Hiroaki Kase

Multivariate analysis of prognostic factors in patients with endometrial cancer

Objective: The prognostic factors of endometrial cancer are closely correlated. A multivariate analysis was carried to compare the importance of each factor. Method: A multivariate analysis was performed of 19 clinicopathologic prognostic factors obtained from 144 endometrial cancer patients who had been surgically treated in our hospital between January 1971 and December 1993. Results: Significant prognostic factors according to the Kaplan‐Meier method were depth of invasion, vascular invasion, nuclear grade, cervical involvement, lymph node metastases, intraperitoneal cytology, serous adenocarcinoma, DNA ploidy, type of hysterectomy and surgery only or combined with chemotherapy or radiotherapy. Multivariate analysis showed that vascular invasion and nuclear grade were more significant than structural grade, histologic subtype or DNA ploidy. Conclusion: Multivariate analysis is useful for extracting important recurrent factors from mutually related prognostic factors. Vascular invasion and nuclear grade are singled out as the most useful histologic prognostic factors.

Germline Copy Number Variations in BRCA1- Associated Ovarian Cancer Patients

We investigated characteristics of germline copy number variations (CNV) in BRCA1‐associated ovarian cancer patients by comparing them to CNVs present in sporadic ovarian cancer patients. Germline CNVs in 51 BRCA1‐associated, 33 sporadic ovarian cancer patients, and 47 healthy women were analyzed by both signal intensity and genotyping data using the Affymetrix Genome‐Wide Human SNP Array 6.0. The total number of CNVs per genome was greater in the sporadic group (median 26, range 12–34) than in the BRCA1 group (median 21, range 11–35; post hoc P < 0.05) or normal group (median 20, range 7–32; post hoc P < 0.05). While the number of amplifications per genome was higher in the sporadic group (median 13, range 7–26) than in the BRCA1 group (median 8, range 3–23; post hoc P < 0.001), the number of deletions per genome was higher in the BRCA1 group (median 12, range 6–24) than in the sporadic group (median 9, range 3–17; post hoc P < 0.01). In addition, 31 previously unknown CNV regions were present specifically in the BRCA1 group. When we performed pathway analysis on the 241 overlapping genes mapped to these novel CNV regions, the ‘purine metabolism’ and ‘14‐3‐3‐mediated signaling’ pathways were over‐represented (Fishers exact test, P < 0.01). Our study shows that there are qualitative differences in genomic CNV profiles between BRCA1‐associated and sporadic ovarian cancer patients. Further studies are necessary to clarify the significance of the genomic CNV profile unique to BRCA1‐associated ovarian cancer patients.

Fas ligand expression in cervical adenocarcinoma: Relevance to lymph node metastasis and tumor progression

OBJECTIVE Adenocarcinoma of the cervix carries a worse prognosis than its squamous counterpart. In particular, tumors with lymph node metastasis have a miserably poor prognosis. Fas ligand (FasL) could allow the tumor cells to evade host immune surveillance and would thus promote tumor survival and possibly metastasis formation. We decided to compare FasL expression in cervical adenocarcinoma with lymph node status to determine whether FasL plays a role in lymph node metastases. METHODS Using immunohistochemistry, we investigated FasL expression in sections of formalin-fixed, paraffin-embedded tissue from 24 cervical adenocarcinomas. We also studied sections of seven cases with lymph node metastases. The percentage of FasL-positive cells in each tumor was recorded. FasL expression in cervical adenocarcinoma was compared with lymph node status. Statistical analysis was performed by using the Fisher exact test and the Kaplan-Meier method. RESULTS FasL expression was detected in 62.5% (15 of 24) of primary lesions. Significantly higher incidence of positive FasL reactivity was demonstrated in 10 of 11 tumors with lymph-vascular space (P = 0.0188), in 10 of 10 with deep stromal invasion (P = 0.0015), and in 8 of 9 cancers with lymph node metastasis (P = 0.0481). All 9 metastatic cervical adenocarcinoma in the lymph nodes showed FasL immunoreactivity in 60.7 +/- 17.7% of the metastatic cancer cells, and 7 (78%) of these had FasL immunoreactivity in greater than 50% of the cells. The survival times of patients with FasL-expressing cervical adenocarcinomas were significantly reduced compared to patients with low FasL-expressing tumors (P = 0.0018). CONCLUSIONS These findings indicate that FasL plays an important role in immune evasion, and progression and metastasis of cervical adenocarcinoma.

Heparanase expression and angiogenesis in endometrial cancer.

Human heparanase has been shown to function in tumor progression, metastatic spread, and tumor angiogenesis. The aim of the present study was to assess heparanase expression in endometrial cancer in correlation with neovascularization and clinicopathological factors. Forty endometrial cancers were obtained from previously untreated patients (median age 55.5, range 33–78 years). The expression of heparanase mRNA was evaluated using a semiquantitative reverse transcriptase-polymerase chain reaction. Tumor angiogenesis was assessed using microvessel counting. The Mann-Whitney U test, one-factor ANOVA test, and Spearman’s test were used to determine the relationship between heparanase expression, microvessel density, and clinicopathological parameters. The expression of heparanase mRNA was detected in 20 of 40 (50%) endometrial cancers, and was significantly correlated with FIGO stage IIIc (p = 0.0075), the presence of lymph-vascular space involvement (p = 0.0041), lymph node metastasis (p = 0.0049), and histological tumor grade (p = 0.0030). Microvessel density was also associated with FIGO stage IIIc (p = 0.027), the presence of lymph-vascular space involvement (p = 0.001), lymph node metastasis (p = 0.038), ovarian metastasis (p = 0.030) and histological tumor grade (p = 0.0030). Moreover, we found a strong positive correlation between heparanase expression and microvessel density (r2 = 0.475, p = 0.0001). These results suggest that the expression of heparanase may influence different malignant behaviors in endometrial cancer.

Elevated serum CA125 and CA19-9 due to the spontaneous rupture of ovarian endometrioma

A 23-year-old woman was suffered from ruptured ovarian endometrioma with an elevated CA125 and CA19-9 concentration; 9537 and 15,653IU/ml, respectively. Rapid decrease in serum CA125 and CA19-9 was recognized before surgery. Such high levels of both antigens have not been reported in a patient with endometriosis.

Prognostic factors and failure pattern in lymph node-negative stage IB and II cervical carcinoma treated with radical hysterectomy and postoperative irradiation.

The aim was to determine the prognostic factors and recurrence pattern in stages IB and II cervical carcinoma patients with negative pelvic lymph nodes. 224 patients with stages IB and II cervical carcinoma underwent radical hysterectomy (RH) from 1982 through 1995. Of 161 patients with negative lymph nodes, 65 patients received postoperative irradiation (RT) and 96 patients were given no further therapy according to surgical pathological findings. The overall 5-year disease-free survival was 94.1%. Two of 96 RH patients (2%) and 10 of 65 RH + RT patients (15%) had recurrence in pelvic and distant sites almost equally. Multivariate analysis revealed deep cervical invasion as the only independent prognostic factor. The 5-year disease-free survival was 98.8% for patients with shallow invasion and 85.8% for patients with deep invasion (p < 0.0001). It is worthwhile to develop new strategies for the lymph node-negative patients with deep stromal invasion.

Failure of High-Dose Chemotherapy with Peripheral Blood Stem Cell Support for Refractory Placental Site Trophoblastic Tumor

Placental site trophoblastic tumor (PSTT) is a rare form of gestational trophoblastic disease. The metastatic and refractory cases have a very poor prognosis. To our knowledge, this is the first report of the application of high-dose chemotherapy with autologous peripheral blood stem cell transplantation (PBSCT) for the treatment of refractory metastatic PSTT. A 36-year-old woman had a metastatic PSTT refractory to several lines of chemotherapy. She was treated with high dose of carboplatin and etoposide with autologous PBSCT. She showed only a temporary response to high-dose chemotherapy with PBSCT support and died of disease.

Case Report: An Exaggerated Placental Site with a Cervical Pregnancy

An exaggerated placental site (EXPS) is an exuberant nonneoplastic proliferation of the intermediate trophoblast at the implantation site. We had a case of an EXPS with a cervical pregnancy. We report on this case, including the patients clinical course and immunohistological findings.

Observations of High Iron Diamine-Alcian Blue Stain in Uterine Cervical Glandular Lesions

We studied epithelial glycoproteins in uterine cervical lesions, including glandular lesions, and investigated whether a more accurate diagnosis could be obtained using high iron diamine-alcian blue (HID-AB) stain and immunostaining with carcinoembryonic antigen (CEA). In addition, we examined the usefulness of preoperative diagnosis using biopsy specimens stained with HID-AB and CEA. Normal endocervical glands showed a predominance of sulfomucin, while adenocarcinoma predominantly showed sialomucin. CEA was highly detected in adenocarcinoma, but not in normal endocervix or in glandular dysplasia, suggesting that this stain has high specificity. The staining patterns of biopsy specimens and hysterectomy specimens were similar. Therefore HID-AB stain and CEA stain may be useful as a supplementary means of diagnosing uterine cervical lesions.

Dysgerminoma with a Slightly Elevated α-Fetoprotein Level Diagnosed as a Mixed Germ Cell Tumor after Recurrence

A pure dysgerminoma shows a normal serum α-fetoprotein level, and mixed germ cell tumors containing endodermal sinus tumor elements have elevated serum α-fetoprotein levels, ranging from >100 to far higher than 1,000 ng/ml. A 40-year-old woman was diagnosed as having a stage Ia pure dysgerminoma with a slight α-fetoprotein elevation (11 ng/ml), after a staging laparotomy, because we could not find any yolk sac element in the original tumor. After 44 months, she had a pelvic recurrent tumor with a significant elevation of the serum α-fetoprotein concentration (1,520 ng/ml); histological examination of a needle biopsy specimen revealed a typical yolk sac tumor. Eventually, her initial tumor was diagnosed as a mixed germ cell tumor. The patient was successfully treated with seven courses of chemotherapy and has been disease free for 22 months. It is necessary to be aware of the possibility of a mixed germ cell tumor containing a yolk sac element, even when the α-fetoprotein level is only slightly elevated.