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10.1245/ASO.2004.11.914
Annals of Surgical Oncology 11:227S-230 (2004)
© 2004 Society of Surgical Oncology
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SUPPLEMENT

Redefining Prognosis in Node-Negative Breast Cancer: Can Sentinel Lymph Node Biopsy Raise the Threshold for Systemic Adjuvant Therapy?

Hiram S. Cody, III, MD, Patrick I. Borgen, MD and Lee K. Tan, MD

From The Breast Service, Department of Surgery (HSC, PIB) and Department of Pathology (LKT), Memorial Sloan-Kettering Cancer Center, New York, New York.

Correspondence: Address correspondence and reprint requests to: Hiram S. Cody III, MD, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021; Fax: 212-794-5812; E-mail: codyh{at}mskcc.org

ABSTRACT

Sentinel lymph node (SLN) biopsy is a new standard of care for axillary node staging in breast cancer, which for the first time allows enhanced pathologic analysis on a routine basis. Although a number of retrospective studies, including our own series with 20-year follow-up, suggest that axillary nodal micrometastases found in this manner are prognostically significant, prospective trials now under way promise a definitive answer to this controversial subject. Enhanced pathology using serial sections and immunohistochemical staining identifies a high-risk minority of conventionally node-negative patients who are converted to node-positive and thereby become candidates for systemic adjuvant chemotherapy. The developmental phase of SLN biopsy, now drawing to a close, has focused on the identification of this node-positive group. Enhanced pathology also identifies a majority of patients who are truly node-negative and whose expectation of long-term survival exceeds that of historic norms for node-negative breast cancer. The next era of SLN biopsy should focus on the characterization of this group. SLN biopsy in breast cancer has already extended the historic trend toward surgical conservatism. By defining more precisely a low-risk cohort of patients, SLN biopsy has the potential to initiate a trend toward medical conservatism as well.

Key Words: Immunohistochemical staining • Node-negative breast cancer • Sentinel lymph node biopsy • Systemic adjuvant therapy

Eleven years since the initial report on sentinel lymph node (SLN) biopsy for melanoma by Morton et al.,1 Krag et al.,2 and Giuliano et al.3 for breast cancer, this procedure has rapidly emerged worldwide as a new standard of care for lymph node staging in these diseases. In breast cancer, an extensive literature validates the SLN concept, proves its feasibility in a wide range of practice settings, establishes criteria for case selection, and addresses a wide range of technical issues. Recent series report at least 95% success in finding the SLN, with 5% or fewer false-negative results among node-positive patients. Although many clear answers have emerged, pressing questions remain, and none of these is more controversial than the identification, significance, and management of SLN micrometastases.

DISCUSSION

Historic Background
While axillary node (ALN) status remains overwhelmingly the single most important prognostic factor in breast cancer, the significance of ALN "micrometastases" (first defined in 1971 by Huvos et al.4 as a tumor deposit smaller than 2 mm) is a subject of long-standing debate. In their initial study of patients treated at Memorial Hospital, Huvos et al.4 reported that the prognosis of patients with micrometastases was comparable to that of node-negative patients, and this observation has been incorporated into the American Joint Committee on Cancer (AJCC) cancer staging manual as recently as the fifth (1997) edition.5 Further studies at the same institution6,7 suggest that long-term survival is progressively worse with increasing size of nodal metastasis, even for patients with a single micrometastasis (compared with that of node-negatives).

More intriguing are 25 separate studies (spanning 50 years) in which ALNs initially read as negative were reanalyzed with enhanced pathologic techniques (serial sections stained by hematoxylin-eosin [H&E] and/or anticytokeratin immunohistochemical [IHC] methods), to determine the frequency and the prognostic significance of ALN micrometastases. All of these studies are the subject of an exhaustive review by Dowlatshahi et al.,8 with two principal observations. First, micrometastases were found in every study but one; 7% to 42% of patients initially staged as node-negative had nodal metastases that were missed. Second, these missed nodal metastases were prognostically significant. Although 18 of the 25 studies were small and inconclusive (lacking statistical power), 6 of the 7 series with more than 100 patients (i.e., the statistical power to detect small survival differences) showed significantly worse disease-free survival (DFS) and/or overall survival (OS) among patients with micrometastases. The largest and most persuasive of these, the Ludwig study (n = 921), showed that micrometastases found by H&E-stained serial sections (in 9% of "node-negative" patients) were associated with significantly worse DFS and OS at 5 years9 and, in a detailed reanalysis, at 10 years10 as well (Table 1).


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  		TABLE 1. Patient survival in the Ludwig studies, at 5 and 10 years of follow-up
 
The Logistical Hurdle
The search for micrometastases in axillary dissection (ALND) specimens is labor-intensive. In the first Ludwig study,9 the investigators examined 12 sections per tissue block and 12 tissue blocks per patient to identify ALN micrometastases in 9% of patients, or 1600 slides to identify one additional node-positive patient. An earlier and equally thorough study by Wilkinson et al.11 generated a comparable number of slides (1449) to find each additional node-positive patient. Following publication of the first Ludwig study in 1990, few institutions had the resources, human or financial, to pursue enhanced pathologic analysis of ALND specimens. This has changed with the advent of SLN biopsy, a targeted examination, which removes a mean of two to three nodes per patient, making the search for micrometastases logistically feasible for the first time.

Micrometastases in the Era of SLN Biopsy
SLN biopsy allows the routine performance of both serial sections and IHC stains for cytokeratins, and each method substantially increases the yield of positive ALNs in breast cancer. Although the College of American Pathologists in its current 2003 breast cancer pathology protocol12 states that a single microscopic section from each lymph node block is considered sufficient for routine examination, the authors acknowledge the detailed and extensive incorporation of enhanced pathologic methods in the sixth edition of the AJCC cancer staging manual.13 They recommend categorizing micrometastases as "isolated tumor cells" not larger than 0.2 mm (pN0), or "micrometastases" 0.2 to 2 mm in size (pN1) and adding the modifier "(i+)" to designate metastases found by IHC alone. Prognostic significance aside, enhanced pathologic analysis of SLNs has other benefits that are substantial. These include improved staging accuracy,14 validation of the SLN hypothesis,15 a reduction in the false-negative rate,16 and the prediction of non-SLN metastasis in SLN-positive patients.17,18 Even when the SLN is positive only on IHC, 10% to 15% of patients undergoing completion ALND will have H&E-positive disease in the non-SLN,18–20 thus becoming conventional candidates for systemic adjuvant therapy.

More controversial is the subject of prognostic significance, especially for SLN micrometastases detected only by IHC. Cote et al.,10 reporting the 10-year results of the Ludwig study (Table 1), show that a single IHC-stained section detected micrometastases more often than 12 H&E-stained sections (20% vs. 7%). Although 10-year DFS and OS were marginally worse in all patients with IHC-detected micrometastases, this difference was significant only in the postmenopausal subset. H&E-detected micrometastases were highly significant in all patients and in postmenopausal women. A curious and unexplained observation is that neither IHC-detected nor H&E-detected micrometastases were prognostically significant in premenopausal women.

Tan et al.21 have recently examined the significance of ALN micrometastases in a cohort of 368 "node-negative" breast cancer patients treated between 1976 and 1978. All had mastectomy with ALND, none had systemic therapy, and median follow-up was 18 years. Following our current SLN pathology protocol (one H&E- and one IHC-stained section from each of two levels 50 µ apart), 2470 paraffin tissue blocks from the ALND specimens were reexamined with serial sections and IHC; 23% of patients (83 of 368) were converted to node-positive, 40% of these (33 of 83) by IHC alone and 60% (50 of 83) by H&E. In comparison with patients who were "truly node-negative", 10-year DFS for patients positive only on IHC or on H&E was worse by 12% and 33%, respectively (Table 2, P < .0001). In a multivariate analysis controlling for tumor size and the presence of lymphovascular invasion, node positivity by H&E was prognostically significant, whereas the significance of IHC-only metastases was borderline.


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  		TABLE 2. Disease-free survival in breast cancer patients who were node-negative on conventional histopathology and received no systemic therapy, based on pathologic reassessment with current MSKCC SLN methodology
 
Two prospective trials, the American College of Surgeons Oncology Group (ACOSOG) Z001022 and the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-32,23 aim to determine the significance of IHC-positive micrometastases in both the SLN and the bone marrow, by blinding the treating physician and patient to the IHC results. Despite a wealth of retrospective data, it remains unproved whether IHC-positive micrometastases in the current era of SLN biopsy will have a prognostic significance independent of other conventional treatment parameters.

Implications of SLN Biopsy for Systemic Therapy
Our own data, like those from the studies cited above, confirm that patients defined as node-negative by conventional histopathologic methods do not have a uniformly favorable prognosis. Enhanced pathology clearly identifies a minority at higher risk: those who are converted to node-positive and thereby become candidates for systemic adjuvant chemotherapy. Perhaps more important, enhanced pathology identifies a majority of patients who are truly node-negative and whose expectation of long-term DFS/OS exceeds that of patients who are node-negative by conventional pathologic methods. In our own data, 10-year DFS in truly node-negative patients exceeded that of conventionally node-negative individuals by about 5% (P = NS), except for those patients with the smallest tumors (Table 3).


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  		TABLE 3. Ten-year disease-free survival (DFS) by tumor size in breast cancer patients who were node-negative on conventional histopathology and received no systemic therapy, based on pathologic reassessment with the current MSKCC sentinel lymph node methodology
 
By current consensus guidelines in the United States,24,25 an estimated 10-year DFS of about 90% is the threshold at which patients should be offered systemic adjuvant therapy. This threshold derives from the classic study by Rosen et al.26 of long-term survival among breast cancer patients treated by radical surgery with no systemic therapy, whose nodes were negative by conventional single-section H&E analysis. DFS was 91% at 10 years and 88% at 20 years for T1N0 patients with tumors less than or equal to 1 cm. The most recent Early Breast Cancer Trialists Collaborative Group meta-analysis27 indicates that only about 3% of such patients would benefit from systemic adjuvant chemotherapy and that the remaining 97% would not. This highlights a major paradox in the evolution of breast cancer treatment over the last decade of the 20th century: as the surgical treatment of breast cancer has become progressively more conservative, systemic adjuvant therapy has become more radical.

SLN biopsy is ending its developmental phase, in which the principal focus was on the identification and significance of the positive SLN, and entering an era in which the negative SLN deserves equal emphasis. Patients whose SLNs are negative on serial sections, H&E, and IHC have a better prognosis than that of historic norms for "node-negative" breast cancer, and the challenge for future investigations will be to redefine those norms. The goal is to enlarge the pool of good-prognosis patients who can avoid not only radical surgery but radical chemotherapy as well.

FOOTNOTES

Sentinel lymph node biopsy is a new standard of care for axillary node staging in breast cancer, which for the first time allows enhanced pathologic analysis on a routine basis. Although a number of retrospective studies suggest that axillary nodal micrometastases found in this manner are prognostically significant, prospective trials now under way promise a definitive answer to this controversial subject.

Received for publication October 31, 2003. Accepted for publication November 20, 2003.

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