Occult Axillary Node Metastasis in Early-stage Breast Cancer: Important or Not?

Abstract & Commentary

By William B. Ershler, MD

Synopsis: In a retrospective review of 267 patients evaluated at M.D. Anderson Cancer Center with apparent early-stage, node-negative breast cancer, 15% were found to harbor "occult" metastases upon more intensive scrutiny of the axillary node specimens. In this series, long-term follow-up indicates that such discovery was not associated with a greater frequency of recurrence or poorer survival.

Source: Wu Y, et al. Occult axillary lymph node metastases do not have prognostic significance in early stage breast cancer. Cancer 2012;118:1507-1514.

Axillary node involvement is well known to be of prognostic importance in patients with breast cancer. However, it is now appreciated that as many as one-third of patients who are considered axillary node negative by routine examination of typically prepared hematoxylin and eosin (H&E)-stained slides will in fact harbor evidence for metastatic involvement when subjected to more rigorous examination, including the use of immunohistochemistry (IHC).1 Such ''occult metastases'' are defined as those not identified in the original H&E section but detected by additional sampling of paraffin blocks, including serial sectioning and/or IHC staining for cytokeratin. Although studies have reported that occult metastases can be identified in 9% to 33% of patients who were considered lymph node negative by standard pathologic processing, the significance of such for the individual patient in terms of prognosis remains to be established.

In the current study, the authors identified 267 patients who underwent axillary lymph node dissection (ALND) between 1987 and 1995 and were lymph node negative according to a routine pathologic evaluation, which included the complete submission of all lymph nodes and an examination of one H&E-stained section per paraffin block. As was the standard of care at that time, patients considered lymph node negative did not receive systemic chemotherapy or hormone therapy. All of the dissected lymph nodes from these patients were re-evaluated by intensified pathologic methods (serial sectioning with H&E levels plus IHC). Occult metastases were categorized by detection method and size. These findings were examined in the context of recurrence rates and overall survival.

Of the 267 patients, 39 (15%) who had lymph node-negative results on routine evaluation of their axillary lymph node dissection specimens had occult metastases identified. Eight of these patients (20%) had macrometastases > 2.0 mm, 15 (40%) had micrometastases (range, > 0.2 mm to 2 mm), and 16 (40%) had isolated tumor cells (≤ 0.2 mm). When compared to the patients without occult metastases, the presence of occult metastases and the size of metastases did not affect recurrence-free or overall survival.

Commentary

The importance of occult metastases has been a controversial topic, with a number of reports indicating negative prognostic implications,1-3 whereas several others, like the current report, indicate a lack of clinical importance.4,5 The topic has been the subject of a recent meta-analysis including 27 studies that demonstrated a small increased risk for disease recurrence and death in patients with breast cancer who have occult lymph node metastasis compared with lymph node-negative patients at 10 years of follow-up.6 Nonetheless, the included studies were quite variable with regard to patients reported, the intensity and techniques used to identify occult disease, and whether they received systemic therapy. In the current report, most patients had small tumors (T1 or T2) and none received systemic therapy. The authors found the presence of occult metastasis did not have clinical significance in terms of recurrence or survival. This finding is in distinct contrast to a very similar study from Memorial which, when compared to the current study was remarkably similar in design, pathological techniques, and length for follow-up.3 Yet, the study population was slightly different. The Memorial cohort included more patients with somewhat larger primary tumors, many of whom presented with symptomatic disease. Thus, they found a greater percentage with occult metastases (23% vs 15%) and such patients had a less favorable prognosis.

Thus, clinicians should be aware that additional more intensive pathological examination of node specimens from patients in whom the routine examination was negative is likely to define a number (between 10-30%) who harbor what is now termed occult metastases. The current report would suggest that such occult metastases are not of clinical importance. However, other reports seem to indicate the opposite conclusion. For the clinical oncologist with a breast cancer patient for whom an addendum to the axillary node pathology report includes the discovery of cancer cells (by IHC, or by additional sectioning), the most likely response will be to consider the patient node positive and proceed accordingly. Although provocative from the perspective of tumor biology, it will take more than this retrospective review for clinicians to have sufficient confidence to ignore such a finding.

References

1. Hainsworth PJ, et al. Detection and significance of occult metastases in node-negative breast cancer. Br J Surg 1993;80:459-463.

2. Querzoli P, et al. Axillary lymph node nanometastases are prognostic factors for disease-free survival and metastatic relapse in breast cancer patients. Clin Cancer Res 2006;12:6696-6701.

3. Tan LK, et al. Occult axillary node metastases in breast cancer are prognostically significant: Results in 368 node-negative patients with 20-year follow-up. J Clin Oncol 2008;26:1803-1809.

4. Millis RR, et al. Occult axillary lymph node metastases are of no prognostic significance in breast cancer. Br J Cancer 2002;86:396-401.

5. Pickren JW. Significance of occult metastases. A study of breast cancer. Cancer 1961;14:1266-1271.

6. de Boer M, et al. Breast cancer prognosis and occult lymph node metastases, isolated tumor cells, and micrometastases. J Natl Cancer Inst 2010;102:410-425.