Independence of the prognostic value of tumor suppressor protein expression in ovarian adenocarcinomas: A multivariate analysis of expression of p53, retinoblastoma, and related proteins.

Accurate estimation of prognosis of ovarian cancer is difficult. For this report, in a group of 73 patients with ovarian adenocarcinomas, clinical factors and protein expression status of p53, retinoblastoma (Rb), and related proteins were evaluated for potential prognostic values. Clinical factors included FIGO stage, age, histopathologic type, and protein expression of p53, Rb, MDM2, p14ARF, p21WAF(1)/CIP(1) was determined by an immunohistochemical technique. Univariate Cox proportional hazard regression analysis was used to determine the significant prognostic value of FIGO stage (P < 0.0001), p53 status (0.0021), and patient age (P = 0.0255), and we report here, for the first time, the significant (P = 0.0072) prognostic value of Rb status. Histopathologic type and MDM2, p14ARF, p21WAF(1)/CIP(1) status did not show any prognostic value. To examine further the independence of prognostic values, we next applied multivariate analysis: We found that FIGO stage (P < 0.0001) and p53 status (P = 0.0108) were independent prognostic factors, while age and Rb status were not. Independence of prognostic value of p53 has heretofore been controversial, but we found a definite independent prognostic value for p53 status in ovarian adenocarcinomas. We also found that selection of appropriate antibodies for immunohistochemistry was essential to obtain significant results. We used five kinds of antibodies for p53 immunolocalization, and correlation with prognosis was obtained by three of these with different grades of statistical significance.

Analysis of E6 variants of human papillomavirus type 33, 52 and 58 in Japanese women with cervical intraepithelial neoplasia/cervical cancer in relation to their oncogenic potential.

The variation of the E6 region of human papillomavirus type 16 (HPV16) is associated with a high risk for cervical carcinogenesis. To see whether the same is the case with HPV33, 52 and 58, known to have high homology with HPV16, we analyzed the E6 sequence variation of these HPVs in 107 Japanese women with cervical intraepithelial neoplasia (CIN) or invasive cervical cancer (ICC): 20 HPV33-positive, 46 HPV52-positive and 41 HPV58-positive cases. HPV33 variants were more frequently observed in CINs I/II than in CIN III/ICCs (71% (5/7) versus 15% (2/13), P=0.02). In HPV52-positive cases, a single E6 variant was detected in 98% of the cases, whereas the prototype accounted for 98% of HPV58-positive cases. In summary, the distribution of E6 variants is different among HPV types tested, suggesting a link between E6 variation and oncogenic potential being type-specific.

Severe liver injury with hematological disorders following the injection of non-ionic contrast medium. A case report.

We describe a dramatic case of severe liver injury and hematological disorders following the injection of non-ionic contrast medium in a 49-year-old woman with endometrial cancer. This case developed into a fulminant hepatitis-like picture that required repeated plasmapheresis and hemodialysis.

Prognostic factors of stage IV epithelial ovarian cancer: a multicenter retrospective study.

OBJECTIVE: In the present study, we conducted a multicenter retrospective analysis to elucidate the prognostic factors of stage IV epithelial ovarian cancer. METHODS: In November 1999, 24 Japanese institutions received questionnaires regarding stage IV epithelial ovarian cancer patients. Eligibility criteria included all patients with stage IV epithelial ovarian cancer who were surgically confirmed and initially treated in each institution between January 1990 and December 1997. Data were collected regarding age, performance status, tumor histologic subtype, site of metastasis, preoperative CA125, cytoreductive surgery, residual disease after cytoreductive surgery, and response to primary chemotherapy. Survival analysis and comparisons were performed by univariate and multivariate methods. RESULTS: Two hundred twenty-five patients with stage IV ovarian cancer were identified. The median age of the patients was 54 years. The most common site of extraperitoneal disease was malignant pleural effusion (39.6%). Of the 225 patients who underwent an attempt at surgical debulking, 70 (31.1%) were optimally cytoreduced. Most patients received platinum-based combination chemotherapy for primary chemotherapy. In multivariate analysis, performance status, histology, and residual disease after cytoreductive surgery were independent prognostic predictors of outcome. The overall median survival for optimally debulked patients was 32 months compared to 16 months for suboptimally debulked patients (P < 0.0001, hazard ratio: 0.415). CONCLUSION: Optimal surgical debulking, performance status, and histology appear to be important prognostic factors of survival in patients with stage IV epithelial ovarian cancer.

A clinicopathological study of postoperatively upgraded early squamous-cell carcinoma of the uterine cervix.

OBJECTIVE: To investigate the clinicopathological backgrounds and diagnostic problems of postoperatively upgraded early squamous-cell carcinomas of the uterine cervix. PATIENTS AND METHODS: A total of 23 patients with postoperatively upgraded early squamous-cell carcinomas who were treated at the Saitama Cancer Center during the period of January 1, 1976, through December 31, 1991, were analyzed clinicopathologically. We reexamined the Pap smears (ectocervix, endocervix), colposcopic findings, punch biopsies, and histological findings of the operative specimens. All patients were divided into one of 3 groups based on each patient's main location of the carcinoma of the cervix: Type A: ectocervical type; Type B: endocervical type; or Type C: combined (ectocervical and endocervical) type. Clinical staging of the uterine cervical carcinomas was done in accordance with the 1994 FIGO rules. RESULTS: The numbers of patients were: Type A, 2; Type B, 10; Type C, 11. Of the 23 patients, 21 (91.3%) had lesions in the endocervical portion at least. Fifteen patients (65.2%) complained of atypical vaginal bleeding. Colposcopic findings suggesting an invasive carcinoma appeared for only 6 patients (26.1%). A cytological reevaluation revealed that the endocervical findings were much stronger than the ectocervical ones in 10 (66.7%) of 15 patients whose smears of both sites could be rechecked. CONCLUSIONS: Even if the preoperative diagnosis was early cervical carcinoma, CIS or Stage Ia1, the signs of atypical vaginal bleeding suggested that the final clinical stage would be upgraded after an operation. Furthermore, when the endocervical cytological findings were much more exaggerated than the ectocervical ones, the possibility of deeply invaded endocervical lesions should be considered.

Fine needle aspiration cytology of adenocarcinoma of the rectovaginal septum. A case report.

BACKGROUND: Adenocarcinoma arising in the rectovaginal septum is exceedingly rare and is difficult to diagnose by pathologic examination prior to surgery because of the anatomic position of the tumor. CASE: A 42-year-old woman presumed to have adenocarcinoma of the rectovaginal septum underwent fine needle aspiration for diagnosis. Although a previously performed biopsy from the posterior vaginal fornix was unsuccessful, fine needle aspiration cytology via the posterior vaginal wall detected adenocarcinoma cells. The cell clusters were composed of cells with enlarged and hyperchromatic nuclei. The nuclei themselves demonstrated round and/or irregular morphologic patterns, with high nuclear/cytoplasmic ratios, and often contained an enlarged, round nucleolus and sometimes multiple ones in a single nucleus. Aniso-nucleosis was severe, and the chromatin patterns ranged from coarse to finely granular. The cytoplasm was narrow and lightly stained. Following fine needle aspiration, the patient underwent posterior exenteration on the basis of the cytologic diagnosis. CONCLUSION: Fine needle aspiration cytology was useful in establishing the preoperative diagnosis of adenocarcinoma of the rectovaginal septum, and curative exenterative surgery could be then performed. To our knowledge, this is the first report of fine needle aspiration cytology of adenocarcinoma at this location.

Endometrial adenocarcinoma with diffused/scattered "intramural" spreads: report of a case and review of the literature.

A case is reported of endometrial adenocarcinoma of the uterus in an 85-year-old patient with an unusual spreading pattern. On macroscopic examination, only a tiny exophytic tumor was found in the uterine cavity, while microscopic examination demonstrated a scattered (scirrhous) spread of the carcinoma cells throughout the myometrium. The tumor occupied about half of the upper uterine corpus. The intramural spread of the tumor could not be seen at the time of macroscopic examination of the uterine cut surface. The tumor cells were attached closely to the serosal membrane, and metastasis to the left ovary was found. Intraoperative cytology detected malignant cells in the ascites. We present here this unusual type of endometrial carcinoma and review our previous report which dealt with pure "intramural carcinomas of the uterine corpus".

A clinicopathological study of postoperative pulmonary metastasis of uterine cervical carcinomas.

OBJECTIVE: To investigate the clinicopathological backgrounds and prognostic factors of uterine cervical carcinomas metastatic to the lung. METHODS: A total of 519 patients with invasive cervical carcinoma (Stage pTIb-IIb) treated by abdominal radical hysterectomy at the Saitama Cancer Center from January 1, 1976 to December 31, 1989 were analyzed clinicopathologically. RESULTS: The frequencies of pulmonary metastasis were 6.4% (24/377) and 11.3% (16/142) in patients with negative and positive pelvic lymph nodes, respectively. Among 24 negative lymph node patients, 15 had pulmonary metastasis only. The overall 5-year survival rate of these 15 patients was 36% after relapse. Of the 15, the prognosis of 12 patients with 1-3 pulmonary metastases only was better, that is, 46% after surgical resection (mean size of resectable tumor = 2.8 cm) and/or chemotherapy. But the other patients died within 3.3 years after relapse. CONCLUSIONS: The occurrence of pulmonary metastasis only, its number (1-3) and size (mean size = 2.8 cm), and no lymph node metastasis are important prognostic factors. For these patients, active surgical resection of the pulmonary lesion(s) and further chemotherapy are recommended in order to improve their prognosis.

Balance of IgG subclasses toward human papillomavirus type 16 (HPV16) L1-capsids is a possible predictor for the regression of HPV16-positive cervical intraepithelial neoplasia.

Human papillomavirus type 16 (HPV16) is known to be a major causative agent of cervical cancer. To test the hypothesis that an enhanced Th1 response favors the natural course of cervical intraepithelial neoplasia (CIN), we measured IgG subclasses toward HPV16 L1-capsids because IgG1/IgG2 balance reflects Th2 and Th1 responses, respectively. We examined IgG2/IgG1 ratios in sera from 67 anti-HPV16 L1-positive women; 18 were cytologically normal women, 29 were CIN patients, and 20 were cervical cancer patients. The IgG2 dominance (IgG2/IgG1 ratio >1) was observed in 94, 48, and 5%, respectively (p < 0.001). The regression rate of CIN lesions was significantly different between patients with and without IgG2 dominance: 83.3% (5/6) versus 16.7% (1/6), respectively (p < 0.05). These findings raise the possibility that IgG2 dominance toward HPV16 L1-capsids, i.e., Th1 dominance, may be a useful marker to predict viral clearance or the regression of HPV16-positive CIN.

Analysis of initial failure site and spread pattern in endometrial carcinoma: a Japanese experience.

Kasamatsu T, Shiromizu K, Takahashi M, Matsumoto K, Shirai T. Analysis of initial failure site and spread pattern in endometrial carcinoma: a Japanese experience. This retrospective study was undertaken in an attempt to identify initial failure sites and spread patterns in patients with endometrial carcinoma in Japan. A retrospective clinicopathologic review of 272 patients treated from 1983 to 1994 at Saitama Cancer Center was performed. Patients underwent total hysterectomy, bilateral salpingo-oophorectomy and pelvic lymphadenectomy. Postoperative external radiation was given to the patients with deep myometrial invasion, high grade tumor, and/or lymph node metastasis. Following surgery, chemotherapy was given to the patients with extrapelvic metastasis. Of the 272 patients, 262 had no residual disease after initial treatment and 10 had confirmed residual disease. Of the 262 patients, 32 (12.2%) suffered recurrence. The recurrence rates for stage I, II, III, and IV were 5.6% (10/178), 5.7% (2/35), 35.3% (18/51), and 100% (2/2), respectively. Of the 32 patients who failed, 6 (18.8%) experienced local failure, 13 (40.6%) had distant failure without peritoneal spread, and 13 (40.6%) had distant failure with peritoneal spread. In distant failure, the incidence of peritoneal spread was highest (50.0%, 13/26), closely followed by that of pulmonary metastasis (46.2%, 12/26). Furthermore, of those patients with residual disease, peritoneal spread was found in 80% (8 of 10). Five of the six patients (83.3%) with local failure survive, but all patients with peritoneal spread have died. Peritoneal dissemination is an important failure pattern and should be considered a top priority in an attempt to improve survival in patients with endometrial carcinoma.

Clinicopathological study of recurrent uterine cervical squamous-cell carcinoma.

OBJECTIVE: To improve prognoses of patients with recurrent uterine cervical squamous-cell carcinoma. PATIENTS AND METHODS: We clinicopathologically analyzed 464 patients with uterine cervical squamous-cell carcinoma (126 positive, 338 negative pelvic lymph-node metastasis) who were treated at the Saitama Cancer Center from January 1, 1976 to December 31, 1991. RESULTS: The recurrence rates of negative pelvic lymph-node metastasis patients were 14. 2% (39/274) in pT1b and 32.8% (21/64) in pT2b. But for positive lymph-node metastasis patients the rates were 39.0% (23/59) in pT1b and 58.2% (39/67) in pT2b. The interval to recurrence was shorter in positive pelvic lymph-node patients than in negative patients. The 5-year survival rates after relapse of negative lymph-node patients with intrapelvic, extrapelvic, and both-sites recurrence were 53, 12, and 40%, respectively. But among distant recurrent sites, lung metastasis in negative lymph-node patients and lymphatic tract metastasis brought relatively fair prognoses. CONCLUSIONS: Regular long-term checks are necessary and active retreatments are recommended for patients with local recurrences, lung metastasis, or lymphatic vessel metastatic lesions.

Leiomyosarcoma of the uterine cervix.

The clinicopathologic features of a patient with uterine leiomyosarcoma arising in the cervix are presented. A 47-year-old Japanese woman was admitted with complaints of hypermenorrhea and abdominal distention. A hysterectomy with bilateral salpingo-oophorectomy revealed a tumor weighing 10.5 kg, which was the largest cervical leiomyosarcoma reported in the literature. She was given eight courses of combination chemotherapy (VADIC and Hydroxyurea, DTIC, Etoposide) and is alive without evidence of recurrence 35 months after the initial therapy.

Random nuclear p53 overexpression pattern in tamoxifen-mediated endometrial carcinoma.

In a previous paper, we suggested that tamoxifen (TAM)-mediated endometrial carcinogenesis may not involve estrogenic pathways because of random estrogen receptor positivity among endometrial carcinomas with and without TAM treatment for breast cancer. DNA adduct formation (reported in rat liver and human endometrium) was considered to be a more plausible mechanism for TAM-mediated carcinogenesis. To examine the reported correlation between DNA adduct formation and p53, the present study examined p53 expression in the endometrial carcinomas reported in the previous study. Seven endometrial adenocarcinomas associated with long-term TAM treatment for breast carcinoma and 4 carcinomas without TAM treatment but with history of breast carcinoma were immunohistochemically investigated for nuclear p53 expression. The bcl-2 product was also examined. Diffuse and intense nuclear reactivity for p53 protein was present in only one TAM-related case. Essentially, no differences were observed in the bcl-2 staining patterns of TAM-treated and -untreated patients with cancer. Thus, p53 overexpression in endometrial carcinomas occurring in patients with breast cancer seems to be not specific for TAM-treated patients, and, if DNA adduct formation has any role in this type of endometrial carcinogenesis, it may not be related preferentially to p53 gene alteration. Further studies are needed to understand the precise mechanism(s) of the endometrial carcinogenesis.

Intramural carcinomas of the uterine corpus: a clinicopathological study.

Cases in which no sizable amount of tumor was observed in the uterine cavity and the main foci of the carcinoma were exclusively confined to the myometrium, were studied pathologically in a series of carcinomas of the uterine corpus. Ten out of 350 carcinomas of the uterine corpus proper fell into this category, and one case of suspicious metastatic corpus tumor from the ovary was also considered. The growth pattern of these tumors was classified into following 6 groups: (a) growth confined to the myometrium, (b) nodular growth in the myometrium with minimal endometrial involvement, (c) scattered (scirrhous) growth in the myometrium with marked shedding of the endometrium, (d) almost complete replacement of the myometrium by carcinoma with endometrial shedding (e) extreme subtype of usual endophytic growth pattern and (f) diffuse, intra-lymphatic spread of secondary tumor. One, 2, 3, 1, 3, and 1 cases of tumors of group, (a)-(f), were observed respectively in our pathological files. A spectrum of initial symptoms, diagnostic procedures, histology and histogenesis of the tumor was described in this report.

Occurrence of apoptotic DNA fragmentation in quiescent and proliferating cells in human endometrial adenocarcinoma tissues and the influence of apoptosis-suppressing effects of bcl-2 products.

In situ estimation of DNA fragmentation by the nick end labelling (NEL) method, and immunohistochemical examination of Ki-67 proliferative antigen and bcl-2 products in human endometrial adenocarcinoma tissues were performed to provide answers to the following two questions; a) does apoptotic DNA fragmentation occur specifically in quiescent cells or in proliferating cells or randomly in both?, b) does the bcl-2 product exert its apoptosis-suppressing effects differentially on carcinoma cells depending on their cell cycle condition?. Serial sections, one micrometer in thickness, from formalin-fixed and paraffinembedded tissues of 9 cases of human endometrial adenocarcinoma were examined. Apoptotic DNA fragmentation was observed in both quiescent (Ki-67 negative) and proliferating (Ki-67 positive) cells. Bcl-2 product-positive tumor cell islands tended to be NEL negative, although a few but non-negligible number of carcinoma cells, including both Ki-67 positive and negative ones, were NEL positive. These results indicate that, at least in human endometrial adenocarcinomas, apoptotic DNA fragmentation and bcl-2 product-independent (DNA) fragmentation occurs non-specifically with respect to the cell proliferation status. Further, the results suggest an altered regulation of cell death processes in human solid tumor tissue in vivo.

Inverse correlation between bcl-2 expression and cell growth fraction in human endometrial adenocarcinoma tissue.

Correlation between expression status of bcl-2 products and cell growth fraction (estimated by immunostaining for Ki-67 antigen) was analyzed in human endometrial adenocarcinoma tissue in situ. For this, serial sections, 2 micrometers thick, from formalin-fixed and paraffin-embedded tissue samples of 10 cases of the carcinoma were examined. Nine out of 10 carcinomas contained both bcl-2 positive and negative nests when examined immunohistochemically. In the remaining one case, no positive reaction for bcl-2 was observed. In general, bcl-2 positive nests tended to contain quiescent (Ki-67 negative) carcinoma cells, and bcl-2 negative nests, on the contrary, a large fraction of proliferating (Ki-67 positive) cells. However, this correlation was not strict, and in a few nests, the level of growth fraction was observed to be similar irrespective of bcl-2 positivity. These results show the complex function(s) of bcl-2 products, when considering their apoptosis-suppressing effects, cell cycle dependence and influence on cell proliferation status. Further, the results suggest an altered regulation of oncogene products in human solid tumor tissue in vivo.

Tamoxifen mediated human endometrial carcinogenesis may not involve estrogenic pathways: a preliminary note.

Seven cases of endometrial adenocarcinoma patients who had experienced long-term tamoxifen treatments as adjuvant therapy of breast carcinoma, were investigated with respect to estrogen receptor (ER) status. Four cases of endometrial adenocarcinoma without tamoxifen treatment but with a previous history of breast carcinoma were investigated for comparison. One of the 7 and two of the 4 cases were positive for ER immunohistochemically. Thus, the frequency of ER positivity in secondary endometrial adenocarcinoma seemed to be at random among tamoxifen-treated and non-treated breast cancer patients. These results suggest that tamoxifen-mediated human endometrial carcinogenesis may not involve estrogenic pathway(s) but may involve other carcinogenic mechanisms such as DNA adduct formation as shown in rat liver tumorigenesis.

Evaluation of apoptosis in human endometrial adenocarcinoma: comparison of nick end labeling and Le(y) antigen immunostaining method.

In situ estimation of DNA fragmentation by the nick end labeling method and immunohistochemical detection of cell surface carbohydrate Le(y) were performed to establish correlation between the results of these two apoptosis-detecting techniques in human solid tumor tissues. Formalin-fixed and paraffin-embedded tissue samples from 10 cases of human endometrial adenocarcinoma were examined and compared by using the two techniques. A substantial fraction of carcinoma cells was found to be definitely stained by both methods, although Le(y) expression did not seem to be positively correlated with DNA fragmentation in the carcinoma tissue. These results suggest that Le(y) expression does not necessarily reflect apoptotic DNA fragmentation, at least in human endometrial adenocarcinomas, and simultaneous application of DNA nick end labeling and Le(y) immunostaining is necessary to show the relevant signs of apoptosis in histologic slides, especially gynecological cancers.