Neutral effect of ultra-low-dose continuous combined estradiol and norethisterone acetate on mammographic breast density.

OBJECTIVE: To compare the effects of two different ultra-low doses of continuous combined hormone therapy and placebo on mammographic breast density in postmenopausal women. METHODS: A subpopulation of 255 postmenopausal women from the CHOICE trial were randomly assigned to 0.5 mg 17beta-estradiol (E2) + 0.25 mg norethisterone acetate (NETA), 0.5 mg E2 + 0.1 mg NETA, or placebo. Women using hormone replacement therapy (HRT) up to 2 months prior to the study were excluded; 154 women fulfilled the inclusion criteria. Mammograms were performed at baseline and after 6 months. Breast density was evaluated by visual classification scales and a computer-assisted digitized technique. RESULTS: No significant differences were detected between the active treatment groups and the placebo group in the digitized quantification. The mean baseline values for density around 20% were unchanged after 6 months. Also, visual classifications showed no increase in breast density in any study group. CONCLUSION: In contrast to currently available bleed-free regimens, the new ultra-low-dose combination of 0.5 mg E2 and 0.1 mg NETA seems to have very little or even a neutral effect on the breast. Both digitized quantification and visual assessment of breast density were unchanged after 6 months. Larger prospective studies should be performed to confirm this new finding.

Testosterone addition during menopausal hormone therapy: effects on mammographic breast density.

OBJECTIVE: To study the effect on mammographic breast density of testosterone addition during combined estrogen/progestogen therapy in postmenopausal women. METHODS: A prospective, randomized, double-blind, placebo-controlled trial. A total of 99 women were given 2 mg 17beta-estradiol and 1 mg norethisterone acetate in combination with either a testosterone patch (300 mug/24 h) or a placebo patch. Mammographic breast density at baseline and after 6 months was assessed by visual classification scales and by digitized quantification. A standardized questionnaire was used to quantify subjective breast symptoms. RESULTS: Visual classifications showed an increase in mammographic density in 18-30% of the women, with no significant differences between the treatment groups. The mean increase of the area of dense breast during treatment according to digitized assessment was 7.4% in the placebo group and 5.4% in the testosterone group. Breast symptoms showed a positive association with the increase in density (r(s) = 0.34; p < 0.01). Symptoms were most pronounced at 2 months of treatment. Density, both at baseline (r(s) = -0.35; p < 0.01) and change during treatment (r(s) = -0.28; p < 0.01) showed a negative association with free testosterone levels. CONCLUSION: The addition of testosterone does not appear to influence mammographic breast density in women concurrently treated with a common oral estrogen/progestogen regimen for a period of 6 months.

Expression of Syndecan-1 in histologically normal breast tissue from postmenopausal women with breast cancer according to mammographic density.

OBJECTIVE: To analyze the expression of Syndecan-1 in dense and non-dense human breast tissue. METHODS: Specimens of histologically normal tissue were obtained from postmenopausal women undergoing surgery for breast cancer. Each tissue block was subject to radiological examination and pair-wise samples of dense and non-dense tissue were collected. Semi-quantitative assessment of immunohistochemical staining intensity for Syndecan-1 and estrogen receptor subtypes was performed. RESULTS: The expression of Syndecan-1 in all tissue compartments was significantly higher in dense than in non-dense specimens. The strongest staining was recorded in stromal tissue. There was a strong correlation between epithelial estrogen receptor alpha and stromal cell Syndecan-1 expression in dense tissue (rs = 0.7; p = 0.02). This association was absent in non-dense tissue. CONCLUSION: An increase of Syndecan-1 in all tissue compartments and a redistribution from epithelium to stroma may be a characteristic feature for dense breast tissue.

Stereotactic core needle biopsy in non-palpable breast lesions. What number is needed?

PURPOSE: To investigate whether three stereotactic core needle biopsies (S-CNB) in non-palpable breast lesion are enough for accurate preoperative diagnosis. MATERIAL AND METHODS: Between September 1994 and December 2000, 523 patients with mammographically detected breast lesions and who proceeded to surgery were preoperatively stereotactically biopsied with an automated 14-gauge biopsy device. Three samples were taken from each lesion irrespective of whether the lesion presented as "microcalcifications only", "microcalcifications and a mass", or a "mass, architectural distorsion, or stellate lesion without microcalcifications". The histopathology was divided into three subgroups: diagnostic, atypia (ranging from atypical cells to probably cancer), and non-diagnostic material. RESULTS: Post-surgical histopathology diagnosed 454 (87%) malignant tumors and 69 (13%) benign lesions. Three S-CNB correctly diagnosed the malignant tumors in 84% in the subgroup "microcalcifications only". In the category "microcalcifications and a mass", the diagnostic accuracy was 97% and in the subgroup "mass, architectural distorsion, or stellate lesion without microcalcifications" 3 S-CNB resulted in 93% correct diagnostic material. In 19 of the 454 patients (4%) 1, 2 or all 3 preoperative S-CNB showed atypia. In 20 patients (4%), all 3 S-CNB were non-diagnostic. Thirteen of these 20 patients had "microcalcifications only" and 7 had a mass without microcalcifications. CONCLUSION: Three S-CNB were enough for correct diagnosis in "masses, architectural distorsions, or stellate lesions without microcalcifications" and in "microcalcifications and a mass", but were not sufficient in "microcalcifications only".

Comparison of stereotactic fine needle aspiration cytology and core needle biopsy in 522 non-palpable breast lesions.

PURPOSE: To compare the accuracy of stereotactic fine needle aspiration cytologies (S-FNAC) and stereotactic core needle biopsies (S-CNB) in non-palpable breast lesions. MATERIAL AND METHODS: Between May 1993 and December 2000, 696 patients with mammographically detected lesions were biopsied both with S-FNAC and S-CNB. S-FNAC was performed with spinal needle 22- or 20-gauge and S-CNB with an automated 14-gauge gun. RESULTS: Of the 696 patients, 522 (75%) underwent breast surgery with postoperative histopathology. In all, 448 of these 522 women (86%) had malignant and 74 (14%) had benign lesions. S-FNAC revealed cancer in 254 (57%) and probable cancer in 48 (11%) (sensitivity 68%, specificity 99.6%) and S-CNB revealed cancer in 388 (87%) and probable cancer in 18 (4%) (sensitivity 90%, specificity 98.8%) of these 448 patients. CONCLUSION: S-CNB was more accurate than S-FNAC in the diagnosis of non-palpable breast cancer.

Comparison of preoperative simultaneous stereotactic fine needle aspiration biopsy and stereotactic core needle biopsy in ductal carcinoma in situ of the breast.

PURPOSE: To compare the preoperative results of stereotactic fine needle aspiration biopsy (S-FNAB) with stereotactic core needle biopsy (S-CNB) performed simultaneously in breast lesions with the postoperative histopathological diagnosis of ductal carcinoma in situ (DCIS) of all histological grades. MATERIAL AND METHODS: 733 consecutive stereotactic biopsies were performed between May 1993 and June 1999. In 72 patients with mammographic findings suspicious of malignancy who were subjected to breast surgery, postoperative histopathology showed DCIS. Preoperatively, S-FNAB and S-CNB had been done simultaneously in all patients, S-FNAB with spinal needle 0.7 or 0.9 mm and S-CNB was performed with an automated 2.1-mm biopsy gun. An average of 3 S-FNABs and 3 S-CNBs were performed in each patient. RESULTS: In 56 (78%) of the 72 patients S-CNB showed DCIS. In 3 patients (4%) the S-CNB revealed "probable carcinoma", in 7 patients (10%) "atypia" and in 6, the lesions were benign. In 34 (47%) of the 72 women S-FNABs showed carcinoma, not otherwise specified. In 6 cases (8%) the S-FNABs showed "probable carcinoma" and in 12 patients (17%) "atypia"; 8 lesions were benign and 12 not diagnostic. CONCLUSION: S-CNB was superior to S-FNAB in diagnosing DCIS. Only 6 patients (8%) received a benign or non-diagnostic preoperative diagnosis with S-CNB compared to 20 patients (28%) with S-FNAB. S-CNB was superior to S-FNAB for preoperative diagnosis of DCIS, but S-FNAB could further increase the sensitivity of the biopsy since it diagnosed cancer in 4 cases where S-CNB showed benign material.

Abnormalities on chest radiographs following radiation therapy for breast cancer.

The aim of this study was to study pulmonary radiological abnormalities with chest radiography following different radiotherapy (RT) techniques for breast cancer with respect to regions and density, and their association with pulmonary complications and reduction in vital capacity (VC). Chest radiographs were performed 5 months following local or loco-regional RT in 167 breast cancer patients. The radiological abnormalities were analysed with a classification system originally proposed by Arriagada and evaluated according to increasing density (0-3) and affected lung regions (apical-lateral, basal-lateral, central-parahilar). The highest-density grades in each region were added together to form scores ranging from 0 to 9. The patients were monitored for RT-induced pulmonary complications. The VC was measured prior to and 5 months following RT. An independent evaluation of 51 patients was performed by a second radiologist to control the reproducibility of the classification system. Increasing scores were associated with loco-regional RT and pulmonary complications (P < 0.001). The mean reduction of VC for patients scoring 0-3 (-30 ml) vs 4-9 (-161 ml) was not statistically significant (P = 0.10). Scores of 4-9 were more frequently observed in older patients (P < 0.001). The independent evaluations by two radiologists revealed good agreement (P < 0.001) and no systematic inter-observer variation. Radiological abnormalities on chest radiographs, scored according to Arriagada, can be used as an objective end point for RT-induced pulmonary side effects in breast cancer.

Effect on sensitivity and specificity of mammography screening with or without comparison of old mammograms.

PURPOSE: To evaluate the effect of old mammograms on the specificity and sensitivity of radiologists in mammography screening. MATERIAL AND METHODS: One hundred and fifty sets of screening mammograms were examined by 3 experienced screeners twice: once without and once in comparison with older mammograms. The films came from a population-based screening done during the first half of 1994 and comprised all 35 cancers detected during screening in 1994, 12/24 interval cancers, 14/34 cancers detected in the following screening and 89 normal mammograms. RESULTS: Without old mammograms, the screeners detected an average of 40.3 cancers (range 37-42), with a specificity of 87% (85-88%). With old mammograms, the screeners detected 37.7 cancers (range 34-42) with a specificity of 96% (94-99%). The change in detection rate was not significant. However, the increase in specificity was significant for each screener (p = 0.0002-0.03). CONCLUSION: Mammography screening with old mammograms available for comparison decreased the false-positive recall rate. The effect on sensitivity, however, was unclear.

Radiological review of incidence breast cancers.

OBJECTIVES: To examine the rate of incidence cancers detectable on review of previous screening mammograms using two reviewing methods. To compare the results with a previous study of interval cancers using the same reviewing methods. SETTING: Almost 50000 women are regularly invited for service screening at Stockholm Söder Hospital. From 1989 to 1993, 119 women were identified with breast cancer detected at screening and the previous round attendance (incidence cancer). METHODS: Screening mammograms, obtained before detection of the incidence cancers, were reviewed first mixed with other screening images (ratio 1:8) and then non-mixed. Reviewers from the screening unit responsible for the mammograms as well as reviewers from other units interpreted all images by both single and double reading. RESULTS: The proportion detected on retrospective review varied between 5% and 50% depending on the review method used and the number of reviewers included to classify a case as truly identified. Generally more cancers were detected when non-mixed samples of mammograms were reviewed than when mixed samples were reviewed (mean increase 23%) and when interpreted by double reading compared with single reading (mean increase 14%). CONCLUSIONS: In an experimental retrospective set up, fewer incidence cancers were identified in mixed than in non-mixed review. Generally more incidence cancers were identified on review (22%) than previously reported for interval cancers (14%), probably reflecting differences in tumour biology and growth. How many women with potentially visible incidence cancers would have benefited from earlier tumour detection still needs to be evaluated.

Nipple discharge disorders: current diagnostic management and the role of fiber-ductoscopy.

Nipple discharge disorders is a field in which there has been both increasing awareness on the part of patients and advances in management. Today secretion from nipples can be classified according to its color, cellularity and biology. To be significant a discharge should be true, spontaneous, persistent and non-lactational. Moreover there are methods to differentiate patients who require surgical intervention from those who do not. Surgically significant nipple discharges are watery, serous (yellow), serosanguineous and bloody. Cytology smears of discharge material have helped to classify the cellular material, providing information about normality, atypia and malignancy and also about papillary formation of the exfoliated cells. Tests such as Hemoccult help to discover occult blood in the secreted fluid. Modern immunological tests can be performed on cytology smears where occurrence of high levels of carcinoembryonic antigen could indicate a latent malignancy. Galactography investigation is today the state-of-the-art approach to investigate patients with nipple discharge disorders and this examination can demonstrate the size, location and extent of an intraductal abnormality. Modern high-resolution ultrasound techniques are helpful in visualizing intraductal disorders and are becoming a good complementary approach if not an alternative to traditional radiology techniques. Recently even MR galactography has been shown to be of diagnostic value, but not as informative as regular galactography. The most sophisticated investigation method, which can also be used therapeutically, is fiber-ductoscopy of the concerned duct in a breast. This technique, although expensive and in its infancy, is a fascinating and promising approach for inspecting the intraductal lumina. In this article the background, current investigation methods and possibilities of the technique are described, as well as the most sophisticated ways to deal with nipple discharge disorders in human breasts.

Two models for radiological reviewing of interval cancers.

OBJECTIVES: To compare two different review methods of examining how many of our interval cancers could be regarded as missed cases (overlooked and misinterpreted owing to observer's error). SETTING: A mass screening programme in Stockholm 1989-91, performed at five independent screening units. 107,846 women attended for screening (70.6% of those invited), and 207 women with interval breast cancers were identified. Interval cancers from two of the units, 104 cases, are reviewed in this study. METHODS: Screening examinations preceding the interval cancer diagnoses were reviewed both mixed with other screening images in a ratio 1:8 and non-mixed. Both internal reviewers (from the two units responsible for the screening mammograms) and external reviewers (from the other units) took part in the study. RESULTS: The proportion regarded as missed cases varied between 7% and 34%, depending on what review method was used, and on the number of reviewers included to identify a case as missed. Mixed reviewing reduced the number identified as missed cases by 50% compared with non-mixed reviewing. Whether the reviewer was internal or external made no difference to the results. CONCLUSIONS: Comparing the rate of missed cases from different studies may be misleading unless the same review method is used. No difference in detection rate could be shown whether the radiologist reviewed images from his/her own screening unit or not. Most of our interval cancers were not regarded as missed cases by either of the two methods.

Abnormalities by pulmonary regions studied with computer tomography following local or local-regional radiotherapy for breast cancer.

PURPOSE: To study pulmonary radiological abnormalities with computer tomography (CT) following different radiotherapy (RT) techniques for breast cancer with respect to regions and density, and their correlation to pulmonary complications and reduction in vital capacity (VC). METHODS AND MATERIALS: CT scans of the lungs were performed prior to and 4 months following RT in 105 breast cancer patients treated with local or local-regional RT. The radiological abnormalities were analyzed with a CT-adapted modification of a classification system originally proposed by Arriagada, and scored according to increasing density (0-3) and affected lung regions (apical-lateral, central-parahilar, basal-lateral). The highest density grade in each region were added together to form scores ranging from 0-9. The patients were monitored for RT-induced pulmonary complications. VC was measured prior to and 5 months following RT. RESULTS: Increasing CT scores were correlated with both local-regional RT and pulmonary complications (p < 0.001). The mean reduction of VC for patients scoring 4-9 (-202 ml) was larger than for patients scoring 0-3 (-2 ml) (p = 0.035). The effect of confounding factors on the radiological scoring was tested in the local-regional RT group. Scores of 4-9 were less frequently seen in the patients who had received adjuvant chemotherapy prior to RT. The importance of the respective lung regions on the outcome of pulmonary complications was tested. Only radiological abnormalities in the central-parahilar and apical-lateral regions were significantly correlated to pulmonary complications. DISCUSSION: Radiological abnormalities detected on CT images and scored with a modification of Arriagada's classification system can be used as an objective endpoint for pulmonary side effects in breast cancer. The described model should, however, be expanded with information about the volume of lung affected in each region before definite conclusions can be drawn concerning each region's relative importance for the development of pulmonary complications. The negative association between sequential chemotherapy and radiological abnormalities should be confirmed in future studies.

Mammographic features, predictors of early ipsilateral breast tumour recurrences?

Mammograms from 69 patients with Stage I/II breast cancer, operated on using breast-conserving surgery between 1987-1990 were blindly re-evaluated in order to predict retrospectively ipsilateral breast tumour recurrences. The study cohort was divided into two groups of 34 and 35 patients. Each group was matched according to age, the time at risk and to presence or absence of an ipsilateral breast tumour recurrence. The mammographic reinterpretation was performed by two radiologists that correctly predicted an ipsilateral breast tumour recurrence in 81%. Mammographic characteristics, such as diffuse microcalcifications, multifocality, solitary densities, especially of stellate type near the nipple and/or spicula in the vicinity of the retroareolar region were more often associated with an ipsilateral breast tumour recurrence. Data from this limited series suggest that certain mammographic features seem to correlate with the ability of the tumour to recur locally. Hence, mammography can play a prognostic role in deciding the treatment of choice in operable breast cancer.

Influence of radiation therapy on lung tissue in breast cancer patients. CT-assessed density changes 4 years after completion of radiotherapy.

CT-assessed density changes in lung tissues were measured in 22 disease-free breast cancer patients 4 years after completion of radiation therapy. All patients had previously undergone similar CT-examinations before treatment, 3 months, and 9 months after radiotherapy. In patients with visible areas of increased lung density at earlier CT-examinations a decrease of focal findings was observed at 4 years. In patients without focal findings, an increase in density relative to that before therapy was observed. The difference between the mean lung density values among those with visible radiological findings and those without was statistically significant both at 3 and 9 months after therapy. However, this difference did not persist at 4 years. These results may indicate a 2-phase development of radiation-induced lung damages--an acute phase and a late phase; the late phase emerging slowly, and in this study detectable 4 years after completion of radiation therapy.

Radiologic appearance of nonpalpable intramammary lymph nodes.

Sixty-four well circumscribed nonpalpable lesions, mammographically evaluated as benign and cytomorphologically verified as lymph nodes, were studied concerning mammographic appearance, size and location within the breast. The great majority, 72%, were situated within the upper-outer quadrant, but lymph nodes were also diagnosed in other areas of the breast. Of the verified lymph nodes 50 (78%) had a lower density at the center than at the periphery. These were the only well circumscribed nodules with a low density center observed in a total of 3,623 nonpalpable lesions stereotaxically needled during the same period. Three of the lymph nodes were verified histopathologically. Till now, none of the other 61 lesions has turned out to be a malignant tumor during a follow-up time from 9 to 15 years. Thus a lesion presenting roentgenologically as a well circumscribed nodule with a central area of decreased density compared to the peripheral part can be confidentially diagnosed as a lymph node by the mammograms alone and no further investigation is indicated.

Dietary habits and mammographic patterns in patients with breast cancer.

Between 1983 and 1986, dietary history interviews were conducted with 238 women aged 50-65 years who had surgery for stage I-II breast cancer. Diagnostic mammograms were coded in line with Wolfe's criteria in N1, P1, P2, and Dy patterns. Women with Dy pattern reported significantly higher intake of total fat, monounsaturated fatty acids (FA), polyunsaturated FA, n-3 FA, n-6 FA in per cent of energy (E%), and alpha-tocopherol in mg/10 MJ. Fat intake was lowest in women with N1 pattern and highest in those having Dy pattern. Patients having ER-rich cancers and Dy pattern reported significantly higher intake of total fat, monounsaturated FA, polyunsaturated FA, n-6 FA (E%), and alpha-tocopherol (mg/10 MJ), as well as significantly lower intake of carbohydrate (E%) and calcium (g/10 MJ). In the stepwise multivariate analysis, the multivariate-odds ratio (OR) for having P2 + Dy patterns was 1.06 (95% confidence interval (CI), 1.02-1.12) for each increment in E% of total fat. In women with ER-rich tumors this OR was 1.09 (95% CI, 1.02-1.16). The highest self-reported body mass index (BMI) was observed in women with N1 + P1 patterns. OR for having P2 + Dy patterns was 0.91 (95% CI, 0.83-0.98) for each increment in 1 kg/m2 of BMI. The results suggest that dietary habits affect the mammographic parenchymal pattern in women with breast cancer and that a high fat intake is associated with a higher proportion of mammograms with Dy pattern in such patients.

Radial scars detected mammographically in a breast cancer screening programme.

Radial scars are getting more and more common since the implementation of mammography as a diagnostic tool in screening women for breast cancer. At the Karolinska Hospital, 18,987 asymptomatic women, between the ages of 50 and 69, were screened for breast cancer by means of mammography during the period August 1989 to May 1991. A total of 735 (3.87%) women were recalled for additional views after initial mammograms and 463 (2.44%) were assessed with the help of cytology. In all 175 (0.92%) women were selected for surgery and 146 (0.77%) had histologically verified cancers. The remaining 29 (0.15%) had non-malignant lesions of which 11 (0.06%) were radial scars. All radial scars were diagnosed on mammograms and later confirmed with histology. The radiologic characteristics were found to be (a) rather thick and long radiating structures accompanied by radiolucent linear structures parallel to some of the spicules, (b) absence of calcifications, (c) radiolucent areas in the central body of the lesion, (d) an average mean size of 6 mm and (e) changing image in different views. Most of the lesions, 73% (8/11), were in moderately dense breasts and there was no specific relation to the right or left breast. A majority of radial scars, 64% (7/11), were found in the upper outer quadrants, 27% (3/11) in the lower outer quadrants and 9% (1/11) in the lower inner quadrant. Literature shows that histology uses many synonyms for radial scars and therefore team work between the radiologists and pathologists is suggested for better conformity of the diagnosis.

Clinical examination, mammographic findings and cytological diagnosis in patients with breast disorders. Results of 9 years' follow-up.

In January through March 1978, 482 consecutive patients sought advice and examination for different kinds of breast disorders at the Breast Unit of Radiumhemmet; 171 of them (32.8%) came without any prior known medical consultation. All patients were seen by a doctor and examined clinically; 385 underwent mammography and 196 fine-needle aspiration for cytology. Combined clinical and mammographic examination showed an estimated specificity with respect to 'breasts with no need of follow-up' of 77%. The corresponding sensitivity was 88%. Fine-needle aspirations showed an estimated specificity and sensitivity of 96% and 88% respectively. In the total material 26 malignant cases were found, of which 16 cancers were detected at the first examination. During a follow-up period of nine years, 10 additional breast cancers were found in the national cancer registry. This number could be compared to the expected number of 6.6 (SIR 1.52, 0.73-2.79) breast cancer cases if the studied women had had the same standardized incidence as the total female Swedish population. The mean number of visits to the Breast Unit was 1.6 for the 466 patients with benign disorders, of whom 322 had no need of follow-up. The mean follow-up time for these 482 patients was 113 days. During the follow-up time, 22 patients died. Ten patients, one of them with a breast cancer diagnosed, emigrated.

Expression of the c-erbB-2 proto-oncogene product and nuclear DNA content in benign and malignant human breast parenchyma.

The expression of the c-erbB-2 proto-oncogene product was investigated immunohistochemically in 474 formalin-fixed and paraffin-embedded human breast tissue samples. The series included 32 benign and 26 hyperplastic lesions, 32 carcinomas in situ and 384 invasive breast carcinomas, 107 of which were less than 1 cm in diameter. Cytometric DNA assessments were performed on histopathologically or cytodiagnostically identified cell nuclei, using image analysis. C-erbB-2 immunoreactivity was not seen in normal parenchyma or in benign and hyperplastic lesions. Mammary carcinomas in situ were more frequently immunoreactive (59%) than invasive neoplasms (23%). Invasive tumours more than 1 cm in diameter immunoreacted more often (26%) than small invasive carcinomas (16%). C-erbB-2 expression in regional lymph node metastases was the same as in the corresponding primary tumours. Significant differences were observed between the c-erbB-2 expression in DNA diploid and aneuploid lesions; for carcinomas in situ the figures were 40% and 72%, respectively. Invasive carcinomas of DNA diploid type rarely showed c-erb-B-2 expression, irrespective of tumour size and nodal status (7-11%). DNA aneuploid tumours were more frequently immunoreactive with increasing levels during progression (32-41%). Our data indicate that genetically stable invasive mammary tumours seem rarely to express the c-erbB-2 protein, even during progression, whereas genetically unstable invasive neoplasms frequently show c-erbB-2 immunoreactivity which increases during tumour progression.