Steroid sulphatase and oestrogen sulphotransferase in human non-small-cell lung carcinoma.

BACKGROUND: Steroid sulphatase (STS) is one of the steroid-metabolising enzymes involved in desulphating inactive steroid sulphates and oestrogen sulphotransferase (EST) sulphates active oestrogen. The roles of both STS and EST have not been examined in oestrogen-dependent non-small-cell lung cancer (NSCLC). METHODS: We evaluated the immunoreactivity of STS and EST in NSCLC cases using immunohistochemistry. The function of STS and EST was further demonstrated using NSCLC cell lines. RESULTS: The immunoreactivity of STS and EST was detected in 49.5% and 27.8% of NSCLC cases, respectively. The immunoreactivity of STS was significantly higher in female adenocarcinoma cases. The STS-positive NSCLCs were also significantly correlated in an inversed manner with tumour size and cell proliferation and tended to be associated with better clinical outcome. However, the immunoreactivity of EST was significantly correlated with intracellular oestradiol concentration. Results of in vitro analysis demonstrated that oestrone sulphate (E1-S) induced and pregnenolone sulphate (Preg-S) inhibited the proliferation in STS-expressing cell lines. The inhibition by Preg-S was reversed by a specific progesterone receptor blocker. Simultaneous addition of E1-S and Preg-S significantly suppressed the proliferation. CONCLUSION: In NSCLC patients, STS is considered a good prognostic factor. Results of our present study also indicated the benefits of potential progesterone therapy for NSCLC patients.

Immunohistochemical analysis of gastrin-releasing peptide receptor (GRPR) and possible regulation by estrogen receptor ßcx in human prostate carcinoma.

Gastrin-releasing peptide (GRP) belongs to the family of bombesin-like peptides. GRP was demonstrated to stimulate the proliferation and invasiveness of androgen-independent prostate carcinoma. GRP mediates its action through the membrane-bound receptor, GRP receptor (GRPR), which is characterized by a high-affinity binding for both GRP and bombesin. In human prostate cancer tissue, GRPR mRNA was reported to be detectable in more than 90% but its immunolocalizaition has not been reported. Therefore, in this study we immunolocalized GRPR in 51 human prostate cancer cases and correlated the findings with several clinicopathological parameters in order to better understand the function and regulation of GRPR in human prostate cancer. GRPR was immnolocalized in carcinoma cells and their values were significantly associated with Gleason score and immunoreactivity of estrogen receptor ßcx (ERßcx) that is one of splicing variants of ligand dependent transcription factor, ERß, and considered to be prognostic factor of prostate cancer patients. The amounts of GRPR and ERßcx mRNA in three prostate cancer cell lines PC-3, DU-145 and LNCaP evaluated by quantitative RT-PCR (qPCR) analysis were also significantly correlated. In addition, we established stable transformants of prostate carcinoma cell line PC-3 introduced with ERßcx, and confirmed that GRPR mRNA was induced in ERßcx over-expressing PC-3 cells by qPCR analysis. These results also suggest that ERßcx contributes to prostate cancer development possibly through mediating GRPR expression in carcinoma cells.

Vaginal tumors with histologic and immunocytochemical feature of gastrointestinal stromal tumor: two cases and review of the literature.

Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the gastrointestinal tract (GI). Although positive immunohistochemistry for c-kit protein (CD117) and CD34 is critical in establishing diagnosis, the clinicopathologic features of CD117-positive mesenchymal tumors without obvious connection to the GI tract are not well documented. We describe the clinicopathologic features of two cases of extra-GIST. Case 1 was a 42-year-old woman who presented with a submucosal tumor located in the posterior vaginal wall. Case 2 was a 66-year-old woman who presented with a mass that bulged from the right side of the middle vaginal wall. Both tumors were excised locally. The results of microscopic examination and immunohistochemistry for both cases indicated the diagnosis of GIST. Case 2, in addition, showed oncogenic mutation in KIT exon 11. Case 1 is healthy without evidence of recurrence 4 years after surgery. Case 2 started imatinib therapy after resection of a recurrent mass. Gynecologists as well as diagnostic pathologists should be aware of GIST manifesting as a vaginal mass. Recognition of microscopic patterns and characteristic immunohistochemical phenotype, plus genetic study, is mandatory for establishing the correct diagnosis of GIST.

Paclitaxel-platinum combination chemotherapy for advanced or recurrent ovarian clear cell adenocarcinoma: a multicenter trial.

The therapeutic effect of a combination of paclitaxel (PTX) and platinum (PLT) in ovarian clear cell adenocarcinoma (CC) patients with measurable disease has yet to be elucidated. In this study, we used retrospective review to evaluate the results of treatment with a combination of PTX and PLT in CC patients with measurable disease. A total of 28 patients with measurable residual CC (15 cases with primary disease, 13 cases with recurrent disease) treated with combination PTX-PLT chemotherapy was identified through medical records from ten institutions. Clinical response to chemotherapy was evaluated using Response Evaluation Criteria in Solid Tumors criteria. Of the 28 cases, 8 of 15 patients with primary disease (53.3%) and 3 of 13 patients with recurrent disease (23.1%) responded to PTX-PLT chemotherapy. The response rate for cases with late recurrent disease (>12 months) was 20% (1/5), whereas the rate was 25% (2/8) for cases with early recurrent (<12 months) or refractory disease. Our results indicate that the combination of PTX and PLT may have greater efficacy against CC than conventional PLT-based chemotherapy that does not include PTX.

Primary ependymoma of the ovary: a case report and literature review.

Ependymoma is a glioma with differentiation toward ependymal cells that usually arises in the central nervous system. Ovarian ependymoma is extremely rare, and the treatment strategies for this disease have not been established. This is the first report of a patient with advanced ovarian ependymoma who received fertility-sparing surgery and is now alive without disease. A 23-year-old Japanese woman, gravida 0, presented with a chief complaint of lower abdominal distension and weight loss. She underwent left salpingo-oophorectomy for suspected ovarian cancer. Microscopic examination revealed a highly cellular tumor composed of small cells with hyperchromatic, round-to-oval nuclei and scanty cytoplasm. Perivascular pseudorosettes, ependymal rosettes, and extensive necrosis were observed. After thorough pathologic examination, she was diagnosed as having stage IIIC ovarian ependymoma. Postoperatively, she received adjuvant chemotherapy and underwent secondary cytoreductive surgery that preserved the uterus and right ovary. Her menstrual cycle has resumed, and she is alive without evidence of disease 16 months after the start of treatment. Although rare, primary ovarian ependymoma must be kept in mind in the differential diagnosis of ovarian tumors, especially in young women. Administration of etoposide-based chemotherapy along with cytoreductive surgery is a potential standard treatment for advanced ovarian ependymoma.

Small cell carcinoma of the endometrium: report of three cases and literature review.

BACKGROUND: Small cell carcinoma of the endometrium is extremely rare. Aim. We reported three cases of this rare tumor and reviewed the literature. CASES: Case 1 was a 54-year-old woman and case 3 was a 58-year-old woman. Both patients presented with vaginal bleeding. Case 2, a 53-year-old woman, had no symptoms and had a vaginal-cervical smear suspicious for malignancy. All patients underwent surgery and their tumors originated in the endometrium. In all three cases, pathological examination revealed small cell carcinoma of endometrium, and immunohistochemical reactivity for one or more neuroendocrine markers was found in all cases. Under electron microscopy in case 2 and case 3, dense core granules in the cytoplasm of tumor cells were found only in case 3. Case 3 was stage IIIA and died of her disease 12 months after surgery. Both cases 1 and 2 were stage IB and alive with no evidence of disease for 28 months and 9 years, respectively. CONCLUSION: Although the prognosis of small cell carcinoma of endometrium is poor, early detection of this disease may contribute to an improved prognosis.

Expression of EBAG9/RCAS1 is associated with advanced disease in human epithelial ovarian cancer.

Oestrogen receptor-binding fragment associated gene 9, EBAG9, is an oestrogen-responsive gene that was identified in MCF-7 human breast carcinoma cell line. It is identical to RCAS 1, a cancer cell surface antigen possibly involved in immune escape. In the present study, we examined the expression of EBAG9/RCAS1 in human epithelial ovarian cancer using immunohistochemistry, immunoblotting and reverse transcription-polymerase chain reaction (RT-PCR). A total of 90 epithelial ovarian cancer cases were examined immunohistochemically by means of the antibodies for EBAG9 and ERalpha. The correlation between EBAG9 immunoreactivity and clinicopathological parameters was examined. mRNA expression of EBAG9 and ERalpha were evaluated by RT-PCR in 22 cases. The expression for EBAG9 and ERalpha was examined by immunoblotting in 12 ovarian cancer cell lines. EBAG9 immunoreactivity was detected in the surface and cytoplasm of carcinoma cells in 46 out of 90 cases (51.1%). EBAG9 expression was significantly higher in serous histology (P=0.0402) and advanced disease (P=0.0206). No significant relationship was detected between EBAG9 immunoreactivity and overall survival (P=0.689). There was a highly significant correlation between EBAG9 and ER immunoreactivity (P<0.0001). The EBAG9 mRNA was detected in 20 out of 22 cases. In all of the cases that were positive for ERalpha mRNA, they were also positive for EBAG9 mRNA. Immunoreactive band corresponding to EBAG9 was detected in 11 out of 12 of ovarian cancer cell lines, and was consistent with ERalpha expression. In conclusion, the wide distribution of EBAG9 and its relation to advanced disease suggest that this protein may play important roles in epithelial ovarian cancer.

Expression of androgen receptor and 5alpha-reductase types 1 and 2 in early gestation fetal lung: a possible correlation with branching morphogenesis.

The bioactive and potent androgen 5alpha-dihydrotestosterone (DHT) has been postulated to be involved in the development of branching morphogenesis in the human fetal lung, but its expression has not been examined. We therefore examined the expression of the androgen receptor (AR) and 5alpha-reductases (type 1 and type 2), which catalyse the conversion of testosterone into DHT, in the human fetal lung using immunohistochemistry and reverse transcription-PCR (RT-PCR). Immunoreactive AR was detected predominantly in the nuclei of epithelial cells of the budding component of the early gestational fetal lung. 5alpha-Reductase type 1 immunoreactivity was detected in the cytoplasm of epithelial cells, whereas immunoreactivity for 5alpha-reductase type 2 was not detected in the samples of human fetal lung examined. RT-PCR also confirmed the presence of AR and 5alpha-reductase in all fetal lung and epithelial cell lines. The results of our present study suggest that DHT may play an important role in epithelial cells, which might include precursor cells, in which both AR and 5alpha-reductases are expressed during branching morphogenesis of the human fetal lung.

EBAG9/RCAS1 in human breast carcinoma: a possible factor in endocrine-immune interactions.

EBAG9 has been recently identified as an oestrogen responsive gene in MCF-7 human breast carcinoma cells. EBAG9 is identical to RCAS1, a cancer cell surface antigen possibly involved in immune escape. In this study, we examined the expression of EBAG9/RCAS1 in human breast carcinomas using immunohistochemistry and reverse transcription-polymerase chain reaction (RT-PCR). EBAG9 immunoreactivity was also associated with various clinicopathological parameters, including intratumoural infiltration of inflammatory cells, to examine the biological significance of EBAG9 in human breast carcinomas. EBAG9 immunoreactivity was detected in the entire surface and cytoplasm of carcinoma cells in 82 out of 91 invasive ductal carcinomas (90.1%). In non-neoplastic mammary glands, EBAG9 immunoreactivity was weakly present on the luminal surface of epithelial cells. Results from RT-PCR (n = 7) were consistent with those of immunohistochemistry. EBAG9 immunoreactivity was significantly associated with estrogen receptor (ER) alpha labelling index (P = 0.0081), and inversely associated with the degree of intratumoural infiltration of mononuclear cells (P = 0.0020), or CD3(+) T lymphocytes (P = 0.0025). This study suggests that EBAG9 is produced via ER in carcinoma cells and inhibits the intratumoural infiltration of T lymphocytes in the context of a possible endocrine-immune interaction in human breast carcinomas.

Expression of 5alpha-reductases in human epithelial ovarian cancer: its correlation with androgen receptor status.

Androgen metabolism and possible actions are considered to play some roles in human epithelial ovarian neoplasms, but the details have not been well studied. We have examined the expression of 5alpha-reductase type 1 and type 2, which catalyze the conversion of testosterone to more active androgen, 5alpha-dehydrotestosterone, and androgen receptor (AR), using immunohistochemistry (104 cases) and reverse transcription-polymerase chain reaction (RT-PCR) (16 cases) as a first step toward understanding the metabolism and possible actions of androgens in human common epithelial ovarian carcinoma. 5alpha-Reductase type 1 was immunopositive in 75 / 104 cases (72.0%), and 5alpha-reductase type 2 in 52 / 104 cases (50.0%) (P < 0.001). There was no significant correlation between patterns of immunolocalization and clinicopathological parameters examined. Median labeling index (LI) for AR was 17.8% (range 0 - 84.4%) which was significantly higher in serous carcinoma than other histological types (P < 0.001). There was a significant positive correlation between 5alpha-reductase type 1 immunoreactivity and AR LI (P = 0.0027), but no significant correlation was detected in 5alpha-reductase type 2. Results of RT-PCR analysis were also consistent with those of immunohistochemistry. The relatively wide distribution of 5alpha-reductase type 1, and its correlation to AR status in human epithelial ovarian malignancies suggest that this isozyme plays important roles in androgen metabolism and actions in these tumors.

Spatial and topological distribution of progesterone receptor A and B isoforms during human development.

Progesterone receptor (PR) is a member of the nuclear receptor superfamily. To date, two isoforms of PR have been identified, PR-A and PR-B. In progesterone responsive tissues, the relative ratio of PR-A and PR-B is considered to contribute to the tissue-specific actions of progesterone. In this study, we examined the distribution of PR-A and PR-B in human fetal tissues ranging from 11 to 40 gestational weeks using immunohistochemistry and RT-PCR analysis. PR immunoreactivity was detected in a wide range of fetal tissues until 20 weeks of gestation, but gradually decreased towards the late gestational period. However, PR continued to remain positive throughout the gestational period in the interstitial cells of Cajal and endocrine tissues. PR-B was demonstrated as the predominant isoform in comparison to PR-A in all fetal tissues examined. These findings suggest that progesterone may be involved in the development of fetal organs throughout the gestational period.

5alpha-reductases in human breast carcinoma: possible modulator of in situ androgenic actions.

The expression of 5alpha-reductase types 1 and 2 was examined in human breast carcinoma using immunohistochemistry and RT-PCR. Immunoreactivity for 5alpha-reductase isozymes was also correlated with various clinicopathological parameters to examine possible local regulatory mechanisms of sex steroids, including progesterone and androgens, in human breast carcinoma tissues. Immunoreactivity for 5alpha-reductase type 1 was detected in the cytoplasm and possibly in the nuclear membrane of tumor cells in 35 of 60 invasive ductal carcinomas (58%), and type 2 signal was detected in 9 of these 60 cases (15%). The results from RT-PCR (n = 8) were consistent with those from immunohistochemistry. A significant positive correlation was detected between 5alpha-reductase type 1 immunoreactivity and androgen and progesterone receptor A or B labeling indexes, and immunoreactivities of 5alpha-reductase type 2, 17beta-hydroxysteroid dehydrogenase type 5, or 3beta-hydroxysteroid dehydrogenase, which recognizes both types I and II. An inverse correlation was detected between 5alpha-reductase type 1 immunoreactivity and tumor size, histological grade, or Ki-67 labeling index. 5alpha-Reductase type 2 immunoreactivity was significantly correlated with 17beta-hydroxysteroid dehydrogenase type 5 immunoreactivity, but not with other parameters. This study suggests that 5alpha-reductase type 1 is mainly expressed in human breast carcinoma, which may play an important role in the in situ production and actions of the potent androgen, 5alpha-dihydrotestosterone, including inhibition of cancer cell proliferation, in hormone-dependent human breast carcinoma.

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.

Conization by harmonic scalpel for cervical intraepithelial neoplasia: a clinicopathological study.

The Harmonic Scalpel((R)) (HS) is a new surgical tool that cuts and coagulates by converting electrical energy into ultrasonic mechanical vibrations. The purpose of our study was to compare HS conization and the loop electrosurgical excision procedure (LEEP) for cervical intraepithelial neoplasia (CIN) with respect to both clinical and pathological features. Fifty-one consecutive women conservatively treated (29 with LEEP and 22 with HS conization) for CIN III were retrospectively reviewed. The background of the patients was similar. Operative time, intra- and postoperative blood loss were not significantly different. With HS conization all specimens were removed in one piece, but with LEEP the median number of specimens obtained per patient was 3.3 (p<0.0001) with a maximum of 5. The depth of thermal artifacts at the endocervical margin was significantly less with HS conization (0.20 mm) than with LEEP (0.30 mm; p = 0.0006). This new method produced an ideal-shaped specimen without increasing complications and thermal artifacts compared with LEEP.

Progesterone receptor isoforms A and B in human epithelial ovarian carcinoma: immunohistochemical and RT-PCR studies.

Human epithelial ovarian carcinoma is well-known as a sex steroid-dependent neoplasm, but the possible biological significance of progesterone receptor (PR) in this cancer remains controversial. Recently, two isoforms of human PR, PRA and PRB, have been characterized and different functional characteristics have been reported for these two isoforms. We therefore examined immunohistochemistry (107 cases) and reverse transcription-polymerase chain reaction (RT-PCR) (16 cases) for PRA, PRB, and oestrogen receptor-a (ER-a). Labeling indices (LI) for PRA and PRB were 2.4 and 43.6, respectively, and the difference was statistically significant. PRB LI, but not PRA LI, as well as performance status, stage, and residual tumour turned out to be independent prognostic factors following multivariate analysis. There was also a significant correlation between ER-a LI and PRB LI (r = 0.595, P < 0.0001), suggestive of a possible interaction between these two receptors. RT-PCR also detected the expression of PR isoform transcripts in the same pattern as was observed with immunohistochemistry. Results of these studies indicate that PRA and PRB both mediate distinct pathways of progesterone action in ovarian carcinoma. Moreover, it is important to examine PRB LI as a prognostic factor in the cases of human epithelial ovarian carcinoma.

Choroidal metastasis presented as the initial symptom of the recurrence from ovarian endometrioid adenocarcinoma: A case report.

Choroidal metastasis from recurrent ovarian cancer is extremely rare. To our knowledge, this report is the first such case of endometrioid adenocarcinoma. A 30-year-old pregnant woman presented to an ophthalmologist in January 1999 because of a rapid visual deterioration. Ophthalmologic evaluation revealed a metastatic choroidal tumor from ovarian cancer which had been diagnosed 10 years ago. After cesarean section, multiple metastases were found including the choroid, scalp, bone, and lung, and she received four courses of single agent carboplatin chemotherapy. She died of disease in July 1999. This case highlights the need to investigate the etiology of visual complaints in patients with a history of ovarian cancer even in the early stage.

Conization of the cervix using harmonic scalpel.

Conization, as a surgical treatment for cervical intraepithelial neoplasm (CIN), is a good method that preserves reproductive functions. Technological developments have introduced a wide variety of energy sources for surgical procedures. Traditional cold knife conization has been replaced by laser conization and by the loop electrosurgical excisional procedure (LEEP). However, laser conization and LEEP have some disadvantages. Laser conization requires expensive equipment. LEEP induces electrocautery artifacts and cannot excise the cervical tissue as a single-piece, because of the various extensions and depths of lesion, so that evaluation of the margins is sometimes not possible. Laser conization and LEEP both generate smoke. The presence of smoke is not only inconvenient, but also dangerous. Harmonic Scalpel (HS), ultrasonic cutting and coagulation system, is a new surgical tool that cuts and coagulates using ultrasonic mechanical vibrations. Eleven women with CIN III underwent conization using HS. HS eliminated the major disadvantages of electrosurgery and laser surgery. No complications during conization were observed. Postoperative hemorrhage was noted in only one patient. Histological diagnosis was not affected by heat or ultrasound. This surgical method using HS is characterized by negligible bleeding, a good visual field not obscured by smoke and resection of an ideal shape that fits the size of the lesion. It is concluded that this method overcomes most problems associated with conization using conventional methods.

Massive intraperitoneal hemorrhage and hypovolemic shock due to rupture of a coronary vessel of a uterine leiomyoma: a report of two cases.

Intraperitoneal hemorrhage due to uterine leiomyoma is extremely rare. Recently, we encountered such two cases and herein describe them. Case 1 involved a 34-year-old, nulliparous woman referred to our hospital because of a sudden onset of shock while she was playing a softball game. She had a large abdominal tumor and a hemoperitoneum, and was diagnosed as having a ruptured ovarian tumor. Exploratory laparotomy showed a rupture of the coronary vein of a large uterine leiomyoma. The patient was treated with myomectomy and did well postoperatively. Case 2 involved a 44-year-old, multiparous woman referred to our hospital because of sudden onset of lower abdominal pain while defecating. She had a uterine leiomyoma and a hemoperitoneum, and was diagnosed as having a ruptured splenic artery. Exploratory laparotomy showed rupture of the coronary artery of a uterine leiomyoma. The patient was treated with total abdominal hysterectomy and did well postoperatively. These cases suggest that intraperitoneal hemorrhage associated with uterine leiomyoma, although rare, should be considered in women with hypovolemic shock and a large pelvic mass.

Ovarian mixed germ cell tumor composed of dysgerminoma, endodermal sinus tumor, choriocarcinoma and mature teratoma in a 44-year-old woman: case report and literature review.

A case of ovarian mixed germ cell tumor in a 44-year-old woman was examined. The tumor was well circumscribed, measured 15 x 11 x 10 cm and appeared solid and partly cystic on the cut surface. Light microscopic examinations revealed that the tumor was composed of four different neoplastic germ cell elements, intermingled with each other. They are: (i) choriocarcinoma, immunohistochemically positive for human placental lactogen (hPL) and human chorionic gonadotropin (hCG); (ii) dysgerminoma, positive for placental alkaline phosphatase; (iii) endodermal sinus tumor positive for alpha-fetoprotein (AFP); and (iv) mature teratoma. Among these histological types, dysgerminoma occupied more than 50% of the neoplasm. The patient was diagnosed as a stage la ovarian mixed germ cell tumor and was subsequently treated with chemotherapy. A second-look laparotomy after completion of chemotherapy revealed no residual tumors in the abdomen and the patient is alive and well 15 months after operation. This is the fourth reported case of ovarian mixed germ cell tumor arising in patients over 40 years old.