[Epidermal growth factor receptor (EGF-R) in human breast cancer--a marker of morphologic-functional differentiation]. / Der Epidermal-Growth-Factor-Rezeptor (EGF-R) im humanen Mammakarzinom--Marker einer morphologisch-funktionellen Entdifferenzierung.

Epidermal growth factor and some related mitogens elicit a biological response in normal and malignant cells by mediation of a specific receptor, the epidermal growth factor receptor (EGF-R). In recent publications the expression of this receptor, a glycoprotein with extensive sequence homology to the erb B-oncogene, has in human breast carcinoma, been claimed to be an excellent indicator of a poor prognosis, superior to conventional prognostic factors such as nodal status and tumour size. To learn about the functional and prognostic role of EGF-R in breast carcinoma, we screened breast cancer tissue from 91 patients for the expression of the receptor by immunohistochemical means, with a monoclonal antibody. The results were compared to the expression of steroid receptors and to morphological and clinical parameters. We detected EGF-R in normal squamous cells of the skin and in epithelial and myoepithelial cells in non-neoplastic lobuli and ducts of the human breast. EGF-R was found in breast cancer tissues of 22 of the 91 patients. Specific staining was observed mainly in the cell membranes, but also to some extent in the cytoplasm. The distribution pattern of the antigen in terms of intensity of staining and number of specifically stained cells varied widely among different and within different regions of the same tumours.(ABSTRACT TRUNCATED AT 250 WORDS)

Immunohistochemical detection of progesterone receptor in formalin-fixed and paraffin-embedded breast cancer tissue using a monoclonal antibody.

The potential for immunohistochemical detection of progesterone receptors (PRs) in routinely formalin-fixed and paraffin-embedded cancer tissues by use of the monoclonal antibody Mi 60-10 (mPR1, Dianova GmbH, Hamburg) was evaluated. The PR content of breast cancer tissue was investigated in 170 cases. A positive reaction to Mi 60-10 was found exclusively in the nuclei of benign or malignant epithelial cells. The distribution of PRs was heterogeneous. Immunohistochemical reaction was scored by multiplying the percentage of positive tumour cells by their prevalent degree of staining (Immunoreactive Score or IRS). The IRS values of formalin-fixed tissues (n = 170) were compared with those in snap frozen tissues (n = 82), with the PR content assayed by a DCC (dextran-coated charcoal) method (n = 170), with histopathological grading according to Bloom and Richardson and with the menopausal status of the patient. There was an acceptable ranked correlation (r = 0.74) between IRS in formalin-fixed and paraffin-embedded parts and snap frozen parts of the same carcinoma. A good correlation (r = 0.72) was also found, when the semiquantitative results of immunohistochemical PR detection in formalin-fixed and paraffin-embedded tissues were compared to PR concentrations measured by a DCC method in tumor cytosols. There was an 80% concordance between the two methods for qualitative discrimination of PR-negative and PR-positive carcinomas. IRS correlated significantly with the degree of histological differentiation of the tumors (P less than 0.001) but not with the menopausal status of the women (P greater than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

[The importance of the SCC antigen in the diagnosis and follow-up of cervix carcinoma. A cooperative study of the Gynecologic Tumor Marker Group (GTMG)]. / Bedeutung des SCC-Antigens in der Diagnostik und Verlausfskontrolle des Zervixkarzinoms. Eine kooperative Studie der Gynäkologischen Tumor-Marker-Gruppe (GTMG).

SCC (squamous cell carcinoma) antigen is a subfraction of tumour antigen TA-4 isolated from cervical squamous cell carcinomas. Serum concentrations of SCC antigen were measured by radioimmunoassay in 382 control subjects, 70 women with cervical intraepithelial neoplasia (CIN), 517 with cervical carcinoma and 203 with other gynaecological carcinomas. Elevated SCC antigen levels (greater than 2.5 ng/ml) were found in 4% of normal controls, in 7% of women with CIN I-III, in 2%-23% with various forms of genital adenocarcinomas, in 55% with primary and in 76% of those with recurrent cervical squamous cell carcinoma. The positivity rate of the antigen was correlated with tumour stage (FIGO) and lymph node involvement of primary cervical squamous cell carcinomas. During long-term follow-up serum levels of SCC antigen were found to be concordant with tumour activity in 74% of cases. Patients with still elevated marker levels after therapy had twice the recurrence rate of women with normal serum values. Routine determination of SCC antigen during follow-up of cervical cancer is recommended.

Detection of squamous cell carcinoma antigen in normal squamous epithelia and in squamous cell carcinomas of the uterine cervix.

Squamous cell carcinoma (SCC) antigen is a subfraction of tumor antigen TA-4 isolated from a cervical squamous cell carcinoma. The specificity of SCC antigen and the factors influencing its release into serum were evaluated. Antigen concentrations were measured in 157 tissue extracts and in 188 sera of patients with nonmalignant or malignant gynecologic diseases. A commercial radioimmunoassay based on polyclonal antibodies (Abbott Laboratories, North Chicago) was used. Cytosol concentrations were significantly higher (P less than 0.005) in normal squamous epithelia (means = 6040 ng/mg cell protein [CP]) and in squamous cell carcinomas (means = 2483 ng/mg CP) of the exocervix than those in normal columnar epithelia and in adenocarcinomas of the endocervix, endometrium, ovary, and breast (means = 1-508 ng/mg CP). Despite the high antigen concentrations in normal squamous epithelia, elevated serum levels (greater than 2.5 ng/ml) were almost exclusively found in patients with cervical squamous cell carcinomas. The sensitivity of SCC antigen as a marker for primary carcinomas was 61%, increasing from 29% in Stage I to 89% in Stage IV. The positivity rate was higher in women with well-differentiated (78%) and moderately differentiated carcinomas (67%) than in those with poorly differentiated tumors (38%). The results show that SCC antigen is not tumor specific. The release into serum is independent of local tissue content, but is apparently influenced by the infiltrative growth, the mass, and the degree of histologic differentiation of the tumor.

Hormone levels in women after hysterectomy.

The serum levels of FSH, LH and estradiol-17 beta (E2) were determined in 110 women aged between 38-48 years who had been hysterectomized 2-10 years previously and were compared with a control group (n = 112). In hysterectomized women both FSH and LH levels were higher than in controls during the whole 12 year period. These differences were significant up to 43 years of age. The hypergonadotropism in hysterectomized women correlates with the higher incidence of climacteric symptoms reported in the literature.

CA 125 in normal tissues and carcinomas of the uterine cervix, endometrium and Fallopian tube. II. Immunoradiometric determination in secretions, tissue extracts and serum.

The study deals with the occurrence of cancer antigen 125 (CA 125) in the normal and neoplastic uterine cervix, endometrium and fallopian tube and its applicability as a tumour marker. CA 125 concentrations were measured in 52 secretion specimens, in cytosol fractions of 97 tissue biopsies and in serum from 47 women with nonmalignant disorders and from 334 patients with carcinomas. High quantities of CA 125 (780-454860 U/ml) were detected in cervical mucus, intra-uterine and tubal fluid, exceeding those in the corresponding serum samples by factors of up to 2000. CA 125 concentrations were 9-53 fold higher in cytosol fractions of normal and neoplastic glandular epithelia of the endocervix and endometrium than in those of cervical squamous epithelia and the cervical wall. Despite similarly high antigen concentrations in normal glandular epithelia and adenocarcinomas serum levels elevated to above 65 U/ml were only found in patients with malignant tumours. The positivity rates in serum increased with tumour extent and were 0-43% for primary and 63-79% for recurrent cervical, endometrial and tubal adenocarcinomas. During long-term follow-up, CA 125 serum concentrations were concordant with the clinical course in 10 out of 11 patients with progressive carcinomas. According to these results, the release of CA 125 into the peripheral blood is apparently dependent on the infiltrative growth and the mass of the tumour rather than on the local tissue concentrations. The clinical use of CA 125 is limited to the detection of advanced adenocarcinomas of the Müllerian duct.

[Receptor-binding capacity for estrogens and progesterone in the uterine cervix during the menstrual cycle and in the postmenopausal period]. / Die Rezeptor-Bindungs-kapazität für Ostrogene und Progesteron in der Cervix uteri während des Zyklus und in der Postmenopause.

In biochemical studies it was found that the binding capacity of cytoplasmatic estrogen and progesterone receptors in the uterine cervix undergo characteristic changes during the menstrual cycle. The highest estrogen binding values were observed by the eighth day, after which there was a significant drop. The highest progesterone binding values were around the twelfth day, followed by a significant drop after ovulation. In sexually mature subjects the estrogen receptors predominated in the mucosa and the progesterone receptors in the myometrium. Therefore, there is obviously a parallel to the receptor content in the corpus uteri. The maximum estrogen and progesterone binding capacities were in each case ascertained some days before the maximum E2 and Pr values were attained in the serum. Hence, the estrogen receptors have already built up in the uterine cervix before optimal functional activity, measured by the cervix score, has been attained. Anti-estrogens given at the beginning of the cycle can disturb this sequence. The high estrogen receptor content in the endometrium at the beginning of the cycle creates the necessary conditions for the explosive, proliferative gland growth around this time, even though the serum estrogen concentration is still relatively low. In the postmenopause the estrogen binding capacity in the uterine cervix was higher than during sexual maturity, while the reverse was the case with the progesterone binding capacity.

Radioimmunoassay of laminin P1 in body fluids of pregnant women, patients with gynaecological cancer and controls.

Laminin P1, a pepsin-resistant fragment of the glycoprotein laminin, was determined in body fluids using a double-antibody radioimmunoassay. The median serum concentrations found were: men 1.32, premenopausal women 1.22, postmenopausal women 1.38 and pregnant women (35th gestational week) 2.18 U/ml. The median concentration in amniotic fluid was 1.90, in urine 0.28 and in follicle cyst fluid 1.74 U/ml. During gestation, rising serum levels of up to 5 U/ml were observed which decreased within a few days after delivery. The cut-off value of laminin P1 for 95% specificity of the normal female control group was found to be 1.8 U/ml. The frequencies of elevated serum concentrations were 11, 18, 23 and 33% in patients with primary malignant lesions of the breast, endometrium, cervix and ovary, respectively, and rose up to 50-51% in patients with recurrent or metastatic gynaecological cancer. Laminin P1 was found in high concentrations in the cytosol fractions of breast cancer biopsies. Long-term sequential determinations of serum levels in 10 individual patients with progressive cancer reflected the course of the disease in 8 cases. Although laminin P1 can be considered as a tumour-associated protein, low sensitivity to primary cancer and insufficient specificity limit its application as a tumour marker and its usefulness in monitoring of patients with gynaecological cancer.

Endogenous as well as exogenous hormonal modulation of lectin binding sites in normal and neoplastic tissue of rat mammary gland.

Free and sialic acid conjugated binding sites for the lectin from Arachis hypogaea (peanut agglutinin, PNA) have been histochemically demonstrated in normal rat mammary tissue and in N-nitrosomethylurea (NMU) induced mammary tumors of rats. The lectin binding sites were predominantly associated with secretory activities of the normal and neoplastic breast tissue (secretory PNA binding sites). In normal breast tissue and in NMU induced mammary tumors the expression of secretory PNA binding sites was reduced after ovariectomy and by the antiestrogen tamoxifen. Estrogen stimulated the formation of free and sialic acid conjugated PNA binding sites in the presence of prolactin. In rat mammary tumors the estrogen induced formation of PNA binding sites was accompanied by an increase of the progesterone receptor concentration in the tumors. Comparative lectinhistochemical, morphological, and biochemical studies on NMU induced rat mammary tumors revealed that the expression of secretory PNA binding sites was associated with a good histologic differentiation and the presence of steroidhormone receptors. Endocrine therapeutic studies showed that tumors responding to therapy possessed higher amounts of secretory PNA binding sites than unresponsive tumors. Therefore secretory PNA binding sites represent a useful histochemical marker for hormone dependence in NMU induced mammary tumors.

[Determination of the SCC antigen in the serum of patients with cervical cancer]. / Bestimmung des SCC-Antigens im Serum von Patientinnen mit Zervixkarzinom.

SCC (Squamous Cell Carcinoma) antigen is a fraction of the tumor antigen TA-4, obtained from squamous cell carcinomas of the cervix uteri. In a retrospective study the clinical significance of SCC antigen was investigated in sera of 119 controls, 30 patients with cervical intraepithelial neoplasia (CIN I-III), 170 women with cervical carcinoma, and 82 patients with other malignant gynecological tumors. Radioimmunoassay was performed with a kit manufactured by Abbott Diagnostics. The limit of the normal range was 2.5 ng/ml. Elevated serum concentrations of SCC antigen were measured in 5% of blood donors, 3% of patients with uterus myomatosus, and 13% of women with CIN I-III. Pathologic SCC antigen concentrations were found in 62% of patients with primary and 73% of women with recurrent cervical squamous cell carcinomas. Only one out of eleven patients with a primary or recurrent adenocarcinoma of the cervix had a slightly elevated antigen level. The positivity rates depended on the spread of the cervical squamous cell carcinomas of the cervix and rose from 32% at FIGO stage I to 83% at stages III/IV. Only 2% of the patients with no evidence of recurrent disease after successful primary treatment of a cervical carcinoma had SCC antigen concentrations exceeding 2.5 ng/ml. The positivity rates were 33% in cases of primary vulval and vaginal carcinomas, 8% in primary endometrial carcinoma, and 15% in primary ovarian carcinoma. None of the women with primary breast cancer had a serum level above 2.5 ng/ml.(ABSTRACT TRUNCATED AT 250 WORDS)

[Monoclonal antibodies in the diagnosis and follow-up of ovarian cancer. CA 125 as a tumor marker. A cooperative study of the Gynecologic Tumor Marker Group (GTMG)]. / Monoklonale Antikörper in Diagnostik und Verlaufskontrolle des Ovarialkarzinoms. CA 125 als Tumormarker. Eine kooperative Studie der Gynäkologischen Tumormarkergruppe (GTMG).

The clinical validity of using the cancer antigen (CA) 125--a surface antigen on malignant epithelial ovarian tumors--for diagnosis and follow-up of ovarian cancer was investigated in a cooperative study. Using a monoclonal antibody (OC 125) to detect CA 125, the sera of 850 patients were analyzed by immunoradiometric assay (IRMA-Kit Centocor). For 199 patients with ovarian cancer, a preoperative sensitivity of 83% and 74% resulted for the usual cut-off points (greater than or equal to 35 and greater than or equal to 65 U/ml respectively). The positivity rates and quantiles correlated with the stage of disease (FIGO) and with the tumor debulking achieved at primary surgery. The most frequent histological types (serous cyst-adenoma and the undifferentiated carcinoma of the ovary) showed the highest positivity rates (80% and 90%, respectively, for cut-off at greater than or equal to 65 U/ml). Elevated CA 125 values were found in 74% of the cases with a relapse and in 79% of the patients with advanced disease (cut-off, greater than or equal to 65 U/ml) in the follow-up of ovarian cancer. We recommend cut-off at greater than or equal to 65 U/ml, because the values for only 1% of the female healthy controls (n = 251) were above this level. Also 17% of the patients with adnexitis and 8% with benign neoplasias of the ovary showed elevated titers. Therefore CA 125 should not be used for mass screening of ovarian carcinoma. However, it is a helpful laboratory tool in the diagnosis of recurrence and the surveillance of patients with ovarian cancer.

[Steroid hormone receptors in normal, dystrophic, dysplastic and carcinomatous vulva tissues]. / Steroidhormon-Rezeptoren in normalen, dystrophischen, dysplastischen und karzinomatösen Vulvageweben.

We employed the agar gel electrophoresis method to determine in 63 samples of vulva tissue the cytoplasmatic receptors for oestradiol, dihydrotestosterone and dexamethasone. Tissues with a binding capacity of more than 5 femtomol/mg (fmol = 10(-15) mol) cell proteins were considered receptor positive. The study comprised 17 normal tissues of the vulva, 13 vulva biopsies at the end of the pregnancy period, 7 dystrophically changed tissues, 11 premalignant changes of the vulva and 15 squamous cell carcinomas. In normal as well as in benign or malignantly changed vulva, specific receptors were found for all the four steroids (ER, PR, DHTR, DExaR). Receptors were most frequent in normal vulva tissue (ER = 94%, PR = 54%, DHTR = 38%, DexaR = 83%) with binding-capacities of 8-650 fmol/mg cell proteins. ER levels were higher during the postmenopausal period than during the premenopausal period. In dystrophia the receptor pattern was almost the same as in healthy tissue. Biopsies conducted at the end of the pregnancy period showed in all cases despite the high endogenous oestrogen levels positive ER values up to 875 fmol/mg cell proteins, whereas PR and DTHR were present in only 20% or 25% with low binding capacities. Loss of receptors, particularly of PR, was seen in premalignant changes (dysplasia of vulva, carcinoma in situ) and in case of squamous cell carcinomas. On comparing the receptor distribution of clinically changed vulva tissue with healthy tissue we found only differences by degree but no fundamental differences in principle.(ABSTRACT TRUNCATED AT 250 WORDS)

[Experiences with CA 125, a tumor marker for malignant epithelial ovarian tumors]. / Erfahrungen mit CA 125, einem Tumormarker für maligne epitheliale Ovarialtumoren.

CA 125 (Cancer Antigen 125) is an antigen identified by means of a monoclonal antibody on the surface of epithelial ovarian carcinoma cells. The serum concentration levels of CA 125 were measured in 41 women with benign and 95 patients with malignant tumours of the ovary. Immunoradiometric determination was effected by means of a kit supplied by Centocor. 35 U/ml was assumed as limit values of the standard range. Enhanced serum concentrations of CA 125 were seen in 5 per cent of the healthy volunteers of a standard group of persons, in 17 per cent of women with benign and in 78 per cent of women with malignant ovarian tumours. Patients without recurrence of tumour after successful primary treatment showed values above 35 U/ml in only 3 per cent of the cases. The incidence of pathological CA 125 serum concentration levels depended upon the histological type of the ovarian tumour and was highest in women with epithelial carcinomas, especially those with serous cystadenocarcinomas (87 per cent). In follow-up examinations of 30 patients with ovarian carcinoma over a period of one to 60 months, CA 125 concentrations correlated with the disease pattern in 90 per cent of the cases. The increases in CA 125 values preceded clinical diagnosis of the relapse by 1-8 months in seven out of twelve women. Routine determination of CA 125 appears advisable in the control of patients with ovarian carcinoma on account of the high sensitivity and specificity during follow-up.

Clinical significance of cancer antigen 125 (CA 125) in ovarian cancer.

Cancer antigen 125 (CA 125), a new ovarian cancer-associated antigen, was studied by radioimmunological determination of serum concentrations in 58 healthy blood donors, in 31 women with benign tumors, and 100 patients with malignant tumors of the ovary. Elevated CA 125 levels were found in 5% of normal controls, in 13% of women with benign tumors, and in 78% of patients with ovarian cancer. After successful antineoplastic treatment, false positive CA 125 values were observed in 4% of tumor-free patients. The incidence of pathological CA 125 serum levels was found to depend on the histogenetic origin of the ovarian tumors and was highest in patients with epithelial serous cystadenocarcinomas (85%). Sequential determinations of CA 125 in 27 patients with ovarian cancer under therapy showed a concordance in 89% of cases between serum concentrations and clinical courses. Elevations of CA 125 were already observed 1-6 months before objective evidence of recurrence. Therefore, the determination of serum CA 125 is recommended in the surveillance of patients with ovarian cancer.

Concentration of placental protein 10 (PP10) in maternal serum and amniotic fluid throughout normal gestation and in pregnancy complicated by fetal growth retardation.

PP10, a new placental glycoprotein, was studied by a specific and sensitive double-antibody radioimmunoassay in maternal serum and other body fluids throughout pregnancy. The mean value of serum PP10 in healthy nonpregnant individuals was approximately 10 microU/l. During normal pregnancy it rose to 3,500 microU/l. The rate of rise was obtained from 78 normal pregnancies with 279 single assay values from weeks 6-40. The shape of the curve resembled that for other placental proteins (HPL, SP1). PP10 levels in amniotic fluid were measured in 145 samples from weeks 13-55 of normal pregnancies and at term. The mean concentration was 500 microU/l until week 18 and then rose slowly. Cord blood contained only trace amounts. PP10 was not found in maternal urine. The concentration in maternal serum and amniotic fluid was higher in twin pregnancies than in singleton pregnancies. In 46 cases with low birth weights the PP10 levels in maternal serum were significantly lower than normal. Simultaneous measurements of PP10 and E3, HPL and SP1 were made in 17 individual follow-up's. PP10 was comparable with E3 and appeared to be better than HPL and SP1 in predicting intrauterine fetal growth retardation.

Serum levels of placental protein 10 (PP10) in women with breast cancer and genital carcinoma and in healthy male and female subjects.

PP10, a recently characterized glycoprotein from human placenta, was studied using a specific double-antibody radioimmunoassay in the serum of about 100 volunteers and 200 cancer patients. Elevated levels (greater than 20 nU/ml) were found in 87% of patients with primary breast cancer, in 100% of those with primary genital tumours and in 78% of patients with recurrent disease. PP10 was also measured in tumour extracts and in some patients with benign tumours. The serum concentration decreased within a few weeks after removal of the tumour. There were no significant correlations of the PP10 level with age, tumour size, histological grading or lymph node involvement. Sequential determinations of PP10 during cytostatic therapy sometimes showed rising levels accompany the development of metastases. PP10 can be regarded as a tumour associated protein and a tumour marker in gynaecological practice.

Klinefelter's syndrome and Breast cancer.

Breast cancer in a patient with Klinefelter's syndrome is reported. Possible correlation between testosterone and estradiol serum levels after testosterone-enanthate substitution, estrogen receptors in tumor tissue and clinical symptomatology are discussed. The various theories of etiology concerning breast cancer in this syndrome are reviewed. The increased conversion of testosterone to estradiol at the therapy with androgens might be responsible for the development of breast cancer in Klinefelter's syndrome. The current way of treatment is described.