Comparison of adjuvant chemotherapy and radiotherapy in patients with cervical adenocarcinoma of the uterus after radical hysterectomy: SGSG/TGCU Intergroup surveillance.

PURPOSE: The authors conducted this retrospective study to evaluate the efficacy of radiotherapy (RT) for high-risk patients with adenocarcinoma (AC) compared with chemotherapy (CT) after radical hysterectomy. MATERIALS AND METHODS: There were 263 patients with AC and 58 with adenosquamous cell carcinoma (ASCC). Of these 321 patients, 151 received adjuvant treatment. Of these 151 patients, 69 received radiotherapy (RT) alone, including concurrent chemoradiotherapy (CCRT) with weekly cisdiamminedichloroplatinum (CDDP), 64 patients received CT alone, and 18 patients received concomitant RT and CT (RT + CT). RESULTS: The five-year overall survival (OS) was 70.9% for patients receiving RT, 79.2% for CT, and 66.2% for RT + CT. Adjuvant treatment did not affect the incidence or the pattern of recurrence. The incidence of lymph node involvement was 9.0% in Stage Ib1, 23.9% in Stage Ib2, 30.8% in Stage IIa, and 41.2% in Stage IIb. CONCLUSIONS: Adjuvant CT may be effective for high-risk patients with cervical adenocarcinoma.

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 non-serous (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 non-serous 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.

[Compliance in antihypertensive therapy: analyses in scientific articles]. / A adesão ao tratamento na hipertensão arterial: análise da produção científica.

The aim of this study was to evaluate scientific articles published between 1991-1995, in order to identify the compliance in antihypertensive therapy, One hundred seven scientific articles were evaluated. The results showed that 68% were related to patient, 63% to pharmacological treatment, 62% general, 39% non pharmacological treatment, 34% organizational factors, and 8% related to disease. Compliance with antihypertensive therapy was the major challenge of hypertension management and to know how this aspect was focalized in scientific articles possible reduce non compliance in hypertension.

Flow cytometric DNA analysis of abnormal endometrium.

Samples of abnormal endometrium, which were composed of 5 cases of atypical hyperplasia (ATH), 12 cases of well differentiated adenocarcinoma (G1), 17 cases of moderately differentiated adenocarcinoma (G2), 11 cases of poorly differentiated adenocarcinoma (G3) and 2 cases of serous papillary adenocarcinoma (SPA), were analyzed by flow cytometry. With respect to the ploidy level, all cases of both ATH and G1 showed diploidy, and the proliferative index (PI) was 14.32 and 16.33, respectively. In contrast, 3 of G2 cases, 3 of G3 cases and all of SPA cases showed aneuploid patterns, and the PI was 21.06, 27.91 and 31.52, respectively. There were statistical differences between the former group and the latter group as to both the ploidy and the PI. It was found that ATH and G1 had similar biological behavior.

The correlation between HPV infection and cell proliferative activity in uterine cervical adenocarcinoma.

To investigate the correlation between human papillomavirus (HPV) infection and cell proliferative activity in uterine cervical adenocarcinoma, in situ hybridization of HPV DNA and immunostaining of proliferative cell nuclear antigen (PCNA) were performed on serial sections of the carcinoma. HPV 16 and 18 DNA was detected in 10 of 33 cases of cervical adenocarcinoma and adenocarcinoma in situ. PCNA was detected in 30 cases. In all 10 HPV-positive cases, PCNA was also demonstrated, and the number of PCNA-positive cells tended to be higher than that in HPV-negative cases. With 1:1 correlation between HPV and PCNA on the nuclei, the coincidence rate was 72% (p < 0.01). These results indicate that HPVs play a role in cell proliferation.

Detection of human papillomavirus DNA in genital condylomata in women and their male partners by using in situ hybridization with digoxygenin labeled probes.

Twelve couples (12 women and their male partners) presenting genital warts were investigated in order to evaluate the sexual transmission of human papillomavirus (HPV) in mutual partners and the localization of HPV DNA. Formalin-fixed, paraffin-embedded biopsy samples of 12 vulvar condylomata, and 12 penile condylomata from male partners were analyzed for the presence of HPV DNA-6, -11, and 16/18 by using in situ hybridization with digoxygenin labeled DNA probes. HPV DNA was identified in 9 women (75%) and in 9 men (75%). HPV-6 was frequently identified, being revealed in 42% of the vulvar specimens, in 67% of the cervical specimens and 58% of the penile specimens. Seven of 9 (77%) positive couples shared the same HPV DNA, and 2 couples harbored different HPV DNA types between the partners. The signal intensity of the HPV DNA was generally strong in superficial cell layers, weak in parabasal or basal cell layers. No malignant lesions resulted from the condyloma acuminatum caused by HPV-6 or -11. There were only mild dysplasia in the both sexes.

Histogenesis of cervical adenocarcinoma with reference to human papillomavirus-18 as a carcinogen.

Human papillomavirus (HPV) DNA is present in adenocarcinoma of the cervix as frequently as in squamous cell carcinoma of the cervix. Recent molecular biologic studies strongly suggested that HPV acts at least as a cocarcinogen in the female genital organs. Thus, a study of the presence of HPV DNA in adenocarcinoma in situ, endocervical glandular dysplasia and microglandular endocervical hyperplasia, three lesions suggested as possible precursor lesions of adenocarcinoma of the cervix, would clarify some aspects of the histogenesis of adenocarcinoma of the cervix. The presence of HPV-6, HPV-16 and HPV-18 in those precursor lesions was studied with highly sensitive in situ DNA hybridization. Fourteen of 21 cases of adenocarcinoma in situ (67%) contained HPV DNA; approximately the same proportion of HPV DNA was seen in invasive adenocarcinoma. Two of 36 cases of endocervical glandular dysplasia contained HPV DNA; both of them were lesions coexisting with adenocarcinoma in situ and thus might have been well-differentiated lesions of adenocarcinoma in situ. HPV DNA was not present in 16 cases of microglandular endocervical hyperplasia. Adenocarcinoma in situ may be the earliest event in HPV infection of the endocervical cells to lead to the development of adenocarcinoma of the cervix.

Human papillomavirus DNA in glandular dysplasia and microglandular hyperplasia: presumed precursors of adenocarcinoma of the uterine cervix.

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.

[Human papillomavirus DNA in vulvar lesions].

In order to study the role of human papillomavirus (HPV) in genital cancer, we attempt to determine the presence of HPV in tumors of the genital tract. In the current study, we have examined 35 histologically diagnosed cases of vulvar lesions in attempts to compare the sensitivities of various methods of detecting HPV. All but 7 vulvar lesions contained HPV DNA by Southern blot DNA hybridization. Detectability of HPV by immunocytochemistry and koilocytosis significantly declined as compared to DNA hybridization. The detection of HPV DNA by in situ hybridization is discussed.

Prognostic significance of the presence of human papillomavirus DNA in patients with invasive carcinoma of the cervix.

Cases of invasive carcinoma of the uterine cervix were analyzed to determine whether the presence or absence of human papillomavirus (HPV) DNA in the neoplasms was a contributing factor to their outcome. The presence of HPV DNA was evaluated using in situ hybridization on formalin-fixed, paraffin-embedded tissue sections. Eighty-five patients with cervical carcinoma who had been surgically evaluated were included in the study. Data from these patients was analyzed retrospectively to determine survival, recurrence, presence of nodal metastases, tumor grade, mode of therapy, peritoneal fluid cytologic results, and age in relation to presence or absence of HPV DNA. No significant statistical differences were found between the HPV-16-positive, HPV-18-positive, and HPV DNA-negative patients.

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.

Prevalence of human papillomavirus type 18 DNA in adenocarcinoma and adenosquamous carcinoma of the uterine cervix occurring in Japan.

To identify whether the incidence of human papillomavirus (HPV) type 18 DNA in adenocarcinoma and adenosquamous carcinoma is attributable to the histological types or geographical differences, the presence of HPV-16 and HPV-18 DNA in carcinoma of the uterine cervix from Japan were studied by in situ hybridization using tritium labeled HPV DNA probes. HPV-18 DNA was detected in 5 of 11 cases (45%) of adenocarcinoma, one case of adenocarcinoma in situ and 2 of 3 cases of adenosquamous carcinoma. In contrast, HPV-16 DNA was detected in 2 of 11 cases (18%) of adenocarcinoma, and 3 of 7 cases (43%) of squamous cell carcinoma. Compared with our previous results (Tase et al. 1988), the present results imply that the prevalence of HPV-18 DNA in carcinoma of the uterine cervix is attributable rather to the histological differences than to the geographical differences.

Human papillomavirus types and localization in adenocarcinoma and adenosquamous carcinoma of the uterine cervix: a study by in situ DNA hybridization.

Formalin-fixed, paraffin-embedded tissues from 108 cases of invasive carcinoma of the uterine cervix, consisting of 40 cases of adenocarcinoma, 44 cases of adenosquamous carcinoma, and, as a control, 24 cases of squamous cell carcinoma were examined for the presence of human papillomavirus (HPV) DNA by in situ hybridization of high sensitivity using tritium-labeled HPV-2, HPV-6, HPV-16, and HPV-18 DNA probes. This method detects five genome copies of homologous HPV DNA per cell. HPV DNA was detected with mixed HPV DNA probes in 17 cases (42.5%) of adenocarcinoma, 16 cases (36.4%) of adenosquamous carcinoma, and in 13 cases (54.2%) of squamous cell carcinoma. The types of HPV DNA in the HPV-positive tissues were also analyzed with each individual probe under high stringency conditions. HPV-18 DNA was detected in all but one case of the HPV DNA-positive adenocarcinoma and one-half of the HPV DNA-positive adenosquamous carcinoma. HPV-16 DNA was detected in one case of the HPV DNA-positive adenocarcinoma, one-half of the HPV DNA-positive adenosquamous carcinoma, and all cases of the HPV DNA-positive squamous cell carcinoma. HPV DNA was confined to the areas of carcinoma and squamous cervical intraepithelial neoplasia (CIN) associated with carcinoma. Among 36 cases in which CIN was associated with adenocarcinoma (9 cases), adenosquamous carcinoma (19 cases), and squamous cell carcinoma (8 cases), the same type of HPV DNA was present in the carcinoma and the associated CIN that constituted 12 cases (3 adenocarcinoma, 5 adenosquamous carcinoma, and 4 squamous cell carcinoma). Two cases (one adenocarcinoma and one adenosquamous carcinoma) contained HPV DNA in the carcinoma but not in the associated CIN. The incidence of HPV DNA did not show a significant correlation with the existence of CIN or histological differentiation of carcinoma.

[Flow cytometric DNA analysis of gynecologic malignant tumors using paraffin-embedded tissue].

We have studied flow cytometric DNA analysis of gynecologic malignant tumors using paraffin-embedded tissue for histopathology. A close correlation was observed between the DNA indices obtained from fresh unfixed tissue and from paraffin-embedded tissue (r = 0.993). The coefficient of variation (CV) for the diploid G0G1 peak of the paraffin-embedded tissue was one and half greater than that obtained from fresh tissue on the average. In the DNA analysis of 64 endometrial carcinomas, DNA aneuploidy was detected in 3% of nuclear grade 1, in 25% of nuclear grade 2 and in 63% of nuclear grade 3. That is, the more abnormal the nuclear findings, the higher the percentage of DNA aneuploidy. In the analysis of 48 ovarian tumors, DNA aneuploidy was detected in 79% of serous adenocarcinoma, in no of mucinous adenocarcinoma, in 17% of endometrioid carcinoma, in all of clear cell carcinoma and dysgerminoma, that is, its incidence was different among histological subtypes.

Immunohistochemical and electron microscopic demonstration of human papillomavirus in dysplasia of the uterine cervix.

Twenty-five cases of dysplasia of the uterine cervix were studied for the presence of human papillomavirus (HPV) by means of immunohistochemical and electron microscopic techniques. Serial sections of the same histological specimen were examined in each case. HPV was detected in 14 cases by both immunohistochemistry and electron microscopy, while 10 cases were negative with both methods. In only one case, there was a discrepancy in the results derived from these two methods. It was concluded that the relation between HPV infection and cervical dysplasia was confirmed and that immunohistochemical and electron microscopic methods led almost to the same result in detecting HPV in cervical dysplasia.

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.

Three-dimensional observations on intermediate filaments of the squamous epithelium of the uterine cervix.

The following conclusions have been drawn from electron-microscopic three-dimentional observations on the intermediate filaments (IFs) of the squamous epithelium from the uterine cervix. (1) IFs form a three-dimensional reticular network and wrap around the intracellular periphery of cells extending from the basal to the superficial layers. (2) In basal and parabasal cells, the IFs are distributed in a pattern radiating from the perinuclear location toward the cellular periphery. (3) The use of PEG-embedding method after detergent-extraction with Triton X-100 and saponin is suitable for the three-dimensional observations on IFs of stratified squamous epithelium from the uterine cervix.

Flow cytometric DNA analysis of human endometrial carcinoma.

Analysis of endometrial carcinoma of 15 cases and the normal endometrium from 12 control cases was made using flow cytometry. The proliferative activity and the ploidy level of the tumors were determined and a comparative study of the tumors classified by the nuclear grade of the tumor was made. In comparison with normal endometrium, endometrial carcinoma tissue had a significantly larger S-phase fraction of the cell cycle. Moreover, among the endometrial carcinoma cases, the percentage of S-phase cells was found to increase with increases in abnormalities of nuclear morphology. Endometrial carcinoma cases had higher levels of G2+M phase fractions than normal endometrium, but not significantly so. The proliferation index of endometrial carcinomas was significantly higher than that in normal endometrium, and it was found that proliferative activity became more robust the more irregular the nuclear morphology. With regard to the ploidy level, all of the normal endometria and Nuclear Grade 1 or 2 endometrial carcinoma cases showed a DNA distribution between diploid and tetraploid. In contrast, Nuclear Grade 3 cases could be subdivided into two groups, one which had a DNA distribution between diploid and tetraploid with an extremely high proliferation index and the other which had an aneuploid DNA stem line.

Immunohistochemical localization of carcinoembryonic antigen in adenocarcinoma of the endocervix and the endometrium.

Immunoperoxidase localization of carcinoembryonic antigen (CEA) was performed on tissue sections of adenocarcinoma of endocervical and endometrial origin to clarify the criteria for their differentiation. Twenty-two (96%) of 23 endocervical and 32 (70%) of 46 endometrial adenocarcinomas revealed positive CEA immunostain. The extent of staining did not seem to correlate with the degree of differentiation in either kind of cancer. Among the positive cases, CEA staining was located over whole cytoplasm in 18 (80%) of 22 positive endocervical adenocarcinomas and on apical surface in 24 (75%) of 32 positive endometrial adenocarcinomas. The pattern of CEA distribution in endocervical adenocarcinoma of endometrioid type was not similar to that observed for primary endometrial adenocarcinoma.

[Immunoperoxidase demonstration of papillomavirus antigen in dysplasia of the uterine cervix].

Recently, it has been widely recognized that human papillomavirus (HPV) infection plays an important role in the etiology of carcinoma of the cervix. Paraffin sections of cervical malignancies and premalignancies were screened for the presence of papillomavirus antigen by means of peroxidase-antiperoxidase (PAP) method. No case of invasive carcinoma, carcinoma in situ or normal cervix revealed positive HPV staining. In 81 cases (18%) of 461 cervical dysplasias, positive reaction for HPV was detected as brown intranuclear precipitates. The mean age of the women with HPV was significantly lower than that of women without HPV. Characteristic findings of histology of the dysplasias with HPV were koilocytosis and binucleation.