Participation of the general gynecologist in surgical staging of endometrial cancer: analysis of cost and perioperative outcomes.

OBJECTIVE: To compare the cost and perioperative outcomes of endometrial cancer staging when the procedure is performed by a gynecologic oncologist alone or when a general gynecologist participates in the procedure. METHODS: A retrospective analysis was performed on a series of women with clinical stage I endometrial cancer treated at a single institution between 1/98 and 12/00. The patients were grouped according to the participation of a general gynecologist in their surgery. The 48 patients in Group 1 underwent surgery with a general gynecologist who consulted a gynecologic oncologist intraoperatively. Group 2 included 77 patients whose procedure was performed completely by a gynecologic oncologist. The two groups were compared with the chi-square, Fisher's exact, and Wilcoxon rank sum tests. Cost analysis included total hospital costs (room, pharmacy, and ancillary services) and total surgical costs (anesthesia, operating room, procedure, and perioperative physician evaluation costs). RESULTS: The groups did not differ in age, type of surgeries performed, distribution of surgical stage, proportion of patients undergoing lymph node sampling (LNS), and length of follow-up. When LNS was performed, Group 2 had a significantly shorter median operative time (170 vs. 180 min; P=0.05) and shorter total time in the operating room (204 vs. 224 min; P=0.02). This group had a lower procedure cost when considered both in terms of payor's cost ($1,414 vs. $2,134; P<0.0001) and physician charge ($7,106 vs. $11,116; P<0.0001). Perioperative physician evaluation was reduced by almost half ($685 vs. $424; P<0.0001) in Group 2. Group 2 had a savings in total surgical cost by payor's cost ($9,142 vs. 10,294; P=0.005) or physician's charge ($14,546 vs. $19,276; P<0.0001), and in combined hospital and surgical cost by payor's cost ($15,664 vs. $17,346; P=0.004) or physician charge ($21,311 vs. $26,328; P<0.0001). Total hospital costs, however, did not differ between groups. CONCLUSION: Operative time and costs increase when general gynecologists participate in the surgical procedure of patients with clinical stage I endometrial cancer. Although perioperative outcomes are similar, the involvement of two surgeons increases the length of the procedure as well as the cost of operating room time and physician reimbursement. The efficient use of limited health care resources must be considered as we plan the surgical approach to endometrial cancer.

Psychometric evaluation of the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity (Fact/GOG-Ntx) questionnaire for patients receiving systemic chemotherapy.

The purpose of this study was to validate the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity (FACT/GOG-Ntx) questionnaire. The FACT/GOG-Ntx is the FACT-G plus an eleven-item subscale (Ntx subscale) that evaluates symptoms and concerns associated specifically with chemotherapy-induced neuropathy. Two groups of women with ovarian cancer completed the FACT/GOG-Ntx: one group with known neurotoxicities and one group of chemotherapy-naive women newly diagnosed with ovarian cancer. Levels of patient neuropathy, severity of toxicity, and patient quality of life from diagnosis of ovarian cancer to 12 months post-diagnosis were assessed. The Ntx subscale significantly differentiated the two groups at baseline and 3- and 6-month follow-ups, demonstrating significantly fewer problems among chemotherapy-naive patients than among patients with known neuropathy. The FACT/GOG-Ntx is a reliable and valid instrument for assessing the impact of neuropathy on health-related quality of life. The Ntx subscale demonstrated sensitivity to meaningful clinical distinctions and change over time.

Evaluating the total costs of chemotherapy-induced toxicity: results from a pilot study with ovarian cancer patients.

PURPOSE: While chemotherapy-related toxicities affect cancer patients' activities of daily living and result in large expenditures of medical care for treatment, few studies have assessed the out-of-pocket and indirect costs incurred by patients who experience toxicity. The objective of this study was to evaluate the feasibility of obtaining detailed and comprehensive cost information from patients who experienced neutropenia, thrombocytopenia, or neurotoxicity during treatment. METHODS: Ovarian cancer patients who experienced chemotherapy-associated hematologic or neurologic toxicities were asked to record detailed information about hospitalization, laboratories, physician visits, phone calls, home visits, medication, medical devices, lost productivity, and caregivers. Resource estimates were converted into cost units, with direct medical cost estimates based on hospital cost-accounting data and indirect costs (i.e., productivity loss) on modified labor force, employment, and earnings data. RESULTS: Direct medical costs were highest for neutropenia (mean of $7,546/episode), intermediate for thrombocytopenia (mean of $3,268/episode), and lowest for neurotoxicity (mean of $688/episode). Indirect costs relating to patient and caregiver work loss and payments for caregiver support were substantial, accounting for $4,220, $3,834, and $4,282 for patients who developed neurotoxicity, neutropenia, and thrombocytopenia, respectively. The total costs of chemotherapy-related neurotoxicity, neutropenia, and thrombocytopenia were $4,908, $11,830, and $7,550. CONCLUSION: Our study has shown that, with the assistance of patients who are experiencing toxicity, estimation of the total costs of cancer-related toxicities is feasible. Indirect costs, while not included in prior estimates of the costs of toxicity studies, accounted for 34% to 86% of the total costs of cancer supportive care.

Protein kinase C alpha expression is inversely related to ER status in endometrial carcinoma: possible role in AP-1-mediated proliferation of ER-negative endometrial cancer.

OBJECTIVE: Tamoxifen is the most widely used antiestrogen to treat all stages of estrogen-receptor (ER)-positive breast cancers. However, tamoxifen acts as a partial estrogen in the uterus and is known to increase the risk of endometrial cancer by two- to threefold. Recent evidence indicates that there is a connection between tamoxifen resistance and activation of the activator protein-1 (AP-1) pathway. We have previously reported a possible role for overexpression of protein kinase C alpha (PKCalpha), an upstream activator of the AP-1 pathway, in hormone-independent breast cancer and antiestrogen-stimulated endometrial tumors. We hypothesize that alterations of the PKC isozyme profile of endometrial carcinomas are similar to that of hormone-independent breast cancer and determine whether specific PKC isozyme alterations correlated with known clinicopathological features of endometrial cancer. METHODS: The PKC isozyme profile of endometrial carcinomas from 42 patients who were not previously exposed to antiestrogens was examined by Western blot. The relationship between PKC isozyme expression and key prognostic factors for endometrial carcinoma including hormone receptor status, tumor grade, stage, size, and depth of myometrial invasion was examined using the Spearman's rho correlation coefficient. RESULTS: As previously found in breast cancers, PKCalpha and estrogen receptor alpha (ERalpha) expression are inversely related (r(s) = -0.35, P = 0.046). We report significant inverse correlations among ER/progesterone receptor (PR) expression and tumor grade (r(s) = -0.49, P = 0.001 and r(s) = -0.44, P = 0.004, respectively), ER, and depth of myometrial invasion (r(s) = -0.40, P = 0.009). There were no other significant correlations between PKC isozyme expression and other key prognostic factors examined. CONCLUSION: This study indicates that, similar to what was previously observed in breast cancer, PKCalpha and ER expression is inversely related in endometrial cancer. PKCalpha expression may be a useful prognostic indicator in endometrial cancers. A model is offered which describes the putative role of PKCalpha overexpression in activation of the AP-1 pathway and increased proliferation of ER negative endometrial cancers.

Workshop Report: Combining the staging system of the International Federation of Gynecology and Obstetrics with the scoring system of the World Heath Organization for Trophoblastic Neoplasia. Report of the Working Committee of the International Society for the Study of Trophoblastic Disease and the International Gynecologic Cancer Society.

During the past 5 years the International Society for the Study of Trophoblastic Disease and the International Gynecological Cancer Society have moved to modify the staging system for trophoblastic disease by combining the staging of the International Federation of Gynecology and Obstetrics (FIGO) with the scoring system of the World Health Organization (WHO). By making significant changes in both, the classification will be more acceptable worldwide leading to uniform use by physicians reporting management results in trophoblastic disease. This is the report of the Rome Workshop, which will be presented for ratification to the FIGO Staging Committee in September 2000.

Cost analysis of second-line therapies for platinum-refractory ovarian cancer: reimbursement dilemmas for Medicare patients.

Currently used options for salvage therapy for epithelial ovarian cancer include intravenously administered paclitaxel or topotecan and orally administered altretamine or etoposide. The response rates for these agents are similar (14-26%), whereas the type and incidence of adverse events differ. Under current legislation, Medicare will reimburse intravenous outpatient chemotherapy regimens only or oral regimens with a marketed intravenous formulation, despite that 89% of cancer patients prefer oral therapies. To compare the out-of-pocket costs and costs to the Medicare system, a cost minimization analysis of treatment with these agents was conducted using published phase II and phase III data. The total cost of treatment was $15,767 for paclitaxel, $18,635 for topotecan, $4477 for altretamine, and $5016 for etoposide. The out-of-pocket costs to the patient were $83, $37, $4477, and $6, respectively. Although a physician's first consideration in choosing a therapy is efficacy and toxicity, current Medicare reimbursement policies restrict patient options for cancer care. Because Medicare adopts managed care and health maintenance organizations into the management of patient care, cost effectiveness will likely become an important consideration in the treatment of cancer.

Oral contraceptive use and risk of gestational trophoblastic tumors.

BACKGROUND: Gestational trophoblastic disease refers to a spectrum of rare benign and malignant gynecologic disorders whose pathogenesis is not well understood. Recent studies from China and the United States have raised the hypothesis that long-term use of oral contraceptives before conception may increase the risk of gestational trophoblastic tumors. A multicenter case-control study of gestational trophoblastic tumors was undertaken to test this hypothesis. METHODS: Telephone interviews were conducted with 235 case patients, including 50 with gestational choriocarcinoma, and 413 control subjects matched on recentness of pregnancy, age at pregnancy, and area of residence. Relative risks (odds ratios) were computed by conditional logistic regression. Reported P values are two-sided. RESULTS: The relative risk estimate for ever having used oral contraceptives before the index pregnancy was 1.9 (95% confidence interval [CI] = 1.2-3.0), and the risk increased with duration of use (P for trend = .05). The estimate was highest for women who used oral contraceptives during the cycle in which they became pregnant (relative risk = 4.0; 95% CI=1.6-10), but there was no consistent pattern according to the time interval since last use. Separate analyses of choriocarcinoma and persistent mole yielded similar results, i.e., the relative risk estimates for oral contraceptive use were 2.2 (95% CI=0.8-6.4) and 1.8 (95% CI=1.0-3.0), respectively. Control for the number of sexual partners, which was independently associated with risk (P for trend = .05), did not materially change the results. CONCLUSIONS: This study, the largest to date, indicates that long duration of oral contraceptive use before conception increases the risk of gestational trophoblastic tumors. These findings may provide clues to the pathogenesis of this rare disease. Changes in use of oral contraceptives are not warranted, however, because the incidence attributable to oral contraceptive use is very low.

PIP: Recent studies in the US and China have suggested that long-term use of oral contraceptives (OCs) before conception increases the risk of gestational trophoblastic tumors. This association was investigated further in a study conducted at 8 US medical centers that specialize in the treatment of this gynecologic disorder. 235 cases, including 50 women with gestational choriocarcinoma, were matched with 413 controls on recentness of pregnancy, age at pregnancy, and area of residence. The relative risk estimate for ever-use of OCs before the index pregnancy was 1.9 (95% confidence interval [CI], 1.2-3.0) and the risk increased with duration of OC use. The relative risk was highest (4.0; 95% CI, 1.6-10.0) for women who used OCs during the cycle in which they became pregnant, but there was no consistent pattern according to the time interval since last OC use. The relative risks for choriocarcinoma and persistent mole associated with OC use were 2.2 (95% CI, 0.8-6.4) and 1.8 (95% CI, 1.0-3.0), respectively. This study, the largest to date, suggests that a long duration of OC use before conception does, indeed, increase the risk of gestational trophoblastic tumors.

The effect of reimbursement policies on the management of Medicare patients with refractory ovarian cancer.

Ovarian cancer patients who are covered by Medicare are faced with therapeutic decisions that require consideration of out-of-pocket costs for oral anticancer agents and complete reimbursement for more expensive intravenous and often more toxic medications. The response rates for oral agents such as altretamine or etoposide are similar to those for intravenous paclitaxel or topotecan (14% to 26%), but the economic considerations differ markedly. Under current legislation, Medicare will completely cover the costs for the two intravenous outpatient chemotherapy regimens, but does not provide any financial support for oral regimens that do not have associated injectable formulations. This is a matter of concern for patients, as 89% prefer oral therapies. We compared the out-of-pocket costs and costs to the Medicare system of oral and intravenous agents used for refractory ovarian cancer, using published phase II and phase III data. The total cost of treatment was $18,635 for topotecan, $15,767 for paclitaxel, $7,721 for etoposide, and $4,477 for altretamine. Conversely, out-of-pocket costs for Medicare patients without Medigap coverage were highest for altretamine, at the full cost of $4,477, whereas Medicare covered all but $83 for topotecan, $37 for paclitaxel, and $66 for etoposide. Current Medicare reimbursement policies may affect patient options for cancer care. These policies are changing and should continue to change as Medicare adopts more managed care strategies.

Ectopic pregnancy causing hemothorax managed by thoracoscopy and actinomycin D.

BACKGROUND: Most patients with extratubal ectopic pregnancies present with vaginal bleeding and lower abdominal pain. We report a case of an extratubal ectopic pregnancy with extra-abdominal manifestations. CASE: An ectopic pregnancy implanted on the diaphragm resulted in spontaneous hemothorax due to trophoblastic invasion into the pleura. Thoracoscopic excision followed by actinomycin D chemotherapy provided successful resolution of the ectopic pregnancy. CONCLUSION: Abdominal pregnancies may have bizarre clinical presentations.

Management of twin pregnancies consisting of a complete hydatidiform mole and normal fetus.

OBJECTIVE: To report the clinical features, management, and outcome of twin pregnancies consisting of a complete hydatidiform mole and a coexisting normal fetus. METHODS: Between 1966 and 1997, seven women with complete hydatidiform mole and coexisting normal fetus were treated at the John I. Brewer Trophoblastic Disease Center of Northwestern University Medical School. Clinical features, including presenting symptoms, gestational dates, hCG levels, and complications, as well as route of delivery or evacuation, pregnancy outcome, genetic analysis, and need for chemotherapy were assessed. RESULTS: Four women required uterine evacuation before 20 weeks' gestation because of vaginal bleeding or medical complications, one woman required an emergency hysterotomy because of hemorrhage at 24 weeks, and two women delivered normal, viable infants at 26 and 34 weeks. The pathologic diagnosis of complete hydatidiform mole was confirmed in each case and the chromosome complement was 46,XX in all molar gestations. Four of seven women required chemotherapy for treatment of nonmetastatic gestational trophoblastic tumors, including both women who delivered viable infants and two of the five women whose pregnancies were evacuated before 24 weeks' gestation. All four patients were treated with five to seven cycles of a 5-day methotrexate regimen and achieved complete remission. CONCLUSION: Patients with a twin pregnancy consisting of a complete mole and a normal fetus are at increased risk for hemorrhage and medical complications, as well as the development of persistent gestational trophoblastic tumor.

Management of high-risk gestational trophoblastic disease.

Multimodality therapy with combination chemotherapy employing etoposide, high-dose methotrexate, actinomycin D, cyclophosphamide and vincristine (EMA-CO), and adjuvant radiotherapy and surgery, when indicated, has resulted in cure rates of 80-90% in patients with high-risk metastatic gestational trophoblastic tumors. However, approximately 25-30% of high-risk patients will have an incomplete response to first-time chemotherapy or will relapse from remission. Most of these patients will have a clinicopathologic diagnosis of choriocarcinoma, metastases to sites other than the lung and vagina, more than eight metastases and/or failed inappropriate previous chemotherapy, resulting in very high World Health Organization scores. Salvage chemotherapy with cisplatin/etoposide, usually in conjunction with bleomycin or ifosfamide, as well as surgical resection of sites of resistant disease in selected patients, will result in a cure in most patients. New technology, such as the use of colony-stimulating factors to prevent treatment delays and dose reductions or high-dose chemotherapy with or without autologous bone marrow transplantation or peripheral blood stem cell support, may play an important role in the future management of patients who develop drug resistance.

Perceptions of cisplatin-related toxicity among ovarian cancer patients and gynecologic oncologists.

BACKGROUND: We conducted a pilot study to evaluate issues related to chemotherapy-induced toxicities by eliciting assessments of toxicity from women with advanced stage ovarian cancer and gynecologic oncologists. PATIENTS AND METHODS: Fifteen ovarian cancer patients and ten gynecologic oncologists completed the survey exercises. All patients surveyed had received at least six courses of a cisplatin-containing chemotherapy regimen. RESULTS: For both patients and physicians, there was good face validity to the utility exercise as assessments of health states with cisplatin were (1) consistently associated with less favorable assessments than the health state with no toxicity and (2) neurotoxicity was viewed less favorably than either ototoxicity or nephrotoxicity. While the 15 patients as a group viewed health states with toxicity more favorably than physicians (P < 0.05 for each toxicity), patient assessments varied, depending on individual experiences with cisplatin. Physician assessments of toxicity were most similar to those obtained from patients who had not experienced cisplatin toxicity and were less favorable than those elicited from patients who had experienced any toxicity. CONCLUSIONS: In deciding upon therapeutic strategies, women with advanced stage ovarian cancer and treating physicians markedly differ in their assessment of the impact of specific toxicities on quality of life.

Leiomyoma causing massive ascites, right pleural effusion and respiratory distress. A case report.

BACKGROUND: Pseudo-Meigs' syndrome, or atypical Meigs' syndrome, occurs when a pelvic mass other than an ovarian fibroma is present with hydrothorax and ascites. Leiomyomas rarely cause this condition. CASE: An otherwise healthy 31-year-old woman presented to the emergency department in acute respiratory distress with massive ascites, pleural effusion and a pedunculated leiomyoma. After receiving mechanical ventilation, she underwent myomectomy and recovered fully within four weeks. CONCLUSION: This unique presentation of pseudo-Meigs' syndrome should be included with malignancy in the differential diagnosis of a pelvic mass with ascites.

Hsp70 and Hsc70 are preferentially expressed in differentiated epithelial cells in normal human endometrium and ectocervix.

Two highly related 70K heat shock proteins, encoded by the hsc70 and hsp70 genes, are located in the nucleocytoplasmic compartment of mammalian cells. In contrast to recent cell lines, which express Hsp70 only when stressed, many human cell lines constitutively express Hsp70. The degree to which this reflects constitutive expression of Hsp70 in normal human tissues has not been extensively examined. In this study, we show by immunoblotting that human Hsp70 is constitutively expressed in the ovary, cervix, and endometrium and, by immunohistochemical analysis using Hsp70- and Hsc70-specific antibodies, that Hsp70 and Hsc70 are expressed in distinctive and predominantly overlapping patterns in the cervix and endometrium. In these two tissues, the highest levels of both proteins are seen in differentiated, non-proliferating epithelial cells, which is surprising in light of previous studies suggesting growth stimulation of hsp70 gene expression. These observations suggest the possibility that in certain human tissues, basal expression of the hsp70 and hsc70 genes is co-regulated.

Intrauterine device use and endometrial cancer risk.

BACKGROUND: Because intrauterine devices (IUD) invoke acute and chronic inflammatory responses in the endometrium, it is possible that prolonged insertion of an IUD could induce endometrial cancer. METHODS: We examined the relation between use of an IUD and endometrial cancer risk using data from a multicentre case-control study involving 405 endometrial cancer cases and 297 population controls. RESULTS: A total of 20 (4.9%) cases and 34 (11.4%) controls reported any use of an IUD. After adjustment for potential confounders, IUD use was not associated with an increased risk of endometrial cancer (RR = 0.56 for ever use; 95% CI: 0.3-1.0). Little reduction in risk was observed among women who last used an IUD within 10 years of the index date (RR = 0.84; 95% CI: 0.3-2.4) but risk was decreased among women who used an IUD in the more distant past (RR = 0.45; 95% CI: 0.2-1.0). Risk did not vary consistently with number of years of IUD use or with years since first use. Risk was not increased among women who used inert devices (RR = 0.46; 95% CI: 0.3-3.6) or those who used devices containing copper (RR = 1.08; 95% CI: 0.1-3.6). CONCLUSION: These data are reassuring in that they do not provide any evidence of an increased risk of endometrial cancer among women who have used IUD.

PIP: IUDs invoke acute and chronic inflammatory responses in the endometrium. The authors therefore explored whether the prolonged insertion of an IUD increases one's risk of developing endometrial cancer. The relation between the use of an IUD and endometrial cancer risk was examined using data from a multicenter case-control study involving 405 endometrial cancer cases and 297 population controls. 20 cases and 34 controls reported using an IUD. After adjusting for potential confounders, IUD use was not associated with an increased risk of endometrial cancer. A small reduction in risk was observed among women who last used an IUD within 10 years of the index date, with the risk further reduced among women who last used an IUD more than 10 years ago. Risk did not vary consistently with the number of years of IUD use or with years since first use. Furthermore, the level of risk was not increased among women who used inert devices or those who used copper-containing devices.

Ovarian carcinoma metastatic to the choroid of the eye.

A case of papillary serous ovarian adenocarcinoma with choroidal metastasis to the eye is reported. Central nervous system metastasis of any kind is rare from this tumor, and only three cases of choroidal metastases have been reported to date. A 67-year-old women presented 2 years after diagnosis of Stage IIIC papillary serous ovarian adenocarcinoma with complaints of a "teardrop"-shaped visual field defect in her right eye. Fundoscopic examination revealed metastasis to the superior-temporal right choroid. No coexisting sites of recurrence were discovered. This case highlights the need to thoroughly and promptly investigate the etiology of visual field complaints in patients with a history of ovarian cancer.

Endometrial adenocarcinoma metastatic to the scalp: case report and literature review.

A rare case of scalp metastasis from endometrial adenocarcinoma, demonstrating the poor prognosis for these patients, is reported. A 56-year-old woman with FIGO Stage IC, Grade 1 endometrial adenocarcinoma presented 15 months after initial surgery and radiation therapy with a scalp metastasis. Metastatic evaluation revealed widespread extrapelvic disease. She did not respond to chemotherapy and died 3 months after recurrence. Her course typifies that of patients with other cutaneous metastases as described in the literature: disease noted elsewhere at the time of recurrence, poor response to therapy, and death within 6 months.

Ovarian carcinoma initially presenting as metastatic axillary lymphadenopathy.

BACKGROUND: Ovarian carcinoma usually presents at advanced stage due to diffuse intraabdominal disease. Presenting signs and symptoms often relate to the degree of intraabdominal spread. It is rare to have distant lymph node metastases, in conjunction with minimal intraabdominal disease, at initial presentation. CASE: A 78-year-old woman was noted to have an enlarged axillary lymph node on a routine, screening mammogram. Biopsy revealed metastatic adenocarcinoma, consistent with primary breast cancer. Physical examination, diagnostic mammogram, and magnetic resonance imaging of the breasts were normal. A pelvic computed tomography scan revealed a 7-cm complex, right adnexal mass. At exploratory laparotomy, there was minimal intraabdominal tumor burden; only a 6-cm right ovarian tumor and a single 1.0-cm nodule adherent to the bladder peritoneum were found. After optimal cytoreductive surgery, she received tamoxifen for presumed metastatic breast cancer. One year later, recurrent disease developed in the pelvis. After reexploration and excision of all gross pelvic disease, a revised diagnosis of recurrent ovarian cancer was made, and therapy was changed to carboplatin and paclitaxel chemotherapy. The patient is currently without evidence of disease. CONCLUSION: Ovarian carcinoma usually presents with signs and symptoms related to the tumor burden within the peritoneal cavity. The finding of isolated, distant metastatic lymphadenopathy with minimal intraabdominal disease is very unusual. Immunohistochemical tumor markers can help determine the origin of a metastatic adenocarcinoma when the clinical presentation is atypical.

Cytoplasmic localization of endothelial constitutive nitric oxide synthase in endometrial carcinomas.

BACKGROUND: Production of nitric oxide by nitric oxide synthase (NOS) has been implicated in numerous physiologic and pathophysiologic processes including mutagenesis. This study was designed to examine the expression of the endothelial constitutive isoform of NOS (ecNOS) in endometrial carcinomas. METHODS: Fifty endometrial carcinomas (42 endometrioid, 4 serous papillary, 2 clear cell, and 2 adenosquamous carcinomas) and 21 normal endometrial gland tissue specimens (5 cases of proliferative, 5 early secretory, 5 mid-secretory, and 5 late secretory and 1 menstrual phase endometrium), previously formalin fixed and paraffin embedded, were immunostained using a commercially available anti-ecNOS monoclonal antibody. Localization of ecNOS staining to the plasma membrane, cytoplasm and nuclei was graded with respect to overall staining intensity (0-3+ scale) and frequency (percentage of immunoreactive cells). RESULTS: Relatively little staining for ecNOS was localized to the plasma membrane in either normal or neoplastic tissues. Normal and hyperplastic endometrial glands demonstrated moderate cytoplasmic and weak nuclear staining in a small percentage of cells. While ecNOS expression was most prominent in epithelial cells, weak expression was also rarely noted in endometrial stroma, blood vessel walls, and endothelium. We found a broad range of ecNOS expression in endometrial carcinomas, predominantly localized to the cytoplasm and nuclei. No statistically significant difference in ecNOS staining frequency or intensity was found between different histologic subtypes of endometrial carcinomas. No apparent correlation was found between ecNOS expression and tumor stage, grade, extension to the lower uterine segment or cervix, nodal or distant metastases, recurrence, or final patient status among patients with endometrioid adenocarcinomas. Endometrioid tumors invading more than 1/2 of myometrial thickness (n = 18) had significantly higher cytoplasmic staining intensity than those tumors limited to the inner 1/2 of myometrium (n = 27; 2.0 vs. 1.3, p < 0.04). Furthermore, a trend toward shorter disease-free survival was noted with increased staining intensity and decreased staining frequency. CONCLUSIONS: Cytoplasmic and nuclear expression of ecNOS, which is primarily limited to the glandular elements of normal endometrium, is also found to be expressed in endometrial carcinoma. Increased ecNOS staining intensity and decreased frequency tends to correlate with decreased disease-free survival. Lastly, increased cytoplasmic ecNOS staining intensity correlates with increased myometrial invasion.

Mutations of the estrogen receptor in endometrial carcinoma: evidence of an association with high tumor grade.

The majority (60-70%) of endometrial cancers express estrogen receptor. Typically, estrogen-receptor-positive endometrial tumors are associated with a more favorable outcome. Despite this, there is often a discrepancy between estrogen receptor expression and clinical outcome of the disease. Although little is known about the exact role of the estrogen receptor in endometrial malignancies, in breast cancer, where such information is abundant, a number of mutations of the estrogen receptor have been identified. To investigate whether mutations of the estrogen receptor gene occur in endometrial cancers we performed single-stranded conformational polymorphism analysis (SSCP) on 35 human endometrial tumors. We detected four point mutations in three different patients. Interestingly, all the mutations were detected in patients who had aggressive endometrial tumors (grade 3). Although we found the incidence of mutations of the estrogen receptor to be low (8.5%) and thus unlikely to be associated with the majority of endometrial cancers, further investigation is needed to elucidate the role of aberrant estrogen receptor expression in the progression of endometrial malignancies.