Affiliations of authors: E. R. Fisher, National Surgical Adjuvant Breast and Bowel Project (NSABP) Pathology Center, Pittsburgh, PA; B. Fisher, NSABP Scientific Director's Office, Pittsburgh.
Correspondence to: Bernard Fisher, M.D., NSABP Scientific Director's Office, Four Allegheny Center, Suite 602, Pittsburgh, PA 15212-5234 (e-mail: bernard.fisher{at}nsabp.org).
Chromosomal instability has long been recognized as a feature of malignant neoplasms. In 1975 (1,2), we described quantitative differences in chromosomal aberrations in premalignant lesions and in methylcholanthrene-induced cancers in rats; in 1978 (3), we noted these differences between women with both premalignant lesions and breast cancer. The use of digital image analysis of the DNA content of intraductal carcinomas (ductal carcinoma in situ, or DCIS) and the invasive cancers associated with them subsequently (4) revealed a close concordance in DNA ploidy and S-phase content. Although it was tempting to consider our observations as evidence that DCIS was a precursor of the invasive component, we were uncertain whether similarity in itself was a reliable indicator of such a pathogenic pathway, since it was possible that an etiologic agent could have induced the same phenotype in both the large ducts and the ductolobular units of the breast. In about 10 000 cases of DCIS associated with overt invasive cancer, one of us (E. R. Fisher) has rarely observed unequivocal microscopic extension of neoplastic elements of DCIS through its ductal basement membrane into the surrounding stroma. Moreover, although gaps in the ultrastructural basement membrane may be identified, no tumor cell extension through them or through intact membranes has been observed with the use of electron microscopy (5). The phenomenon of microinvasion associated with DCIS lacks a clear definition, since it is more easily explained by what it isn't rather than by what it is (6). In that regard, ipsilateral breast tumor recurrences of invasive cancer following excision of DCIS are a conundrum, since we have observed that the survival of patients with DCIS is 98% through 8 years of follow-up, despite the finding that 40% of such recurrences were invasive and that about 50% of deaths occurred in the absence of an ipsilateral breast tumor recurrence (7-10).
In this issue of the Journal, Waldman et al. (11) have attempted to determine whether DCIS recurrences observed after conservative excision of DCIS were due to subsequent growth of the initial tumor that had not been completely excised or constituted new foci of DCIS. With the use of comparative genomic hybridization (CGH), they observed a high degree of concordance in the chromosomal alterations in the initial and the recurrent DCIS lesions of 17 of 18 patients. This finding led them to conclude that the recurrences were residual tumors.
We have no reason to challenge the importance of the CGH technique. The application of such molecular tools in the identification of the substructure and biology of breast cancer could result in findings of significance. The authors fail to note, however, whether the findings obtained using CGH represent just another marker or possess any etiologic or biologic significance. They also fail to provide information about the molecular characterization of cells in a DCIS that is not followed by local recurrencedata that are crucial to the support of their thesis. Moreover, the authors' review of the extant literature concerning the pathology, natural history, and treatment of DCIS is limited and has, thus, led them to erroneously claim to having initially described certain aspects of DCIS lesions and their recurrences. We have often emphasized the similarity of morphologic appearances of index and recurrent DCIS (6,8-15). In addition, our studies have revealed that the majority of such recurrences are within or close to the site of the excised index lesionanother feature that is consistent with such events representing "residual" tumor. The authors' data also confirm our findings (6,8,10-14) that there is no unique comedo histologic type of DCIS and that comedo necrosis occurs with both cribriform and solid types of DCIS and with lesions whose cells exhibit poor (high) as well as good (low) nuclear grade.
We have been somewhat uncomfortable with our perception that such recurrences are, for the most part, residual lesions. Waldman et al. (11) attribute them to "the persistence of neoplastic cells rather than to newly arising lesions." Such a statement appears plausible, however, only when applied to invasive rather than to in situ ductal cancer. It is difficult to imagine neoplastic cells differentiating into neoplastic ducts with their attendant basement membranes, myoepithelial cells, and other components that would have to occur if "neoplastic cells" can develop into ducts containing DCIS. In actuality, individual cells are rarely seen at lines of resection that are involved with DCIS. A more cogent inquiry might consider whether residual DCIS actually grows so that it becomes a detectable recurrence. Individually involved ducts do not appear to increase in unit size but rather in unit numbers. That circumstance is apparent from the observation of the morphologic similarity of the index and recurrent lesions. On the other hand, it may be speculated that ducts in the vicinity of the index lesion that appear morphologically normal may have submicroscopic changes that have the potential to develop into DCIS and, subsequently, a recurrence. Perhaps such cells may be identified by CGH or other techniques. Such a scenario would satisfy an older concept of neoplasia that attributes tumor development to a wide field of origin. If valid, this thesis would be in keeping with the view that ipsilateral breast tumor recurrences not only are the result of residual cells but also occur de novo. That circumstance would support our thesis that evaluating margins by relying on the histologic demonstration of tumor transection represents a crude assessment of the phenomenon. In that regard, it should also be noted that our most recent analyses (10) failed to indicate that margin involvement is an independent predictor of recurrence. All of these considerations are concordant with the findings from our B-24 trial, which tend to put the status of margin assessment into better perspective (16), in that they demonstrate a reduction in the multifocal or multicentric recurrences of DCIS as a result of radiation therapy and tamoxifen administration to all patients regardless of the margin involvement of their tumors.
One of the most disconcerting aspects of the study by Waldman et al. (11) relates to the authors' conclusion that their study findings are "consistent with treatment paradigms requiring wide surgical margins and/or postoperative radiation therapy" and that "residual DCIS may be left behind when surgical margins are less than 10 mm, as previously suggested" (17,18). Not only are these statements ambiguous, they are also contradictory in that one might conclude from them that obtaining "wide surgical margins" might not be necessary if radiation therapy is administered. If that indeed is the case, their thesis can be viewed as the result of inductivist reasoning, in that it is more expansive than is justified from the limited data that the authors present. Because their statement about the need for obtaining surgical margins of 10 mm or more has the potential for adversely influencing clinical practice, a few of the comments that we have made with regard to that issue need to be re-emphasized (19). It has not been proven that one specific measurement of the width of tumor-free breast tissue (e.g., 2, 5, or 10 mm) that should surround an excised tumor is better than another. Unfortunately, the credibility of the investigations that have given rise to the concept of "wide" margins (17) has been impaired by the use of retrospectively accumulated information that has been gathered over two decades from studies in a relatively few patients who did not have to meet a set of sufficiently rigid criteria for eligibility. Unlike randomized trials, the methodology used to obtain such information fails to ensure that the groups being compared are sufficiently similar so that any difference in outcome observed is due to the variable being evaluatedin this case, the width of the margin of normal breast tissue surrounding a tumor. Although all surgeons should attempt to obtain tumor-free specimen margins, a 1-cm tumor-free margin encompassing the entire circumference of a tumor cannot always be obtained for reasons other than those related to the extent of the tumor. Moreover, it is blatantly wrong if such a restrictive policy results in a mastectomy or impairs the cosmesis of a lumpectomy (12). While we commend research efforts directed toward obtaining better local control after DCIS and for identifying patients for whom radiation therapy should be omitted, we believe that the studies cited by Waldman et al. serve only to suggest further directions for prospective evaluations with scientifically appropriate study design considerations.
It is apparent that the study by Waldman et al. (11) has provoked a number of unanswered questions about DCIS. Perhaps the results of CGH or other newer techniques will help to resolve some of these issues. It is our view that the findings from CGH could serve as a marker for the identification of cells involved with DCIS. Whether those findings would provide a better predictor for recurrence than more readily and easily demonstrated features of DCIS, such as degree of comedo necrosis (10), remains to be proven. It appears that, at present, however, there is no justification for its use as a guide to treatment.
REFERENCES
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6
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