Toru Tase

Gastrointestinal immunophenotype in adenocarcinomas of the uterine cervix and related glandular lesions : a possible link between lobular endocervical glandular hyperplasia/pyloric gland metaplasia and 'adenoma malignum'

Gastrointestinal phenotype in cervical adenocarcinomas was examined by immunohistochemistry and correlated with morphologic features. Antibody panels included anti-MUC2, MUC6, CD10, chromogranin A (CGA) and HIK1083. In addition, expression of p16INK4, a cyclin-dependent kinase inhibitor which is expressed in a variety of high-risk HPV-related conditions, was studied. A total of 94 invasive adenocarcinomas including 20 minimal deviation adenocarcinomas (MDAs) and 72 adenocarcinomas in situ (AIS) were examined. MDAs were most frequently positive for HIK1083 and/or MUC6, two representative gastric markers, with a rate of 95%, followed by intestinal-type adenocarcinomas (IAs) with a rate of 85% whereas only 27% of 56 usual endocervical-type adenocarcinomas (UEAs) were positive. MUC2, a goblet cell marker, was positive in 85% and 25% of IAs and MDAs, respectively, while in only 14% of UEAs. CD10 was positive in 15% of IAs, indicating incomplete intestinal differentiation without a brush border in most of the cases. CGA-positive cells were frequently seen in MDAs and IAs with rates of 60% and 62%, respectively. Nuclear and cytoplasmic p16INK4 positivity was identified in 93% of UEAs, whereas 30% of MDAs were positive for p16INK4. Results in AISs were comparable to their invasive counterparts, but morphologically usual-type AISs identified in eight cases of MDA were frequently positive for HIK1083 (75%) and MUC6 (63%), and p16INK4. Of note was the existence of lobular endocervical glandular hyperplasia (LEGH) with atypical features including cytologic abnormalities, and/or papillary projection, which were identified in this study in pure form (n=3) or in association with MDAs (n=6), but not in cases of other types of adenocarcinomas. These observations indicate that gastrointestinal phenotype is frequently expressed in MDAs and IAs, and there seems to be a possible link between MDA, and LEGH and morphologically usual-type AIS with gastric immunophenotype in histogenesis. Frequent absence of p16INK4 expression in MDAs suggests a possibility that high-risk HPV does not play a crucial role in development of MDAs, in contrast to the majority of endocervical adenocarcinomas. p16INK4 immunohistochemistry appears to be a promising diagnostic tool, but pathologists should be aware of frequent negative staining in MDAs, which can be a source of erroneous diagnosis.

Human papillomavirus DNA in adenocarcinoma in situ, microinvasive adenocarcinoma of the uterine cervix, and coexisting cervical squamous intraepithelial neoplasia.

Previously, human papillomavirus (HPV) DNA, mainly HPV-18 DNA, was detected in more than 40% (17/40 cases) of invasive adenocarcinoma of the uterine cervix in our laboratory. In order to identify HPV DNA in the precursor lesions of adenocarcinoma of the cervix, 11 cases of adenocarcinoma in situ containing microinvasive adenocarcinoma and 10 cases of adenocarcinoma in situ were studied for the presence of HPV DNA by in situ hybridization using highly sensitive 3H-labeled HPV-16 and HPV-18 DNA probes. HPV types present in cervical squamous intraepithelial neoplasia (CIN) coexisting with adenocarcinoma in situ and microinvasive adenocarcinoma were also studied. Apart from the coexisting CIN II-III with glandular neoplasms, 48 cases of CIN III (severe dysplasia and squamous carcinoma in situ) removed by conization or hysterectomy and known to be free of adenocarcinoma were used for comparison. HPV DNA was detected in 64% of microinvasive adenocarcinoma, 70% of adenocarcinoma in situ, and 63% of the control CIN III. HPV-18 DNA was the preponderant type of HPV DNA found in adenocarcinoma in situ and microinvasive adenocarcinoma. All cases of HPV DNA-positive microinvasive adenocarcinoma contained the same type of HPV DNA as the lesions of coexisting adenocarcinoma in situ. CIN coexisting with microinvasive adenocarcinoma or adenocarcinoma in situ contained the same type of HPV as identified in the glandular lesions, whereas all of the HPV DNA-positive control CIN III cases contained HPV-16 DNA. These results suggest that adenocarcinoma in situ is a precursor lesion of adenocarcinoma of the cervix that contains HPV DNA, and that CIN coexisting with adenocarcinoma may be a result of a metaplastic process of adenocarcinoma or of bidirectional differentiation of the affected reserve cells.

Clinical outcome and risk factors for recurrence in borderline ovarian tumours

We investigated the long-term prognosis of borderline ovarian tumours and determined risk factors for recurrence. One hundred and twenty-one borderline ovarian tumours treated between 1994 and 2003 at the participating institutions in the Tohoku Gynecologic Cancer Unit were retrospectively investigated for clinical stage, histopathological subtype, surgical technique, postoperative chemotherapy, the presence or absence of recurrence, and prognosis. The median follow-up period was 57 months (1–126 months). One hundred and nine cases (90.6%) were at clinical stage I. The histopathological subtypes consisted of 91 cases of mucinous tumour (75.2%), 27 cases of serous tumour (22.3%), and three cases of endometrioid tumour. Conservative surgery was used in 53 cases (43.8%), radical surgery in 68 cases (56.2%), a staging laparotomy in 43 cases (35.5%), and postoperative adjuvant therapy in 30 cases (24.8%). Recurrence was found in eight cases, but no tumour-related deaths were reported. Although no significant difference in disease-free survival rate was seen between different clinical stages, the difference in disease-free survival rate between serous and nonserous (mucinous and endometrioid) types was significant (P<0.05). The 10-year disease-free survival rate was 89.1% for the radical surgery group and 57.4% for the conservative surgery group – this difference was significant (P<0.05). In the conservative surgery group, cystectomy and serous tumour were independent risk factors for recurrence. Although recurrence was observed, the long-term prognosis of borderline ovarian tumour was favourable, without tumour-related deaths. Considering the favourable prognosis, conservative surgery can be chosen as far as the patient has a nonserous tumour and receive adnexectomy. However, in cases of serous type and/or receiving cystectomy special care should be given as relative risk rates of recurrence elevate by 2–4-folds.

Malignant transformation arising from mature cystic teratoma of the ovary: a retrospective study of 20 cases.

Objectives: Mature cystic teratoma (MCT) of the ovary rarely undergoes malignant transformation (MT). Malignant transformation carries a significantly worse prognosis than epithelial ovarian cancer, regardless of whether postoperative chemotherapy or radiotherapy is applied. The rarity of this tumor has posed a significant challenge to developing standardized postoperative management protocols. The aim of this study was to review our experience with MT and to describe our current treatment practices. Methods: A retrospective chart review of these patients was performed that identified 20 women treated for MT of MCT at our centers between 1988 and 2008. Results: The median age was 52.5 (range, 29-77) years. Fifteen patients had squamous cell carcinoma (SCC), and 5 patients had other histological subtypes. The International Federation of Gynecology and Obstetrics stage distribution was as follows: 11 were stage I, 4 were stage II, 4 were stage III, and 1 was stage IV. All patients underwent an initial laparotomy. Eleven patients received adjuvant treatment: 8 were treated with chemotherapy, 2 with concurrent chemoradiation therapy, and 1 with radiation therapy. Platinum-based chemotherapy was the first-line regimen. The overall 1-year survival rate was 70%. Significant correlations between overall survival and age, stage, and residual tumor were presented (P = 0.044, P = 0.0107, P < 0.0001, respectively). Eight patients with advanced stage died of their disease. Four patients, however, were treated with adjuvant chemotherapy or concurrent chemoradiation therapy and survived more than 1 year. One stage III patient had a disease-free interval of 2 years. Two cases of SCC treated with combination platinum/taxane chemotherapy temporarily responded. In the other 2 cases of SCC, concurrent chemoradiation therapy with nedaplatin also resulted in tumor regression. Conclusions: The prognosis of MT is highly dependent on age, stage, and optimal cytoreduction. Adjuvant treatment has not been standardized, although our experience supports the use of combination platinum/taxane chemotherapy.

Case-control study of coffee consumption and the risk of endometrial endometrioid adenocarcinoma.

This study examined the association between coffee consumption and the risk of endometrial endometrioid adenocarcinoma (EEA) in Japan by a case–control design. The cases consisted of 107 women less than 80 years of age from two medical centers who had been histopathologically diagnosed to have EEA. The controls, selected from the participants of a cancer-screening program, were 214 women, with two controls selected for each case (matched for age and for area of residence). A self-administered questionnaire containing questions to determine dietary and beverage consumption, as well as reproductive history, was distributed to the cases and controls. Conditional logistic regression analysis was used to estimate the odds ratio (OR) of EEA for three levels of coffee consumption with adjustment for potential confounding factors. The multivariate-adjusted OR of EEA for individuals in the highest tertile of coffee consumption (2 to 3 cups or more/day) was 0.4 [95% confidence interval (CI), 0.2–0.9], and that of cases in the intermediate tertile (5 to 6 times/week-1 cup/day) was 0.6 (95% CI, 0.3–1.2), relative to the individuals in the lowest tertile of coffee consumption (3 to 4 times or less/week) (P for trend=0.014). The above association was observed in postmenopausal women (P for trend=0.016), but not in premenopausal women (P for trend=0.90). This study thus revealed an inverse dose–response relationship between coffee consumption and the risk of EEA, and its strong association in postmenopausal women but not in premenopausal women.

Challenges in breast and cervical cancer control in Japan

Since the mid-1990s, there has been an increasing incidence of, and mortality from, cervical and breast cancers in Japan. Such an increase has raised concerns over the efficiency of Japans screening programmes for these cancers. Although citizens benefit from universal health coverage, the Japanese health insurance system mostly focuses on tertiary prevention and disease treatment, while secondary prevention (screening) is low priority. Citizens have multiple opportunities to be screened for cancer-either through programmes organised by municipalities, or individual or collective, opportunistic and comprehensive health check-ups on a voluntary basis. Despite this, however, participation is as low as 35% of the target population for both cancers. In this Policy Review, we discuss the challenges in the prevention of breast and cervical cancers in Japan, particularly focusing on the structure of the National Health Insurance system and the National Cancer Control Plan, reasons for low participation as a result of social and political attitudes, as well as providing recommendations to overcome these challenges. Japanese women would benefit from new measures to increase participation, a national data surveillance programme to monitor screening activities, and the implementation of a quality assurance system among all providers.

Phase II clinical study of the combination chemotherapy regimen of irinotecan plus oral etoposide for the treatment of recurrent ovarian cancer (Tohoku Gynecologic Cancer Unit 101 Group Study).

Objective: To evaluate the efficacy and safety of the combination chemotherapy regimen of irinotecan plus oral etoposide for the treatment of patients with recurrent ovarian cancer after previous treatment with platinum and taxane agents. Patients and Methods: A total of 42 patients with recurrent ovarian cancer who had an evaluable lesion and provided informed consent for participation in the present study were analyzed. Irinotecan was administered intravenously at a dose of 60 mg/m2 on days 1 and 15. Etoposide was administered orally at a daily dose of 50 mg/body weight from days 1 to 21. A 28-day period comprised one cycle. The tumor response, adverse events, progression-free survival, and overall survival were examined. Tumor response was evaluated based on the Response Evaluation Criteria in Solid Tumors and the serum CA125 levels (Gynecologic Cancer Intergroup criteria). Adverse events were assessed according to the NCI-CTCAE (version 3.0). Results: Partial response was observed in 21 patients, stable disease in 14 patients, and progressive disease in 7 patients. The response rate was 50.0%, and the clinical benefit (partial response + stable disease) rate was 83.3%. Hematological toxicities of at least grade 3 severity included leukopenia in 21 patients (50.0%), neutropenia in 22 patients (52.4%), thrombocytopenia in 1 patient (2.4%), anemia in 9 patients (21.4%), and febrile neutropenia in 3 patients (7.1%). Nonhematological toxicities of at least grade 3 severity included queasy feeling in 5 patients (11.9%), vomiting in 3 patients (7.1%), and diarrhea in 2 patients (4.8%). Acute myeloid leukemia occurred in one patient (2.4%). Conclusions: It is suggested that combination chemotherapy with irinotecan plus oral etoposide offers significant clinical benefit to patients with recurrent ovarian cancer previously treated with platinum and taxane agents.

Human Papillomavirus DNA in Glandular Dysplasia and Microglandular Hyperplasia: Presumed Precursors of Adenocarcinoma of the Uterine Cervix

&NA; Presumed precursors of adenocarcinoma of the uterine cervix were investigated with specific techniques to identify human papillomavirus (HPV) DNA. The presence of HPV DNA in 36 lesions of glandular dysplasia and 16 lesions of microglandular hyperplasia of the uterine cervix was studied by in situ hybridization using 3H‐labeled HPV 16 and HPV 18 DNA probes. Only two of 36 lesions (6%) of glandular dysplasia contained HPV 18 DNA, although 64% of coexisting adenocarcinoma in situ, microinvasive adenocarcinoma, and cervical squamous intraepithelial neoplasia III lesions contained HPV 18 and/or HPV 16 DNA. Two lesions of HPV 18 DNA‐positive glandular dysplasia coexisted with adenocarcinoma in situ that contained the same type of HPV DNA. None of the microglandular hyperplasia lesions contained HPV 16 DNA or HPV 18 DNA. These results suggest that, if HPV infection is an initial step toward carcinogenesis, it is unlikely that glandular dysplasia and microglandular hyperplasia are precursor lesions of adenocarcinoma of the uterine cervix. A large proportion of glandular dysplasia may represent reactive lesions of endocervical columnar epithelium. Two lesions of HPV 18 DNA‐positive glandular dysplasia may represent well‐differentiated components of adenocarcinoma in situ of the uterine cervix. (Obstet Gynecol 73:1005, 1989)

Immunohistochemical demonstration of papillomavirus antigen in cervical dysplasia and vulvar condyloma

Biopsies from 30 cases of vulvar condyloma, 460 cases of cervical dysplasia, 30 cases of carcinoma in situ and 75 cases of invasive carcinoma of the cervix were screened for the presence of human papillomavirus (HPV) antigen by means of the peroxidase-antiperoxidase method. Positive reaction for HPV was detected in 14 cases of condyloma and 80 cases of dysplasia as a brown intranuclear precipitate in the superficial layer of the epithelium. None of the cases of carcinoma in situ and invasive cancer were positive for HPV. The mean age of the women with HPV-positive dysplasia was significantly lower than that of the women with HPV-negative dysplasia. Condylomatous dysplasia showed a significantly higher positive rate than did noncondylomatous dysplasia. Cases of condylomatous dysplasia with severe stromal inflammation were negative for HPV more frequently than those with mild stromal inflammation.

Gastric-type endocervical glandular neoplasms associated with aberrant p16 expression and K-RAS gene mutation in Peutz-Jeghers syndrome

In this report, unique endocervical glandular lesions exhibiting gastric differentiation were examined in a patient with Peutz‐Jeghers syndrome. The result of the human papillomavirus (HPV) in situ hybridization (ISH) for the hysterectomy specimens was negative, but they demonstrated a papillary mucinous adenocarcinoma at the proximal endocervix continuous to atypical lobular endocervical glandular hyperplasia. Both contained MUC6‐positive neutral mucin in cytoplasm, and showed different immunoreactivity to p16, Ki‐67, and p53. Moreover, they harbored the identical K‐RAS gene mutation suggesting that there was a common origin. Somatic K‐RAS mutation and defective function of p16 may have been involved in the tumorigenesis of these unusual mucinous neoplasms.