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

Intratumoral pO2 predicts survival in advanced cancer of the uterine cervix.

Experimental evidence suggests that the hypoxic fraction in a solid tumor may increase its malignant potential and reduce its sensitivity towards non-surgical treatment modalities (e.g. standard irradiation, certain anticancer agents). However, the clinical importance of tumor hypoxia remains uncertain since valid methods for the routine measurement of intratumoral O2-tensions in patients have so far been lacking. A clinically applicable standardized procedure has been established which enables the determination of intratumoral oxygen tensions in advanced cervical cancers by use of a computerized polarographic needle electrode histography system. Tumor oxygenation as measured by this method represents a novel tumor feature which can be individually determined for each tumor and which is independent from other known oncological parameters. The results of an interim analysis of an open prospective clinical trial to evaluate the prognostic significance of tumor oxygenation based on the survival data of the first 31 patients are presented. Fifteen patients have been treated by primary radiation, 11 patients received multimodality therapy including irradiation. After a median follow-up of 19 months (range 5-31 months), Kaplan-Meier-life table analysis showed significantly lower survival and recurrence-free survival for patients with a median pO2 of < or = 10 mmHg compared to those with better oxygenated tumors (median pO2 > 10 mmHg). The Cox proportional hazards model revealed that the median pO2 and the clinical stage according to the FIGO are independent, highly significant predictors of survival and recurrence-free survival. We conclude from these preliminary results that tumor oxygenation as determined with this standardized procedure appears to be a new independent prognostic factor influencing survival in advanced cancer of the uterine cervix.

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.

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.

Immunohistochemical demonstration of carcinoembryonic antigen (CEA) in 120 mammary carcinomas and its correlation with tumor type, grading, staging plasma-CEA, and biochemical receptor status.

Antisera to CEA were used for the immunohistochemical localization and quantification of this antigen in 120 Bouin-fixed, paraffin embedded mammary carcinomas. These results were compared to tumor type, grading, staging, biochemical receptor status, cytosolic CEA-levels of the same tumors, and preoperative plasma CEA-levels. Mammary carcinomas were usually characterized by a low percentage of CEA-positive tumor cells: 50.9% of the cases contained more than 5% CEA-positive tumor cells and were therefore defined as being CEA-histopositive in this study. A relation could be shown between CEA-histopositivity and the histologic tumor type. The majority of invasive lobular carcinomas, tubular, and cribriform carcinomas was CEA-negative (72%). Conversely, 70% of invasive ductal carcinomas were CEA-positive. There was a significantly higher percentage of CEA-histopositivity in grade III tumors than in grade I/II carcinomas. The results obtained by quantification of the immunohistochemical staining of CEA were positively correlated with the results obtained by cytosolic CEA-assay. The overall concordance between tissue and plasma determinations of CEA was found to be 57.1%. A positive trend could be found between CEA-positivity and staging. However, no correlation was observed between CEA-positivity and estrogen receptor status.

[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.

[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.

[The feasibility of magnetic resonance tomography in the diagnosis of non-palpable breast tumors]. / Möglichkeiten der Magnetresonanztomographie in der Diagnostik nicht palpabler Mammatumoren.

This study deals with the role of MRI in elucidating clinically silent lesions of the breast with indeterminate changes on mammography. MRI localisation of suspected lesions was possible in all cases by using double coils after contrast enhancement of the glandular tissue, independent of the findings on mammography. Inability to demonstrate micro-calcification did not prove a disadvantage. MRI cannot provide a definite tissue diagnosis, since there is overlap between the appearances of malignant and benign lesions.

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.

Influence of chemotherapy on hormone receptor concentration in a xenotransplanted endometrial cancer.

There is growing evidence that chemotherapy may influence the hormone receptor capacity in human carcinomas. The consideration of this assumption may be of importance for the therapeutic management of tumors with metastatic spread which underwent previous adjuvant chemotherapy. Therefore we investigated the influence of six different kinds of chemotherapy on the hormone receptor concentration and the percentage of receptor positive cells in xenotransplanted endometrial cancer. Our results can be summarized as follows: (1) We find neither a significant decrease in hormone receptor capacity after chemotherapeutic treatment (biochemical determination), nor do we see a decrease in the percentage of ER/PR pos. cells (immunohistochemistry). (2) On the other hand, there is no increase in hormone receptor concentration inducible by chemotherapy and no increase in ER/PR pos. cells immunohistochemically.

[Prognostic factors in medullary breast cancer]. / Prognostische Faktoren beim medullären Mammakarzinom.

In 55 patients with medullary carcinoma of the breast follow-up data over an average period of 68.1 +/- 35.3 months were recorded. The histological slides of all tumors were retrospectively classified according to the same criteria. The parameters registered were: tumor-size, histological grading, receptor status, necrosis of tumor tissue, cellularity of the stroma, status of axillary nodes, reactive changes of axillary nodes and tumor invasion of lymphatic vessels. The importance of each parameter registered for disease-free survival and overall survival was calculated statistically using the log-rank-test. Of all parameters, only the nodal status of the axilla proved prognostically significant. Metastases of axillary nodes were demonstrable in only 31% of all MC. The incidence of nodal involvement proved to be less than in non medullary breast cancers. In 15 (27.3%) of the patients, progression of the tumor occurred. All women with distant metastases i.e. 12 (21.8%) died of the disease, whereas patients with only local recurrence of breast cancer are still alive. 72.7% of the patients showed relapse-free survival. Other parameters of proven prognostic value in breast cancers like receptor status and histological grading were of no relevance to the survival in MC. Prediction of prognosis depends on the correct classification of the tumor subgroup according to strict microscopical and macroscopical criteria.

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.

[Posterior exenteration with plastic reconstruction in advanced vulvar cancer]. / Die hintere Exenteration mit plastischer Wiederherstellung beim fortgeschrittenen Vulvakarzinom.

Between 1984 and 1990, twenty-four patients suffering from advanced primary (7) or recurrent (17) valvular carcinoma were treated by posterior exenteration and myocutaneous reconstruction of the defect. During a follow-up of 34 months, the overall survival was 49%. Eight patients died. Tumour diameter and tumour-free margins of the resected specimens were the most important prognostic factors. In all cases, an improved quality of life could be achieved by the operation. It is concluded that, even in extremely difficult situations, posterior exenteration, followed by plastic reconstruction entails an essential benefit for the patient.

Differential loss of E-cadherin expression in infiltrating ductal and lobular breast carcinomas.

The epithelial-specific cell-cell adhesion molecule E-cadherin was analyzed immunohistochemically on tissue sections of 89 human primary infiltrating breast carcinomas, using monoclonal antibodies 6F9 (for cryostat sections) and 5H9 (for cryostat and paraffin sections). The tumors included 41 well and moderately differentiated infiltrating ductal carcinomas (IDCs) most of which (78%) showed strong linear staining at the cell borders at a level, as high as luminal cells of normal mammary glands. The 26 poorly differentiated, more highly malignant IDCs examined also were all positive for E-cadherin, although a higher proportion of them (54%) showed reduced staining, which was heterogeneous and dotted over the cell borders. In contrast, 19 of 22 infiltrating lobular carcinomas (ILCs), which were either of the dispersed (classical), solid, or the mixed type, did not express E-cadherin, whereas three cases showed weak staining. In situ lesions of ILCs and pure lobular carcinoma in situ (four cases) were all E-cadherin negative, whereas intraductal carcinomas (11 cases) exhibited mostly strong staining. The results were confirmed by Western blotting. The data indicate that loss of E-cadherin expression is an early event in the formation of the lobular type of breast carcinomas. The absence of E-cadherin signifies a partial loss of epithelial differentiation and may account for the extended spread of lobular carcinoma in situ and the peculiar diffuse invasion mode of ILC. The generation of dedifferentiated IDCs can only in part be correlated with reduced expression of the intercellular adhesion molecule E-cadherin. Other factors are obviously also involved during invasion of this carcinoma type.

[MR tomography of cystosarcoma phylloides. A case report]. / MR-Tomographie des Cystosarcoma phylloides. Ein Fallbeispiel.

This is the first time a report is being published in medical literature on the MR imaging of a cystosarcoma phylloides tumour after intravenous contrast agent administration. MR tomography enabled complete visualisation of the tumour even in the region close to the thoracic wall, as well as clear delineation against the non-tumorous glandular tissue. This means that the limits along which complete extirpation of the tumour could be performed, were determined accurately before the operation, such complete removal being imperative to avoid tumour recurrence.

Immunohistochemical evaluation of growth fractions in human breast cancers using monoclonal antibody Ki-67.

We performed immunohistochemical analyses of 568 breast/cancer specimens using Ki-67, a monoclonal antibody specific for a nuclear antigen present in proliferating cells. The specimens were divided into three groups (I-III) according to the proportion of Ki-positive cells detected. These findings were compared with features of tumor extension as well as with certain prognostic variables. There was no detectable correlation between Ki-67 reactivity and either tumor size or node involvement. In contrast, a statistically significant correlation was found between Ki-67 reactivity and tumor grading, in that G-I tumors had small growth fractions, while a high proportion of G-III tumors exhibited strong (group III) Ki-67 positivity. When growth fractions were compared with biochemical receptor status, a significant difference was detected between tumors with negative and positive findings for receptors. The same co-variation was observed with respect to the overexpression of neu-protein P185, with most neu-positive carcinomas being strongly positive for Ki-67 (group III). In the relapse cases examined, there was a close correspondence between Ki-67 reactivity and the duration of the disease-free period. Long-term observation of patients with primary breast carcinoma revealed that, with regard to overall survival, the less reactive groups I and II differed significantly from group III. With respect to disease-free survival, no difference was detectable between Ki-groups II and III, but when these two groups together were compared with group I, a significant trend emerged. Similar results for both overall and disease-free survival were obtained for subgroups of pT2 and G-II carcinomas as well as for receptor expression.(ABSTRACT TRUNCATED AT 250 WORDS)

[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.