Archive for October, 2007.
Imaging
The most common presentation of DCIS is that of abnormal calcifications on routine screening mammography. In the NSABP B-17 randomized trial, 83% of patients had mammographic findings only. Several different patterns of calcifications suggest DCIS. The hallmark of high-grade DCIS is small linear calcifications that follow the pattern of a duct. These tend to represent the comedo necrosis often seen in grade III lesions. An indeterminate or pleomorphic cluster of calcifications or, occasionally, small masses can also indicate DCIS. When intraductal carcinoma is diagnosed on needle-localized biopsy or core biopsy of indeterminate calcifications, it should be carefully noted whether the calcifications are actually associated with the DCIS itself. Often, calcifications occur in benign breast tissue, and DCIS is only incidentally detected in the surrounding parenchyma. Such findings can lead to a clinical dilemma if there are multiple other foci of calcifications, and can erroneously lead to a mastectomy in an effort to remove all such mammographic findings.
In general, mammography remains an excellent diagnostic modality for the detection of DCIS, but it does not provide an accurate assessment of the extent of disease. Holland et al have demonstrated that standard two-view mammography underestimates the extent of DCIS, especially of low-grade lesions, by as much as 2 cm in almost half of patients. Other imaging modalities are being explored in an attempt to better define the pattern of DCIS in the breast. Magnetic resonance imaging with contrast has demonstrated promise in better defining the extent of lesions, thereby refining surgical decision-making. Furthermore, the patterns of contrast uptake and washout on MR imaging probably reflect abnormal angiogenesis. In the future, such radiographic data may help predict which lesions have the potential to progress to invasive disease.
Predictors of Recurrence Following Treatment for Ductal Carcinoma In Situ
The recurrence rate following simple mastectomy for DCIS ranges from 0 to 2%. A critical evaluation of the factors leading to recurrence of intraductal carcinoma following mastectomy has not been possible because of the small number of events in each series. However, recurrence data collected from patients treated with breast-conserving surgery suggest that the events resulting in local failure are multifactorial. There is controversy concerning the relative importance of each variable in determining local control following breast-conserving therapy, but large studies conducted in the past decade have increased the understanding of the complex interactions of patient, tumor, and treatment factors in determining recurrence.
Family History of Breast Cancer
Few studies have been specifically designed to determine whether a history of breast cancer in a first-degree relative places a woman at increased risk of recurrence following breast-conserving surgery for DCIS. At least two reports, however, indicate that family history may have a measurable effect. In a small study of women undergoing breast-conserving surgery and adjuvant radiation for DCIS, 4 of 10 patients with recurrence were found to have a positive family history, compared with 5 of 44 of those women who did not have a recurrence. This finding was statistically significant ( P = 0.03). In another study of patients undergoing treatment for DCIS, the 10-year actuarial rate of local recurrence was found to be 37% for women with a positive family history, compared with 9% for women without a family history of breast cancer. These findings suggest that genetic factors may not only play a role in increasing the incidence of breast cancer but may also lead to greater difficulty in maintaining durable local control.
Age at Diagnosis and Menopausal Status
In studies published to date, the two variables of age and menopausal status have not been separately evaluated in multivariate analysis. In one report of 133 patients with DCIS treated with wide excision and irradiation, Silverstein found that age was not a predictor of recurrence on univariate analysis ( P = 0.3). At least three other studies, however, have demonstrated that postmenopausal status or older age confers a beneficial effect on local recurrence. In one cohort study of 709 women diagnosed with DCIS, patients who were premenopausal at the time of diagnosis were more than twice as likely to have a recurrence than postmenopausal women. This result was statistically significant but did not take into consideration such factors as margin status and patient preference for one treatment over another. It does, however, argue for a more aggressive treatment for younger patients who appear to have a worse tumor biology and more years to be at risk for recurrence. Such considerations may give rise to either more extensive surgery or more frequent use of adjuvant irradiation in these patients.
Tumor Necrosis and Nuclear Grade
The presence of necrosis in DCIS has long been recognized to be associated with poor prognosis. Numerous studies have now demonstrated higher local recurrence rates for intraductal carcinomas containing a comedo component, regardless of whether treatment included adjuvant radiotherapy. Statistical analysis has recently suggested that the presence of necrosis alone may not be as important as cellular architecture and nuclear grade. Lagios reported on a long-term follow-up study of 79 patients treated with complete excision without irradiation and found that 19% of high-grade tumors recurred by 26 months whereas 10% of intermediate tumors recurred within 87 months. There were no recurrences in the low-grade group at 124 months of mean follow-up. Interestingly, the recurrences seen in the high-grade group occurred within a much shorter interval than those in the intermediate group. These findings are corroborated by others who have found nuclear grade to be the most significant predictor of recurrence on both univariate and multivariate analysis.
The concept of disease-free interval has been further explored by data from the Joint Center for Radiation Therapy, which showed no significant difference in long-term recurrence rates between low-grade and high-grade lesions. Solin found that at 5 years following treatment, high-grade DCIS had a 12% recurrence rate compared with 3% for low-grade lesions. By 10 years of follow-up, however, the difference in recurrence rates between the two groups was not statistically significant (18% versus 15%, respectively), again supporting the view that one of the major differences between low- and high-grade lesions may be the time to progression rather than the potential to progress.
The Role of Chemoprevention
Tamoxifen
Tamoxifen, a nonsteroidal compound with mixed estrogenic and antiestrogenic effects, has repeatedly shown effectiveness in decreasing recurrence rates of invasive breast cancer, particularly in women with estrogen receptor (ER)-positive tumors. Tamoxifen has also consistently demonstrated the ability to reduce the incidence of contralateral breast cancer, an observation that has led to the institution of several tamoxifen-based prevention trials. The NSABP trial (P-01), by far the largest prevention study to date, demonstrated that tamoxifen reduces the risk of developing both invasive and noninvasive breast cancer by 40%. Two other European prevention studies have not been able to demonstrate a statistically significant risk reduction, but these trials lack the statistical power of P-01. Additional criticisms of these trials involve poor compliance, high attrition, and the fact that many women, especially in the Italian study, were taking hormone replacement therapy. An important difference between the P-01 and United Kingdom studies was that positive family history was one of the major inclusion criteria for the latter trial. This study is ongoing and may shed light on the use of tamoxifen for women with a strong family history for breast cancer. The role of tamoxifen in treating DCIS is now established. Recent reports from NSABP B-24, which randomly assigned patients undergoing excision and irradiation for DCIS to either placebo or tamoxifen, show that tamoxifen further reduces DCIS recurrence. The effect of tamoxifen on reducing both primary and recurrent breast cancers is remarkably consistent across all trials, with an average relative risk reduction of about 50%.
One would anticipate that tamoxifen therapy alone could also reduce both the recurrence of DCIS and the progression of DCIS to invasive cancer following lumpectomy, even in the absence of radiation therapy, but these studies have not yet been conducted. The NSABP B-24 study found that, for the population studied, the risk of developing contralateral invasive breast cancer (CBC) was nearly as high as the risk of developing ipsilateral invasive breast cancer (IBC) after irradiation. In the placebo group, the cumulative 5-year risk of invasive CBC was 2.4%, and for IBC it was 3.4%. These rates were reduced to 1.8% and 2.1% with tamoxifen. The cumulative incidences of DCIS after 62 months of follow-up in the placebo arm were 5.2% in the ipsilateral breast and 1.0% in the contralateral breast, and these risks were reduced to 4.3% and 0.2%, respectively, for the patients who received tamoxifen.
In a recent meta-analysis of the NSABP trials, the cumulative risk of CBC (both invasive and intraductal) for women with a cancer diagnosis was 5.1% after 5 years, which was reduced to 1.9% in women who took tamoxifen. The NSABP trial showed a cumulative 5-year breast cancer risk of 4.4% for women on placebo versus a risk of 2.4% for women on tamoxifen. It would therefore be reasonable to offer a trial that enables women to use hormone therapy alone to reduce the risk of invasive breast cancer recurrence and of contralateral breast cancer following lumpectomy for DCIS. This therapy may be especially important for small DCIS lesions in which the recurrence rates are low and the risk of contralateral breast cancer is almost as high as the risk of IBC recurrence after lumpectomy without radiation therapy.
The primary concern regarding the widespread use of tamoxifen involves its effect on other end organs. Tamoxifen appears to have a protective effect on bone mineral density in postmenopausal women, although in the P-01 trial its ability to reduce the fracture rate was only marginally significant. The P-01 trial also showed a reduction in the lipid profiles with tamoxifen use, but there was no clear effect on cardiovascular events during the short follow-up interval. Unfortunately, tamoxifen has additional estrogenic effects that are adverse, especially in postmenopausal women. The effect of tamoxifen on the endometrial lining increases the risk of uterine cancer, probably by at least two-fold. In the NSABP P-01 trial, in which more than 13,300 women were randomly assigned to either tamoxifen or placebo, the cumulative risk of developing endometrial cancer in postmenopausal women was 13/1000 in the tamoxifen arm versus 5.4/1000 in the placebo arm. The endometrial cancers were all early stage and treated by hysterectomy, but a 5-year cumulative risk of 1.3 must be placed into the context of other projected benefits. In the tamoxifen arm there was also an increase in venous vascular events of approximately two-fold over the control arm.
New Compounds
The deleterious side effects of tamoxifen have spurred great interest in the development of new agents that have antiestrogenic effects at the level of both breast and uterine tissue while maintaining the beneficial estrogen-like effects on bone mineral density and the cardiovascular system. This group of compounds has been termed selective estrogen receptor modulators, or SERMs, and the best studied is the agent raloxifene (marketed as Evista), which was developed to prevent osteoporosis in postmenopausal women. Raloxifene also lowers serum concentrations of total and low-density lipoprotein cholesterol and does not stimulate the endometrium. Preliminary evidence suggests that raloxifene may be useful in the prevention of breast cancer; however, there is no experience to date in premenopausal women, and data on the effectiveness of raloxifene for women with established breast cancer are very limited.
Initially intended to be an alternative to hormone replacement therapy, raloxifene has been tested for its effect on bone mineral density and fractures but not for its effect on breast cancer. Nevertheless, some striking data were gathered from the Multiple Outcomes of Raloxifene Evaluation Study (MORE trial). In this large randomized study, 7705 postmenopausal women with osteoporosis were treated with raloxifene (60 or 120 mg/d). Raloxifene significantly reduced bone mineral density loss and the fracture rate compared with placebo. Also, after a median follow-up of 33 months, there was a 70% decrease in the risk of both breast cancer (relative risk = 0.26) and endometrial cancer (relative risk = 0.38, P = not statistically significant) compared with women who received placebo. A meta-analysis of nine raloxifene trials involving a total of 10,575 women was recently presented, and after 40 months of follow-up, the drug was associated with a 55% reduction in the relative risk of developing invasive breast cancer compared with placebo use, based on 67 breast cancer events. As in the P-01 trial, the incidence of only estrogen receptor-positive breast cancers appears to be reduced. At present, however, there are few data to show that raloxifene is effective in the treatment of invasive breast cancer, and its use is not recommended except in the context of a clinical trial.
One of the newest “designer estrogens” is LY353381 hydrochloride, a SERM-3 compound that is structurally similar to raloxifene. Like raloxifene, it appears to act as a potent estrogen antagonist in both uterine and mammary tissues while maintaining bone density and lowering serum cholesterol. A clinical trial is currently being planned to test tamoxifen versus SERM-3 in women with DCIS who have chosen breast-conserving surgery, regardless of use of irradiation. Results from this trial should be available 5 years from the start date of accrual.
Technical Considerations and Recommendations
Wide excision for DCIS is appropriate in patients with limited extent of disease. Careful attention must be paid to the margin status, although intraoperative decision-making is hampered because intraductal lesions are for the most part not distinguishable from normal surrounding tissue. Precise anatomic orientation is critical in identifying the location of any positive margins, and careful attention must be paid to inking the specimen correctly. These measures will greatly facilitate any subsequent reexcision. The rate of reexcision for positive or close (<1 mm) margins has been estimated to be as high as 55%, and this number may be even higher in tertiary breast cancer referral centers, where the inspection of margins tends to be more exhaustive.
The accurate determination of the true size of DCIS lesions is challenging. Therefore, both the extent of disease in a given slide and the number of blocks involved with disease should be recorded. Also, it must be noted whether microcalcifications are associated with DCIS within the excised specimen, because this factor is especially important in the evaluation of subsequent residual calcifications. Finally, the authors and others recommend routine follow-up mammography after definitive excision and before starting irradiation. This simple step may guide management and help distinguish between residual incompletely excised calcifications and those that are the result of postsurgical or radiation changes.
Axillary Lymph Node Dissection
Current data indicate that the incidence of axillary lymph node metastases in pure DCIS is 0 to 1%, obviating the need for axillary dissection in these patients. For complicated cases with an associated mass and questions of microscopic invasion, axillary lymph node dissection has a role, but these are a very small fraction of DCIS cases. Axillary lymph node dissection has been shown to be associated with substantial rates of lymphedema, for which treatment options remain limited. Unfortunately, many women still undergo axillary dissection when they are treated for DCIS. Although the number has dropped during the last decade, Winchester et al have shown that as many as 40% of patients still undergo this procedure and that continued efforts to educate women and their physicians are critical. The use of sentinel node biopsy has been proposed in treating DCIS, but when it is undertaken, it should be performed as part of a clinical trial.
The Role of Adjuvant Radiation
The role of irradiation in the treatment of DCIS continues to evolve. Many studies have now conclusively demonstrated approximately a 50% reduction in local recurrence with the addition of radiotherapy to surgical excision. The most compelling data come from The National Surgical Adjuvant Breast and Bowel Project trial (NSABP) B-17, a prospective trial that randomly assigned 818 patients to surgery only or to surgery plus irradiation. The most recent update of this study, with a mean follow-up of 90 months, shows a reduction in noninvasive ipsilateral breast tumors (IBT) from 13.4% to 8.2% ( P = 0.007), with a similar reduction in invasive IBT from 13.4% to 3.9% ( P = < 0.0001). This study has been criticized for suggesting that all patients, regardless of clinical or tumor characteristics, should undergo radiotherapy, rather than providing more selective recommendations based on subgroup analysis. Furthermore, the study has limited applicability, because the majority of lesions in this trial were very small tumors. A prospective randomized study designed by the Radiation Therapy Oncology Group (RTOG) is scheduled to open by mid-2006 to address some of these issues. Included will be patients diagnosed with DCIS of up to 2.5 cm who will be placed on tamoxifen therapy, then randomly assigned to lumpectomy only or to lumpectomy with irradiation. The goals of this study include the identification of those variables that may allow a more individualized use of radiotherapy in the treatment of DCIS.
Natural History of Ductal Carcinoma In Situ
Undoubtedly, the improved availability of mammographic screening has dramatically increased the detection rate of DCIS, resulting in an earlier and possibly overly aggressive intervention at this stage of breast cancer. Autopsy series suggest that the prevalence of undetected DCIS is close to 9% in the overall population, and it is likely that many of these lesions can remain undetected and be clinically insignificant for many decades. The consequences of treating DCIS by observation alone are unclear. Current understanding of the disease suggests that, without treatment, a certain percentage of high-grade lesions will probably progress to invasive disease within 5 to 10 years. The natural history of low-grade intraductal carcinoma is more debatable, and the answer is critical: early surgical intervention in low-grade DCIS may represent over treatment, because the majority of these neoplasms, if they progress to invasive disease, do so over a much longer period of time. Furthermore, ethical considerations make longitudinal studies to address these issues impossible.
Indirect evidence pertaining to the natural history of DCIS can be obtained from early studies examining the long-term recurrence rates in women treated for DCIS with biopsy only. Page and Dupont reported a small series of 28 women who had undergone surgery only for cribriform or micropapillary DCIS between 1952 and 1968 and found that 7 of 28 patients developed invasive cancer within 10 years, all within the same quadrant as the index lesion. Furthermore, 2 additional women were diagnosed with invasive breast cancer at 15 and 31 years following their diagnosis of DCIS, suggesting that the increased risk for developing invasive disease may continue long after the diagnosis of low-grade DCIS has been made. Betsill reported similar results on a cohort of 24 women who underwent biopsy only for DCIS. He concluded that in long-term follow-up (mean 21.6 years) 39% of women with DCIS treated with biopsy alone developed invasive cancer in the ipsilateral breast.
These studies demonstrate that low-grade DCIS also progresses to invasive cancer but do not elucidate which patients are at highest risk for progression to more aggressive disease. What is clear, however, is that the risk of developing invasive cancer may persist even two decades after diagnosis of DCIS if an initial complete excision is not performed. One of the most challenging areas for research and intervention will be to identify those factors responsible for the transition from DCIS to invasive cancer, to avoid the over treatment of the large percentage of women with DCIS who will probably never progress to clinically significant disease.
Treatment Considerations and Management of Ductal Carcinoma In Situ
Surgery
Mastectomy
The recurrence rate following mastectomy for DCIS has been shown to be between 0 and 2% on long-term follow-up. There is thus no role for adjuvant irradiation following mastectomy for DCIS. This procedure remains the standard against which the outcomes of all other therapy must be compared but is the most aggressive of the treatment options. Mastectomy still, however, remains the procedure of choice in those patients with large or high-grade lesions or in women with multicentric disease. Advances in breast reconstruction techniques have allowed many women to undergo mastectomy without the disfiguring sequelae. The most significant advance in recent years has been the introduction of skin-sparing mastectomy, in which the breast tissue is excised by a periareolar incision. Large retrospective studies have now shown that this technique does not result in higher local breast cancer recurrence rates.
Breast Conservation
The widespread successful use of breast-conserving treatment for invasive cancer has focused efforts to identify which women with DCIS may be appropriately treated with wide excision rather than mastectomy. Attempts have been made to classify patients with DCIS into prognostic categories, as for invasive cancer. The Van Nuys Prognostic Index (VNPI) originated by Silverstein is perhaps the best known among these classification systems. The VNPI assigns patients an overall score taking into account three factors: the size of the DCIS, the width of the closest margin, and the differentiation (grade) of the tumor cells.
Silverstein evaluated 333 patients who were treated with breast-conserving surgery and divided them into three different recurrence-risk groups based on the VNPI score (3-4, 5-7, or 8-9). With a median follow-up of 70 months, he found that the 8-year actuarial local disease-free survival rates for the three groups were 97%, 77%, and 20%, respectively. For the purposes of analysis, patients were stratified by treatment (wide excision or wide excision and irradiation). Silverstein found that adjuvant irradiation offered a significant therapeutic benefit only in the VNPI intermediate group. The low-risk group had an excellent prognosis, so irradiation conferred very little absolute benefit. Irradiation reduced the likelihood of recurrence in high-risk patients, but even those treated with adjuvant radiotherapy had very high failure rates, with only 30% of patients in this group enjoying long-term local control. These data, although retrospective, are compelling because they represent the experience of a large number of patients treated at a single institution with identical tissue handling and analysis. Thus, although the prospective randomized trials eliminate individual physician bias, Silverstein’s data are valuable in that they control for process.
The Van Nuys data suggest that surgical treatment alone can lead to a lower risk of recurrence. Patients with a low VNPI score may be treated with wide excision, because the recurrence rates are in the 3% to 4% range. The use of adjuvant irradiation in addition to wide excision is suggested for intermediate-score tumors, for which the long-term local recurrence rates may be reduced from about 28% to 15%. A high VNPI score would merit consideration of simple mastectomy because of the excessive local recurrence rates (25% and 45%, with and without irradiation at 4 years, respectively) seen with breast-conserving treatment in this group. This classification system allows the generalized formulation of a treatment plan, but it takes into consideration only three prognostic factors. It should be remembered that other variables that may affect recurrence rates for DCIS are not included in the VNPI analysis.
Significance of Cellular and Genetic Changes in Ductal Carcinoma In Situ
The last decade has seen an explosive growth in the understanding of the changes that occur at the cellular and genetic level in all cancers, and increasing attention is being focused on such changes in DCIS. p53 has long been known to be an important tumor-suppressor gene in lung, colon, and breast cancers. Recently, p53 mutations have been identified in 7% to 37% of intraductal carcinomas but have not been found in areas of epithelial hyperplasia. In some studies, aberrant p53 expression appears to be associated with higher nuclear grade. Microdissected specimens of DCIS both with and without invasion have been studied, and the identical p53 mutation was identified in both the DCIS and the invasive component. This finding indicates that the genetic alterations seen in infiltrating cancers have already occurred at the preinvasive level, but the mechanism by which the phenotypic transformation occurs has not yet been elucidated. It is known, however, that the prevalence of p53 mutations is greater in DCIS than in invasive breast cancers, and thus it is probable that not all of these lesions progress to invasive disease. This has also been noted in HER2/ neu expression: 90% of high-grade DCIS lesions over express HER-2/ neu, but only 40% to 50% of high-grade invasive lesions show over expression.
It has been shown that a greater degree of apoptosis is seen in DCIS than in invasive cancers, and, furthermore, that higher grade DCIS exhibits more abundant apoptosis than lower grade lesions, probably reflecting the greater growth fraction seen in high-grade disease. The degree of apoptosis appears to be independent of p53 expression and has not yet been fully explained. These data, however, strongly suggest that aberrant cell cycle regulation plays a role in the transition between atypia and in situ carcinoma.
PRAD-1/cyclin D1 has been implicated as the relevant oncogene on chromosome 11q13 and is seen frequently in breast and other epithelial cancers. This gene may be a marker of early malignant transformation, because its expression is found in 18% of atypical ductal hyperplasia, in 76% of low-grade DCIS, in 87% of high-grade comedo-type DCIS, and in 83% of invasive breast cancer. To date, however, the precise role of cyclins and cyclin-dependent kinase inhibitors such as p21 (waf-1), p15, and p27, which may act as tumor-suppressor genes, has not been well studied for DCIS.
The presence of genetic abnormalities in DCIS has been clearly demonstrated in studies examining loss of heterozygosity (LOH) and microsatellite instability (MI) in microdissected specimens of DCIS. Loss of heterozygosity is associated with 70% of noncomedo DCIS and with 79% of comedo DCIS. Interestingly, DCIS associated with an invasive breast cancer has been found to share LOH at one or more loci with the infiltrating component. Microsatellite instability has been reported in one study in 22% of DCIS at two or more loci and in 30% at a single locus. Such genetic changes were correlated with higher grade and c- erbB-2 positivity. Further research will be needed to define the relationship between such genetic alterations and the clinical behavior and prognosis of DCIS.
The presence of increased angiogenesis has also been explored. Studies have shown that high-grade DCIS exhibits an increase in both stromal and periductal vascularity. Evidence shows that VEGF mRNA expression is greater in DCIS than in adjacent normal cells in 96% of cases. High-grade tumors showed increased VEGF expression more often than low-grade tumors. Thus, even at the preinvasive stage, alterations at the genetic or translational level allow DCIS to establish and maintain the neovascularization necessary for tumor growth. These alterations may provide a target for therapeutic interventions in the future.
The compilation of research on molecular markers leads to the compelling observation that DCIS and invasive cancer are clearly distinct from normal cells and from each other but appear to be virtually identical at the molecular and genetic levels. Possible factors leading to progression from DCIS to invasive cancer include the interaction with the surrounding stromal environment. Promising avenues for further investigation include the study of myoepithelial cells, stromal interactions, angiogenic signals, and DNA repair mechanisms.
Papillary and Micropapillary
Papillary or micropapillary DCIS is a low- to moderate-grade subtype of intraductal carcinoma composed of a uniform population of cells that forms papillary extensions into the ductal spaces. These projections may coalesce to create an “arcuate” or “Roman bridge” pattern. This subtype is well-differentiated and is only rarely seen in conjunction with cellular necrosis.
Cribriform
The cribriform subtype is the most commonly encountered architectural pattern of DCIS and is identified by ductal epithelium organized into extracellular lumina, often creating a “lacy” appearance. The cells are usually of uniform size and shape with a large, centrally placed nucleus. Occasionally, the cribriform pattern may be associated with cellular necrosis, and the nuclear grade can range from well- to poorly differentiated.
Solid
The solid pattern of DCIS is characterized by complete obliteration of the ductal lumen by cellular proliferation. Although the cellular pattern is often monotonous, the tumor grade can range from very well-differentiated lesions to the more frequently seen high-grade neoplasms.
Comedocarcinoma
Comedocarcinoma has been shown to carry the worst prognosis among all architectural subtypes. It is identified by the presence of necrotic cellular debris within the ductal lumen. Although the presence of comedo histology was once thought to be the most important histologic determinant of prognosis, it has recently been realized that nuclear grade is probably the more important factor. In comedocarcinoma, the cells are typically large, with marked nuclear atypia, and calcifications are often present in association with the necrosis. Microinvasion, when present, is most likely to occur in conjunction with dense, high-grade, comedo-type lesions, and often necessitates treatment as a T1a invasive carcinoma.
Multicentricity in Ductal Carcinoma In Situ
Multicentricity is defined as disease present in more than one quadrant of the breast and was historically used to justify mastectomy for DCIS. Serial sub gross analysis of breast specimens following mastectomy for intraductal carcinomas has, however, demonstrated a low incidence of true multicentricity. Holland’s data showed that only 1 patient in 60 had multiple foci of tumor separated by 4 or more cm. The incidence of multifocal disease, defined as distinct tumor foci separated by at least 1 cm of intervening tissue, was somewhat higher, at 8%. Interestingly, the well-differentiated DCIS were more likely to demonstrate a multifocal distribution pattern than the poorly differentiated tumors (70% versus 10%). It has been postulated that this finding may reflect a field-defect phenomenon in well-differentiated DCIS that may not apply to poorly differentiated intraductal cancers or to invasive disease.
In the literature, estimates of multicentricity in DCIS range widely, from 2% to 78%. This discrepancy is attributable to differences in both the definition and mode of detection, with some authors defining multicentric disease as foci of tumor found in more than one quadrant, regardless of proximity to the index lesion. What has become clear, however, is that, contrary to initial dogma, treatment of DCIS with breast-conserving surgery can be oncologically appropriate in many patients, and higher grade intraductal lesions may be more amenable to lumpectomy because of their lower likelihood of multifocality. This question has not been specifically addressed in the large prospective randomized trials, which have excluded patients with either large or high-grade tumors. Some higher grade DCIS lesions, however, are still more optimally treated with mastectomy, as poorly differentiated intraductal cancers are often larger at diagnosis and frequently span more than one quadrant.