Epithelioid trophoblastic tumor of the uterus in a postmenopausal woman: a case report and review of the literature.

We report an epithelioid trophoblastic tumor (ETT), a recently delineated type of gestational trophoblastic tumor (GTT), discovered in the uterus of a 66-year-old woman. She had been treated for a hydatidiform mole 17 years previously without chemotherapy. The resected uterus contained a solid/cystic tumor located entirely within the myometrium. Microscopically, there was an epithelial-like growth pattern. The tumor was circumscribed, with a pushing border, and the tumor cells grew in cords, nests, and sheets within which were aggregates of hyaline material and necrotic debris. Most tumor cells were mononuclear and had an epithelioid appearance with distinct cell borders, eosinophilic cytoplasm, and nuclei with occasional indistinct nucleoli. Scattered multinucleated cells consistent with syncytiotrophoblastic cells were also present. Immunohistochemical staining revealed strong diffuse reactivity for cytokeratins (CK7, AE1/AE3, CAM 5.2, CK18) and epidermal growth factor receptor, and focal reactivity, mainly in syncytiotrophoblastic cells, for beta-human chorionic gonadotropin, human placental lactogen, and inhibin-alpha. The histologic and immunohistochemical features were characteristic of ETT, and helped to distinguish the tumor from other trophoblastic tumors and squamous cell carcinoma. An unusual observation was a high mitotic count, reflected in a Ki-67 proliferative index of 68.6%. Our findings indicate that ETT, like other types of GTT, can occur in postmenopausal women, even years after a gestational event.

An approach to analysis of large-scale correlations between genome changes and clinical endpoints in ovarian cancer.

This report describes analyses of associations of genome copy number abnormalities in ovarian cancers with clinical features using genome-wide graphical and analytical procedures. These studies show that tumor grade is a better indicator of the extent of genomic progression than stage, that loss of chromosome 4 occurs preferentially in high-grade tumors, and that gains of 3q26-qter, 8q24-qter, and 20q13-qter occur frequently in low-grade and low-stage tumors and thus may be early events in ovarian cancer development. In addition, loss of chromosome 16q24 and a total number of independent genome copy number aberrations >7 are associated with reduced survival duration. The association of loss of 16q24 (D16S3026) with decreased survival duration was confirmed by quantitative PCR. Regions that frequently are abnormal and associated with altered survival duration are strong candidates for higher resolution analysis and gene discovery and may be useful markers for prediction of clinical outcome.

Prediction of deep myometrial invasion in patients with endometrial cancer: clinical utility of contrast-enhanced MR imaging-a meta-analysis and Bayesian analysis.

PURPOSE: To determine if, in a patient with an endometrial cancer, in addition to the knowledge of tumor grade, preoperative magnetic resonance (MR) imaging findings contribute to treatment stratification and specialist referral. MATERIALS AND METHODS: By using a MEDLINE literature search and institutional pathology reports, pretest probabilities for myometrial invasion were correlated with tumor grade. Likelihood ratios (LRs) were obtained through summary receiver operating characteristics. RESULTS: The mean pretest probabilities of deep myometrial invasion were derived from seven articles (1,875 patients) and from 125 institutional pathology reports. LRs for the prediction of myometrial invasion with contrast-enhanced MR imaging were derived from nine studies (742 patients); positive and negative LRs were 10.11 and 0.1, respectively. The mean weighted pretest probabilities of deep myometrial invasion in patients with tumor grades 1, 2, or 3 were 13%, 35%, or 54%, respectively. Posttest probabilities of deep myometrial invasion for grades 1, 2, or 3 increased to 60%, 84%, or 92%, respectively, for positive and decreased to 1%, 5%, or 10%, respectively, for negative MR imaging findings. CONCLUSION: Use of contrast-enhanced MR imaging significantly affects the posttest probability of deep myometrial invasion in patients with all grades of endometrial cancer and could be used to select patients for specialist referral.

MR imaging of clear cell sarcoma (malignant melanoma of the soft parts): a multicenter correlative MRI-pathology study of 21 cases and literature review.

OBJECTIVE: To evaluate MR imaging and pathology findings in order to define the characteristic features of clear cell sarcoma of the soft tissues (malignant melanoma of the soft parts). DESIGN AND PATIENTS: MR examinations of 21 patients with histologically proven clear cell sarcoma of the musculoskeletal system were retrospectively reviewed and assessed for shape, homogeneity, delineation, signal intensities on T1- and T2-weighted images, contrast enhancement, relationship with adjacent fascia or tendon, secondary bone involvement, and intratumoral necrosis. In 19 cases the pathology findings were available for review and for a comparative MR-pathology study. RESULTS: On T1-weighted images, lesions were isointense (n=3), hypointense (n=7) or slightly hyperintense to muscle (n=11). Immunohistochemical examination was performed in 17 patients. All 17 specimens showed positivity for HMB-45 antibody. In nine of 11 lesions with slightly increased signal intensity on T1-weighted images, a correlative MR imaging-pathology study was possible. All nine were positive to HMB-45 antibody. CONCLUSIONS: Clear cell sarcoma of the musculoskeletal system often has a benign-looking appearance on MR images. In up to 52% of patients, this lesion with melanocytic differentiation has slightly increased signal intensity on T1-weighted images compared with muscle. As the presence of this relative higher signal intensity on T1-weighted images is rather specific for tumors displaying melanocytic differentiation, radiologists should familiarize themselves with this rare entity and include it in their differential diagnosis when confronted with a well-defined, homogeneous, strongly enhancing mass with slightly higher signal intensity compared with muscle on native T1-weighted images.

In vivo and in vitro ovarian carcinoma growth inhibition by a phosphatidylinositol 3-kinase inhibitor (LY294002).

Phosphatidylinositol 3-kinase (PI3-K) induces mitogenesis, cell growth, and cell transformation. Amplification of the gene encoding the P110alpha subunit likely is an important event in ovarian cancer progression, and PI3-K inhibitors are possible therapeutic agents for this disease. We evaluated effects of LY294002, a potent inhibitor of PI3-K, on growth of ovarian carcinoma in vivo and in vitro, and on ascites formation in vivo. Athymic mice were inoculated i.p. with the ovarian cancer cell line OVCAR-3. Seven days after inoculation, mice were treated with or without LY294002 (100 mg/kg of body weight) for 3 weeks. Body weight and abdominal circumference were measured twice weekly. At the end of the experiment, mice were sacrificed, ascites volume was measured, and tumors were excised. Mean tumor burden in the LY294002-treated group was reduced by approximately 65% versus controls. Virtually no ascites developed in the treatment group; mean volume of ascites in controls was 3.3 +/- 0.38 ml. OVCAR-3 cells also were cultured in vitro without and with LY294002 (1, 5, and 10 microM) for 24 h. The number of cells in 1, 5, and 10 microM LY294002-treated wells was reduced by 27, 56, and 75%, respectively, versus controls. In vivo and in vitro morphological studies demonstrated that LY294002 induced marked nuclear pyknosis and diminished cytoplasmic volume in the tumor cells, confirmed as apoptosis. Thus, LY294002 significantly inhibits growth and ascites formation of ovarian carcinoma in vivo and markedly inhibits ovarian cancer cell proliferation in vitro, suggesting an important role of PI3-K inhibitors as a potentially useful treatment for women with ovarian carcinoma.

Prostate cancer: localization with three-dimensional proton MR spectroscopic imaging--clinicopathologic study.

PURPOSE: To assess the efficacy of combined magnetic resonance (MR) imaging and three-dimensional (3D) proton MR spectroscopic imaging in the detection and localization of prostate cancer. MATERIALS AND METHODS: MR imaging and 3D MR spectroscopic imaging examinations were performed in 53 patients with biopsy-proved prostate cancer and subsequent radical prostatectomy with step-section histopathologic examination. The prostate was divided into sextants. At MR imaging, the presence or absence of cancer in the peripheral zone of each sextant was assessed independently by two readers (readers 1 and 2) unaware of the findings at 3D MR spectroscopic imaging and histopathologic examination. At 3D MR spectroscopic imaging, cancer was diagnosed as possible if the ratio of choline plus creatine to citrate exceeded 2 SD above population norms or as definite if that ratio exceeded 3 SDs above the norm. RESULTS: On the basis of sextants, sensitivity and specificity, respectively, for MR imaging were 77% and 61% (reader 1) and 81% and 46% (reader 2) with moderate interreader agreement (kappa = 0.43). The 3D MR spectroscopic imaging diagnosis of definite cancer had significantly higher specificity (75%, P < .05) but lower sensitivity (63%, P < .05). Receiver operating characteristic analysis showed significantly (P < .001) improved tumor localization for both readers when 3D MR spectroscopic imaging was added to MR imaging. High specificity (up to 91%) was obtained when combined MR imaging and 3D MR spectroscopic imaging indicated cancer, whereas high sensitivity (up to 95%) was obtained when either test alone indicated a positive result. CONCLUSION: The addition of 3D MR spectroscopic imaging to MR imaging provides better detection and localization of prostate cancer in a sextant of the prostate than does use of MR imaging alone.

Prostate cancer: prediction of extracapsular extension with endorectal MR imaging and three-dimensional proton MR spectroscopic imaging.

PURPOSE: To determine if the addition of three-dimensional (3D) proton magnetic resonance (MR) spectroscopic imaging to endorectal MR imaging helps diagnose extracapsular extension (ECE) of prostate cancer. MATERIALS AND METHODS: Endorectal MR imaging and 3D MR spectroscopic imaging were performed in 53 patients with prostate cancer before radical prostatectomy. MR imaging studies were evaluated by two independent readers unaware of histopathologic findings. The presence of ECE was graded on a five-point scale. At 3D MR spectroscopic imaging, cancer was diagnosed if the ratio of choline plus creatine to citrate was 2 or more SDs above normal. The accuracy of MR imaging alone was compared with that of combined MR imaging and 3D MR spectroscopic imaging, with use of the step-section histopathologic results as the standard of reference. RESULTS: For the less experienced reader, the addition of 3D MR spectroscopic imaging to MR imaging significantly improved accuracy (area under the receiver operating characteristic curve [Az] = 0.75 vs Az = 0.62, P < .05). For the more experienced reader, the addition improved accuracy but not significantly (Az = 0.86 vs Az = 0.78). The addition also reduced interobserver variability (Az = 0.86 vs Az = 0.75). CONCLUSION: The addition of 3D MR spectroscopic imaging to MR imaging improves accuracy for less experienced readers and reduces interobserver variability in the diagnosis of ECE of prostate cancer.

Importance of atypical glandular cells of uncertain significance in cervical cytologic smears.

OBJECTIVE: To determine the clinical implications of atypical glandular cells of uncertain significance (AGCUS) in cervical cytologic smears. STUDY DESIGN: Retrospective analysis. RESULTS: Eighty-eight of 32,181 (0.27%) cervical smears obtained during the study period contained AGCUS. Of the 47 women with AGCUS, 16 had intraepithelial or invasive neoplasms (34%; 95% confidence interval, 21-49%), including 9 low or high grade squamous intraepithelial lesions, 1 adenocarcinoma in situ of the cervix, 3 adenocarcinomas of the cervix, 2 adenocarcinomas of the endometrium and 1 adenoid basal cell carcinoma of the cervix. CONCLUSION: The high prevalence of cervical and endometrial neoplasia among women with the isolated finding of AGCUS on cervical cytologic smears warrants a thorough diagnostic evaluation.

Preoperative staging of cervical carcinoma: phased array coil fast spin-echo versus body coil spin-echo T2-weighted MR imaging.

OBJECTIVE: This study was performed to compare the diagnostic efficacy of MR imaging in the preoperative evaluation of invasive cervical cancer using the pelvic phased array coil in combination with fast spin-echo T2-weighted imaging and the body coil in combination with conventional spin-echo T2-weighted imaging. MATERIALS AND METHODS: Ninety-four women (22-68 years old) with invasive cervical cancer underwent MR imaging (at 1.5 T) using a body coil conventional spin-echo protocol (n = 62) or a phased array coil fast spin-echo protocol (n = 32). Imaging preceded surgery by no more than 5 weeks. MR images were evaluated for tumor size, local stage, and nodal metastasis using surgical pathology as the standard of reference. RESULTS: Overall staging accuracy for the body coil conventional spin-echo protocol (89%) was not significantly different from that of the phased array coil fast spin-echo protocol (91%). Both techniques also achieved similar accuracy in diagnosing parametrial invasion (95% versus 94%) and lymph node metastases (85% versus 91%) and in tumor sizing (correlation coefficient, .93 versus .94). CONCLUSION: In the preoperative staging of cervical carcinoma by MR imaging, both the newer (phased array coil fast spin-echo protocol) and the older (body coil conventional spin-echo protocol) techniques achieved similarly high accuracies in local staging, assessment of parametrial invasion, and evaluation of tumor size. Decreased imaging time and increased image resolution are advantages of the newer technique, although in our series they did not increase staging accuracy.

Chorionicity inaccurately predicted by early ultrasound: a case report.

Ultrasound has been found to be extremely accurate in diagnosing the chorionicity of multiple gestations. Prenatal counselling and/or planning for selective termination is most often based on the sonographic prediction of chorionicity. We present a case of triplet pregnancy in which early sonographic prediction of chorionicity did not match the pathological diagnosis at delivery.

Occult virilizing ovarian tumours in postmenopausal women: problems in evaluation with reference to a case.

A 53-year-old postmenopausal presented with hirsutism, acne, receding hairline, male-pattern baldness, and deepening of voice developing over the last five years. Her left ovary had been removed at the age of 38 years old for a benign cyst and vaginal hysterectomy was performed one year later for cervical carcinoma. She had taken premarin 0.625 mg daily since her surgeries. Initial hormonal studies revealed elevated serum concentrations of total testosterone 524 ng/dL (N: 6-86 ng/dL), free testosterone 20.9 pg/mL (N: 0.3-2.7 pg/mL), and 17-hydroxyprogesterone 270 ng/dL (N: < 70 ng/dL); but normal baseline concentrations of dehydroepiandrosterone-sulfate, androstenedione, and cortisol. Computed tomographic (CT) scans of the adrenals and ultrasonography of the pelvis were negative. Magnetic resonance imaging (MRI) of the abdomen and pelvis similarly were non-revealing. She was given glucocorticoids without effect. Subsequently, retrograde selective venous sampling showed a marked testosterone gradient in the right ovarian vein. A laparoscopic right oophorectomy was performed and a 11 mm Leydig cell tumour of hilus cell type was detected on histologic examination. Postoperative testosterone levels returned to normal and she had slow regression of hirsutism. Our case illustrates that a virilizing ovarian neoplasm can be small and elude imaging studies. We suggest bilateral oophorectomy for postmenopausal women with severe recent-onset virilization and without Cushing's syndrome and with normal adrenal imaging. This approach avoids unnecessary investigations and delays in definitive management.

Human umbilical vessels and cultured umbilical vein endothelial and smooth muscle cells lack detectable protein and mRNA encoding estrogen receptors.

OBJECTIVE: To identify and characterize estrogen receptors in human umbilical vascular tissues and in cultured cells derived from the human umbilical vein. METHODS: Human umbilical vein endothelial (HUVE) and human umbilical vein smooth muscle (HUVSM) cells were isolated. Immunohistochemical, radioligand binding. Western immunoblotting, and reverse transcription-polymerase chain reaction (RT-PCR) methods were used to detect estrogen receptors in vascular tissues and in cells derived from the umbilical cord. RESULTS: Estrogen receptor protein was not detected in either umbilical vessel tissue or in isolated HUVE or HUVSM cells. Messenger RNAs for the classic estrogen receptor (alpha) and estrogen receptor beta isoforms also were undetectable by RT-PCR. CONCLUSION: These findings suggest that the effects of estradiol observed in this widely used vascular model are mediated by very low concentrations of receptors that evade standard methods of detection. Alternatively, this steroid may affect umbilical vascular cells through mechanisms that do not involve the classic genomic estrogen-receptor pathway.

A decline in myometrial nitric oxide synthase expression is associated with labor and delivery.

The mechanisms that maintain relative uterine quiescence during pregnancy remain largely unknown. A possible role for nitric oxide has recently emerged, however, the expression of nitric oxide synthase within human myometrium at midgestation, a time when the uterus is normally quiescent, has not been investigated. The purpose of this study was to identify cell types in human myometrium that contain inducible nitric oxide synthase (iNOS), and to examine changes in its expression during pregnancy and labor. We found that iNOS is expressed in smooth muscle cells of pregnant myometrium. Expression of iNOS was highest in myometrium of preterm not-in-labor patients. At term, iNOS expression fell by 75%, and was barely detectable in preterm in-labor or term in-labor specimens. There was no staining in the myocytes of nonpregnant myometrium. Western blotting also revealed a similar pattern of changes in iNOS expression. In summary, iNOS expression in the myocytes of human myometrium is increased greatly during pregnancy, and declines towards term or with labor. Significantly, preterm inlabor patients also had a large decline in iNOS expression. These data suggest that changes in myometrial iNOS expression may participate in the regulation of uterine activity during human pregnancy.

Detection of extracapsular extension of prostate carcinoma with endorectal and phased-array coil MR imaging: multivariate feature analysis.

PURPOSE: To determine which magnetic resonance (MR) imaging features are most predictive of extracapsular extension of prostate carcinoma. MATERIALS AND METHODS: In 77 patients who had stage pT2 or pT3 prostate carcinoma, MR images were retrospectively reviewed by three readers with varying experience in interpretation of endorectal coil images of the prostate gland. MR imaging features assessed were broad tumor contact, smooth capsular bulge, irregular bulge, obliteration of the rectoprostatic angle, and asymmetry of the neurovascular bundle. Multivariate logistic regression analysis was performed to determine the relative value of each MR imaging feature. RESULTS: At multivariate analysis, obliteration of the rectoprostatic angle and asymmetry of the neurovascular bundle were most predictive of extracapsular extension, with a specificity of up to 95% and sensitivity of 38%. Poor-quality images reduced accuracy for all readers. The most experienced reader demonstrated overall accuracy of 77% in determination of extracapsular extension. CONCLUSION: Obliteration of the rectoprostatic angle and asymmetry of the neurovascular bundle were most indicative of extracapsular extension. Reader experience plays an important role in the ability to interpret prostate MR images and is an important contributor to interobserver variability.

Microglandular adenocarcinoma of the endometrium: a form of mucinous adenocarcinoma that may be confused with microglandular hyperplasia of the cervix.

Microglandular adenocarcinoma of the endometrium may cause diagnostic problems because of its bland cytologic appearance and its histologic similarity to benign microglandular hyperplasia of the cervix. We present two cases of microglandular adenocarcinoma and discuss the clinical, pathologic, and immunohistochemical findings. Both patients were postmenopausal women, one of whom was taking exogenous hormones. Endometrial biopsy specimens contained polypoid tissue fragments, within which were microcystic spaces lined by flattened, cuboidal, or columnar cells. Solid nests or sheets of tumor cells surrounded glands in some tissue fragments. The nuclei were uniform and bland, and mitotic figures, although readily identifiable, were infrequent (1 per 10 high-power fields). A majority of tumor cells contained intracytoplasmic mucin. Numerous neutrophils were present in gland lumens and tissues. Immunohistochemical stains for carcinoembryonic antigen and TAG72 (B72.3) revealed focal moderate to intense apical and cytoplasmic staining; immunostains for p53 protein were negative. One carcinoma was confined to the endometrium, whereas the other invaded into the inner one-third of the myometrium. Both patients were well after a limited follow-up of 1 year. Microglandular adenocarcinoma is a distinctive variant of endometrial carcinoma that is most likely a form of mucinous adenocarcinoma.

Bacillary angiomatosis of the cervix and vulva in a patient with AIDS.

BACKGROUND: Bacillary angiomatosis is a clinicopathologic entity that most often is identified in the skin of patients with AIDS. This report presents an example of bacillary angiomatosis of the female genital tract. CASE: Bacillary angiomatosis presented as red-purple nodules of the vulva and cervix in a 32-year-old woman with AIDS. Histologic examination revealed the lobular epithelioid vascular proliferation and hazy clumps of bacteria that characterize bacillary angiomatosis. The diagnosis was confirmed on Warthin-Starry-stained issue and by blood cultures, which were positive for Bartonella (Rochalimaea) henselae. CONCLUSION: Accurate diagnosis of this infection is important because 1) bacillary angiomatosis is commonly mistaken for Kaposi sarcoma, 2) it is effectively treated with inexpensive antibiotics, and 3) undiagnosed and/or untreated bacillary angiomatosis may lead to overwhelming disseminated infection and death.

Ovarian steroid regulation of vascular endothelial growth factor in the human endometrium: implications for angiogenesis during the menstrual cycle and in the pathogenesis of endometriosis.

The human endometrium undergoes a complex process of vascular and glandular proliferation, differentiation, and regeneration with each menstrual cycle in preparation for implantation. Vascular endothelial growth factor (VEGF) is an endothelial cell-specific angiogenic protein that appears to play an important role in both physiological and pathological neovascularization. To investigate whether VEGF may regulate human endometrial angiogenesis, we examined VEGF messenger ribonucleic acid (mRNA) and protein throughout the menstrual cycle and studied the regulation of VEGF by reproductive steroids in isolated human endometrial cells. By ribonuclease protection analysis, VEGF mRNA increased relative to early proliferative phase expression by 1.6-,2.0-, and 3.6-fold in midproliferative, late proliferative, and secretory endometrium, respectively. In histological sections, VEGF mRNA and protein were localized focally in glandular epithelial cells and more diffusely in surrounding stroma, with greatest VEGF expression in secretory endometrium. Consistent with these in vivo results, the treatment of isolated human endometrial cells with estradiol (E2), medroxyprogesterone acetate (MPA), or E2 plus MPA significantly increased VEGF mRNA expression over the control value by 3.1-, 2.8-, and 4.7-fold, respectively. The VEGF response to E2 was rapid, with steady state levels of VEGF mRNA reaching 85% maximum 1 h after the addition of steroid. E2 also caused a 46% increase in secreted VEGF protein, and the combination of E2 and MPA caused an 18% increase. VEGF expression in endometriosis, an angiogenesis-dependent, estrogen-sensitive disease was similar to that seen in eutopic endometrium. Peritoneal fluid concentrations of VEGF were significantly higher in women with moderate to severe endometriosis than in women with minimal to mild endometriosis or no disease. VEGF, therefore, may be important in both physiological and pathological angiogenesis of human endometrium, as it is an estrogen-responsive angiogenic factor that varies throughout the menstrual cycle and is elevated in women with endometriosis.

Postarthroplasty histiocytic lymphadenopathy in gynecologic oncology patients. A benign reactive process that clinically may be mistaken for cancer.

BACKGROUND: A distinctive histiocytosis occurs in the regional draining lymph nodes after large joint replacements, resulting in lymphadenopathy that may mimic cancer both grossly and microscopically. Postarthroplasty histiocytic lymphadenopathy has most often been observed in males during surgery for prostate cancer. METHODS: The authors present three examples of postarthroplasty histiocytic lymphadenopathy that occurred in gynecologic oncology patients. We studied the clinical, histologic, and immunohistochemical features of all three cases and the ultrastructure of one of them. RESULTS: Most involved lymph nodes were enlarged, but histiocytosis was also seen in normal sized lymph nodes. Microscopically, histiocytes with abundant granular cytoplasm were present in the lymph node parenchyma, and, to a lesser extent, in the sinuses. Normal lymph node architecture was variably effaced and the histiocytic infiltrate extended focally into the perinodal tissue. Small, black metal particles were present in the histiocytes in every case. Birefringent polyethylene particles were a prominent finding in all three cases as confirmed by positive modified oil red O staining, and, in one case, by electron microscopy. The histiocytes were strongly immunoreactive for CD68, but immunostains for S100 protein, MAC 387, and cytokeratin were negative. CONCLUSIONS: Enlargement of the lymph nodes in cancer patients who have had large joint replacements may be due to a benign histiocytosis rather than to metastatic cancer. The histologic features of the lymphadenopathy are distinctive and recognizable in routine histologic preparations. Polyethylene wear particles shed from joint prostheses are the most common substances in the histiocytes and are the most likely cause of the histiocytosis.

Serum concentrations of estradiol, progesterone, and levonorgestrel are not determinants of endometrial histology or abnormal bleeding in long-term Norplant implant users.

The objective of this study was to determine the relevance of serum estradiol, progesterone and levonorgestrel concentrations to endometrial histology and uterine bleeding associated with long-term Norplant implants use. Eighteen five-year users of Norplant implants had endometrial biopsies and determinations of serum estradiol, progesterone and levonorgestrel concentrations. Correlations among these factors and uterine bleeding were calculated. Proliferative endometrium (but not sex steroid levels) was associated with abnormal bleeding. Neither ovarian steroid nor levonorgestrel concentrations was a predictor of abnormal bleeding. Hyperplastic changes were not seen even with high estradiol and low levonorgestrel levels.

PIP: At the gynecologic clinic of San Francisco General Hospital in California, 18 women aged 27-44 who had used Norplant contraceptive implants for the full 5 years of effectiveness and who had at least 1 year of recurrent episodes of vaginal bleeding agreed to have an endometrial biopsy and a venipuncture for determination of serum estradiol, progesterone, and levonorgestrel levels. Investigators wanted to learn whether hormonal factors contributed to abnormal bleeding patterns in women who had used levonorgestrel-releasing contraceptive implants for 5 years. At the time of biopsy and venipuncture, 13 (72%) women had normal bleeding patterns. Two women had no apparent follicular activity. Six other women (44%) had a low estradiol level (i.e., 100 pg/ml). 14 women (77%) had no signs of luteal development (i.e., progesterone level 3 ng/ml). None of the women had hyperplastic endometrium. The endometrial index was used to describe endometrial histology and ranged from secretory to proliferated characteristics of the endometrium. It differed significantly between Norplant users with normal bleeding and those with abnormal bleeding (0.32 [a mixture of secretory and proliferative characteristics, but especially secretory characteristics] vs. 0.9 [close to full proliferation of the endometrium]; p 0.01). Serum estradiol, progesterone, and levonorgestrel levels were not significantly different between the two groups. These findings suggest that a proliferative endometrium, rather than sex steroid levels, was linked to abnormal bleeding. Thus, abnormal bleeding among long-term Norplant users is probably not a risk factor for developing endometrial cancer.

Vascular endothelial growth factor localization in human ovary and fallopian tubes: possible role in reproductive function and ovarian cyst formation.

Vascular endothelial growth factor (VEGF) is a potent angiogenic factor that also increases vascular permeability. We hypothesized that VEGF plays a role in the regulation of cyclic ovarian angiogenesis in women, and that its ability to increase vascular permeability may be an important factor in the production of fallopian tube effluent and fluid formation in ovarian cysts. To examine these hypotheses, we assessed VEGF expression in ovaries and fallopian tubes from premenopausal (n = 10) and postmenopausal (n = 4) women. Immunohistochemical analysis for VEGF was performed using a rabbit polyclonal antibody directed against human VEGF. In normal ovaries from premenopausal women, VEGF within healthy follicles was localized to the thecal cell layer, with minimal VEGF peptide detected in the granulosa cell layer. VEGF was not expressed in atretic follicles or a degenerating corpus luteum. However, intense VEGF immunostaining was observed within the highly vascularized corpora lutea in all specimens examined. In normal ovaries from postmenopausal women, VEGF was detected only in epithelial inclusion cysts and a serous cystadenoma. In specimens from both pre- and postmenopausal women, the luminal epithelium of the fallopian tube as well as smooth muscle cells and pericytes lining small and large blood vessels within the tube and hilum of the ovary exhibited specific staining for VEGF. Based on these data, we suggest that during reproductive life, VEGF plays a role in the growth and maintenance of the ovarian follicle and corpus luteum by mediating angiogenesis. In addition, VEGF within the fallopian tube luminal epithelium may increase vascular permeability and modulate tubal luminal secretions. Similarly, VEGF in the epithelial lining of benign ovarian neoplasms may contribute to fluid formation in ovarian cysts.