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EDITORIAL |
From The Breast Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York.
Correspondence: Address correspondence to: Hiram S. Cody III, MD, Memorial Sloan-Kettering Cancer Center, 1275 York Ave., New York, NY: Fax: 212-794-5812; E-mail: codyh{at}mskcc.org
To the question "Is axillary node staging required in patients with duct carcinoma in situ (DCIS) of the breast?" there are two possible responses: a short answer and a long one.
The short answer is a simple and unambiguous "no." By definition, neither DCIS nor any in situ cancer can possibly metastasize and the treatment is therefore local. The appropriate management of DCIS starts with a surgical excision of the primary site sufficient to obtain a negative histologic margin. Cure results from local control. The goal of adjuvant radiotherapy and/or tamoxifen in this setting is likewise the prevention of local recurrence. Distant metastasis is simply not a concern because survival should be virtually 100%. Three major randomized clinical trials (NSABP B-17,1,2 B-24,3 and EORTC 108534) largely support the short answer. The addition of radiotherapy or radiotherapy plus tamoxifen enhances local control but has not (at 4–8 years of follow-up) improved survival more than that obtained by excision alone: 98% to 99%. Therefore, neither axillary lymph node dissection (ALND) nor sentinel lymph node (SLN) biopsy is indicated for DCIS.
The long answer is "yes, selectively," and this is the position we support. DCIS represents a morphologically and biologically heterogeneous mix of lesions with varying malignant and/or metastatic potential. With experience comes skepticism, and the wary surgeon faced with a pathologic diagnosis of "DCIS" will immediately ask the question: "Is it really DCIS?" The grounds for skepticism are many:
In the era when all DCIS was treated by mastectomy, the response of many surgeons to the above uncertainties was simply to perform a low ALND in all cases.9 DCIS now comprises 20% to 25% of all new breast cancer diagnoses, and an increasing proportion of these are treated with breast conservation; in this setting, the morbidity of a conventional ALND to find metastases in fewer than 1% of DCIS patients seems excessive. SLN biopsy, more accurate and less morbid than ALND,10 is a new standard of care for patients with invasive breast cancer. We believe it will play a significant role in the management of DCIS as well.
Cox and his colleagues at the Moffitt Cancer Center were the first to report in a series of publications11–14 the results of SLN biopsy in DCIS, finding positive SLN in 6% to 9% of consecutive unselected patients. Our own use of SLN biopsy for DCIS has been more selective;15 over a 2-year period (1997–1999, 1 year after we first began to do SLN biopsy) we performed SLN biopsy in 21% of all cases of DCIS, those "high-risk" patients in whom we were concerned that invasion might be present. Our guiding principle then and now is a very simple one: the purpose of SLN biopsy in high-risk DCIS is to identify those patients with a missed invasive component.
Our "high-risk" DCIS patients had one or more of the following: a palpable or mammographic mass, suspicion of microinvasion, high-grade histology, or extensive disease requiring mastectomy. Of 76 patients, 9 (12%) had positive SLN, prompting a complete histopathologic review of all 9. We found microinvasion in one, LVI in two, and H&E-detected macrometastases in three cases (in the SLN of two and in the completion ALND of one). That is, by conventional staging and treatment criteria, 6 of 76 (8%) high-risk DCIS patients were found to be at a substantially higher risk of metastasis than would be expected for DCIS alone and were upstaged accordingly. These six comprise only 1.7% of all DCIS patients seen during this 2-year period.
The significance of micrometastases detected only by immunohistochemistry (IHC) remains a subject of controversy. Retrospective studies using enhanced histopathologic methods on "negative" axillary nodes16,17 suggest that IHC-detected micrometastases confer a 10% to 15% worse survival, and two elegant prospective trials18,19 have found that IHC-detected bone marrow micrometastases have an independent prognostic impact exceeding that of conventional criteria. We find these data to be compelling, but a definitive answer to the significance of SLN micrometastases found only by IHC must await the results of studies in progress. Systemic adjuvant chemotherapy cannot yet become standard treatment for patients with DCIS whose SLN are positive only on IHC.
DCIS by definition cannot metastasize, yet patients diagnosed as having DCIS can indeed die of metastatic breast cancer. Although most patients who die of DCIS have first developed an invasive recurrence20 (the presumed source of metastasis), some develop distant metastasis as a first event. This was the case for 5 of 14 breast cancer-related deaths in the NSABP trial2 and 4 of 24 in the EORTC trial.4 The observation of distant metastasis from an in situ cancer is not a paradox. We would argue that these patients had missed invasive cancers at the outset, and hypothesize that SLN biopsy might have revealed this metastatic potential.
Lagios and Silverstein 21 strongly disagree and criticize our work15 in the May issue of Annals of Surgical Oncology, arguing that SLN biopsy for DCIS is a "dangerous and unwarranted direction." They suggest that IHC-detected micrometastases are artifactual; we have seen no evidence of displacement artifact in any of our carefully reviewed cases. They suggest that IHC-detected micrometastases are prognostically insignificant; the persuasive and growing body of retrospective and prospective studies referenced above suggests that they are significant. They state that we do not distinguish between IHC- and H&E-detected SLN metastases; we do. They suggest that we routinely recommend chemotherapy for our DCIS patients whose SLN are positive only on IHC; we do not. They state that SLN techniques will not be useful in predicting which DCIS patients will develop invasive recurrence; we never claimed that they would.
Finally, they argue the importance of a thorough tissue examination in all cases of DCIS. Here we agree entirely. The surprise finding of a positive SLN in patients thought only to have DCIS led us to go back and discover features which upstaged six of nine SLN-positive patients using conventional staging criteria. But should one look first to the breast tissue (ignoring the axilla), or proceed directly to the SLN in DCIS patients at a high risk of occult invasion? The correct answer for this high-risk subset of DCIS patients is probably "both."
Lagios and Silverstein argue that patients with missed invasion are best identified through more careful scrutiny of the breast tissue itself. Of their own carefully studied patients with DCIS,20 the only patients who developed distant metastasis had previously developed an invasive recurrence as a first event. Central pathology review identified missed invasive cancers in 2% of the NSABP5 and 3% of the EORTC6 patients. In our own experience, three of nine SLN-positive patients (33%) were upstaged from Tis to T1 disease after pathologic review.
We argue that SLN biopsy in high-risk DCIS will prove more useful than re-examination of the breast. Countless studies confirm that axillary node status is a more important predictor of survival than tumor characteristics. Our focus in performing SLN biopsy for high-risk DCIS is not simply to find missed invasive foci in the breast, but to identify that small subset of microinvasive cancers with metastatic potential.
SLN biopsy in this setting has a number of other advantages over examination of the breast alone. First, most DCIS is treated nationwide without the benefit of expert pathologic review. Second, surgical pathology remains an imperfect science even in the best of hands, and sampling error in the examination of breast specimens is a widespread and unsolved problem; the larger the specimen the greater the potential for error. Unexpected nodal metastases will never be identified if the examination is limited to the breast. Third, SLN biopsy is feasible in a wide range of practice settings.22 Fourth, the technology to perform serial sections and IHC stains on the SLN is universally available. Fifth, an unexpectedly positive SLN can prompt a pathologic "second look" or "second opinion" that otherwise might have been deemed unnecessary; six of our nine SLN-positive patients had additional findings on review. Finally, those few high-risk DCIS patients found to have lymph node macrometastases will actually become legitimate candidates for systemic adjuvant therapy.
For breast cancer in general, great effort is expended to achieve small differences in outcome. This is particularly true in DCIS, where survival rates remain high regardless of treatment. Very few patients with DCIS will ever develop distant metastasis, but some will. We must do whatever we can to protect our patients from the diagnostic uncertainty of conventional pathologic techniques, and SLN biopsy gives the skeptical surgeon one more tool to identify metastatic potential. Is it really DCIS? Not always.
Received for publication June 8, 2001. Accepted for publication June 20, 2001.
REFERENCES
This article has been cited by other articles:
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  H. S. Cody III Sentinel Lymph Node Biopsy for DCIS: Are We Approaching Consensus? Ann. Surg. Oncol., August 1, 2007; 14(8): 2179 - 2181. [Full Text] [PDF]
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 C. Mazouni, F. Peintinger, S. Wan-Kau, F. Andre, A. M. Gonzalez-Angulo, W. F. Symmans, F. Meric-Bernstam, V. Valero, G. N. Hortobagyi, and L. Pusztai Residual Ductal Carcinoma In Situ in Patients With Complete Eradication of Invasive Breast Cancer After Neoadjuvant Chemotherapy Does Not Adversely Affect Patient Outcome J. Clin. Oncol., July 1, 2007; 25(19): 2650 - 2655. [Abstract] [Full Text] [PDF]
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G. H. Lyman, A. E. Giuliano, M. R. Somerfield, A. B. Benson III, D. C. Bodurka, H. J. Burstein, A. J. Cochran, H. S. Cody III, S. B. Edge, S. Galper, et al. American Society of Clinical Oncology Guideline Recommendations for Sentinel Lymph Node Biopsy in Early-Stage Breast Cancer J. Clin. Oncol., October 20, 2005; 23(30): 7703 - 7720. [Abstract] [Full Text] [PDF]
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H. M. Kuerer and L. A. Newman Lymphatic Mapping and Sentinel Lymph Node Biopsy for Breast Cancer: Developments and Resolving Controversies J. Clin. Oncol., March 10, 2005; 23(8): 1698 - 1705. [Full Text] [PDF]
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