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EDITORIALS |
From the Department of Surgery, Yale New Haven Breast Center, New Haven, Connecticut.
Correspondence: Address correspondence to: Donald R. Lannin, MD, Department of Surgery, Yale New Haven Breast Center, 800 Howard Avenue, Lower Level 38, New Haven, Connecticut 06510; Fax: 203-785-2329; E-mail: donald.lannin{at}yale.edu
In recent years, the following case has frustrated almost all of our hospital tumor boards: a woman presents with a small, otherwise favorable, breast cancer whose sentinel node shows a small cluster of cytokeratin positive cells beneath the capsule. Pathologists gleam at exhibiting their diagnostic prowess and the remarkable sensitivity of available technology. The surgeon is proud to be able to make this diagnosis in such a minimally invasive fashion. The medical oncologist surmises that this woman may well be among the 25% to 30% of patients with classically negative lymph nodes who will develop a recurrence by 10 years. The scientifically minded in the group, however, point out that available data regarding the patient’s prognosis are extremely limited, and data regarding treatment decisions for her are virtually nonexistent. In the end, a lot of hand-wringing results and the consensus usually remains that it is better to "err on the side of caution" and treat her as a node-positive patient would be treated.
The existence of occult micrometastases in axillary lymph nodes of women with breast cancer has actually been recognized for many years. As early as 1990, the Ludwig trial suggested a worse prognosis for women with axillary micrometastases.1,2 The impracticality of examining every node in an axillary dissection for micrometastases made this a clinically uncommon concern. Today, with the widespread adoption of sentinel node biopsy, debate over the clinical relevance of micrometastases seems to be a daily occurrence. Because of this, the 6th edition of the American Joint Committee on Cancer (AJCC) Staging Manual has adopted specific definitions.3 A "micrometastasis" is a tumor deposit, usually seen on hematoxylin and eosin (H&E) staining that is between 0.2 and 2 mm in diameter. Such nodes are designated as pN1mi to distinguish them from the more traditional macrometastases. "Isolated tumor cells"(ITC), on the other hand, are defined as single cells or small groups of cells with a maximal diameter of 0.2 mm. Such deposits are usually detected only by immunohistochemistry but, on occasion, can be confirmed by H&E stains. Such nodes are designated pN0(i+). This designation was specifically chosen to discourage physicians from treating such a patient as node-positive.
The obvious problem in determining the significance of micrometastases is that these patients are relatively uncommon, their prognosis, at worst, remains relatively good, and because sentinel node biopsy has only been performed for the last few years, it will take a long time to get the answer by following a group of patients prospectively. Two prospective trials, the American College of Surgeons Oncology Group Z10 trial and the NSABP B32 trial4,5 have completed patient accrual and eventually should give us this information.
In this issue of the Annals of Surgical Oncology, Susnik et al.6 give us a glimpse of what the prospective trials may eventually show us. They performed an elegant case-control study where they retrospectively studied a well-defined group of patients with stage 1 breast cancer in whom the 15-year outcome was known. They chose 48 patients who eventually developed metastases and compared them with an age- and stage-matched group of 48 patients who did not develop metastases. They then reexamined all 1539 lymph nodes from their axillary dissections using three levels and cytokeratin immunostaining. The results were clear: 33% (16/48) of the patients who ultimately developed metastases had occult disease in their lymph nodes compared to 10% (5/48) who did not develop metastases. The difference was most striking for micrometastases (10 vs. 1), but was not significant for isolated tumor cells (6 vs. 4). Thus, clearly micrometastases larger than 0.2 mm are associated with a worse prognosis. The significance of isolated tumor cells <0.2 mm is still unclear. The data do provide some support for the notion that a portion of patients with isolated tumor cells may have had cells dislodged during their breast surgery that are just passing through the nodes and are biologically meaningless.7,8
What does this study mean for the practicing surgeon? The results would seem to validate the AJCC decision to designate micrometastases between 0.2 and 2 mm as N1 disease and isolated tumor cells <0.2 mm as N0 disease. It seems likely that women with micrometastases have a worse prognosis. This would be consistent with some9–11 but not all12 other large studies. It should be pointed out, however, that the results of this study were not confounded by chemotherapy, because these node-negative patients treated more than 15 years ago did not routinely receive adjuvant therapy. It is possible that patients treated today on the Z104 or B325 study may not have such a dramatic effect because the association of micrometastases with prognosis may be dampened by the effect of adjuvant systemic treatment.
We still do not have enough information, however, to base treatment decisions on the presence or absence of micrometastases. This study would seem to provide some justification for treatment for patients with micrometastases >0.2 mm with adjuvant systemic therapy. Because today many of these node-negative patients routinely receive adjuvant therapy anyway, the change may not be that significant except for the occasional small, good risk tumor that may have otherwise remained untreated. The most intriguing question is whether the patient with a true negative sentinel node by immunochemistry may receive such a good prognosis that adjuvant therapy should not be considered. The answer to this question will have to await other large, long-term studies.
Received for publication April 2, 2004. Accepted for publication April 12, 2004.
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