP and TJ therapy. 2. Peak pain at days 3-4 of paclitaxel that appeared during TJ therapy disappeared during weekly TP therapy, while numbness persisted to a lesser extent with weekly TP therapy than with TJ therapy. 3. Numbness was observed to accumulate in some subjects but not in others during weekly TP therapy. CONCLUSION: The patients' subjective symptoms were able to be objectively evaluated with the questionnaires. Weekly paclitaxel was observed to reduce neurotoxicity, which might be reinforced in combination with CDDP.

A large-scale gene expression comparison of microdissected, small-sized endometrial cancers with or without hyperplasia matched to same-patient normal tissue.

PURPOSE: Type I endometrial cancer is accompanied by hyperplasia and type II endometrial cancer is not. The purpose of our study is to identify genes involved in carcinogenesis of endometrial cancer, especially those differentially expressed by type I and type II cancers. EXPERIMENTAL DESIGN: Using a cDNA array technique, we examined expression of 1176 cancer-related genes in endometrial cancer cells sampled from 21 tumors with a diameter of <10 mm, and we compared the expression patterns of the tumor cells with expression patterns of corresponding normal endometrial cells. Of these, 10 cases were type I cancers, and 11 cases were type II cancers. Laser capture microdissection directed precise separation of cells of interest from stromal cells. In cancer cells relative to normal cells, we identified genes that were commonly up- and down-regulated. Then we identified genes differentially expressed by the two types of cancer. Finally, in situ protein expression of some of these gene products was examined using immunohistochemistry. RESULTS: Of 1176 genes examined, 32 genes were up-regulated, and 58 were down-regulated in cancer cells (P < 0.05). Between the two types of cancer, 45 genes were highly expressed in type I cancers, and 24 were highly expressed in type II. Immunohistochemistry confirmed that P-cadherin expression was cancer specific, and vascular endothelial growth factor-C and MLH1 expression were limited to type I and type II cancers, respectively. CONCLUSIONS: A more accurate way of assessing gene expression during endometrial carcinogenesis shows evidence of providing candidate genes for use in conquering endometrial carcinoma.

A randomized study of primary bleomycin, vincristine, mitomycin and cisplatin (BOMP) chemotherapy followed by radiotherapy versus radiotherapy alone in stage IIIB and IVA squamous cell carcinoma of the cervix.

BACKGROUND: To determine whether neoadjuvant chemotherapy would improve disease control and clinical outcome of patients with locally advanced cervical cancer undergoing radiotherapy. MATERIALS AND METHODS: Sixty-one patients with primary invasive squamous cell carcinoma of the cervix of stage IIIB or IVA were randomized to receive either three courses of chemotherapy followed by radiotherapy (CT + RT) or radiotherapy alone (RT). The chemotherapy regimen consisted of bleomycin, vincristine, mitomycin and cisplatin (BOMP). The radiotherapy was carried out by the use of a combination of external beam radiation and intracavitary brachytherapy. RESULTS: The response rate of the chemotherapy (complete or partial response) in the CT + RT group was 72% (3 + 20 out of 32). The 5-year survival rates were 52% in RT group and 43% in the CT + RT group with no significant difference. Recurrence outside the irradiated field occurred in 17% (5 out of 29) in the RT group, whereas it was 25% (8 out of 32) in the CT + RT group. CONCLUSION: Despite the high response rate of BOMP chemotherapy, the combination (CT + RT) failed to improve the survival of patients with locally advanced cervical cancer when compared with radiotherapy alone. It was also noteworthy that the incidence of distant metastasis was not reduced by the use of neoadjuvant chemotherapy.

Early invasive cervical adenocarcinoma: its potential for nodal metastasis or recurrence.

OBJECTIVE: To investigate the potential for nodal spread or recurrence in patients with early invasive cervical adenocarcinoma. The possible application of the International Federation of Gynecology and Obstetrics (FIGO) classification (1994) to this variant was also examined. DESIGN: Retrospective observational study. SETTING: Gynaecological oncology division of Cancer Institute Hospital, Japan. POPULATION: 302 patients with FIGO Stage 0-IIB cervical adenocarcinoma treated surgically at the Cancer Institute Hospital. METHODS: Clinicopathological analysis was performed on 47 patients with early invasive cervical adenocarcinoma in whom the depth of stromal invasion was 5 mm or less. All patients underwent radical hysterectomy and pelvic lymphadenectomy. RESULTS: In 30 patients with a depth of tumour invasion of 3 mm or less, no lymph node metastasis was found, while two patients developed recurrence; one had a depth of invasion of 3 mm and a horizontal tumour spread of 3 mm, and the other had horizontal spread of more than 7 mm. In 17 patients with a depth of invasion from 3 to 5 mm, there was also no lymph node metastasis, but two patients developed recurrence; one had horizontal tumour spread of 7 mm or less, and the other had horizontal spread of more than 7 mm. CONCLUSIONS: Early invasive cervical adenocarcinoma with a depth of invasion of 3 mm or less and a horizontal spread of 7 mm or less has little potential for nodal metastasis or recurrence. It seems possible that the FIGO definition (1994) of early cervical cancer may be applicable in its present form to early cervical adenocarcinoma.

Villoglandular papillary adenocarcinoma of the uterine cervix with bulky lymph node metastases.

A patient with stage IIb cervical adenocarcinoma underwent Wertheim hysterectomy with pelvic lymphadenectomy and bilateral adenexectomy followed by radiotherapy. Review of histologic sections diagnosed villoglandular papillary adenocarcinoma (VGPA) with metastatic lymph nodes. The patient has been disease-free for 17 years. This patient is the third case of VGPA with lymph node metastasis ever reported.

Genetic alterations related to lymph node metastasis and peritoneal dissemination in epithelial ovarian cancers.

Genetic alterations are assumed to be necessary for the development and progression of ovarian cancer. However, the genetic alterations that occur during lymph node metastasis and peritoneal dissemination are poorly understood. In the present study, we used comparative genomic hybridization to detect genetic alterations in 30 tumors from patients with primary ovarian cancers and analyzed the associations of these genetic alterations with clinical stage and surgical pathological factors, such as histological grade, lymph node metastasis, and peritoneal dissemination. The total number of genetic alterations per tumor ranged from 0 to 39, with an average of 17.7 alterations per tumor. Among the genetic alterations in ovarian cancers, gains on chromosomes 8q and 3q and losses on chromosomes 17p, 18q, and 4q were observed frequently. Although the difference in total numbers of genetic alterations between early-stage tumors and advanced-stage tumors was not significant, the difference was significant when high-grade cancers were compared with low-grade cancers. Eight regions on seven chromosomes showed genetic alterations related to lymph node metastasis or peritoneal dissemination. Gain at 11q13-q14 and loss at 17q11.2-q21 were related not only to lymph node metastasis and peritoneal dissemination but also to clinical stage and histological grade.