Quantitative nuclear morphometry by image analysis for prediction of recurrence of ductal carcinoma in situ of the breast.

Clinical management of ductal carcinoma in situ (DCIS) remains a challenge because significant proportions of patients experience recurrence after conservative surgical treatment. Unfortunately, it is difficult to prospectively identify, using objective criteria, patients who are at high risk of recurrence and might benefit from additional treatment. We conducted a multi-institutional, collaborative case-control study to identify nuclear morphometric features that would be useful for identifying women with DCIS at the highest risk of recurrence. Tissue sections of archival breast tissue of 29 women with recurrent and 73 matched women with nonrecurrent DCIS were stained for DNA, and nuclei in the DCIS lesions were evaluated by image analysis. A clear correlation between mean fractal2_area (FA2) and nuclear grade was observed (P < 0.001), allowing an objective determination of nuclear grade. Several nuclear morphometric features, including mean and variance of variation of radius, mean area, mean and variance of frequency of high boundary harmonics (FQH), and variance in sphericity, were found to be useful in discriminating recurrent from nonrecurrent DCIS subjects. However, the nuclear features associated with recurrence differed between high- and low-grade lesions. For lesions with high FA2 (nuclear grade 3), mean variation of radius, mean FQH, and mean area alone yielded recurrence odds ratios of 4.55 [95% confidence interval (CI) 0.45-45.96], 3.86 (95% CI, 0.88-16.98), 2.90 (95% CI, 0.31-27.2), respectively. Using a summed feature model, high-FA2 lesions showing three poor prognostic features had an odds ratio of 15.63 (95% CI, 1.22-200), compared with those with zero or one poor prognostic feature. Lesions with low mean FA2 (nuclear grade 1 or 2) showing high variances in sphericity and FQH had an odds ratio of 7.71 (95% CI, 1.77-33.60). Addition of other features did not enhance the odds ratio or its significance. These results suggest that nuclear image analysis of DCIS lesions may provide an adjunctive tool to conventional pathological analysis, both for the objective assessment of nuclear grade and for the identification of features that predict patient outcome.

The influence of margin width on local control of ductal carcinoma in situ of the breast.

BACKGROUND: Ductal carcinoma in situ is a non-invasive carcinoma that is unlikely to recur if completely excised. Margin width, the distance between the boundary of the lesion and the edge of the excised specimen, may be an important determinant of local recurrence. METHODS: Margin widths, determined by direct measurement or ocular micrometry, and standardized evaluation of the tumor for nuclear grade, comedonecrosis, and size were performed on 469 specimens of ductal carcinoma in situ from patients who had been treated with breast-conserving surgery with or without postoperative radiation therapy, according to the choice of the patient or her physician. We analyzed the results in relation to margin width and whether the patient received postoperative radiation therapy. RESULTS: The mean (+/-SE) estimated probability of recurrence at eight years was 0.04+/-0.02 among 133 patients whose excised lesions had margin widths of 10 mm or more in every direction. Among these patients there was no benefit from postoperative radiation therapy. There was also no statistically significant benefit from postoperative radiation therapy among patients with margin widths of 1 to <10 mm. In contrast, there was a statistically significant benefit from radiation among patients in whom margin widths were less than 1 mm. CONCLUSIONS: Postoperative radiation therapy did not lower the recurrence rate among patients with ductal carcinoma in situ that was excised with margins of 10 mm or more. Patients in whom the margin width is less than 1 mm can benefit from postoperative radiation therapy.

Interobserver reproducibility of the Lagios nuclear grading system for ductal carcinoma in situ.

Several studies have shown an association between high nuclear grade or necrosis of ductal carcinoma in situ (DCIS) lesions and the risk of local disease recurrence in patients with DCIS treated surgically with less than mastectomy. Although criteria for separating low from high nuclear grade lesions have been published, no information exists regarding interobserver reproducibility (IR). To assess IR in the classification of DCIS, six surgical pathologists from four institutions used the Lagios grading system to grade 125 DCIS lesions. Before meeting to evaluate the cases, a training set of 12 glass slides, including cases chosen to present conflicting cues for classification, was mailed to the participants with a written criteria summary. This was followed by a working session in which criteria were reviewed and agreed on. The pathologists then graded the lesions independently. The area of interest was marked on each slide before grading. After initial grading, the pathologists met again to resolve discrepant lesion classifications. A complete agreement among raters was achieved in 43 (35%) cases, with five of six raters agreeing in another 45 (36%) cases. In no case did two raters differ by more than one grade. The pairwise kappa agreement values ranged from fair to substantial (0.30 to 0.61). Generalized kappa value indicated moderate agreement (0.46, standard error = 0.02). Kappa statistics for the distinction between grades 1 and 2 and 2 and 3 were 0.29 and 0.48, respectively, (standard error = 0.02). Only one of the six raters differed significantly in scoring. With adherence to specific criteria, IR in the classification of DCIS cases can be obtained in most cases. Although these pathologists made a few grading system modifications, further refinements are needed, especially if grading will influence future therapy.

Outcome after invasive local recurrence in patients with ductal carcinoma in situ of the breast.

PURPOSE: To detail the outcome, in terms of local recurrence, local invasive recurrence, distant recurrence, and breast cancer mortality for patients previously treated for ductal carcinoma in situ (DCIS). PATIENTS AND METHODS: Clinical, pathologic, and outcome data were collected prospectively for 707 patients with DCIS accrued from 1972 through June 1997. RESULTS: There were 74 local recurrences; 39 were noninvasive (DCIS) and 35 were invasive. Fifty-one percent of patients with invasive recurrences presented with stage 1 disease; the remainder presented with more advanced disease. Invasive local recurrence after mastectomy was a rare event that occurred in 0.8% of patients. Invasive recurrence after breast preservation was more common and occurred in 7.4% of patients. The 8-year probability of breast cancer mortality after breast preservation was 2.1%, a number that is likely to increase with longer follow-up. The 8-year breast cancer-specific mortality and distant-disease probability for the subgroup of 74 patients with locally recurrent disease was 8.8% and 20.8%, respectively. If only the 35 invasive recurrences are considered as events, the 8-year breast cancer-specific mortality and distant-disease probability was 14.4% and 27.1%, respectively. CONCLUSION: Invasive local recurrence after breast-preservation treatment for patients with DCIS is a serious event that converts patients with previous stage 0 disease to patients with disease that ranges from stage I to stage IV. These results, however, indicate that most DCIS patients with local recurrence can be salvaged.

Ductal carcinoma in situ of the breast: reproducibility of histological subtype analysis.

Historically, two major strata of ductal carcinoma in situ (DCIS) have been linked to outcome, the presence or absence of comedo type and size. Our initial approach in classification was dichotomous, often favoring the comedo type with most worrisome implications to foster agreement in diagnosis. We have now tested guidelines that foster agreement in the modified Lagios three-tiered system. Sixteen cases of DCIS were selected, reflecting a spectrum of histological subtypes, with specific inclusion of cases in which consensus in classification using a dichotomous (comedo/noncomedo) scheme would be difficult. Six independent observers reviewed a minimum of five color 35-mm slides from each case at two separate occasions. The aim was to subclassify each case based on architectural pattern, nuclear grade, and presence or absence of tumor necrosis (Modified Lagios Classification, Lagios et al, Cancer 1989). After initial review, emphasizing placement of each case into a high- or low-grade category, there was disagreement in seven cases (44%), confirming our aim to choose cases with uncertain cues for classification. Agreement was achieved in 94% of cases by allowing re-review with emphasis on inclusion of an intermediate-grade category. Our study also suggests that pure micropapillary DCIS and apocrine DCIS warrant independent classification as "special type" DCIS. Our small pilot study suggests that, with adherence to specific criteria, most DCIS cases can be easily and consistently classified into the following five categories: (1) high grade, (2) intermediate grade, (3) low grade, (4) pure or predominantly micropapillary, and (5) pure apocrine. Our six observers independently reached a final concordance of 94% despite selection of cases in which consensus in a dichotomous classification was difficult. This was achieved predominantly by accepting an intermediate category of DCIS with intermediate nuclear features and limited necrosis. Confirmation of the applicability of the Modified Lagios Classification awaits completion of a much larger multi-institutional study in which statistical significance and interobserver variation can be better defined.

Ductal carcinoma in situ. The success of breast conservation therapy: a shared experience of two single institutional nonrandomized prospective studies.

A combined database of 342 patients with DCIS treated by lumpectomy alone versus lumpectomy and radiation therapy with a median 82-month follow-up is summarized in this joint study. Reproducible subtype classification and common methods of mammographic-pathologic correlation and complete tissue processing are unique features of this database, and they permit outcome to be analyzed by pathologic subtype, size, and margine status. Striking differences are noted in local control rates analyzed by subtype, which were largely independent of irradiation (see Table 1). Analysis of local recurrence-free survival restricted to those cases with a 10 mm or larger free margin width revealed no significant differences between the irradiated and nonirradiated groups. The local recurrence rates were 5% in those treated by lumpectomy alone and 4.5% in those treated by lumpectomy and irradiation (Table 4). Although differences in local recurrence rates for DCIS with a 10 mm plus free margin, with or without irradiation, were noted, they were not large. For DCIS patients with adequate (10 mm or more) or intermediate (1-9 mm) margin width, there was a reduction in local recurrence limited to the high-grade subtype (group III) with radiation therapy; an absolute 8% reduction for those with adequate margins and 11% for those with intermediate margins, but the difference was significant only for the latter group (Table 5). However, no significant differences were noted for the lower grade DCIS subtypes (groups I and II). For DCIS patients with inadequate margins (i.e., less than 1 mm), irradiation provided no benefit for local control. We conclude that an adequate surgical excision for DCIS, defined as a free margin of 10 mm or more, largely makes moot the question of local control related to pathologic subtype and treatment modality. Specifically, adequately excised high-grade (group III) DCIS received a benefit for local control from radiation therapy of only 8% within the median follow-up period. This difference is not significant. The impact of DCIS size or extent on local recurrence is much smaller than margin width (see Table 3). Significant differences achieved by radiation therapy were demonstrable only for the smallest size group (15 mm or less) in the highgrade subtype (group III). Differences in local recurrence rates for low and intermediate subtypes (group I and II) based on radiation therapy could not be demonstrated within the three size categories used in the study. We conclude that although adequate margins are more difficult to achieve for larger or more extensive DCIS, size alone is not a prohibition to breast conservation.

Use of predictors of recurrence to plan therapy for DCIS of the breast.

Despite the results of the National Surgical Adjuvant Breast and Bowel Project B-17, there continues to be debate regarding the most appropriate treatment for patients with ductal carcinoma in situ (DCIS) of the breast. Numerous clinical, pathologic, and laboratory factors can aid clinicians and patients wrestling with the difficult treatment decision-making process. Our research has shown that nuclear grade, the presence of comedo-type necrosis (coagulative necrosis), tumor size, and margin width are all important predictors of local recurrence in patients with DCIS. We used these factors to devise the Van Nuys Prognostic Index (VNPI), which assigns lesions a score from 1 to 3 for each of three factors: tumor size, margin width, and pathologic classification (determined by nuclear grade and necrosis). By scoring DCIS lesions according to this index, it may be possible to identify subgroups of patients who do not require irradiation, if breast conservation is elected, as well as patients whose recurrence rate is potentially so high, even with breast irradiation, that mastectomy is preferable.

A prognostic index for ductal carcinoma in situ of the breast.

BACKGROUND: There is controversy and confusion regarding therapy for patients with ductal carcinoma in situ (DCIS) of the breast. The Van Nuys Prognostic Index (VNPI) was developed to aid in the complex treatment selection process. METHODS: The VNPI combines three significant predictors of local recurrence: tumor size, margin width, and pathologic classification. Scores of 1 (best) to 3 (worst) were assigned for each of the 3 predictors and then totaled to give an overall VNPI score ranging from 3 to 9. Three hundred thirty-three patients with pure DCIS treated with breast preservation (195 by excision only and 138 by excision plus radiation therapy) were studied with detection of local recurrence as the end point. RESULTS: There was no statistical difference in the 8 year local recurrence free survival in patients with VNPI scores of 3 or 4, regardless of whether or not radiation therapy was used (100% vs. 97%; P = not significant). Patients with VNPI scores of 5, 6, or 7 received a statistically significant 17% local recurrence free survival benefit when treated with radiation therapy (85% vs. 68%; P = 0.017). Patients with scores of 8 or 9, although showing the greatest relative benefit from radiation therapy, experienced local recurrence rates in excess of 60% at 8 years. CONCLUSIONS: DCIS patients with VNPI scores of 3 or 4 can be considered for treatment with excision only. Patients with intermediate scores (5, 6, or 7) show a 17% decrease in local recurrence rates with radiation therapy. Patients with VNPI scores of 8 or 9 exhibit extremely high local recurrence rates, regardless of irradiation, and should be considered for mastectomy.

Duct carcinoma in situ: biological implications for clinical practice.

Duct carcinoma in situ (DCIS) has become an important, however controversial, focus of breast cancer management only since the advent of effective film mammography and the development of an increased interest and utilization of breast conservation therapy. Prior to 1975, DCIS remained an infrequent biopsy finding in patients who presented with a palpable mass, nipple discharge, or clinical Paget's disease. The vast majority of such patients harbored extensive noninvasive disease and frequently were found to have occult invasive breast cancer at mastectomy, which was the only method of available treatment. The significance of small foci of DCIS as detected mammographically and the implications of DCIS in conjunction with invasive carcinoma for breast conservation therapy were slowly learned over the next two decades. This paper reviews current studies of DCIS with a particular focus on practical applications for management.

Classification of duct carcinoma in situ (DCIS) with a characterization of high grade lesions: defining cohorts for chemoprevention trials.

In the last 6 years a number of non-randomized, predominantly single institutional trials of breast conservation therapy (BCT) with DCIS, have demonstrated that it constitutes a very heterogeneous group of diseases with markedly different risks of local recurrence and invasive transformation. There has been a consensus that DCIS, which exhibits a "comedo" morphology, generally defines a high risk group. Most studies, moreover, have identified the same two features, nuclear grade and necrosis, as contributing most significantly to prognosis. Nuclear grade and necrosis have been identified as independent prognostic variables in several studies. High nuclear grade DCIS which exhibits comedo necrosis defines the majority of all DCIS which will result in local recurrence and invasive transformation after BCT. Studies utilizing image cytometry, to determine ploidy and S-phase fraction and immunohistochemical studies of proliferation and oncogene distribution have shown a significant association with morphologically identified high nuclear grade and aneuploidy, high S-phase fraction or proliferation rate, presence of HER-2/neu and P53 oncogenes and absence of estrogen receptors. Generally the inverse of this association is seen with low nuclear grade DCIS. However, initial hopes that these adjunctive studies would identify subsets within the high nuclear grade group which might be more likely to recur have not been fulfilled.

Heterogeneity of duct carcinoma in situ (DCIS): relationship of grade and subtype analysis to local recurrence and risk of invasive transformation.

Morphologic analysis of nuclear grade and extent of necrosis can provide reproducible classification of subclinical duct carcinoma in situ (DCIS) which strongly separates DCIS into three risk groups. For subclinical lesions of small size, risk is largely limited to local recurrences only, half of which, however, are invasive events. Local recurrences are seen much more frequently with high grade DCIS. Most local recurrences following breast conservation therapy represent residual disease in the immediate vicinity of the biopsy site. Stromal and cellular host reactions may provide additional prognostic information.

Pathology and clinical evolution of ductal carcinoma in situ (DCIS) of the breast.

The therapy of ductal carcinoma in situ is controversial, but is being more and more decided by the pathologic evidence. What we know of the natural history of ductal carcinoma in situ is that the comedo and non-comedo examples seem quite different. As detailed in several reviews, the information from studies following patients after biopsy alone indicate a great difference between the small non-comedo examples of ductal carcinoma in situ and the larger comedo DCIS. The currently available evidence from cases which have been treated by planned surgical excision without radiation therapy would indicate that the non-comedo examples of DCIS may be adequately treated by this modality as indicated in several recent studies.