Tadashi Hayasaka

Inhibition of inhibitor of nuclear factor-κB phosphorylation increases the efficacy of paclitaxel in in vitro and in vivo ovarian cancer models

We investigated whether inhibition of nuclear factor-κB (NFκB) increases the efficacy of paclitaxel in in vitro and in vivo ovarian cancer models. Treatment of paclitaxel-sensitive Caov-3 cells with paclitaxel transiently activated the phosphorylation of Akt, the phosphorylation of IκB kinase (IKK), and the phosphorylation of inhibitor of NFκB (IκBα). Paclitaxel also caused a transient increase in NFκB activity, followed by a decrease in NFκB activity. We show an association between Akt and IKK and show that the phosphorylation of IKK induced by paclitaxel is blocked by treatment with a phosphatidylinositol 3-kinase inhibitor (wortmannin or LY294002). Furthermore, interference of the Akt signaling cascade inhibits the transient induction of IκBα phosphorylation and NFκB activity by paclitaxel. Inhibition of NFκB activity by treatment with an IκBα phosphorylation inhibitor (BAY 11-7085) attenuated both basal and transient induction of IκBα phosphorylation by paclitaxel. Treatment with BAY 11-7085 also enhanced the inhibition of NFκB activity by paclitaxel for up to 24 hours. In addition, treatment with BAY 11-7085 decreased the viability of cells treated with paclitaxel. Moreover, treatment with BAY 11-7085 increased the efficacy of paclitaxel-induced inhibition of intraabdominal dissemination and production of ascites in athymic nude mice inoculated intraperitoneally with Caov-3 cells. These results suggest that paclitaxel transiently induces NFκB activity via the phosphatidylinositol 3-kinase/Akt cascade and that combination therapy with paclitaxel and an NFκB inhibitor would increase the therapeutic efficacy of paclitaxel.

Small cell neuroendocrine carcinomas of the uterine cervix: a histological, immunohistochemical, and molecular genetic study.

Small cell carcinomas of the uterine cervix are rare tumors with an aggressive behavior. Although these tumors can exhibit neuroendocrine differentiation, the criteria for neuroendocrine differentiation are subjective and not well defined. In this study, the authors tentatively defined small cell neuroendocrine carcinoma (SCNEC) as a tumor composed of small cells with at least two of the following: argyrophilic cytoplasm, chromogranin A immunoreactivity, and synaptophysin immunoreactivity. We found 10 cases fulfilling these requirements. Five of the 10 tumors were composed mainly of small (“oat”) cells and 5 of mainly larger “intermediate” cells. The majority of both subtypes showed an insular pattern. Three of the 10 SCNECs were pure, whereas the other seven were mixed with adenocarcinoma and/or squamous cell carcinoma or cervical intraepithelial neoplasia. In addition to the definitional markers noted earlier, the tumors were immunoreactive for serotonin (6 cases), somatostatin (5), gastrin (3), glucagon (1), and pancreatic polypeptide (1). No tumors were immunoreactive for cytokeratin 20. Human papillomavirus (HPV)-18 was detected in all of the pure tumors and both the SCNEC and adenocarcinomatous components in four of the mixed tumors. No other types of HPV were detected. The tumors showed a relatively low frequency of loss of heterozygosity for representative tumor suppressor gene sites; p53 mutations were found in only one case.

Mucin expression in nonneoplastic and neoplastic glandular epithelia of the uterine cervix.

Although it is well known that the uterine cervix contains mucin-producing glandular epithelium, only a few studies have described the changes in mucin that accompany malignant transformation. In this study the authors evaluated the characteristics of mucin expression in the normal endocervical epithelium and mucinous and endometrioid adenocarcinomas of the uterine cervix. The normal endocervical epithelium was characterized by predominant sulfomucin and MUC1 expression in all sites and MUC5AC expression in the surface epithelium, while MUC2 was not detected at all and pyloric gland type mucin (using antibody HIK1083) was detected in less than 1% of cases. Cervical adenocarcinomas, especially mucinous adenocarcinomas, showed marked variability in mucin expression that included mucins of pyloric gland and intestinal type.

Ovarian tumors with functioning stroma: a clinicopathologic study with special reference to serum estrogen level, stromal morphology, and aromatase expression.

Ovarian tumors with functioning stroma often show estrogenic manifestations. The range of serum estrogen level, however, has not been analyzed, nor the correlation with the stromal morphology. We reviewed the preoperative serum level of estradiol (E2) in 20 postmenopausal ovarian tumors that contained lutein- or theca-like cells in the stroma. Tumor histology included mucinous (n=7), endometrioid (n=4), clear (n=4), or Brenner tumor (n=2), carcinosarcoma (n=2), and Krukenberg tumor (n=1). Overall, the preoperative serum level of E2 ranged widely from 12.1 to 162.4 pg/mL (reference range, 10–30 pg/mL). The range of serum E2 was 24.9 to 162.4 pg/mL (mean, 58.0 pg/mL) in 7 tumors containing lutein-like cells, and 12.1 to 157.8 pg/mL (mean, 57.0 pg/mL) in 13 tumors containing theca-like cells alone. There was no significant difference in the serum E2 level between the 2 groups. To determine whether the functioning stroma is capable of final conversion of androgens to estrogens, the expression of P450 aromatase was examined immunohistochemically. P450 aromatase was exclusively expressed in the stromal cells, both lutein- and theca-like cells, in 16 tumors. In all tumors, however, it was focally or sparsely distributed, and there was no correlation between the immunoreactivity for P450 aromatase and the serum E2 level. These findings indicate that the functioning stroma, regardless of cell morphology, has a capacity for converting androgens to estrogens, but a significant amount of serum estrogens is finally qualified in the aromatase-rich peripheral tissues.

Intravenous Leiomyomatosis with Cardiac Extension

Intravenous leiomyomatosis with cardiac extension is an extremely rare uterine tumor. We report here a case of a patient with a uterine leiomyoma which extended into the right atrium through the left ovarian vein, progressing into the left renal vein along the inferior vena cava. Complete one-stage removal of the tumor was performed using cardiopulmonary bypass, and the patient has shown a favorable outcome. Successful therapy for intravenous leiomyomatosis is dependent on total surgical excision of the tumor, cessation of ovarian function and avoidance of postoperative estrogen replacement therapy.

Primary mucinous adenocarcinoma of the vagina: Possibility of differentiating from metastatic adenocarcinomas

Primary vaginal adenocarcinomas are rare neoplasms. Herein is reported a case of primary vaginal mucinous adenocarcinoma with an interesting mucin profile, presumably arising from a lesion of adenosis in a patient without in utero exposure to diethylstilbesterol (DES). The patient, a 44‐year‐old woman, had undergone vaginal total hysterectomy 10 years previously for myoma uteri corporis. The histological features of the vaginal intramural tumor found in this patient resembled those of mucinous adenocarcinoma of the endocervical type. Therefore, it was necessary to determine whether or not the tumor was metastatic from an occult cervical adenocarcinoma. However, the adenocarcinoma cells of the present case did not contain sulfomucin at all, being different from most mucinous adenocarcinoma cells of the endocervical type. Moreover, there were foci of adenosis adjacent to the adenocarcinoma foci, which also did not contain sulfomucin. These findings indicate that the mucinous adenocarcinoma arose from vaginal adenosis. Further studies are necessary to investigate whether lack of sulfomucin expression is a characteristic feature of vaginal adenosis.

Ovarian carcinoid exhibiting double function

A case of a 58‐year‐old woman with ovarian carcinoid exhibiting double function is reported. She had suffered from constipation and hirsutism before surgery. Pathological examination revealed that many carcinoid tumor cells were immunohistochemically positive for peptide YY, which inhibits intestinal motility and many peripheral steroid cells. After surgery the patient recovered from constipation immediately. Although the serum level of testosterone also immediately decreased, hirsutism remained for about 2 years. These clinical manifestations are considered to be due to peptide hormone‐producing tumor parenchymal cells and testosterone‐producing functioning stromal cells. This is the first report of clinically manifested double‐functioning ovarian carcinoid; one function is due to tumor cells themselves and another function is due to stromal cells.

Characteristic features of ovarian borderline tumors with invasive implant

Objective: Since ovarian borderline tumor with invasive implant behaves as carcinoma, it should be managed like carcinoma. Since its characteristic features have not been reported, its preoperative diagnosis was thought to be impossible. We evaluated the features of MRI and macroscopic appearance in two cases of ovarian borderline tumor with invasive implant. Methods: Borderline tumor with invasive implant was evaluated in two patients by MRI and macroscopic examination. Results: In these patients, MRI revealed profuse papillary projections. Although the lesion showed high signal intensity on contrast-enhanced T1-weighted images compared with that on T1-weighted ones, most of the signal intensity on T2-weighted images was high, suggesting that the lesion is an assembly of vesicles and an obvious solid part is absent. The macroscopic appearance of the tumor showed profuse papillary projections consisting of many vesicles perforating and extending far beyond the ovarian capsule, without a solid part. The histological findings indicated serous borderline tumors with invasive implant. Conclusion: In these two cases, we found the characteristic features of serous borderline tumor with invasive implant by MRI and macroscopic examination. Our findings may be of clinical value since the preoperative information about the possibility of invasive implant may be quite important for the management of borderline tumor with invasive implant, especially for young patients wishing to bear children.

Endometrioid adenocarcinoma with a functioning stroma

A case of a 70‐year‐old woman with endometrioid adenocarcinoma of the ovary with functioning stroma is presented. The symptom was postmenopausal bleeding. The preoperative level of serum estradiol was as high as 162.4 pg/mL, and serum gonadotropin levels were suppressed. The endometrial tissue showed hyperplastic changes. The surgical specimens consisted of a multilocular cystic ovarian tumor of 95 mm in diameter and an enlarged uterus. Histologically, the tumor was composed of proliferating, atypical, columnar cancer cells resembling early secretory endometrial cells, and condensation of plumed stromal cells resembling theca lutein cells. The diagnosis of endometrial adenocarcinoma of the ovary with functioning stroma was made. After surgery, the serum levels of estradiol decreased and of follicle‐stimulating hormone increased. Almost all types of ovarian tumor have been reported to be associated with endocrine abnormalities. Mucinous epithelial ovarian tumors most commonly present with estrogenic stroma, although the frequency of endometrioid adenocarcinoma with functioning stroma is very low. Here, a rare case with the patients clinical course and histopathologic findings is reported.