Uterine papillary serous carcinoma (UPSC) is an aggressive form of endometrial cancer, that has a dismal prognosis [1-3]. Since its etiology is virtually unknown, physicians and research scientists who battle this disease have tried to identify its precursor lesions in order to improve disease management through early detection.

Objective. The objective was to determine the role of cytology in the pretreatment evaluation of women with clinical findings consistent with ovarian cancer who are being considered for neoadjuvant chemotherapy. Methods. Pretreatment cytology slides were available for review from 60 of 72 consecutive patients treated with platinum-based neoadjuvant chemotherapy who were believed to have ovarian cancer based on clinical findings. Fifty of the 72 patients had evidence of both intraabdominal and extraabdominal tumor spread prior to treatment. Fifty-three of 66 patients had CA125 values >500 U/mL, 34 being >1500 U/mL. Pretreatment cytology was compared to surgical specimens obtained following chemotherapy. Results. Cytologic findings were consistent with ovarian cancer in 55 patients, not consistent with ovarian cancer in 4 cases, and insufficient for diagnosis in one case. Forty-seven of the 60 patients underwent surgery. Forty-two of 43 patients with cytology consistent with ovarian cancer had epithelial ovarian cancers at surgery. One had no pathologic evidence of disease. Three of the 4 patients thought not to have cytology consistent with ovarian cancer underwent surgery following neoadjuvant chemotherapy. Two had ovarian epithelial cancers and one had a mesonephric adenocarcinoma. The one patient with cytology insufficient for diagnosis also had an epithelial ovarian cancer at diagnosis. Conclusions. Cytology proved to be extremely helpful in supporting the clinical impression of an apparent advanced ovarian cancer. When the cytologic diagnosis does not match the clinical impression, communication between the cytologist or pathologist and the clinician is essential.

Background. Successful treatment of endometrial hyperplasia with progestins is commonly accompanied by the finding of an inactive or suppressed endometrium after therapy. However, approximately 30% of the endometrial hyperplasia cases do not respond to progestins and hyperplastic glands persist. The Fas/FasL system is known to play a role in tissue remodeling as a result of changes in menstrual hormone levels. The aims of this study are to examine Fas/FasL expression in endometrial hyperplasia of pre-and postprogestin treatment samples and to study the Fas/FasL regulation in vitro with Ishikawa cells after progestin stimulation. Design. Pre-and posttreatment paraffin-embedded endometrial hyperplasia tissue samples from 26 women were examined by immunohistochemistry for changes in Fas/FasL expression related to the administration of progestins. Among 26 patients, 18 were successfully treated with progestins and 8 failed treatment. Fas/ FasL positivity was defined by the presence of 10% or more immunoreactive epithelial cells in each specimen. In positive cases, a percentage or an immunoscore of immunoreactive cells was given by counting 500 cells. Cell viability was evaluated by the MTT assay. The in vitro effects of progesterone on Fas/FasL expression and apoptosis in Ishikawa cells were examined by using Western blot and TUNEL assays, respectively. Results. Fas immunoreactivity was present in 4/26 (15%) preprogestin cases with an average of 16% of the epithelial cells expressing Fas. FasL was expressed in 21/26 (80%) pretreatment cases with an average of 42% of the hyperplastic glandular cells being positive. In postprogestin cases, an increase of Fas expression (14/18, 77%) with an average of 47% stained cells was seen in responders (P<0.001), while FasL was found in 16/18 (89%) responders with an average of 65% of cells positive (P=0.587). In nonresponders, no significant changes in Fas/FasL expression were detected compared to pretreatment samples. With in vitro Ishikawa cells, a slight increase (10–20%) of Fas and FasL protein expression was detected after 24 h of progesterone treatment, but a more significant increase (220–343%) of both Fas and FasL expression was found after 48 h of withdrawing progesterone, which parallels apoptotic activity. Conclusions. The Fas/FasL system may be involved in the development of endometrial hyperplasia. Part of the molecular mechanisms of progestin therapy for endometrial hyperplasia is through upregulation of Fas/FasL expression. Dysregulation of Fas/FasL expression in hyperplastic endometrium may be part of the molecular mechanisms for nonresponders to progestin treatment. Intermittent, rather than continuous, progestin treatment may be more effective clinically for the treatment of endometrial hyperplasia.

Objectives. Loss of PTEN tumor suppressor gene function characterizes most (63%) endometrial precancerous lesions (endometrial intraepithelial neoplasia, EIN) and up to 83% of endometrioid endometrial cancers. Because systemic progestins are known to promote involution of precancerous endometrial lesions, we tested the hypothesis that this therapy preferentially leads to clearance of immunohistochemically detected PTEN-null endometrial glands in a variety of histopathologic settings. Methods. PTEN immunohistochemistry of pre and postprogestin-treated endometria was successfully performed on 17 women presenting with an intake endometrial biopsy diagnosis of "hyperplasia". Intake biopsies were rediagnosed using EIN criteria as 5 normal (proliferative or secretory), 4 anovulatory, 3 polyps, and 5 EIN endometria. The persistence of PTEN-null glands in progestin-treated patients was compared to that seen previously in rebiopsied normal proliferative endometrium of endogenously cycling premenopausal women. Results. Ten of 17 women prehormonal therapy had PTEN-null glands in the initial biopsy, and 90% (9/10) of these disappeared in the postprogestin sample. This contrasts with only 17% (2/12) involution in the endometria of normal cycling women (Fishers exact test P=0.002, Odds Ratio 45). Conclusions. We conclude that progestin therapy promotes involution, or disappearance, of PTEN-null endometrial glands relative to the persistence rate seen for normal cycling women. This effect occurs among PTEN-null glands having a variety of histopathologic presentations.

Objective. The aim of this study was to investigate the role of apoptosis during progestin therapy for the treatment of endometrial hyperplasia. Methods. Pre-and posttreatment paraffin-embedded endometrial tissue samples from 19 women with endometrial hyperplasia were examined for changes in glandular cellularity and apoptotic activity related to the administration of progestins. Twelve patients were successfully treated with progestin therapy and 7 patients failed treatment. Glandular cellularity was assessed based on calculating the average number of cells per gland obtained on histologic examination of hematoxylin and eosin stained tissue sections. Apoptotic activity was assessed on the same tissue sections by counting the average number of apoptotic cells per 10 high power fields (hpf) using the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling (TUNEL) assay. The effects of progesterone on apoptotic activity in a low-grade endometrial adenocarcinoma cell line (Ishikawa cells) was also examined using an ELISA cell death detection kit. Results. Glandular cellularity significantly decreased with progestin therapy in both treatment outcome groups. The reduction in cells per gland was significantly greater in the group of successfully treated cases compared to the treatment failures (P 5 0.005). However, within the successfully treated group, in situ detection of apoptotic cells using the TUNEL assay showed no statistical difference between pre-and posttreatment endometrial samples. Interestingly, a significant decrease in apoptosis was found in posttreatment samples of the group with persistent hyperplasia. The average number of apoptotic cells detected in 10 hpf was reduced from 7.9 prior to treatment to 3.1 after progestin therapy (P 5 0.03). In the progesterone-treated Ishikawa cell line, an increase in apoptotic activity started at 24 h, reached a peak at 48 h, and continued up to 72 h of hormone treatment. At 48 h, apoptotic activity was 42.6% greater than in the untreated control (P 5 0.04). By 72 h of progesterone treatment, apoptosis was 37.2% greater in the treated cells compared to the noninoculated cells (P 5 0.04). Conclusions. Progestin-induced apoptosis may occur during the early period of treatment for endometrial hyperplasia. Compared to the fully responsive group, persistent endometrial hyperplasia may have intrinsically different molecular mechanisms in response to progestin therapy.