Histopathology grading in small breast cancers < or = 10 mm--results from an area with mammography screening.

Histopathological malignancy grading using the Bloom-Richardson classification of ductal cancers was performed for 248 invasive ductal breast cancers < or = 10 mm operated 1978-1985. There were significantly more grade 1 lesions in the prevalence screening round. Grade 3 was correlated with aneuploidy, higher S-phase (SPF), and more receptor negative tumours. There were also significantly more positive lymph nodes in grade 3 lesions, 18% compared to 5% and 12% respectively for grades 1 and 2 (p < 0.05). In life table analysis for survival, when the high risk group of grade 3 lesions was compared to the grade 1 and 2 lesions combined, five-year disease-free survival was 84.6% vs. 99.1% (p < 0.001). With good training and care from the pathologist, malignancy grading seems useful for prognostication of eventual recurrence and death. In tumours 10 mm or smaller only grade 3 lesions need to be included in follow-up systems and should probably have adjuvant treatment. Malignancy grading is especially good in small ductal breast cancers where grading can always be performed while other prognostic determinations are hampered by shortage of material. Lymph node positivity is also low in this group.

Update of the Swedish two-county program of mammographic screening for breast cancer.

The results of the Swedish two-county trial of mammographic screening for breast cancer are presented, updated to December 31, 1990, which is an average of 10.8 years follow-up per person. The main result of the trial in terms of breast cancer mortality remained the same: compared with the control group, the group invited to screening had a relative breast cancer mortality of 0.70 (P = 0.0002) with 95% confidence interval (0.58, 0.85). Analysis of survival showed that relative to the control group, the cancers detected at prevalence screen, incidence screens, and in the interval between screens had a good prognosis, whereas cancers detected in those who had refused screening had a very poor prognosis. When adjusted for tumor size, lymph node status, and tumor grade (differentiation), the better survival associated with incidence screen and interval detection was largely accounted for, indicating that the benefit of incidence screening is largely achieved through the effect of screening on the three prognostic variables, notably size of the tumor. Results indicate that to achieve a substantial mortality reduction, 50% of screen-detected invasive cancers should be less than 15 mm in diameter, at least 30% of screen-detected grade 3 tumors should be less than 15 mm, and at least 70% of screen-detected tumors should not have lymph node metastases. The percentage of grade 3 tumors of a given size should be the same in screen-detected cancers as in clinically detected, and breast cancer prevalence at first screen should be at least three times the expected incidence rate in the absence of screening. This should be achieved without the recall rate for further examination exceeding 9%, and procedures including further imaging techniques and fine needle aspiration or core biopsy should be used before resorting to surgical biopsy. These aims can be achieved in specialist screening centers if particular attention is paid to resources for screening and diagnostic evaluation, specialist training of clinical and technologic screening staff, and ongoing monitoring of mammographic quality, recall rates, and the attributes of the tumors detected.

Breast screening, prognostic factors and survival--results from the Swedish two county study.

The results of the Swedish two-county study are analysed with respect to tumour size, nodal status and malignancy grade, and the relationship of these prognostic factors to screening and to survival. It is shown that these factors can account for much of the differences in survival between incidence screen detected, interval and control group cancers but to a lesser extent for cancers detected at the prevalence screen where length bias is greatest. Furthermore, examination of the relationships among the prognostic factors and mode of detection indicates that malignancy grade, as a measure of inherent malignant capacity, evolves as a tumour grows. The proportion of cancers with poor malignancy grade is several fold lower for cancers of diameter less than 15 cm than for cancers greater than 30 cm, independent of the length bias of screening. The implications of these findings for screening frequency are briefly discussed.

Cytometric and histopathologic features of tumors detected in a randomized mammography screening program: correlation and relative prognostic influence.

Cytometric determination of S-phase fraction and ploidy type was performed on 430 tumors detected within a randomized trial of mammographic screening. The results were compared to several histopathologic features. A high S-phase fraction was estimated in tumors with a high grade of malignancy and other histopathologic findings related to rapid tumor progression, including lack of tubule formation, a high mitotic index, marked nuclear pleomorphism, multifocal cancer growth, tumor emboli in lymphatic and blood vessels, tumor necrosis, and inflammatory reaction. DNA aneuploidy was correlated with a high malignancy grade, frequent mitoses, a high degree of nuclear pleomorphism, vascular invasion, necrosis, and the presence of noninvasive ductal carcinoma. Both cytometric variables were inversely related to the degree of elastosis. Positive nodes, large tumor size, DNA aneuploidy, a high S-phase fraction, high grade of malignancy, lack of tubule formation, as well as high mitotic index and pleomorphism, presence of multifocal cancer, and vascular invasion, predicted a significantly shorter distant recurrence-free interval after a median follow-up time of 46.6 months. Elastosis and the presence of estrogen and progesterone receptors indicated favorable prognosis. In the multivariate analysis, only lymph node status, tumor size, S-phase fraction, and multifocal growth pattern had independent prognostic value.

Influence of S-phase fraction on metastatic pattern and post-recurrence survival in a randomized mammography screening trial.

Using static cytofluorometry, S-phase was determined on the primary tumors of 421 patients with breast carcinomas in stages I-III diagnosed 1981-85 during the second and third screening rounds of a randomized trial evaluating the effect of mammographic screening. Through December 1988, 82 patients had developed local and/or distant recurrence, 51 of whom had died of cancer during the same period. The distribution among sites of recurrence differed between patients with tumors detected by mammography screening and cancers diagnosed due to clinical symptoms. The mean S-phase fraction was highest in patients with liver or brain metastases and lowest in patients with metastases in subcutaneous and cutaneous tissue and lymph nodes only. In univariate analysis, survival after first recurrence was significantly associated with the site of primary recurrence, the disease-free interval, and node status and tumor size at diagnosis, as well as the S-phase level. The median survival period was 31.3. months for patients with a S-phase fraction below 6%, and 10.7 months in cases with S-phase exceeding 10%. Neither ploidy nor the estrogen receptor content had significant influence on post-recurrence survival. In Cox's multiple regression analysis, only metastatic site, disease-free interval, and S-phase fraction showed significantly independent prognostic value.

Cytometric characterization and clinical course of breast cancer diagnosed in a population-based screening program.

A randomized controlled trial evaluating mammographic screening was started in two Swedish counties in 1977. In one of these, Ostergötland county, the authors performed static cytofluorometry on 161 cancers detected at the second and third screening rounds, 50 interval cancers, and 219 cancers appearing in the nonscreened control group during the same time period. The median follow-up time was 42 months. No difference in mean S-phase was found between screening and control group cancers, but interval cancers, appearing between two screenings, had increased mean S-phase levels (P = 0.01) compared to both of the other groups. A high S-phase fraction was associated with distant recurrence in both node-negative and node-positive tumors. Aneuploid tumors were more often found in the control group (67%) and among interval cancers (72%) than among screening detected cancers (55%, P = 0.02). In Cox's multivariate analysis, including all patients, the lymph node status, tumor size, estrogen receptor content, and S-phase all contributed independent prognostic information about the clinical course. DNA ploidy predicted the outcome in simple but not in multivariate Cox's analysis. When analyzing screening-detected cancers separately, only the S-phase significantly predicted distant recurrence in multivariate analysis. In tumors with local recurrence, a high S-phase implicated an increased, although not statistically significant, risk for distant recurrence. Survival with metastatic disease was significantly influenced by the S-phase level (P = 0.002). The authors conclude that S-phase fraction provides valuable kinetic information related to the clinical outcome for all stages of the disease and serves as a prognostic factor in screened populations, which have tumors predominantly in early stages.

Follow-up of two treatment modalities for ductal cancer in situ of the breast.

In a mammography screening programme for the early detection of breast cancer 66 cases of ductal cancer in situ of the breast (DCIS) were diagnosed between 1978 and 1984 and prospectively followed up. In the beginning of the study period, DCIS was treated by mastectomy without axillary clearance but sector resection has been performed increasingly. Since 1982 the latter procedure has become standard treatment. Radical resection was confirmed by specimen X-ray and histopathological examination of whole organ sections. No postoperative radiotherapy was given. Twenty-eight women had mastectomy and 38 had sector resection. The median follow-up times were 77 and 60 months respectively. In the mastectomy group postoperative monitoring did not reveal any local recurrence but one contralateral new invasive cancer was discovered. In the sector resection group five recurrences were found. Three of the latter were new cases of DCIS and two appeared as small invasive cancers (stage I). Mastectomy will cure ductal cancer in situ but has a greater morbidity. Sector resection has been established as the method of choice in stage I invasive cancer and is probably also safe in DCIS. The possible beneficial effect of postoperative local radiotherapy after sector resection for DCIS is currently being analysed in a randomized trial which started in Sweden in 1987.

Secretory carcinoma of the breast in adults: emphasis on late recurrence and metastasis.

Secretory (so-called juvenile) carcinoma of the breast, first described in children, occurs also in adult women, predominantly in the third decade. Less commonly it is seen in older age groups, up to the eighth decade. We report five patients with this tumour; one, a female aged 73, is the oldest age at which the tumour has been recorded, and one is the first report in an adult male in whom the disease recurred after 20 years, only the second recorded death attributable to this tumour type. Secretory carcinoma in adults is potentially more aggressive than in childhood. Nodal metastases are more frequent and sometimes more extensive. Recurrence of tumour after surgery developed in four of our five patients at 3, 8, 15 and 20 years. Slow growth and delayed recurrence are characteristic of many of these tumours. Death from systemic metastases is rare, but may ensue either rapidly or following a long latent period after treatment. Prolonged follow-up is needed to assess accurately the biological behaviour of this tumour.

Surgical biopsy of non-palpable mammary lesions. Technique and results.

In a randomized controlled trial with mammographic screening for early detection of breast cancer, 314 non-palpable breast lesions were examined by open biopsy between 1978 and 1983. These biopsies were performed after the lesions had been indicated by the hooked wire technique. In 185 cases the findings turned out to be benign while 129 proved to be malignant. Satisfactory initial biopsies were achieved in 95% of the cases. A model for the management of mammary lesions found in such a screening programme is described and some difficulties are discussed.

Effects of repeated mammographic screening on breast cancer stage distribution. Results from a randomised study of 92 934 women in a Swedish county.

A randomised controlled trial of mass screening for breast cancer by single-view mammography was begun in Sweden in 1977. All women aged 40 and older and resident in the counties of Kopparberg and Ostergötland were enrolled. The present report is confined to the Ostergötland study, which started in 1978 and comprised 92 934 women. After randomisation, which was done on the basis of communities rather than individuals, 47 001 women were allocated to the study group and offered repeated mammographic screening; 45 933 were allocated to the control group. As compliance among women over 74 years of age was poor these were excluded from the present report. The yearly incidence of stage II or more advanced breast cancers after the initial screening round up to and including the second was reduced by 40 per cent in the study group compared with the controls. This effect was less marked in the age group 40-49. After 5.5 years average from the date of entry the absolute number of women with stage II-IV disease in the control group exceeded that for the study group by 44, whereas there was a large excess of cancer in situ and stage I cancer in the study group.

Reduction in mortality from breast cancer after mass screening with mammography. Randomised trial from the Breast Cancer Screening Working Group of the Swedish National Board of Health and Welfare.

A randomised controlled trial to investigate the efficacy of mass screening with single-view mammography in reducing mortality from breast cancer was started in Sweden in 1977. 162 981 women aged 40 years or more and living in the counties of Kopparberg and Ostergötland were enrolled in the study and divided at random into 2 groups. Each woman in the study group was offered screening every 2 or 3 years depending on age. Women in the control group were not offered screening. This report is confined to the 134 867 women aged 40-74 years at date of entry. The results to the end of 1984 show a 31% reduction in mortality from breast cancer and a 25% reduction in the rate of stage II or more advanced breast cancers in the group invited to screening. 7 years after the start of the study the excess of stage I cancers in the study group largely outweighs the deficit of advanced cancers.

Photometric studies on nuclear DNA content and area in different laryngeal epithelia.

A photometric study of different laryngeal epithelia was performed. The nuclear DNA content and area for epithelia with keratosis, hyperplasia, and moderate dysplasia were comparable to normal. These lesions cannot therefore be considered to be premalignant photometrically. The photometric values for carcinoma in situ and severe dysplasia were comparable to that for invasive carcinoma. Long-term follow-up has to be performed to evaluate the biological significance of these different lesions.

Paraganglioma involving the larynx.

Paraganglioma is a rare tumor in the upper respiratory tract. More than 30 paragangliomas have been reported arising in the larynx but only a few in the trachea. The organoid arrangements of the cell nests reproduce the classic 'Zellballen' of the normal gland. Neurosecretory granules can be seen at electron microscopy. Angiography may be a valuable diagnostic adjunct. Malignant degeneration may occur. The 44-year-old woman reported had a dumbbell-shaped tumor involving the subglottic larynx but with its largest portion outside the larynx and within the left lobe of the thyroid gland. The tumor may very well have arisen from the inferior laryngeal paraganglia. An important differential diagnosis is hemangiopericytoma, which was the preoperative diagnosis in this case. A laryngectomy including the left lobe of the thyroid gland was performed and there is no sign of local recurrence or metastases 7 years after operation.

Juvenile laryngeal papilloma: histologic and photometric evaluation of atypia.

Juvenile papillomas are the most common proliferative laryngeal lesion in children. Atypia may be present but is difficult to interpret owing to the basically benign character of the lesion. A histologic and clinical classification of 23 cases of juvenile laryngeal papillomas was performed following the criteria suggested by Quick and co-workers in 1979 and intended to enable the clinical course to be more accurately predicted. The various histologic types of papillomas were characterized by single-cell microdensitometry. The photometric study verified the increase in the relative width of the proliferative zone with the degree of atypia. Severe atypia was the only histologic type associated with hypertetraploid nuclei. The frequent occurrence of mild atypia was unrelated to the clinical course. The moderate and severe degrees of atypia were more common during periods of relatively frequent operations. Severe atypia was rare but in one patient it heralded the development of invasive carcinoma.

Origin of carcinoma in secretory endometrium--a study using a whole-organ sectioning technique.

Uteri from four patients with endometrial adenocarcinoma and concomitant "functioning" endometrium were examined by a whole-organ sectioning technique. All showed one or several "progesterone-refractory" mucosal areas or polyps, mainly in the tubal recesses. In one patient the adenocarcinoma obviously originated in a fundal polyp, and in the others the tumors could have arisen in mucosal areas not adequately responding to progesterone. These findings do not in fact contradict the "unopposed estrogen" theory of the genesis of endometrial carcinoma.

A fast and reliable system for microcomputerized DNA cytofluorometry in tumour pathology.

A microcomputerized cytofluorometry system based on a Leitz MPV 3 cytophotometer, and intended for DNA measurements in tumour pathology is described. The system has been equipped with a reference channel for correction of excitation light instability. The importance of the adjustment of the epi-illumination for optimal performance of the reference channel is stressed, and a detailed description is provided. An apparatus variability well below 1% CV is obtained even during periods of marked instability of the arc-lamp. Software for conventional cytofluorometry with which about 200 cells can be measured in 20 min is presented. In addition a measuring technique where cells are not positioned, but are just passed through the excitation light spot is described. Preliminary results on cytocentrifuged specimens of human cancers indicate that this system is at least three times faster than conventional fluorometry. The increased speed of measurements considerably extends the possibilities to evaluate cell proliferation using static cytofluorometry. The measuring capacity of course is dependent upon the quality of the specimen. In well prepared cytocentrifuged specimens 1000 cells have been measured in 35 min.

Histopathological subgrouping of WHO II urothelial neoplasms by cytophotometric measurements of nuclear atypia.

The grade of nuclear atypia was objectively assessed in 21 cases of non-invasive WHO II transitional cell bladder neoplasm. Measurements were performed by stage scanning absorbance cytophotometry, registering nuclear optical density, nuclear area, and the variability of these two factors, in 5 microns thick Feulgen-stained paraffin sections. The material was subgrouped into a 2- and a 2+ group according to the degree of histopathological atypia. Cytophotometrically determined atypia showed close correlation to the subjectively judged atypia, and there was no overlap between 2- and 2+. A difference in tumour ploidy level between different WHO II tumours is the most likely explanation of the grouping recorded.

Cytophotometric characterization of the WHO grades of transitional cell neoplasms.

The WHO classification of urothelial bladder tumours is widely used, but does not seem to be entirely satisfactory. The main problem is the unhomogeneous WHO II group, and borderline cases in particular are difficult to evaluate histopathologically. Objective assessment of atypia would allow more reliable correlation between morphology and biological behaviour of the tumours to be made. We describe measurements of atypia in 3 characteristic cases of papillary bladder tumour of each WHO grade I, II, and III using Feulgen-DNA-cytophotometry. The mean optical density and nuclear area is determined in 5 micron thick tissue sections. The optical density and nuclear area for each specimen are plotted in a scatter diagram, and the position and variability of the cluster are evaluated. Cytophotometric characterization resulted in defined groups of WHO-graded tumours, and due to this encouraging result the method will be applied in a more comprehensive study of WHO II carcinomas.

Residual carcinoma after intracavitary irradiation of endometrial carcinoma, stage I. A study of whole-organ sections.

Surgical specimens from 87 patients with endometrial carcinoma, stage I, preoperatively treated by intracavitary irradiation were investigated by a whole-organ sectioning technique. Re-examination of the curettage material showed cancer stage 0 in 8 (9%) and carcinoma state I in 79 cases (91%). In the stage I cases 57% showed residual carcinoma localized mainly to the myometrium of the uterine body and cornuae. Histological changes inthe carcinoma were unevenly distributed, but tumors growing close to the external uterine surface were well preserved. In 40.5%, no carcinoma was present, and in 2.5% the changes found could not be classified. Correlated to disparity in irradiation technique, no significant difference could be demonstrated in the incidence or localization of residual carcinoma. The most important single pretreatment factor combined with the presence of residual carcinoma was myometrial fragments with infiltrating carcinoma in the curettage material (MICC). Computerized analysis of combinations of factors showed that all patients aged over 60 years with a uterine-sound length exceeding 8 cm had residual carcinoma. Only 2 patients with infiltration of the myometrium had a completely destroyed carcinoma. The findings indicate that it is unlikely that endometrial carcinoma state I with myometrial invasion will be eradicated by intracavitary irradiation.

HISTOSCAN: computer program for cytophotometry in tissue sections and its application in the evaluation of nuclear atypia.

The grading of nuclear atypia has a great and well recognized value when predicting the malignancy of neoplastic processes. Although the basic criteria for the grading are generally agreed upon, in the individual case, the final judgement is to some extent still a matter of subjectivity, which naturally impairs reproducibility. The present paper describes a method for quantification of variability of nuclear size and Feulgen-stainability. By plotting the mean optical density against the area value in a scatter-diagram, a cluster is obtained, the size of which reflects the degree of nuclear atypia. The measurements are performed in tissue sections using stage scanning cytophotometry. A computer program--HISTOSCAN--has been developed which enables measurements in highly cellular tissues. The system is also insensitive to the influence of light scattering, a factor of importance when measuring in tissue sections. The performance of the program is tested in both imprints and tissue sections.