DCIS is a heterogeneous disease varying in clinical presentation, morphology and behaviour. In an attempt to reflect this heterogeneity, several histopathological classification systems have been proposed. These are based on nuclear morphology, growth pattern, cytonuclear differentiation and the presence or absence of necrosis, in various combinations. Some of these classification systems provide poor reproducibility, thereby limiting their clinical practice [6
]; however, others give more acceptable levels of reproducibility and have been shown to be clinically relevant. The Van Nuys classification system is based on nuclear grade and necrosis, yielding three subgroups of DCIS – non-high-grade without necrosis, non-high-grade with necrosis and high-grade with or without necrosis – that show an association both with local recurrence and disease-free survival [7
]. The classification system recommended by the National Coordinating Group for Breast Screening Pathology in the United Kingdom [8
] classifies the disease into three groups on the basis of cyto-nuclear features, with low-grade DCIS being composed of small regular cells, often showing a cribriform or micro-papillary architecture. High-grade DCIS is composed of large, pleomorphic cells with frequent mitotic figures, often having a solid architecture and associated necrosis. Intermediate-grade DCIS shows nuclear features intermediate between low- and high-grade DCIS. This classification system has also shown clinical relevance, with high-grade DCIS exhibiting a higher frequency of recurrence than low-grade DCIS [9
Careful analysis of large series of cases is essential to establish accurate information on disease behaviour. In the Van Nuys series of 866 DCIS patients, there were a total of 98 recurrences, 46% invasive and 54% non-invasive, with the probability of an invasive recurrence at 8 years calculated to be 6.4% and breast cancer-specific mortality to be 1.1% [10
]. This correlates well with other studies reporting mortality rates of approximately 1.5% to 2.0% at 10 years [1
Bijker and colleagues [11
] followed up 775 cases of DCIS as part of a randomised clinical trial of breast conserving surgery for DCIS with or without radiotherapy. Recurrence was detected in 125 cases at a median follow-up of 5.4 years: 65 developed recurrent DCIS whilst 60 developed invasive breast cancer. In addition to histological type (nuclear grade, architecture and necrosis), other factors found to be related to the rate of recurrence included young patient age, mode of presentation with recurrence being more common in symptomatically detected lesions, extent of disease and margin status. Radiotherapy reduced the risk of recurrence compared to local excision alone, although recurrence was still high in patients with involved or not-stated margins, supporting previous studies emphasising the importance of margin status [12
]. Interestingly, whereas intermediate- and high-grade DCIS showed significantly higher risk of recurrent DCIS compared to low-grade DCIS, the risk of recurrence as invasive disease was independent of DCIS grade. The outcome of the invasive disease differed markedly between the grades, however, with the risk of distant metastasis and death being significantly higher in recurrences secondary to high-grade DCIS [11
]. It has previously been shown that the grade of DCIS corresponds to the grade of subsequent invasive carcinoma [13
] and together with genetic studies showing different patterns of chromosomal alterations in DCIS and invasive carcinomas of different grades [14
] these findings support the proposal that different grades of DCIS represent distinct disease entities that give rise to different pathways of disease evolution.
In view of these data, it could be argued that treatment of DCIS should focus particularly on preventing recurrence in high-grade DCIS, since this is most likely to progress to life-threatening disease. However, several studies that report the long-term follow-up of patients with DCIS treated with biopsy alone have been important in highlighting the progression potential of lower-grade lesions.
Betsill and colleagues [15
] reported on the outcome of 10 patients with low-grade DCIS treated with biopsy alone with a mean follow-up of 21.6 years, and found that 7 had developed invasive carcinoma at an average interval of 9.7 years (range of 7 to 30 years). In the most recent report from the long-term follow-up study of Page and colleagues [4
] in which 28 women with small low-grade DCIS were treated with biopsy alone, 11 women developed invasive breast cancer (39.3%). Of these, 7 were diagnosed within 10 years of their biopsy, 1 within 12 years and 3 over 23 to 42 years. Five of the 11 women who developed invasive carcinoma died of metastatic disease, with a mean follow-up of 31 years. In all cases, the invasive carcinoma developed in the same quadrant of the same breast that the biopsy had been taken, supporting the proposal that this represents disease progression rather than de novo
Comparable findings come from the Nurses Health Study [5
], which showed that of 13 patients with DCIS treated by biopsy alone, 10 developed recurrent disease: 6 developed invasive carcinoma and 4 developed recurrent in situ
disease. Invasive carcinoma developed in patients with DCIS of all grades, including 2 of 6 with low-grade disease (at 5 and 18 years post-biopsy), 2 of 6 intermediate-grade DCIS (at 5 and 16 years post-biopsy) and 2 of 3 with high-grade DCIS (at 4 and 5 years post-biopsy). Taken together, these studies suggest that whilst progression to invasive disease is more rapid in high-grade DCIS, all grades have significant potential to progress.
A much lower recurrence rate was reported by Eusebi and colleagues [16
], who found 11 of 80 women with DCIS treated with biopsy alone developed invasive carcinoma at a mean follow-up of 17.5 years. This is likely to reflect the inclusion of a proportion of cases categorised as pure clinging DCIS. In the report from Bijker and colleagues [11
], an analysis of recurrence rate in relation to histological subtype of low-grade DCIS revealed that none of 59 cases of clinging DCIS developed recurrence, in contrast to low-grade cribriform lesions, which exhibited similar recurrence rates to high grade DCIS. To reflect this very low risk of recurrence and progression, clinging DCIS is now categorised under the heading of 'flat epithelial atypia', and this illustrates the value of such long-term studies to help refine diagnostic categories.