Role of gonadotropins in malignant progression of sex cord stromal tumors produced by sequential auto- and isogenic transplantation of ovarian tissue in ovariectomized rats.

PURPOSE: In this study the effect of continuous stimulation of gonadotropins on sex cord stromal tumors in the rat was examined. METHODS: Sex cord stromal tumors were induced by transplantation of ovaries under the splenic capsule of ovariectomized rats. Beginning 180 days after transplantation, these tumors were taken out and cut into several pieces, which were then retransplanted (by isotransplantation) under the splenic capsule of 80 either intact or ovariectomized rats. RESULTS: Most of the tumor grafts grew up to a median size of 0.7 cm in ovariectomized rats. However, some of the tumors recovered from recipient rats that were retransplanted with donor tumors differed significantly from the others. Characterized by a high mitotic rate, nuclear atypia, size (up to 3.8 cm) as well as growth in intact animals, these tumors were defined as malignant. They could be kept in culture and always led to the development of metastases after retransplantation into other rats. CONCLUSION: Benign sex cord stromal tumors can show malignant growth after transplantation. This study for the first time demonstrates that gonadotropins are involved in the induction of ovarian malignancies.

Biological and prognostic significance of stratified epithelial cytokeratins in infiltrating ductal breast carcinomas.

The biological significance of the differential expression of cytokeratin (CK) polypeptides in breast carcinomas is unclear. We examined the CK profiles of 101 primary infiltrating ductal breast carcinomas using monoclonal antibodies directed against 11 different CKs and against vimentin. Two major CK phenotypes were distinguished: first, a phenotype expressing only the simple-epithelial CKs 7 (variably), 8, 18 and 19, and secondly, a bimodal phenotype co-expressing significant amounts of one or more of the stratified-epithelial CKs 4, 14 and 17. The vast majority of G1 and G2 carcinomas had the simple-epithelium phenotype, as did a subgroup of G3 carcinomas. Interestingly, the majority (62%) of G3 carcinomas exhibited the bimodal phenotype, with the expression of CKs 4, 14 and 17 being statistically correlated with poor histological differentiation and absence of steroid hormone receptors. The distribution of vimentin only partially overlapped with that of these stratified-epithelial CKs. Prognostic analyses suggested that the presence of CKs 4, 14 and/or 17 was associated with short overall and disease-free survival in subgroups comprising G3, oestrogen-receptor-negative and vimentin-negative tumours. In node-positive tumours the correlation between these CKs and a shorter disease-free interval attained statistical significance (log rank, 0.0096). Thus, abnormal CK profiles in ductal breast carcinomas appear to reflect disturbed regulation of differentiation-related gene expression programmes and may prove to be of clinical value.

[Interventional methods in breast diagnosis. Histological vs. cytological evaluation of core cut biopsies of the breast]. / Interventionelle Techniken in der Mammadiagnostik. Histologische versus zytologische Beurteilung von Stanzbiopsien der Mamma.

High speed core cut biopsies of breast tumors, sonographically or stereotactically guided, allow an histological examination of the tumor without surgery. It can be used prior to operation for the confirmation of a breast cancer and it can avoid unnecessary breast surgery in benign tumors. Unfortunately, only some centers are equipped with a pathology unit that allows an immediate histological examination. But often these institutes are provided with an experienced cystologist. Thus, the question arises if a cytology taken from the core cut biopsy is as reliable as an histological examination. In a prospective study we performed unroll-cytologies in core cut biopsies of 173 breast tumors in 169 patients consisting of 122 malignant and 51 benign tumors. Histology of core cut biopsies was proven by operational histology in all malignant and in 5 benign tumors. Histology of core cut biopsies could not be judged in 2 cases (lymphoma, gallert carcinoma). Cytological slide preparations were technically inadequate in 4 cases. The false negative rate of histology was 1/120 and 27/120 in cytology. Histology compared with cytology showed the following results: sensitivity 99.2% versus 77.5%, specificity 100% versus 95.9%, positive predictive value: 100% vs. 97.8%, negative predictive value: 98.1% vs. 63.5%, and accuracy: 99.4% vs. 82.8%. The sensitivity of cytology was much worse than that of histology of core cut biopsies. Thus, in our opinion cytology can provide a quick diagnostic orientation, but it cannot replace the more reliable histological examination. Diagnostic or therapeutic decisions should be based upon the more reliable histological results.

[Basaloid squamous epithelial carcinoma of the mouth mucosa]. / Das basaloide Plattenepithelkarzinom (BSC) der Mundschleimhaut.

The basaloid-squamous carcinoma (BSC) that was first described in 1986 by Wain et al. for the head and neck region is a rare distinct variant of squamous cell carcinoma (SCC). The cardinal histopathologic feature is a biphasic cellular pattern of basaloid and squamous components. BSC has been confused with solid adenoid cystic carcinoma (ACC). Although the number of reported cases is small, BSC appears biologically virulent, with a propensity to aggressive local behavior, early regional and distant metastasis, and subsequent poor survival. We report the clinicopathological characteristics of 4 new cases and compare their immunohistochemical features with those of solid ACC and conventional SCC. Our results show that BSC, ACC and SCC react to CK 5/6. SCC is CK 10- and CK 13-positive, while BSC and ACC are negative for these markers. BSC and ACC react to CK 8, but in ACC only the luminal cells are CK 8 positive: therefore ACC has a glandular pattern. Our findings indicate that the immunohistochemical differences between BSC and ACC can facilitate their differential diagnosis. Because the biologic behavior of BSC differs from ACC and SCC, distinction among these tumor types is warranted.

Correlation of high lactate levels in head and neck tumors with incidence of metastasis.

Using quantitative bioluminescence imaging, tissue concentrations of ATP, glucose, and lactate were registered in biopsies that were taken from primary tumors of human head and neck at the time of first cancer diagnosis. From 15 patients investigated at present, 6 had locoregional lymph node metastasis, 6 had no detectable metastatic spread, 2 biopsies contained dysplasias, and 1 biopsy consisted exclusively of normal mucosal and submucosal tissue. There was no correlation between staging or grading and any of the metabolic parameters measured. Mean lactate concentrations (+/-SD) were significantly higher and scattered over a wider range in tumors with metastatic spread (12.3 +/- 3.3 mumol/g) in comparison with malignancies in patients without metastasis (4.7 +/- 1.5 mumol/g). Despite the low number of patients, these differences were statistically highly significant (P < 0.005; Mann-Whitney). Neither ATP nor glucose contents showed such a correlation with the emergence of metastasis. Mean lactate contents of the two dysplasias were 0.1 and 3.5 mumol/g; that of the normal tissue was 0.1 mumol/g. Although these findings have to be verified in a higher number of patients, the present data indicate that elevated lactate levels in primary tumors of head and neck may be associated with a high risk of metastatic spread. With the underlying mechanisms remaining to the investigated, lactate imaging is possibly useful as an early indicator of the malignant potential of tumors in patients.

Autoimmune findings resembling connective tissue disease in a patient with Castleman's disease.

Multicentric angiofollicular lymphnode hyperplasia (multicentric Castleman's disease) may be associated with acute phase reaction and several autoimmune features. Since lymphadenopathy is a common feature in connective tissue disease, a clear distinction between the different disease entities may be difficult. We describe a 26-year-old male patient with predominant cervical lymphadenopathy, hepatosplenomegaly and polyserositis, diagnosed as collagen disease. He showed several autoimmune features including autoimmune haemolytic anaemia, cryoglobulinaemia, positive antinuclear and anti smooth muscle antibodies, serum immune complexes and a sensorimotor polyneuropathy. Under immunosuppressive therapy with prednisolone and azathioprine, only partial remission was achieved. Repeated lymph node biopsy together with the clinical features led to the diagnosis of multicentric Castleman's disease in this patient nine years later. Interleukin-6 (IL-6) seems to play an important role in the pathogenesis of clinical and serum biochemical features in patients with Castleman's disease.

[Interventional techniques in breast diagnosis: ultrasound controlled puncture biopsy]. / Interventionelle Techniken in der Mammadiagnostik: sonographisch gezielte Stanzbiopsie.

From May 1, 1992 to April 30, 1993, we performed 307 ultrasonic guided, high-speed core cut biopsies. In 119 of the 307 women, we dispensed with further surgical and histological procedures when the tentative diagnosis from complementary mammary diagnostic procedures revealed no pathological findings and concurred with the histological results of the core cut biopsy. In 188 women, the biopsy was followed by surgical intervention and correlation of the histological findings. This group of patients showed a sensitivity of 98%, a specificity and positive predictive value of 100%, and a negative predictive value of 91%. If we combine the results of the complementary mammary diagnostics (including the core cut biopsy), then the sensitivity, specificity, and positive and negative predictive values for this surgically and histologically confirmed group of patients reach 100%. In trained hands, the ultra-sonic-guided, high-speed core cut biopsy is a reliable means for determining the histological nature of lesions detected in ultrasonic scans. This technique has been perfected in our facility. Along with preoperative carcinoma detection, it permits us to avoid unnecessary operations when, under defined conditions, there are no pathological findings.

Association between tumor hypoxia and malignant progression in advanced cancer of the uterine cervix.

Experimental tumors contain a significant fraction of microregions that are chronically or transiently hypoxic. Experimental evidence showing that hypoxia (and subsequent reoxygenation) may have a profound impact on malignant progression and on responsiveness to therapy is growing. The clinical relevance of tumor oxygenation in human solid malignancies is under investigation. We have developed and validated a clinically applicable method for measurement of tumor oxygenation in locally advanced cancer of the uterine cervix using a computerized polarographic electrode system. Applying this procedure in patients with cervical cancers

[Stent implantation as a palliative therapeutic measure in stenosing tumors of central airways]. / Stentimplantation als palliative Therapiemassnahme bei stenosierenden Tumoren der zentralen Atemwege.

PURPOSE: Stent implantation was used to treat patient with malignant tracheobronchial obstructions to determine the effectiveness in producing symptomatic palliation. METHODS: 18 patients (15 men and three women; median age 57 years) with malignant tracheobronchial stenosis were treated by application of metal stents (15 Palmaz-, 10 Gianturco-, 4 Wallstents). The indication for stent implantation was given in 13 patients by clinically significant dyspnea, besides in 5 patients by therapy resistant postobstructive pneumonia. RESULTS: In 17 patients correct positioning of the stents was achieved and the symptoms completely disappeared until tumor related death. Median survival was 137 days (min. 10 days to max. 322 days). In one patient symptoms recurred three months after stent implantation. CONCLUSION: The application of metal stents in patient with malignant tracheobronchial obstruction appears to be a useful palliation procedure. The treatment was well tolerated and very effective.

[Upper inflow congestion as initial manifestation of idiopathic mediastinal fibrosis]. / Obere Einflussstauung als Erstmanifestation der idiopathischen Mediastinalfibrose.

In about 90% of superior vena caval obstructions the cause is a neoplasm, generally a carcinoma of the right upper lobe. Fewer than 5 percent are due to inflammatory disease of the mediastinum. A case of idiopathic, fibrosing mediastinitis with occlusion of the superior vena cava is described. The clinical symptoms, radiographic finding, diagnostic and therapeutic aspects are discussed.

Hypoxia and Radiation Response in Human Tumors.

This study demonstrates by an updated analysis of an ongoing prospective study that tumor oxygenation, as measured with a validated standardized polarographic needle electrode method before treatment, powerfully predicts the prognosis of patients receiving radiotherapy for intermediate and advanced stage cancer of the uterine cervix. First evidence for a host component in tumor oxygenation based on a significant correlation between median pO(2) values determined in normal subcutaneous fatty tissue and in cervical cancer is also presented. Further investigations are necessary to clarify whether tumor hypoxia is just a marker of intrinsic tumor aggressiveness or whether the negative impact of tumor hypoxia on survival is related to radiobiological mechanisms caused by hypoxia per se, which may include (1) the reduced oxygen enhancement effect, (2) increased radioresistance due to expression of genes for cell cycle delay and stress proteins, and/or (3) accelerated tumor progression to more radioresistant and metastatic variants by increased genetic heterogeneity.

Assessment of myometrial infiltration and preoperative staging by transvaginal ultrasound in patients with endometrial carcinoma.

In recent years, the incidence of carcinoma of the endometrium has shown an upward trend, such that it is currently the most frequently encountered malignant tumor of the female genital tract. An accurate preoperative diagnosis of the extent and spread of such carcinomas is of crucial importance for the selection of a therapeutic approach appropriate to the stage and infiltration of each particular tumor. In a prospective study of 80 patients with a carcinoma of the endometrium, performed at the Department of Obstetrics and Gynecology of the University of Mainz, we compared the preoperative findings of transvaginal sonography with the postoperative histological results with respect to the following parameters: endometrial thickness, demarcation of the boundary of the endometrium, myometrial infiltration depth and staging. In all of these patients, sonography revealed a distinct increase in the thickness of the endometrium. In all cases, the structure of the endometrium was found to be heterogenous, with an irregular and poorly delineated boundary. Assessments of the depth of tumor infiltration and the tumor staging obtained by transvaginal sonography were found to correlate with the histological findings in 85% and 87.5% of the cases, respectively. Thus, in cases of endometrial carcinoma, transvaginal sonography has an essential role to play in devising an individualized operative treatment program that takes into account the extent, spread and stage of the tumor.

Tumor vascularity--a novel prognostic factor in advanced cervical carcinoma.

OBJECTIVE: In the search for the optimal treatment of advanced cervical cancer, the identification of valid prognostic factors obtainable without histopathologic investigation of the entire tumor and the locoregional lymph nodes is of paramount interest. Tumor microvessel density has recently been demonstrated to correlate strongly with disease aggressiveness in breast cancer and other malignancies. METHODS: We established a computerized image analysis system to quantify tumor microvascularity by using the closest-individual method, which determines the distribution of distances from random points within the tumor to the closest microvessel (DTCMV). Tumor microvascularity was assessed in paraffin sections of two cylindrical 2 x 20-mm core biopsies obtained transvaginally from the 12 and 6 o'clock positions of each tumor and then immunohistochemically stained for Factor VIII-related antigen. The oncologic relevance of tumor vascularity is studied in an open prospective trial. RESULTS: Tumor vascularity was quantified in 42 patients with cervical cancers > 3 cm in largest diameter, FIGO stages Ib-IVa. This new parameter representing pathophysiological tumor-host interactions was independent of various other patient and tumor characteristics, including age, FIGO stage, tumor size, differentiation, lymph node metastases and lymphatic space involvement. Thirty-nine patients were treated with curative intent either by primary surgery (n = 22) or radiation (n = 17). After a median observation time of 18 months (range 4-41 months), the patients with higher tumor vascularity (mean DTCMV < 83 microns) had significantly shorter disease-free (P = 0.025) and overall (P = 0.032) survival probabilities than patients with lower tumor vascularity (mean DTCMV > or = 83 microns). Cox regression analysis identified tumor vascularity as the strongest independent prognostic factor in this group of patients. CONCLUSIONS: The assessment of tumor microvascularity by computerized image analysis of defined tumor biopsies could become a novel means of predicting tumor aggressiveness in non-early cervical cancer.

[Effect of the proliferation rate on the course of node negative breast carcinoma]. / Einfluss der Proliferationsrate auf den Krankheitsverlauf von nodalnegativen Mammakarzinomen.

In 250 patients with node-negative breast cancer and no systemic adjuvant therapy the impact on the prognosis of the variables age, histological tumour type, tumour size, histological grade, receptor status and localisation of the tumour within the breast, was studied. Patients were followed over a mean period of 60 (range 7-164) months. In a subset of 124 cases additional examination of the growth fraction rate, detected by immunohistochemical determination of antibody Ki-67 and semiquantitative measurement of the stained tumour cell nuclei was performed. In 43 cases, measurement of S-phase fraction by flow cytometry was also performed. By univariate analysis, the histological tumour type (ductal/non-ductal), histological grade and growth fraction rate (< = 20%/> 20% tumour cell nuclei stained by antibody Ki-67) were found to exert a significant influence on distant disease-free and overall survival. Cox' multivariate regression exhibited histological tumour type and growth fraction rate to be independent predictors of distant disease-free and overall survival. Additionally, age was found to be an independent variable of distant disease-free survival. Measurement of growth fraction rate by immunohistochemical detection of Ki-67 antigen is a fairly simple and easily applicable procedure. It should be discussed whether a growth fraction rate of more than 20% could be an indication for adjuvant chemotherapy in patients with node-negative breast cancer.

[In vitro NMR spectroscopy of healthy, pathologically changed and carcinomatous breast tissue samples correlated with histological findings]. / In-vitro-NMR-Spektroskopie an gesunden, mastopathisch veränderten und karzinomatös befallenen Brustdrüsengewebsproben, korreliert mit histologischen Befunden.

Of 57 patients with clinically suspected mamma carcinoma 121 samples were analysed by in vitro 1H-NMR spectroscopy at 300 MHz and correlated with histological data. Within the relevant spectral region between 2.7 and 4.1 ppm strong signals were observed from fat, (phosphoryl-) choline, (phospho-) creatine, and carnitine. Furthermore, with high regularity, 8 weak, partly overlapping signals were resolved and attributed to glucose, glycine, threonine, serine, inositol, and sucrose. Their intensities were determined by an iterative fitness program. From the intensity ratios, different kinds of tissue could be distinguished based on spectroscopic criteria. Healthy or mastopathically modified tissue could be discriminated from more than 50% carcinoma affected tissue with a specificity of better than 99.5%. This fact is explained by the lower content of fatty acids in the malignant tissue. Differences between spectra of healthy of mastopathically affected tissue were only small.

Are pelvic side-wall recurrences of cervical cancer biologically different from central relapses?

BACKGROUND: By using the Combined Operative and Radiotherapeutic Treatment (CORT) procedure, pelvic side-wall recurrences of gynecologic malignancies arising in a previously irradiated pelvis may be locally controlled. Local control of central relapses may be achieved by exenteration alone. If, in cervical cancer, both relapse patterns are biologically different (as hypothesized by some investigators), distinct disease courses after local treatment may be expected. METHODS: Since June, 1989, 32 pelvic recurrences of cervical cancer were treated for local control in this institution. The median size of the recurrent tumors was 5 cm (range, 2-9 cm); 84% of the patients had been extensively irradiated in the pelvis. Therapy of 14 centrally located recurrences was exenteration alone. In 18 patients with relapses fixed to the pelvic wall and histologically confirmed intralesional resection planes, the CORT procedure was applied. RESULTS: After a median observation of 24 months (range, 5-48 months) 7 patients with central recurrences and 11 patients with pelvic wall recurrences had progressive disease in the pelvis and/or distantly. The site of recurrent tumor progression was similar in both groups. Stratified Kaplan-Meier and univariate Cox regression analysis identified recurrent tumor size, age, and recurrence-free intervals, but not relapse location as prognostic factors. Only size of the recurrent tumor significantly influenced survival in the multivariate Cox analysis. CONCLUSIONS: These results suggest that central and pelvic wall recurrences of cervical cancer do not exhibit pronounced biologic differences. Patients with large (> or = 5 cm) recurrences have a poor prognosis in spite of extended radical treatment irrespective of tumor location. Efforts should be made to detect isolated pelvic relapses at a smaller tumor size to enhance the chance for long term survival after local control by exenteration and CORT.

Value of routine abdominal and lymph node sonography in the follow-up of breast cancer patients.

OBJECTIVE: The aim of this study was to review usefulness and intervals for abdominal sonography during the follow-up of breast cancer patients. Additionally, we assessed the value of regional lymph node sonography in patients with possible locoregional recurrence. SUBJECTS: Retrospectively, 2657 abdominal ultrasound examinations of 414 patients and 299 sonographic examinations of the regional lymph nodes in 227 patients after surgical treatment for breast cancer were evaluated. RESULTS: Follow-up abdominal sonography revealed metastases in 6.8% of patients, and in 1% of examinations. There was no dependence on the initial T- or N-stage. At sonography of the regional lymph nodes in patients with suspicious palpatory findings metastatic nodes were found in 15.9% of patients, and in 12% of examinations. CONCLUSION: Risk-adapted follow-up intervals for abdominal sonography cannot be proposed, regular examinations are not recommended. Lymph node sonography is useful and promising in the evaluation of suspicious palpatory findings.

[Reliability of imaging procedures in multi-visceral gynecologic operations of the pelvis]. / Zuverlässigkeit bildgebender Untersuchungsverfahren bei multiviszeralen gynäkologischen Operationen im kleinen Becken.

Between March 1989 and December 1992, a total of 85 pelvic exenterations were performed in the Department of Gynaecology and Obstetrics of the University of Mainz. To assess the accuracy of preoperative Magnetic Resonance Imaging (MRI) and Computer Tomography (CT) with regard to tumour localisation and spread, the results of 28 MRI and 14 CT examinations were compared with the postoperative histological findings. For this widely varying patient group that had undergone a broad range of previous treatments, MRI produced an accurate forecast in 56% of cases (CT, 36%). In 33% of the patients tested, the diagnosis based on MRI was partially correct (CT, 43%), whereas the MRI results fundamentally disagreed with the actual findings in 11% of cases (CT, 21%). We conclude that both MRI and CT are of great value in the planning of operations and for informing patients about their condition; however, in individual cases, an intraoperative quick-section diagnosis is necessary to provide details of tumour spread. If the extent of tumour spread is uncertain, the results of CT and/or MRI should not deter the surgeon from the radicality of the planned operative intervention.

[Extrapulmonary manifestation of sarcoidosis in the breast]. / Extrapulmonale Manifestation der Sarkoidose in der Brustdrüse.

Sarcoidosis is, pathologico-anatomically speaking, a granulomatous disease that can involve almost any organ. However, a histologically confirmed involvement of the mammary gland after exclusion by differential diagnosis of granulomatous mastitis and mycobacterial or fungal sonographic and mammographic image would rather suggest a fibroadenoma of the breast. However, a malignant process such as for instance a mucinous carcinoma of the breast should always be excluded by differential diagnosis, especially if there are concomitant general symptoms of disease.