Albrecht Pfleiderer

Estrogen and progesterone receptors in endometrial cancer and their prognostic relevance

Three hundred and nine malignant endometrial tumors were biochemically analyzed with respect to estrogen (ER) and progesterone (PR) receptors. Fifty-seven percent of endometrial carcinomas were ER and PR positive (greater than or equal to 50 fmole/mg of cytosol protein); 24% were negative for both receptors. Five sarcomas and 16 of 21 mixed mullerian tumors were receptor negative. Receptor status correlated with clinical stage and grade of histological differentiation, but not with myometrial invasion. Anamnestic data on patients showed no differences between those with receptor-negative and receptor-positive tumors. Five-year survival rate (stage I) and median survival time (stages II-IV, recurrences) for patients with ER+/PR+ and ER-/PR+ endometrial cancer were significantly better than for ER-/PR- and ER+/PR- patients. A multivariate analysis demonstrated progesterone receptor as a significant prognostic factor next to clinical stage. Estrogen receptor had no significant prognostic relevance. A retrospective analysis of gestagen treatment and progesterone receptor status confirms the importance of PR, possibly independent of hormonal treatment.

The occurrence of epidermal growth factor receptors and the characterization of EGF-like factors in human ovarian, endometrial, cervical and breast cancer

SummaryIn this study we investigated the presence of epidermal growth factor receptors (EGF-R) and the tissue levels of EGF-like factors (EFG-F) in ovarian, endometrial, cervical and breast carcinomas. EGF-R were found in 33/40 (83%) cervical, 15/26 (58%) endometrial, 64/141 (45%) ovarian, and 19/59 (33%) breast carcinomas. The highest number of EGF-R binding sites was detected in cervical carcinomas followed by endometrial, breast and ovarian carcinomas. The tissue concentrations of EGF-like factors, were investigated in extracts of 63 ovarian, 25 breast, 12 cervical, 14 endometrial carcinomas and in 21 biopsies of nonmalignant tissue such as myometrium and ovaries. The extracts of nonmalignant tissues had a mean EGF-F level of 1.5±0.7 ng/mg with a concentration range from 0 to 4 ng/mg. The mean EGF-F levels of malignant tissues were: ovarian carcinomas 4.2±1.5 ng/mg (range 0–15 ng), endometrial carcinomas 4.5±1.7 ng/mg (range 0–12 ng), cervical carcinomas 4.15±1.1 ng/mg (range 0–8) and breast carcinomas 3.16±1.1 ng/mg (range 0–10 ng). About 30% ovarian, endometrial and cervical carcinomas and 16% breast carcinomas, respectively, had enhanced EGF levels from 5 ng/mg to 15 ng/mg compared to nonmalignant tissues. The EGF-F of tissue extracts consists of EGF and transforming growth factor TGFα) as shown by the results of EGF and TGFα radioimmunoassays. It is assumed that in some tumors the EGF-F tissue levels influence the number of biochemically detectable EGF binding sites.

Occurrence of epidermal growth factor receptors in human adnexal tumors and their prognostic value in advanced ovarian carcinomas

Ninety-eight different malignant adnexal tumors were analyzed for the presence of epidermal growth factor (EGF)-specific binding sites and binding parameters were calculated by Scatchard plot analysis [G. Scatchard, Ann. N.Y. Acad. Sci. 51, 660-672 (1949)]. Thirty-four biopsies were EGF receptor (EGF-R) positive with dissociation constants (KD) of 0.5-12 X 10(-9) M and binding capacities (Bmax) of 2-250 fmol/mg. One tumor had a KD of 60 X 10(-9) M and a Bmax of 1660 fmol/mg. The correlation of EGF-R status with clinical parameters showed no significant differences in primary, metastatic, or recurrent tumors, histological subtype, tumor differentiation, and tumor residual after primary surgery. As an inverse correlation, EGF-R-positive tumors are 39% and EGF-R-negative tumors 60% progesterone receptor positive. A response to chemotherapy was noticed in 50% of EGF-R-positive ovarian carcinomas with a mean survival time of patients of 28 months. The response rate of EGF-R negative ovarian carcinomas was 12% with a mean survival time of 16 months. Regarding the treatment schedule the major differences were noticed in the cis-platinum plus cyclophosphamide treatment group. These results suggest that the biology of ovarian carcinomas is influenced by growth factors and their receptors, which can be used as prognostic factors.

Color Doppler flow criteria of breast lesions

Color Doppler technique has been available for several years. The sensitivity of the equipment has improved and allows for assessment of tumor vascularity. We investigated multiple parameters in 258 patients, with 176 benign and 82 malignant lesions to define characteristic flow criteria. Median (25-75% quartiles) and p-values are given for benign vs. malignant lesions. Number of tumor vessels: 2 (1-2) vs. 8 (5-14), p < 0.0001; mean peak systolic flow velocity: 11.1 cm/s (6.4-14.9) vs. 18.8 cm/s (13.7-25.1), p < 0.0001; maximum flow velocity: 12.5 cm/s (6.7-18) vs. 32.5 cm/s (22.5-47.3), p < 0.0001; sum of all systolic flow velocities: 18.9 cm/s (7-34.2) vs. 147 cm/s (71.3-266.7), p < 0.0001; minimum systolic flow velocity: 8.9 cm/s (5.4-12.1) vs. 9 cm/s (6.3-11.3), p > 0.05; average resistance index (RI): 0.68 (0.58-0.72) vs. 0.75 (0.67-0.81), p > 0.05; maximum RI: 0.71 (0.65-0.78) vs. 0.88 (0.78-0.99), p < 0.0001; minimum RI: 0.64 (0.57-0.68) vs. 0.64 (0.53-0.71), p > 0.05; average A/B ratio: 3.1 (2.7-3.7) vs. 4.3 (3.2-7.7), p < 0.0001; maximum A/B ratio: 3.4 (2.9-4.6) vs. 8.4 (4.5-9.9), p < 0.0001; minimum A/B ratio: 2.8 (2.3-3.2) vs. 2.9 (2.2-3.5), p > 0.05. The data analysis shows that flow resistance in malignancies is increased. This is in contrast to gynecological malignancies, where an increased diastolic flow indicates that flow resistance is decreased.

Flow-cytometric prognostic factors for the survival of patients with ovarian carcinoma: A 5-year follow-up study

Fresh surgical specimens of 37 patients with previously untreated ovarian carcinomas were investigated by means of flow cytometry. The aim of the study was to look for cellular prognostic factors, in addition to the well-known clinical prognostic factors, of survival time for these patients. All patients underwent chemotherapy after surgery, and all patients had a minimum of 5 years of follow-up. Patients with diploid or near-diploid tumors (DNA index less than or equal to 1.25) survived significantly longer than those with aneuploid tumors (DNA index greater than 1.25, P = 0.02). Patients whose tumors showed a high proportion of SG2M phase cells (greater than 17%) or a low proportion of G0/G1 phase cells had shorter survival times than those with tumors with a low proportion of SG2M phase tumor cells (less than or equal to 17%, P = 0.01) or a high proportion of G0/G1 phase tumor cells. There is no significant relationship between cytometric data and stage. Different surgical procedures, cytostatic treatment, histological tumor type, and differentiation had no significant effects on the survival time of patients in this study. Thus, the data from this study demonstrate strong cytometric prognostic factors of the survival of patients with ovarian carcinomas.

Quantitative flow measurements for classification of ovarian tumors by transvaginal color Doppler sonography in postmenopausal patients

Color Doppler and Duplex measurements were obtained in 83 (42 benign, 41 malignant) ovarian tumors in postmenopausal patients. An ATL UM9/HDI was used. The following flow criteria were analyzed: lowest resistance index (RI) and pulsatility index (PI), total number of arteries and number of central arteries and the maximum, mean and sum of systolic, end‐diastolic and time‐averaged maximum velocities of all intratumoral vessels. In 98% of malignant and in 85% of benign lesions, vessels were detected. All flow criteria showed highly significant differences between benign and malignant tumors (p < 0.0001). However, there was a considerable overlap between benign and malignant tumors (e.g. the median of the lowest RI was 0.62 (range 0.26–1.0) for benign and 0.40 (0.22–0.66) for malignant tumors; the median of the maximum systolic velocity was 17.5 cm/s (range 5.2–61.5 cm/s) for benign and 47.05 cm/s (14.6–105.0 cm/s) for malignant tumors).

Therapeutic strategies in cervical pregnancy

Cervical pregnancy is a rare condition associated with a high maternal morbidity rate. Standard recommendations for the management of this ectopic pregnancy are not available. This paper presents a case report and reviews the respective literature. In many cases hysterectomy was the ultimate solution. In order to avoid hysterectomy chemotherapy using methotrexate has been suggested. Local injections of prostaglandins or vasopressin have also been proposed. Based on data collected from the literature and our own experience it is concluded that the management of cervical pregnancy requires individualized therapeutic strategies to minimize the rate of hysterectomies.

Increasing incidence of CD44v7/8 epitope expression during uterine cervical carcinogenesis.

Splice variants of the cell surface glycoprotein CD44 (CD44v) have been implicated in the progression of various human tumors. In the present study, we have examined the expression pattern of a CD44v epitope encoded by the adjacent variant exons v7 and v8 during human cervical carcinogenesis. While only 1/11 normal cervical squamous epithelia was positive for this epitope by immunohistochemistry, 4/21 samples of low‐grade squamous intra‐epithelial lesions (LSIL), 17/35 samples of high‐grade squamous intra‐epithelial lesions (HSIL), 11/12 samples of the HSIL subgroup of carcinoma in situ and 17/17 cases of invasive cervical carcinoma showed CD44v7/8 epitope expression. In addition to CD44 variant expression, we have analyzed 67 lesions for the presence of HPV16/18‐DNA using PCR. Most of the samples expressing the v7/8 epitope were also HPV16‐positive (29/32), whereas only 17/35 of the v7/8‐negative samples were HPV16‐positive. HPV18 DNA was found in only one invasive carcinoma. Our data suggest that high‐risk HPV infection may precede CD44v7/8 expression and that the number of samples expressing the CD44v7/8 epitope increases during carcinogenesis and reaches nearly 100% at the carcinoma in situ stage. This CD44 epitope could, therefore, serve as a diagnostic marker of cervical squamous cell carcinomas and as a possible target for CD44v7/8 epitope‐directed therapies.

p53 Mutation and MDM2 amplification are rare even in human papillomavirus‐negative cervical carcinomas

Background. Mutation of the p53 tumor suppressor gene is the most commonly found genetic alteration in human cancer. The E6 gene product of human papillomavirus (HPV) 16 and 18 can inactivate the p53 protein by promoting its degradation. Because most HPV‐positive cervical carcinoma cell lines contain wild‐type p53 whereas HPV‐negative cell lines have point mutations in the p53 gene, a major role in the development of HPV‐negative cervical cancer has been attributed to p53. Recent studies, however, have observed no consistent presence of p53 mutation in HPV‐negative primary cervical carcinomas. The MDM2 oncogene, which forms an autoregulatory loop with the wild‐type p53 protein, has been found amplified in a high percentage of human sarcomas, thus abolishing the antiproliferative function of p53.

Diagnostic formula for the differentiation of adnexal tumors by transvaginal sonography

Objective : To create a strategy for sonographic differentiation of benign and malignant adnexal tumors in premenopausal and postmenopausal patients. Methods : Multiple sonomorphologic criteria were analyzed prospectively in 754 tumors. Four hundred were found in premenopausal and 354 in postmenopausal women. In a logistic regression model, relevant criteria were selected, and a diagnostic formula for tumor differentiation was derived. Results : There were 165 malignant tumors, of which 37 (9.2%) were found in premenopausal and 128 (36.2%) in postmenopausal women. In both groups, the criteria of solid phase and ascites were the most significant. Further important diagnostic criteria were structure and tumor size in premenopausal women and cyst architecture and tumor surface in postmenopausal women. These results allowed an estimation of the probability of malignancy. Using a cutoff point of 10% for the probability to classify tumors as malignant, the sensitivity and specificity in premenopausal patients were 86.5% and 92.6%, respectively, with an accuracy of 92%. In postmenopausal women, the sensitivity, specificity, and accuracy were 93%, 82.7%, and 86.6%, respectively. Assuming a prevalence as given in the study, the positive and negative predictive values were 54.4% and 98.5% in premenopausal and 75.3% and 95.4% in postmenopausal women. Conclusions : With four binary criteria, a useful diagnostic formula for tumor differentiation was obtained. However, estimates for sensitivity, specificity, and accuracy may be too optimistic because they were derived from the same data that were already used for model selection.