Sensitivity, specificity and predictive values of breast imaging in the detection of cancer.

In an observational follow-up study we determined whether the combined use of mammography and breast ultrasonography is an appropriate diagnostic tool to select patients with symptomatic breast disease who need additional pathological evaluation. Mammography and ultrasound were used as complementary diagnostic modalities in 3014 consecutively referred and mainly symptomatic patients. Sensitivity, specificity, predictive values and likelihood ratios were calculated according to standard procedures. Virtually complete follow-up was obtained by correlating the radiological diagnosis with clinical records, final pathological findings, records from the Cancer Register and data from questionnaires sent to the general practitioners of all the referred patients. After an average follow-up period of 30 months, the sensitivity for breast cancer detection was 92.0% and the specificity 97.7%. A positive predictive value of 68.0%, a negative predictive value of 99.6%, a positive likelihood ratio of 40 and a negative likelihood ratio of 0.08 were found. The mean diagnostic delay as a result of false negative examinations was 9 months (range 0-20 months). We conclude that breast imaging in routine daily practice, consisting of the integral use of mammography and ultrasonography, is an appropriate tool in the detection of cancer and should be included in the work-up of symptomatic breast disease.

Efforts to improve interobserver agreement in histopathological grading.

The present study aimed to assess the interobserver variation in histopathological grading of 88 slides by four experienced pathologists who, before the start of the study, reached consensus about the method of grading through a joint session behind a discussion microscope. The results were compared with two previous studies, the first assessing the observer variation under normal conditions, the second doing the same after theoretical agreement about which morphological characteristics were relevant for grading. In the present study the pathologists first made a provisional diagnosis on low power view, followed by a final diagnosis on high power view, scoring various morphological characteristics as in the second study. The unweighted and weighted group kappa values for the final diagnosis were 0.41 and 0.71 respectively in the present study (after the consensus meeting), compared to 0.33 and 0.70 respectively in the second study (after only theoretical consensus), and 0.28 and 0.55 in the first study (without consensus). We conclude that a consensus meeting appears to be useful to improve the interobserver agreement.

Sources of interobserver variation in histopathological grading of cervical dysplasia.

The present study aimed to assess where the interobserver variation in grading cervical dysplasia stems from. Four experienced pathologists examined 93 histological slides, after they agreed on which morphological characteristics should be considered relevant for grading. They scored 6 morphological characteristics for each slide and assigned it to a degree of dysplasia. Compared to a previous study, the interobserver variation showed a statistically significant improvement: the weighted group kappa value increased from 0.55 to 0.69. For the scores of the individual characteristics considerable interobserver variation was observed: weighted group kappa values ranged from 0.28 to 0.49. The pathologists slightly differed in which characteristics they considered most important for their grading. The agreement on the degree of dysplasia turned out to be better than the agreement on the morphological characteristics on which this diagnosis is based. In the discussion, a few explanations for this paradoxical finding are put forward.

Immunohistochemical analysis of oestrogen and progesterone receptors of eutopic and ectopic endometrium in the rabbit model of endometriosis: the effect of pregnancy.

Oestrogen receptors (ER) and progesterone receptors (PR) were measured in the rabbit model of endometriosis in eutopic and ectopic endometrium of pregnant animals (n = 7) and controls (n = 7). Immunostaining of cryostat sections of ectopic and eutopic endometrium was performed using monoclonal antibodies against ER and PR. Levels of ER and PR were 'evaluated' in a semi-quantitative manner using a modified histoscore. The ER and PR content in stromal and glandular cells was not different in eutopic and ectopic endometrium in either pregnant or non-pregnant control animals. There was a significant difference between the PR content of the glandular epithelium of pregnant animals and controls for both eutopic (P less than 0.02) and ectopic (P less than 0.001) endometrium. The disappearance of glandular PR and the persistence of stromal PR suggest that the function of the glandular endometrium is mediated by the paracrine and autocrine action of stromal cells. The decidual cells are likely to produce substances that may be of importance in embryo implantation and early pregnancy.

The effect of beta-carotene on the regression and progression of cervical dysplasia: a clinical experiment.

In order to gain insight into the causality of the relation between beta-carotene and cancer, we performed a randomized placebo-controlled trial in which the effect of beta-carotene on the regression and progression rates of cervical dysplasia were examined. The experimental group (n = 137) received a supplemental dose of 10 mg of beta-carotene daily for 3 months. The control group (n = 141) received placebo capsules. As the outcome parameter, two definitions of regression and progression were used, which were based on the degree of dysplasia before and after the medication period. The number of patients who showed progression was too small to allow conclusions. No effect of beta-carotene on the regression percentages was observed: OR = 0.68 (95% CI: 0.28-1.60) using the broad definition; and OR = 1.22 (95% CI: 0.43-3.41) with the strict definition. A secondary analysis, in which the effect of the total intake of beta-carotene (diet + medication) on the regression percentages of cervical dysplasia was studied, did not show a positive effect either. The paper discusses to what extent issues in the study design may have masked a potential effect and how our results affect the evidence for a causal relation between beta-carotene and cancer.

Mitigation of pulmonary oxygen toxicity in premature lambs with intravenous antioxidants.

Deficiencies of antioxidants and increased free radical generation may explain the high incidence of bronchopulmonary dysplasia in premature infants. Long-acting antioxidants such as polyethylene glycol (PEG) conjugated superoxide dismutase (SOD), and catalase might modify this process. We delivered 32 premature lambs, 16 pairs of twins, by cesarean section at 125-141 days of gestation (term 146 days) and stabilized them on ventilators in normocapnic hyperoxia for a period of 8 h. One lamb of each twin pair received an intravenous dose of 7,500-50,000 IU/kg of PEG-SOD and of 37,500-1,000,000 IU/kg of PEG-catalase at birth. Their siblings acted as controls. Mean airway pressure, arterial pressure, and heart rate were recorded continuously. Arterial blood gases and pH were obtained every 30 min. After sacrifice, standardized lung biopsies were prepared for quantitative morphometrics and electron microscopy. Administration of PEG antioxidants at birth reduced the influx of neutrophils and macrophages into the lung and damage to arterioles, bronchiolar mucosa, and type II pneumocytes without major changes in alveolar surface area or pulmonary function. These effects were dose-related and detectable even at the lowest doses of PEG antioxidants administered.

Intestinal lymphangiectasia without protein loss in a child with abdominal pain.

A 7-year-old white girl presented with recurrent abdominal pain because of gastroesophageal reflux. At endoscopy, we found intestinal lymphangiectasia in the duodenal biopsy. There were no physical signs, nor any laboratory evidence of enteric protein loss.

Interobserver variation in histopathological grading of cervical dysplasia.

In order to assess the variability among histopathologists in grading cervical dysplasia, four experienced histopathologists examined the same set of 106 biopsy specimens and assigned them to one of five diagnostic categories. These were: no dysplasia, mild dysplasia, moderate dysplasia, severe dysplasia and carcinoma in situ. The histopathologists did not discuss the grading criteria beforehand. There was considerable disagreement among the pathologists: unweighted group kappa 0.28, weighted group kappa 0.56. It appeared that all grades of dysplasia were equally difficult to distinguish from adjacent categories. Various explanations for this interobserver variation are put forward.

Granular cell tumor of the breast.

Three cases of granular cell tumor of the breast are reported. Granular cell tumor of the breast is a rare benign tumor with a malignant appearance both clinically, radiologically and macroscopically. The cytology is quite characteristic although the tumor clinically often resembles a carcinoma. Frozen section can be misinterpreted, unnecessary mastectomy or axillary dissection can be prevented by careful cytological examination.

A rabbit model of endometriosis.

Since not all problems in endometriosis can be studied in the human, there is need of an animal model. We transplanted endometrial tissue of the rabbit into the peritoneal cavity and studied the changes after 12 weeks. At that time the endometrial implants in the rabbit had become cystic structures. The macroscopic and histologic appearance was consistent with endometriosis. Hormonal supplementation turned out not to be necessary. Microsurgical techniques prevented the formation of tubo-ovarian adhesions. This makes the rabbit model suitable for studying the influence of endometrial implants on fertility.

Quantification of oestrogen receptors in breast cancer: radiochemical assay on cytosols and cryostat sections compared with semiquantitative immunocytochemical analysis.

A radiochemical oestrogen receptor assay on cytosol was correlated with a radiochemical and an immunohistochemical oestrogen receptor assay using cryostat sections from 50 breast cancer specimens. Oestrogen receptors were reliably quantitated in 6 micron cryostat sections with Scatchard analysis using radiolabelled oestradiol, and a good quantitative and qualitative relation with cytosol oestrogen receptor assay was found. Parallel sections were used for routine histological tissue verification and for direct comparison with immunohistochemistry for oestrogen receptor. Specific immunoperoxidase staining with a rat monoclonal antibody was scored by semiquantitative evaluation of the staining intensity of cancer cell nuclei. Oestrogen receptor scoring was highly reproducible when performed by the same observer. The semiquantitative immunohistochemical oestrogen receptor score correlated significantly better with the radiochemical assay on sections than with cytosol assay. Oestrogen receptor in breast cancer can be reliably assayed by semiquantitative evaluation of cryostat sections immunostained for oestrogen receptor, but only if the procedure is adequately standardised. The results underline the importance of cellular heterogeneity as a cause of variation in oestrogen receptor assay evaluation in breast cancer.

A comparison of high-frequency oscillation superimposed onto backup mechanical ventilation and conventional mechanical ventilation on the distribution of exogenous surfactant in premature lambs.

Twenty-six premature lambs were treated by tracheal instillation of [14C]labeled natural sheep surfactant before the onset of breathing or after the establishment of respiratory distress syndrome 30 min after birth. Half of both groups were subsequently ventilated for 3 h with 100% O2 by conventional mechanical ventilation (CMV) and half by high frequency oscillation superimposed onto backup mechanical ventilation (HFOV). Mean airway pressure, arterial blood pressures, and heart rate were recorded continuously. Arterial blood gases and pH were obtained every 15 min. After sacrifice, the distribution of radiolabeled surfactant was quantified and alveolar expansion was evaluated by morphometrics. At comparable oxygenation, mean airway pressures were significantly lower in the lambs treated with surfactant at birth (groups CMV-B and HFOV-B) than in lambs on CMV and treated with surfactant during RDS (group CMV-R). Mean airway pressures in both groups of lambs on HFOV (groups HFOV-B and HFOV-R) were comparable at values lower than in group CMV-R and higher than in group CMV-B. The distribution of radiolabeled surfactant was more homogeneous in lambs treated at birth and not different for both types of ventilatory assistance. Morphometrics demonstrated significantly better expansion of the alveoli of lambs ventilated with HFOV than of those on CMV, irrespective of the timing of surfactant administration. These results indicate that prophylactic surfactant administration at birth leads to a better distribution of surfactant than rescue treatment with surfactant after the establishment of respiratory distress syndrome and is not affected by a subsequent type of ventilatory assistance.(ABSTRACT TRUNCATED AT 250 WORDS)

Progression of a benign epithelial ampullary tumor to adenocarcinoma.

Benign tumors of the extrahepatic biliary ducts are rare. The high recurrence rate following local resection of these benign tumors is well known, but the development of one into a malignant tumor has received little attention. The recurrence 4 years after local excision of a benign periampullary tumor that developed into a well-differentiated papillar adenocarcinoma is described in this case report. Radical resection was performed by means of a pancreatoduodenectomy. The literature concerning the progression of benign extrahepatic tumors to adenocarcinomas is reviewed.

Primary malignant fibrous histiocytoma of the liver--a case report with immunocytochemical observations.

A case of a primary sarcomatous tumour in the liver of an elderly female is reported. The tumour consisted of bundles of spindle cells focally in a storiform pattern, intermingled with bizarre giant cells. Immunocytochemically, carcinoembryonic antigen, alpha-fetoprotein, keratin, desmin and type IV collagen could not be demonstrated. Most tumour cells, however, expressed vimentin, whereas a granular cytoplasmic immunoreactivity for alpha-1-antitrypsin and alpha-1-antichymotrypsin was shown in the giant cells. Ultrastructurally the tumour cells did not show any characteristics of epithelial derivation. The morphological and immunocytochemical data justify the conclusion that the tumour should be classified as a malignant fibrous histiocytoma.

The basement membrane in endometriosis.

Disruption of the BM can be found in metastasizing neoplasms. It has been suggested that also in some patients with endometriosis the BM is lacking, depending on the severity of disease. Thus studying the aspect of the BM would enable characterization of the disease and possibly have a prognostic value with respect to (medical) treatment. We studied the aspect of the BM in 16 patients with endometriosis, 4 in each of the stages of the rAFS classification, and demonstrated all endometriosis lesions in all patients to be surrounded by a continuous and intact BM. We conclude that studying the BM in endometriosis offers no advantage in determining the prognosis of the disease and its possible response to therapy.

Patterns of basement membrane deposition in benign and malignant breast tumours.

We have examined epithelial basement membranes in tissue samples of seven normal breasts, 64 benign breast lesions and 63 malignant breast tumours by immunocytochemistry, using polyclonal antisera specific for type IV collagen. In normal breast tissue as well as in all benign tumours a continuous basement membrane was found at the epithelial stromal interface. In benign proliferative lesions, epitheliosis and papillomatosis could be more accurately distinguished with basement membrane staining. This approach also facilitated the differentiation between sclerosing adenosis and tubular carcinoma, since the tubules in sclerosing adenosis are surrounded by a continuous basement membrane whereas in tubular carcinoma basement membranes are almost entirely absent. In radial scar lesions the tubules were always surrounded by intact basement membranes, which underlines the fact that these are benign lesions. In breast carcinoma we could not detect a relationship between histological grade and the extent of basement membrane deposition. However, in different tumour types the basement membrane alterations varied. In infiltrating lobular carcinoma of the alveolar type, fragments of basement membrane were found, whereas in the classic and trabecular type, basement membranes were absent, suggesting that the alveolar type may be an intermediate phase in the progression of lobular carcinoma in situ to infiltrating lobular carcinoma. It is concluded that basement membrane immunocytochemistry, using antibodies to type IV collagen, is useful in the differentiation between benign and malignant breast lesions and in the classification of breast neoplasms.

Prevention of oxygen toxicity with superoxide dismutase and catalase in premature lambs.

The use of high oxygen concentrations and high mean airway pressures during mechanical ventilation of premature newborn infants with respiratory distress syndrome leads in 20%-30% of the survivors to chronic lung disease. This study explores if exogenous polyethylene glycol conjugated superoxide dismutase (PEG-SOD) and catalase (PEG-CAT) mitigate oxygen toxicity in premature lambs with respiratory distress syndrome. Six pairs of premature lambs were delivered by cesarean section and treated by tracheal instillation of 60 mg natural sheep surfactant/kg/body weight. After birth, all lambs were ventilated with 100% oxygen, and one of each pair received a single intravenous injection of 1 million U/kg PEG-CAT and 50,000 U/kg PEG-SOD. At 8 h of age or after respiratory failure was established, the lambs were killed and the lungs were removed intact. Lung damage was assessed by microscopy. The arterial blood gases, pH, and mean airway pressures of the lambs treated with PEG-SOD/PEG-CAT did not differ from those of the controls. Mean PaO2 was greater than 140 mmHg during the first 4 h of the experiments. In the lambs treated with PEG-SOD/PEG-CAT, SOD and CAT levels were very high during the study period and less bronchiolar epithelial damage and lung hemorrhages were found at microscopy.

Magnetic resonance imaging of the normal female pelvis.

9 healthy volunteers were examined by magnetic resonance imaging in order to describe the anatomy of the normal female genital tract as seen by this technique. The visualization of the bony and pelvic skeleton and the muscles surrounding these structures is excellent. Due to high contrast resolution relatively small structures like the femoral blood vessels can be positively identified. Imaging of the small bowel is disappointing. Visualization of the rectum and sigmoid colon is relatively good. In the uterine wall three distinct layers can be identified. An interpretation of the origin of these layers based on comparison with macroscopic and microscopic examination of sections of uterine tissue is given. Further research is needed to demonstrate possible cyclic changes in the appearance of the uterus. The ovaries could not be identified with certainty.

Successful treatment of tuberculous brain abscess.

A case of tuberculous brain abscess occurred in spite of 4 months' treatment of pulmonary tuberculosis with a triple drug anti-tuberculous regimen. Surgical removal and further chemotherapy were successful.

Adenocarcinoma of the endometrium with glassy-cell features--immunohistochemical observations.

A case of adenocarcinoma of the endometrium with glassy-cell features is reported and histochemical and immunohistochemical data are provided together with a review of the relevant literature. The microscopical features of glassy-cell carcinoma appear to be highly characteristic and diagnostic. The tumour is considered to be a distinctive and poorly differentiated type of adenosquamous carcinoma originating in the cervix or the endometrium. We studied the expression of several differentiating characteristics and detected the presence of secretory component and lysozyme in some tumour cells, whereas keratin and prekeratin were consistently absent. Since in normal uterine mucosa immunoreactivity for lysozyme is restricted to endocervical and isthmic epithelium, the presence of this antigen in the tumour would favour an endocervical or isthmic origin of the tumour cells. Furthermore our results suggest that this peculiar type of tumour is not poorly differentiated and that the assertion that glassy-cell carcinoma is a variant of adenosquamous carcinoma is open to doubt.