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Originally published as JCO Early Release 10.1200/JCO.2005.05.5301 on March 27 2006 © 2006 American Society of Clinical Oncology.
Sentinel Node Micrometastases and Non-Sentinel Nodes in Breast Cancer: How Much Do We Need to Know?Virginia Commonwealth University, Medical College of Virginia School of Medicine and the Massey Cancer Center, Richmond, VA Arguably, the transition from routine axillary lymph node dissection (ALND) to sentinel lymph node (SLN) biopsy has been one of the most important improvements in quality of life for women with breast cancer in the past four decades, rivaling the substitution of breast-conserving treatment for mastectomy. As with any new surgical procedure, the details of how to perform it and how to utilize the information gained have raised many new questions. Key among these is whether patients with positive SLNs need to undergo a completion ALND or whether some subset (or perhaps even all such patients) could avoid the potential morbidity of the more radical procedure. With the opportunity for pathologists to examine just a few lymph nodes in detail, the clinical significance of finding previously unrecognized micrometastases in SLN with techniques such as immunohistochemistry (IHC) and even polymerase chain reaction assays also has not been determined. Because of the uncertainty whether such findings have any meaning for the prognosis or treatment of women with breast cancer, some guidelines recommend against even performing these specialized tests on the SLNs of breast cancer patients, or at least have registered uncertainty about their usefulness.1-3 Many institutions, including our own, have abandoned IHC on SLN, at least until the time that it becomes clearer what to do with the information. This is not to say that SLN should not be carefully and exhaustively examined by serial sectioning and hematoxylin and eosin (H&E) staining, so as not to miss micrometastases.
In this issue of the Journal of Clinical Oncology, Houvenaeghel et al4 report on an analysis of data on 700 patients from multiple French centers to determine the rate of nonsentinel lymph node (NSLN) involvement in patients with SLN micrometastases. They set out to determine what factors might be predictive of positive NSLN and thus to identify a subset of patients in whom ALND might be avoided. A number of primary tumor characteristics (size, lymphovascular invasion [LVI], and histologic type) significantly influenced the likelihood of finding positive NSLN, as did the method of detection (H&E or IHC only). In contrast, they found that the size of micrometastases, even down to the level of isolated tumor cells, did not significantly affect the odds of finding metastases in NSLN. It could have been that the lack of specific data on size of micrometastases in many patients, plus the possibility that method of detection may have been a surrogate for metastasis size, eliminated size as a significant independent variable. Importantly, all of the NSLN in this series were examined by H&E only; the "actual" incidence of NSLN positivity if they had been examined by IHC would certainly have been higher.5 Despite the fact that method of detection was a significant predictor of NSLN positivity in both univariate and multivariate analysis, the authors concluded that patients with SLN positive only on IHC, regardless of size, have a high enough risk of other nodes being positive to justify routine ALND, unless the tumors were small ( Using a similar retrospective multivariate analysis, investigators at Memorial Sloan-Kettering Cancer Center (MSKCC; New York, NY), have described a nomogram that can be used to calculate the odds of finding positive NSLN after a positive SLN biopsy.9,10 This tool, which is available online (http://www.mskcc.org/nomograms), uses tumor size, type and grade, LVI, multifocality, estrogen receptor (ER) status, method of detection of the SLN metastases (frozen section, H&E, IHC), and the numbers of positive and negative SLN as significant variables in the model. Size of micrometastases was not included in the analysis, even though their own and other studies have found this to be a significant predictor of NSLN positivity.11-14 One potential weakness of the MSKCC model may have been that some patients with positive SLN who did not undergo ALND were understandably excluded from the data set, a potential source of bias that may exist in other publications related to this issue. Nevertheless, this model performed very well in predicting NSLN involvement prospectively in a subsequent cohort of patients and outperformed clinical judgement.9,10 Data from the National Surgical Adjuvant Breast and Bowel Project's (NSABP) Protocol B-32 presented at the most recent San Antonio Breast Cancer Symposium (SABCS) in December 200515 also suggest that it is difficult to define a subset of patients with such a low risk of NSLN involvement that ALND would not be justified. This trial randomized patients to either SLN and routine ALND or SLN biopsy with ALND only if SLN was positive. However, IHC examination of the SLN from patients in this trial was not taken into account, because IHC was done centrally and the results were not known to the treating physicians, who remain blinded. Thus, if SLNs were positive only by IHC, ALND would not have been performed at all in group 2. This might also explain what was considered by many to be a relatively high false-negative rate for SLN biopsy in group 1 (9.7%).16 When the IHC results are eventually revealed, it may be that many of the case subjects who had positive NSLN and "falsely negative" SLN will be found to have IHC-positive SLNs. This trial, along with the results from the American College of Surgeons Oncology Group (ACOSOG) Z0010 trial, will give a definitive answer to how likely we are to miss positive NSLN by not performing IHC examination or by omitting ALND in patients with N0(i+) SLNs (SLN with micrometastases found only with IHC). But does "missing" these nodes make any difference to the patients' outcomes or their treatment? In the ACOSOG Z0010 trial, IHC was not used to classify SLN as positive, and patients with negative SLN by H&E had a very low rate (0.2%) of axillary node recurrences at a median follow-up of 31 months.17 As noted by Houvenaeghel et al, others have found that regional recurrence is higher if patients with positive SLN are not subjected to ALND, but in the report they cited,18 the patients who did not undergo ALND included patients who had positive SLN by H&E as well as those detected by IHC only. At the 2005 SABCS, Charles Cox et al19 reported that women with N0(i+) nodes had outcomes similar to women with N0(i–) disease. However, women with N0(i+), especially those with T2 or T3 tumors, did have a considerable risk of having metastases to NSLN. Although the outcome data for the IHC-detected metastasis patients included those with positive NSLN, one might presume that separate analysis of prognosis in patients with IHC-detected SLN micrometastases and positive NSLN would show worse outcomes than for "truly" node-negative patients, but this was not shown. In fact, this assumption may not be justified, because the overall outcomes, especially distant metastases and survival, depend a great deal on adjuvant treatment decisions. And this is where proponents of either side of the IHC-ALND controversy might say, "just do the math." It is doubtful that ALND in and of itself has much impact on patient survival, but treatment decisions based on pathologic nodal staging could. So, if we look carefully at the subsets of patients delineated in the current French study, we would find that patients with T1a or T1b tumors, who are unlikely to receive adjuvant chemotherapy if their nodes are negative, are also unlikely to have positive NSLN if metastases are detected in the SLN by IHC only (Table 6 of Houvenaeghel et al4). Thus, ALND is very unlikely to change their prognosis or treatment. For patients with larger tumors (> 1 cm), the odds of finding positive NSLN with N0(i+) SLN goes up progressively as the primary tumor size increases (from 8.3% to 33.3%, in the absence of LVI). But most of these patients would receive systemic chemotherapy anyway, based on tumor size and histology alone. One could argue that the choice of chemotherapy regimen would be affected by the presence of nodal disease; for example, a taxane might be added. So, if we "do the math," and analyze the impact on a patient with a 2.5-cm tumor without LVI and an IHC-positive SLN, the French report indicates that the chance of having positive NSLNs would be a little less than 10%. Then, those patients might have an absolute increase in survival of 5% to 6% by the addition of a taxane to anthracycline-based therapy. Although this analysis may not be absolutely "BC" (biostatistically correct), it is evident that we must decide for a given patient whether the morbidity of an ALND is justified by the sometimes small potential increase in survival that might result from altering systemic therapy. As other factors such as gene expression profiles become more important in predicting prognosis and potential benefit from chemotherapy, the impact of nodal status may decrease even further. Similar reasoning applies to the decision to add regional/chest wall radiotherapy (RT). Especially if one reserves adjuvant regional RT for patients with more than three positive nodes, it is evident from Table 7 of the Houvenaeghel et al article that, other than for patients with large tumors, very few patients had three or more NSLN nodes positive. Depending on how many sentinel nodes were positive in these patients, most of these patients would not receive regional or postmastectomy RT. For those with larger tumors, in whom the odds of having three or more positive nodes are higher, many would be offered regional RT regardless of the NSLN status. In summary, the study by Houvaenagel et al demonstrates that a number of factors can be used to predict the likelihood of finding NSLN with metastases in patients with SLN positive for micrometastases, but size of the SLN micrometastases may not be an independent predictor. Their conclusion from the data is that few patients with positive SLN can avoid an ALND, regardless of the extent of SLN involvement. At this point in time, the standard of care for patients with H&E-positive SLN is to proceed with a completion ALND. Unfortunately, the ACOSOG Z0011 trial designed specifically to address this question could not be completed. Ultimately, this decision should depend on how the status of NSLN will affect treatment decisions and overall patient outcome, and this is not clear. Even less clear, despite the data presented in the current French study, is the value of IHC evaluation of SLN in addition to careful H&E examination of serial sections. The comparison of outcomes for the two arms of NSABP Protocol B-32 may provide the most definitive answer to the question of whether omitting IHC examination of SLN, and therefore ALND, in some patients in group 2 has any significant impact on patient outcome. Author's Disclosures of Potential Conflicts of Interest The author indicated no potential conflicts of interest. Author Contributions
REFERENCES 1. The Association of Directors of Anatomic and Surgical Pathology: ADASP recommendations for processing and reporting of lymph node specimens submitted for evaluation of metastatic disease. Mod Pathol 14:629-632, 2001[Medline] 2. Fitzgibbons PL, Page DL, Weaver D, et al: Prognostic factors in breast cancer: College of American Pathologists Consensus Statement 1999. Arch Pathol Lab Med 124:966-978, 2000[Medline] 3. Lyman GH, Giuliano AE, Somerfield MR, et al: American Society of Clinical Oncology guideline recommendations for sentinel lymph node biopsy in early-stage breast cancer. J Clin Oncol 23:7703-7720, 2005 4. Houvenaeghel G, Nos C, Mignotte H, et al: Micrometastases in sentinel lymph node in a multicentric study: Predictive factors of non-sentinel lymph node involvement. J Clin Oncol 24:1814-1822, 2006 5. Chu KU, Turner RR, Hansen NM, et al: Sentinel node metastasis in patients with breast carcinoma accurately predicts immunohistochemically detectable nonsentinel node metastasis. Ann Surg Oncol 6:756-761, 1999[Abstract] 6. Calhoun KE, Hansen NM, Turner RR, et al: Nonsentinel node metastases in breast cancer patients with isolated tumor cells in the sentinel node: Implications for completion axillary node dissection. Am J Surg 190:588-591, 2005[Medline] 7. Chagpar A, Middleton LP, Sahin AA, et al: Clinical outcome of patients with lymph node-negative breast carcinoma who have sentinel lymph node micrometastases detected by immunohistochemistry. Cancer 103:1581-1586, 2005[CrossRef][Medline] 8. Chung MA, Steinhoff MM, Cady B: Clinical axillary recurrence in breast cancer patients after a negative sentinel node biopsy. Am J Surg 184:310-314, 2002[CrossRef][Medline] 9. Van Zee KJ, Manasseh DM, Bevilacqua JL, et al: A nomogram for predicting the likelihood of additional nodal metastases in breast cancer patients with a positive sentinel node biopsy. Ann Surg Oncol 10:1140-1151, 2003 10. Specht MC, Kattan MW, Gonen M, et al: Predicting nonsentinel node status after positive sentinel lymph biopsy for breast cancer: Clinicians versus nomogram. Ann Surg Oncol 12:654-659, 2005 11. Weiser MR, Montgomery LL, Tan LK, et al: Lymphovascular invasion enhances the prediction of non-sentinel node metastases in breast cancer patients with positive sentinel nodes. Ann Surg Oncol 8:145-149, 2001 12. Chu KU, Turner RR, Hansen NM, et al: Do all patients with sentinel node metastasis from breast carcinoma need complete axillary node dissection? Ann Surg 229:536-541, 1999[CrossRef][Medline] 13. Reynolds C, Mick R, Donohue JH, et al: Sentinel lymph node biopsy with metastasis: Can axillary dissection be avoided in some patients with breast cancer? J Clin Oncol 17:1720-1726, 1999 14. Kamath VJ, Giuliano R, Dauway EL, et al: Characteristics of the sentinel lymph node in breast cancer predict further involvement of higher-echelon nodes in the axilla: A study to evaluate the need for complete axillary lymph node dissection. Arch Surg 136:688-692, 2001 15. Julian TB, Anderson S, Brown A, et al: Continued technical results of NSABP B-32: Does a positive sentinel node biopsy require an axillary dissection? Breast Cancer Res Treat 94:S12, 2005 (suppl 1; abstr 20) 16. Julian TB, Krag D, Brown A, et al: Preliminary technical results of NSABP B-32, a randomized phase III clinical trial to compare sentinel node resection to conventional axillary dissection in clinically node-negative breast cancer patients. Breast Cancer Res Treat 88:S11-S12, 2004 (suppl 1; abstr 14) 17. Posther KE, McCall LM, Blumencranz PW, et al: Sentinel node skills verification and surgeon performance: Data from a multicenter clinical trial for early-stage breast cancer. Ann Surg 242:593-599, 2005[Medline] 18. Naik AM, Fey J, Gemignani M, et al: The risk of axillary relapse after sentinel lymph node biopsy for breast cancer is comparable with that of axillary lymph node dissection: A follow-up study of 4008 procedures. Ann Surg 240:462-468, 2004[CrossRef][Medline] 19. Cox C, Vrcel V, Riker A, et al: Significance of sentinel lymph node micrometastasis on survival for patients with invasive breast cancer. Breast Cancer Res Treat 94:S12-S13, 2005 (suppl 1; abstr 21) Related Article
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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