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Keywords:

  • low-grade;
  • ductal carcinoma in situ;
  • natural history;
  • long-term follow-up

Abstract

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  2. Abstract
  3. REFERENCES

BACKGROUND

Opportunities to study the natural history of ductal carcinoma in situ (DCIS) are rare. A few studies of incompletely excised lesions in the premammographic era now recognized as DCIS have provided critical insights into its proclivity for local recurrence in the original site. At the time the biopsies in the current study were originally examined, small DCIS was not diagnosed and, by default, these women were treated by biopsy only.

METHODS

The authors report the latest results from a follow-up study, which was published originally in 1982, of 28 women with low-grade DCIS who were treated by biopsy only. These women were from a large, prospectively identified, completely characterized cohort.

RESULTS

Eleven of 28 women developed invasive breast carcinoma (IBC), all in the same breast and quadrant from which their low-grade DCIS biopsy was taken. Seven IBCs were diagnosed within 10 years of the DCIS biopsy, 1 was diagnosed within 12 years of the DCIS biopsy, and the remaining 3 IBCs were diagnosed over 23–42 years. Five of these women, including 1 woman who developed IBC 29 years after her DCIS biopsy, developed distant metastasis, which resulted in death 1–7 years after the diagnosis of IBC.

CONCLUSIONS

The natural history of low-grade DCIS can extend greater than 4 decades, with IBC developing at the same site as the previous DCIS in the majority of women. This natural history differs markedly from that of patients with high-grade DCIS and from the outcome of patients with any completely delimited DCIS excised to negative margins. Cancer 2005. © 2005 American Cancer Society.

Opportunities to study the natural history of ductal carcinoma in situ (DCIS) are rare. Before 1980, DCIS usually was diagnosed by the clinical finding of a breast mass or nipple discharge. In this article, we report the latest results of a previously published follow-up study of 28 women with small, low-grade, noncomedo DCIS who were treated by biopsy only.1, 2 These patients were recognized retrospectively by Page et al. during their larger review of surgical pathology diagnoses and original histologic slides for 11,760 consecutive biopsies performed at Vanderbilt, Baptist, and St. Thomas Hospitals from 1950 through 1968, as described previously.1, 3, 4 In the 1950s and during most of the 1960s, when these biopsies originally were examined, small DCIS was not diagnosed; therefore, by default, these women were treated by biopsy only after a benign interpretation. In historic perspective, it also should be recalled that atypical ductal hyperplasia (ADH), as it is defined specifically today, was often diagnosed as DCIS in the 1970s.

The current study was initiated in the mid-1970s to determine the natural history of DCIS after treatment by biopsy only. Follow-up on this group of women was reported previously in 19821 and 1995.2 In the current report, additional, extended follow-up data are provided on the original cohort of 28 women over a total of 46 years, with a median follow-up of 31 years for women who did not develop carcinoma. Eleven of 28 women (39.3%) have developed invasive breast carcinoma (IBC), all in the same quadrant and in the same breast from which the original biopsy with DCIS was taken. Seven women were diagnosed within 10 years and 8 women were diagnosed within 15 years of their original biopsy. The remaining 3 women developed IBC at 23 years, 29 years, and 42 years. The first of the 2 women who had invasive carcinomas identified since the 1995 report was diagnosed 12 years after her original biopsy. The tumor, which was treated by mastectomy, was of no special type and of unknown grade with 17 negative lymph nodes. The patient died 15 years later of unrelated causes. The second woman developed IBC in 2001, 42 years after her initial biopsy, and underwent excisional biopsy for an intermediate grade tumor with tubular and lobular features. At the time of last follow-up, the patient was alive and without local recurrence or distant metastasis 3 years after her invasive carcinoma diagnosis, and 45 years after her original diagnosis of DCIS.

An additional woman developed a low-grade DCIS in 1992 that involved multiple, clustered papillomas centered in the same quadrant of the same breast as the initial biopsy with DCIS. It was detected at the time of her first mammogram at age 58 years, 27 years after her original biopsy. She underwent bilateral mastectomies and at the time of last follow-up was alive and well without recurrence 12 years later.

Five of 11 women who developed IBC had died of metastatic disease at the time of last follow-up. Four women died within 5 years of diagnosis, and 1 woman died within 7 years of diagnosis. Of the remaining 6 women, 5 women had died from other causes at an average of 13.4 years after diagnosis and at an average of 24.2 years after the original biopsy with DCIS. The morbidity graph (Fig. 1) illustrates that any woman with noncomedo DCIS who has not received definitive treatment remains at risk for a prolonged period after this diagnosis. The risk of invasive carcinoma is greatest in the first 15 years and declines slightly as follow-up is extended. This suggests that these women may have stable carcinoma for decades. There is now good evidence that planned local excision with complete histologic examination and assurance of clear margins results in efficient and effective cure in most instances.5–7 This has led to a rapidly growing consensus that the natural history of small, low-grade DCIS differs markedly from that of high-grade DCIS. This fact emphasizes the need for consideration of less aggressive therapy (local excision only) when these lesions are limited in size, and the recurrence interval may well be beyond a reasonable life expectancy for the patient.

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Figure 1. This chart illustrates the cumulative incidence of invasive breast carcinoma (using the Kaplan–Meier method) for women with small, noncomedo ductal carcinoma in situ (DCIS) at biopsy who were followed without further therapy. Deaths from breast carcinoma are noted by crosses.

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The women in this cohort are from a large, prospectively identified cohort that has been completely characterized. The methodology and findings of our study are strikingly similar to those of Betsill et al.,8 who examined all available histologic slides from 8609 benign biopsies performed from 1940 through 1950 at Memorial Sloan Kettering Cancer Center in New York. These authors identified 25 women with previously undiagnosed low-grade DCIS who were treated by biopsy only. Among 10 women with long-term follow-up, which averaged 21.6 years, 7 women developed IBC at an average of 9.7 years after their initial biopsy (range, 7–30 years), all in the same breast in which the DCIS was found. These findings and our current results are highly relevant to current circumstances, because they likely represent the only information that ever will be available on the natural history of low-grade DCIS. In addition, with the now common practice of mammographic screening, the incidence of these lesser examples of DCIS has increased dramatically.

Small, low-grade, noncomedo DCIS is the pivotal lesion in understanding the borderline between malignancy and nonmalignancy in the female breast. Noncomedo DCIS is a nonobligate precursor that involves a very long clinical evolution to invasive carcinoma in approximately 50% of women. Therefore, over time, any residual DCIS either remains dormant after biopsy alone, expands extensively as in situ disease, or progresses to invasive carcinoma with metastatic and death-dealing capacity. These invasive carcinomas, with few exceptions, arise in the same quadrant of the same breast as the original biopsy.

The current series and the series reported by Betsill et al.8 provide important biologic validation of the diagnostic criteria currently used to delimit small noncomedo DCIS lesions. They indicate a striking dividing point biologically and histopathologically between low-grade DCIS lesions and the cytologically similar but lesser lesions of ADH.3, 9 ADH indicates a small, generalized, increased risk of breast carcinoma in both breasts that is approximately one half that of low-grade DCIS lesions, and these cancers may occur at any site rather than in a local region.3, 4 Recognition of ADH as a lesion limited in size, as well as completeness or purity of its cell population, has refined and confined the definition of DCIS. Distinction of small examples of DCIS from ADH is one of the most critical intersections of histopathology and clinical management today. The practical difference between these diagnoses is that DCIS, left without further treatment, predicts for a regional risk and will eventuate in invasive carcinoma in the same site in the same breast in 30% of patients within 15 years.

A major barrier to achieving a greater level of understanding among clinicians and patients regarding the diagnosis and therapy of DCIS is the erroneous idea that DCIS is one disease. Evidence now overwhelmingly demonstrates that DCIS is a spectrum of disease ranging from extensive, high-grade lesions, most likely requiring mastectomy for eradication, to small, low-grade lesions, which can be cured effectively by excision alone. It is also clear that there is a middle ground in which excision plus radiation therapy is valid. This requires separation and stratification of different forms of DCIS based on a combination of their natural history and the extent of mammary involvement to guide rational therapeutics.10 Precise case definitions are of critical importance to these considerations.

The findings of Betsill et al. and of the current series,1, 2, 8, 11 supplemented by later studies in patients with DCIS who underwent planned excision,5–7 provide a rational basis for prognostication and therapeutic recommendations for noncomedo DCIS. Fundamental to these studies was the careful definition of each lesion, primarily by size and histologic features.1, 2, 9 We now know that margin status is the critical delimiting element and the most important determinant of local recurrence.12 In fact, pathologic review of a subset of the cases that comprised the two largest cooperative trials for treatment of DCIS, the National Surgical Adjuvant Breast and Bowel Project B-17 and the European Organization for Research and Treatment of Cancer (EORTC), demonstrated that most local failures were in women with high-grade DCIS and with positive or unknown margin status13, 14 and that treatment with radiation therapy reduces but does not eliminate this risk.13, 14

Finally, short-term outcomes (median follow-up, 5.4 years) from the EORTC trial show that patients with high grade DCIS have the greatest risk of developing life-threatening distant metastasis after invasive local recurrence.14 Given the critical differences in natural history between high-grade and low-grade DCIS, it would be reasonable to expect that a few women with inadequately treated, lower grade lesions also would exhibit distant spread as their follow-up interval is extended.13, 14 In addition, because of the therapeutic implications, it will be important to document the degree to which these events will represent a threat to life or even will occur within the lifetime of the woman. In summary, the current series and the series reported by Betsill et al.8 have provided validation of the criteria currently used to delimit small, noncomedo DCIS lesions. In conjunction with subsequent studies of women with DCIS who underwent planned excision,5–7 these findings provide strong evidence that a limited and completely delimited DCIS can be cured successfully by excision alone. Finally, the results indicate a striking dividing point biologically and histopathologically between low-grade DCIS and the cytologically similar but lesser lesions of ADH.3, 9

REFERENCES

  1. Top of page
  2. Abstract
  3. REFERENCES