Serum tetranectin and CA125 in endometrial adenocarcinoma.

BACKGROUND: CA125 and tetranectin (TN) are prognostic markers in ovarian cancer. This study examines the values of these markers in endometrial cancer. MATERIALS AND METHODS: TN and CA125 were determined preoperatively in 99 patients with primary endometrioid adenocarcinoma and evaluated in relation to tumor grade, stage and cancer survival. RESULTS: The CA125 levels correlated significantly with tumor stage. Dichotomized according to a cut-off level of 35 U/ml, CA125 significantly correlated with cancer death. Multivariate regression analysis of cancer survival time showed that CA125 > 35 U/ml was not an independent factor when stage was introduced. TN levels were within the normal range in all patients and did not show any association with tumor grade, stage or survival. CONCLUSIONS: The study confirmed the role of CA125 as a prognostic factor in endometrial cancer and may be of aid in pointing out patients at high risk, whereas tetranectin did not show any prognostic effect.

Multiple pregnancies with single intrauterine demise. Description of twenty-eight pregnancies.

METHODS: Retrospective study of multiple pregnancies and deliveries with single intrauterine demise, in a five years' study period. RESULTS: Of a total of 13,840 deliveries in the study period, 355 represented multiple pregnancies with two or more fetuses from conception: 310 twin pregnancies and 45 triplets or higher. Twenty-eight multiple pregnancies were complicated by single intrauterine death: in six cases (group A) as first trimester spontaneous fetal loss, in nine cases (group B) due to selective fetal reduction, and in thirteen pregnancies as spontaneous intrauterine demise occurring in the second or third trimester (group C). In group A, no specific cause of death was proven. In group C, four cases of death were caused by twin transfusion syndrome, three cases by severe intrauterine growth retardation, four cases by placental insufficiency, one case by placental abruption striking one of the twins, whereas the last death was undefined. In group A, mean gestational age at delivery was 33 completed weeks. In group C, five monochorionic pregnancies were delivered at median gestational age 30 weeks and seven dichorionic pregnancies at 34 weeks (the chorionicity was indefinite in one case). The neonatal complications of the forty-two live born babies included prematurity problems only, except for one case of congenital anemia in a transfusion syndrome donor twin. None of the mothers showed signs of intravascular coagulopathy. CONCLUSION: The main problem for the surviving twin was prematurity - not the sibling's death.

[Listeriosis in the third trimester of pregnancy]. / Listeriosis i tredje trimester-graviditet.

A case of fatal intrauterine listeriosis in the third trimester of pregnancy is described. The patient presented with preterm labour and was delivered by emergency caesarean section on suspicion of foetal distress. The child was stillborn. The diagnosis was based on specific histopathological findings in the foetus and the placenta.

[The prognostic significance of progesterone receptor level in endometrial cancer]. / Den prognostiske betydning af progesteronreceptorindhold ved endometriecancer.

Oestrogen receptor (ER) and progesterone receptor (PR) contents were determined by biochemical (dextran charcoal-coated (DCC) assay) and immunohistochemical (ICA) methods in biopsies from 145 primary endometrial adenocarcinomas. Correlations between receptor contents and cancer specific survival were examined in a multivariate analysis including histopathological characteristics. Median patient follow-up time was 67 months with 18 cancer deaths. "High" PR levels correlated significantly (p = 0.004) with survival, independently of stage risk group (stages Ia-Ib vs Ic-IV). Patient age and histological grade were prognostic factors in a univariate setting but these parameters were eliminated in the multivariate model. The association between PR contents and cancer survival suggests that determination of PR can be of importance in the evaluation of endometrial cancer.

The combination of p53 and age predict cancer specific death in advanced stage (FIGO Ic-IV) of endometrial carcinoma of endometrioid type. An immunohistochemical examination of growth fraction: Ki-67, MIB-1 and PC10; suppressor oncogene protein: p53; oncogene protein: p185 and age, hormone treatment, stage, and histologic grade.

OBJECTIVE: Early surgical stage (FIGO Ia + b) is an excellent predictor of survival in endometrial carcinoma of endometrioid type (EC), in contrast to advanced stage which only predict cancer specific death (CSD) in approximately 20-30% of the patients. The value of growth fraction, p53 and p185 as predictor of CSD in EC was studied. STUDY DESIGN: One hundred and eleven patients (45% hormone-users) with EC were entered prospectively and consecutively into an immunohistochemical study of growth fraction (Ki-67, MIB-1 and PC10), suppressor oncogene protein (p53) and oncogene protein (p185). RESULTS: All markers except p185 intercorrelated significantly, although weakly, however, marked differences were found in median values of the markers of growth fraction (GF). It was shown that immunohistochemical demonstration of p53 and p185 proteins and stage correlates independently with CSD in EC. CONCLUSION: The study indicates that the markers of GF do not give exact information about the proliferative compartment of the EC, and it is shown that p53 correlate to CSD, while stage indicate crude death.

Progesterone receptor levels independently predict survival in endometrial adenocarcinoma.

Estrogen receptor (ER) and progesterone receptor (PR) contents were determined by biochemical (dextran charcoal-coated (DCC) assay) and immunohistochemical (ICA) methods in biopsies from 145 primary endometrial adenocarcinomas and those with eligible receptor measurements were analyzed with respect to correlations to cancer-specific survival in a multivariate analysis including histopathological characteristics. Median patient follow-up time was 67 months with 18 cancer deaths. The PR-DCC and ER-DCC values were dichotomized according to levels previously found by us to correspond to the best agreement between receptor status as determined by the DCC and ICA methods (130 fmol/mg cytosol protein for ER, 114 fmol/mg for PR). Using these thresholds, we found by multivariate analysis that "high" PR-DCC levels (> 114 fmol/mg) correlated significantly (P = 0.004) with survival, independent of stage risk group (Ia + b vs Ic-IV). Patient age and histologic grade were prognostic factors in a univariate setting, but these parameters were eliminated in the multivariate model. While the PR-ICA scores also correlated significantly and independently with survival, the predictive effect of PR-ICA positivity alone could not be statistically evaluated due to the number of cases with eligible ICA values. However, we suggest that owing to a close correlation between DCC and ICA results, PR-ICA status may provide significant prognostic information when DCC measurements are not available.

Endometrial adenocarcinoma of endometrioid subtype with squamous differentiation: an immunohistochemical study of MIB-1 (ki-67 paraffin), cathepsin D, and C-erbB-2 protein (p185).

Differences in the immunohistochemical expression of Cathepsin D, C-erbB-2 protein (p185), and growth fraction (MIB-1) in glandular and squamous epithelium in adenocarcinoma of endometrioid subtype were studied together with Cathepsin D in macrophages. The findings were correlated with conventional prognostic parameters. A search for human papilloma virus (HPV) (probes 6/11, 16/18, and 31/33/51) by in situ hybridization was also performed. Formalin-fixed and paraffin-embedded tissues from 61 adenocarcinomas with > 10% squamous epithelium were studied. MIB-1 was very low in squamous epithelium, no correlation was found between MIB-1 in squamous and glandular epithelium, and only the glandular epithelium correlated with depth of invasion and stage, indicating that glands are most important with regard to prognosis. Cathepsin D expression in macrophages was significantly increased in advanced stage and may be of prognostic value, but more studies on tissue sections are needed to evaluate the relationship between its expression in tumor cells and other cells. p185 showed no value as a prognosticator. Finally, our study found HPV infrequently in endometrial carcinomas.

Estrogen receptor determination in endometrial carcinoma: ligand binding assay versus enzyme immunoassay.

We compared concentrations of cytosolic estrogen receptors (ERc) measured in 35 postmenopausal endometrial carcinomas by ligand binding method (LBA) (dextran-coated charcoal assay) and enzyme immunoassay (EIA). Correlations between ERc, nuclear estrogen receptors (ERn) determined by EIA, and cytosolic progesterone receptors (PR) measured by LBA were also studied. While ERc concentrations determined by LBA and EIA were highly correlated (r: 0.94), ERc values detected by LBA were approximately twice those found by EIA (median values of ERc: 155 vs. 64 fmol/mg cytosol protein, DCC vs. EIA). The percentages of ERc positive tumors were 89% by LBA and 77% by EIA. The median fraction of total ER present as ERn was 63%. PR levels correlated positively with ERn concentrations (r: 0.73). We explore possible reasons why greater concentrations of ERc are determined by estradiol binding than by the ER-EIA kit in endometrial cancer.

p53 protein and c-erbB-2 protein (p185) expression in endometrial adenocarcinoma of endometrioid type. An immunohistochemical examination on paraffin sections.

The expression of both the nuclear protein p53 tumor suppressor gene product and the transmembrane C-erbB-2 protein oncogene product (p185) correlates to risk factors and outcomes in different tumor types. Their value as prognosticators in endometrial adenocarcinoma of endometrioid type (EC) has not been determined. Paraffin sections were examined immunohistochemically to study the expression of p53 protein and p185 in 112 patients with EC. p53 protein was overaccumulated in 34% and p185 in 13% of the tumors. p53 protein correlated with mitotic count and nuclear grade. Both p53 protein and p185 correlated significantly with outcome. However, they did not correlate with each other or with architectural grade or stage (which defines a high risk group), indicating a role as adjuvant prognosticators in EC. Stage and outcome did correlate, however. Both p53 protein and p185 antibodies work well on routine, formalin-fixed, paraffin-embedded tissue and are easily used in routine diagnostic procedures.

Expression of MIB-1 (paraffin ki-67) and AgNOR morphology in endometrial adenocarcinomas of endometrioid type.

Cell kinetic information is an important adjuvant to histologic grading and to stage in some malignant tumors. Some studies have shown that in endometrial carcinomas, flow cytometric S-phase correlates with known prognostic parameters. In the current study, the expression of silver-stained nucleolar organizer regions (AgNORs) and MIB-1 (ki-67-paraffin) was assessed on paraffin sections in 112 endometrial adenocarcinomas of endometrioid type (EC) (49 hormone users, 63 nonusers). The AgNOR morphology correlated significantly with MIB-1, mitotic count, and nuclear and architectural grade, but not with stage or previous hormone treatment. MIB-1 correlated with all the above parameters except myometrial invasion and stage. Only myometrial invasion and stage correlated with short-term outcome; in such cases tumors from hormone users and nonusers were pooled. The median MIB-1 value was significantly lower in EC from hormone users compared with EC from nonusers; moreover, when tumors from hormone users and nonusers with poor outcome were examined separately, only 29% (four of 14) of the tumors expressed MIB-1 less than the medians in the respective groups, indicating that a prognostic cutoff point may be different in the two groups. Because hormone replacement therapy is very common, this observation has implication for future studies of growth fraction in EC. This is the first study to show that AgNOR morphology is significantly correlated with other markers of growth fraction and histologic grade.

Plasma oestrogens in postmenopausal women with endometrial cancer.

OBJECTIVE: To study plasma levels of estrogens and androgens, sex hormone-binding globulin (SHBG) and follicle stimulating hormone (FSH) in postmenopausal patients with endometrial cancer. DESIGN: Patients and controls were matched for age, body mass index, parity and years since menopause. SETTING: Department of Obstetrics and Gynaecology, Hvidovre Hospital, Denmark. SUBJECTS: Fifty postmenopausal patients with endometrial cancer and 54 matching controls. MEASUREMENTS: Plasma levels of SHBG, FSH, oestrone, oestradiol, oestrone-sulphate, dehydro-epiandrosterone sulphate, testosterone, and androstenedione were measured by radio-immunoassays. Free fractions of oestradiol and testosterone were calculated according to levels of SHBG and albumin. RESULTS: The levels of oestradiol, free oestradiol, and oestrone were elevated (P < 0.001) in patients compared with controls (oestradiol: 51 (45-59) vs 37 (34-41) pmol/l; free oestradiol: 0.69 (0.59-0.80) vs 0.48 (0.42-0.54) pmol/l; oestrone: 180 (159-204) vs 119 (107-133) pmol/l (mean values (95% CI) in patients vs controls)). Furthermore, an increased oestrone:androstenedione ratio (0.095 vs 0.072, P < 0.01) was found in patients. SHBG correlated negatively (P < 0.001) with body mass, while the free fractions of oestradiol and testosterone correlated positively (P < 0.01) with body mass, in both patients and controls. Multiple regression analysis showed that the differences in oestrogen levels between the two groups persisted when controlling for the effect of body mass, age, years since menopause, parity, and levels of SHBG and FSH. CONCLUSION: Patients with endometrial cancer exhibit increased plasma levels of oestradiol and oestrone. Speculatively, these oestrogens may result from an increased oestrone conversion from androstenedione, an increased ovarian and adrenal secretion of androstenedione, or alternative oestrogen production routes. The present findings support the hypothetical role for oestrogens in the aetiology of endometrial cancer.

Proliferative activity as revealed by Ki-67 in uterine adenocarcinoma of endometrioid type: comparison of tumours from patients with and without previous oestrogen therapy.

The Ki-67 antibody recognizes a nuclear antigen related to cell proliferation, which in some studies has been shown to reflect the aggressiveness of tumours. The percentage of Ki-67-positive cells was estimated by immunohistochemistry on frozen tissue sections from 73 adenocarcinomas of endometrioid type (EC) (40 tumours from patients who had never received postmenopausal oestrogen treatment and 33 tumours from patients with previous postmenopausal oestrogen treatment). The Ki-67 content was weakly but significantly (P < 0.05) correlated to nuclear grade, architectural grade, and crude mitotic count, but not to stage or progesterone receptors. Ki-67 expression in EC from patients with previous oestrogen therapy was much lower (median 10 per cent Ki-67) than that in EC from patients who had never received oestrogen treatment (median 24 per cent Ki-67), suggesting that a prognostic cut-off point may be different in tumours from the two groups of patients. The mitotic count discriminated the two groups of patients to a much smaller degree. It is also shown that a quick qualitative Ki-67 estimate can replace the time-consuming quantitative assessment.

Progesterone receptor content in endometrial carcinoma correlates with serum levels of free estradiol.

OBJECTIVE: To study a possible relationship between serum levels of estrogens and androgens and the tumor content of estrogen receptors and progesterone receptors in endometrial cancer. STUDY DESIGN: Fifty postmenopausal patients were included. Receptors were determined biochemically in tissue cytosol by dextran charcoal-coated assay and immunohistochemically on frozen sections. Serum sex hormones were measured by radioimmunoassays. MAIN FINDINGS: Tumor biochemical progesterone receptor content correlated positively (p < 0.05) with free estradiol serum levels. No correlations were observed between estrogen receptor content and any of the serum sex hormones. The progesterone/estrogen receptor ratio, calculated from the biochemical values, correlated positively (p < 0.05) with the serum levels of free estradiol. This relation was not affected by tumor histologic grade or stage. Furthermore, this ratio correlated positively with body mass index, probably reflecting a correlation between body mass and serum estrogens. Biochemical and immunohistochemical receptor values were correlated. CONCLUSIONS: These findings suggest that hormonal regulation of receptor levels may remain preserved in at least some endometrial cancer cells.

Proliferating cell nuclear antigen in endometrial adenocarcinomas of endometrioid type correlated with histologic grade, stage, previous hormonal treatment, and survival.

Only a small number of endometrial carcinomas have been examined for proliferating cell nuclear antigen. The results indicate that a high proliferating cell nuclear antigen content correlates with a poor prognosis. One hundred eight endometrial carcinomas of endometrioid type were examined with the monoclonal antibody PC10 (48 tumors from postmenopausal estrogen users and 60 tumors from nonusers). The PC10 content was weakly but significantly correlated with mitotic count and architectural grade, but not with nuclear grade, stage, or survival. PC10 values in estrogen users were much lower (median, 14%) than in nonusers (median, 26%); the difference was independent of histologic grade and stage. After a median follow-up of 30 months (range, 12 to 66 months) 17 patients had died. The cause of death was established as cancer in only nine cases. No overall difference in PC10 values existed between survivors and nonsurvivors. However, if only the estrogen nonusers were examined the survivors showed a mean PC10 value of 27%, while the nonsurvivors showed a mean PC10 value of 45%. The present study indicates that carcinomas from patients with and without previous hormonal treatment are different with regard to their PC10 content. The quantitative and qualitative estimates of PC10 correlated well.

Estrogen and progesterone receptors in endometrial carcinoma: comparison of immunohistochemical and biochemical analysis.

In 159 endometrial carcinomas, estrogen (ER) and progesterone receptors (PR) were determined biochemically by dextran-coated charcoal (DCC) assay and immunohistochemically (ICA) on frozen sections. ICA receptor content was estimated by a total histologic score (HSCORE), including all tissue components, and by a cancer HSCORE, including malignant cells only. These scores were closely correlated. A single biopsy was found to be representative for each tumor. ER-DCC status was positive in 90.3% and PR-DCC status in 92.2% of the tumors. ER total HSCORE was positive in 47% and PR total HSCORE in 89% of tumors. ER and PR correlated inversely with tumor grade (p < 0.001). Correlations were found between ER and PR content determined by either method (DCC: r = 0.77; ICA: r = 0.50), as well as between DCC and ICA content (ER: r = 0.52; PR: r = 0.76). The association between DCC and ICA was affected by the tumor grade: the DCC values decreased relatively more than total HSCOREs with increasing grade. The sensitivity of ICA against DCC assay was 56% for ER and 86% for PR. Maximal agreement between receptor status as determined by ICA and by DCC would result from a DCC cutoff level of 130 fmol/mg for ER and 114 fmol/mg for PR.

Expression of epidermal growth factor receptors in human endometrial carcinoma.

Little data exist on the expression of epidermal growth factor receptors (EGF-Rs) in human endometrial cancer. EGF-R status was studied in 65 patients with endometrial carcinomas and in 26 women with nonmalignant postmenopausal endometria, either inactive/atrophic endometrium or adenomatous hyperplasia. EGF-R was identified on frozen tissue sections by means of an indirect immunoperoxidase technique with a monoclonal antibody against the external domain of the EGF-R. Seventy-one percent of the carcinomas expressed positive EGF-R immunoreactivity. In general, staining was most prominent at the cell membranes, with a varying pattern in individual carcinomas. EGF-R expression was not correlated with histologic grade, surgical stage, or estrogen/progesterone receptor status evaluated immunohistochemically or biochemically in adjacent tissue sections of the tumor. Ten of 13 (77%) atrophic/inactive endometria and seven of 13 (54%) endometria with adenomatous hyperplasia were EGF-R positive, with an immunostaining pattern rather similar to that of the carcinomas.

Endometrial cancer in postmenopausal women with and without previous estrogen replacement treatment: comparison of clinical and histopathological characteristics.

Clinical and histopathological features of postmenopausal endometrial cancer were studied in 63 patients who had received exogenous estrogens previously and in 76 patients who had never been exposed to estrogens. All treatments were primarily surgical. Estrogen users were younger than nonusers (P < 0.001). Body mass index, age at menarche and menopause, parity, and blood pressure were comparable in the two groups. Prevalence of diabetes mellitus was higher in nonusers (P < 0.01). Tumor stage was earlier (P < 0.001) and the histologic grade was lower (P < 0.001) in estrogen users compared to nonusers, and the frequency of clear cell and adenosquamous carcinoma was lower in estrogen users. Myometrial invasion was less pronounced in estrogen users, independently of grade and stage (P < 0.01). Number of mitoses correlated significantly with grade and with estrogen use. Features such as squamous metaplasia and "foam" cells were not related to tumor grade or use of estrogens. The receptor content correlated inversely with grade but was not related to estrogen use. Duration of estrogen treatment was not associated with tumor stage and grade. Our findings support the theory that endometrial cancer of estrogen users may be less aggressive than cancer of nonusers.

Stereological estimate of nuclear volume in endometrial adenocarcinoma of endometrioid type: reproducibility and intra-tumour variation.

Stereological volume weighted mean nuclear volume estimate (Vv) is reported to be highly reproducible and to provide excellent prognostic information for some tumours. The aim of the present study was to investigate the reproducibility and the intra-tumour variation of nuclear Vv and compare it with a morphometric nuclear estimate, i.e. the mean shortest nuclear axis, and with conventional histopathological parameters used in the grading of endometrial adenocarcinomas. Sixty-three endometrioid adenocarcinomas were included in the study. Both Vv and mean shortest nuclear axis showed an acceptable reproducibility and the correlation between them was moderate (Spearman test; rs = 0.8). One-third of the tumours showed a marked intra-tumour variation. A considerable discrepancy between Vv and/or mean shortest nuclear axis and nuclear and architectural grade was found.