Contemporary Evaluation of Breast Lymph Nodes in Anatomic Pathology

Beth T. Harrison, MD; Jane E. Brock, MBBS, PhD


Am J Clin Pathol. 2018;150(1):4-17. 

In This Article

Management of the Axilla in the Setting of a Positive Sln: Amaros and Beyond

Further evidence that completion ALND can be avoided in most patients with clinically node-negative, early-stage breast cancer is provided by the AMAROS trial.[33] The AMAROS trial, published in November 2014, was a European RCT enrolling from nine different countries. It investigated completion ALND vs axillary radiotherapy in patients who had T1 or T2 tumors, no palpable lymphadenopathy, and at least one positive SLN (n = 4,806). The SLN mapping procedure was standardized to dual radioisotope and blue dye tracers. Local treatment was breast-conserving therapy (BCT) and whole-breast irradiation or mastectomy with or without irradiation of the chest wall. ALND, if performed, was limited to levels I and II and required removal of at least 10 lymph nodes. Adjuvant systemic therapy was optional.[33]

Most patients had small (T1) invasive carcinomas of the ductal subtype (78%-82%). Tumor grade followed the usual distribution (grade 1, 23%-24%; grade 2, 46%-48%; and grade 3, 26%-29%). Most were treated with BCT (82%) and some form of systemic therapy (90%; 77%-79% hormonal therapy and 61% chemotherapy). At least one SLN was identified in 97% of cases, positive in 30% of cases. The number of positive SLNs was one in 43% to 45% of cases, two in 27% to 32%, three in 15% to 17%, or four or more in 10% to 11%. Macrometastases were more common (59%-62%) than micrometastases (29%) and isolated tumor cells (10%-12%). On completion ALND, no further positive nodes were found in 67% of cases, one to three additional positive nodes in 25%, and four or more in 8%.[33]

The end point was axillary recurrence at 5 years. Of those randomized to ALND, 33% of patients had additional positive lymph nodes. Axillary recurrence was 0.43% (95% CI, 0.00–0.92) after ALND and 1.19% (95% CI, 0.31–2.08) after axillary radiotherapy. There was no difference in DFS and OS (93.3% in ALND arm vs 92.5% in radiotherapy arm). Of note, DFS and OS in the patients who had negative sentinel nodes were 87.9% and 95.4%, respectively. Lymphedema was noted significantly more often after ALND (23%) than after axillary radiotherapy (11%).[33]

The AMAROS trial investigators concluded that both axillary radiotherapy and surgical dissection provide excellent and comparable axillary control but that radiotherapy is preferable due to the lower incidence of lymphedema. However, it must be noted that shoulder mobility and overall quality of life were not different between the two groups. Therefore, some in the surgery community have suggested that it is difficult to justify a change in practice based on these results alone.[40] Another major criticism of this trial is that there were unexpectedly fewer axillary recurrences than predicted, which suggests that it might not have been sufficiently powered to address the primary end point of noninferiority of 5-year axillary recurrence. Moreover, the study follow-up period was short (median, 6.1 years) and possibly inadequate, given that tumor recurrences occur beyond this time frame, especially in ER-positive disease. In fact, a worrisome divergence in OS between the two arms after 10 years has been noted, with only 50% survival in the radiotherapy group vs 80% in the surgical dissection group.[40] One hypothesis for this difference in survival is that there may be an imbalance in molecular prognostic factors (ER, progesterone receptor, human epidermal growth factor receptor 2, and Ki-67) between groups.[40,41] Molecular prognostic factors were not evaluated in this trial, and the lack of information regarding tumor biology is perhaps its most significant shortfall. One final limitation is that the results cannot be applied to women receiving neoadjuvant therapy, but this will be addressed in the Alliance A11202 trial (see below for discussion).

One final trial of interest is the POSNOC (positive sentinel node observation or clearance) trial, which is currently accruing in the United Kingdom with a goal of 1,900 patients. It should fill in some of the gaps in the literature to date. Women who have early-stage breast cancer (T1/T2), either unifocal or multifocal, and macrometastases in one or two SLNs (without ENE) will be randomized to no further axillary therapy, completion ALND, or axillary radiation therapy. Of note, OSNA is one of the acceptable methods for stratification of patients as having macro- or micrometastatic disease. Patients can undergo either BCT or mastectomy, but those who undergo neoadjuvant chemotherapy will be excluded. All patients must receive adjuvant systemic therapy—chemotherapy, endocrine therapy, or HER2-targeted therapy as appropriate. The primary outcome will be axillary recurrence at 5 years.[42]

Just as pathologists have difficulty accepting that they do not need to find all the micrometastases and isolated tumor cells in SLNs, clinicians have difficulty accepting that they are knowingly leaving disease behind in the axilla in almost 30% of patients with positive SLNs. It is difficult to accept that local and systemic adjuvant therapy will take care of residual disease and, ultimately, that one is doing no harm. It is helpful to remember that the false-negative rate of SLNB alone (~9%) far exceeds the rate of axillary recurrence, and so most occult axillary metastases do not result in regional recurrence or affect DFS or OS.

Despite any misgivings, the results of these recent clinical trials have had a significant influence on clinical practice recommendations and patterns. ASCO clinical practice guidelines published in 2014 recommend against ALND for women who have early-stage breast cancer (T1-T2) and one or two SLN metastases (size irrelevant) and who will undergo BCT and whole-breast irradiation.[3] It should be noted that the women who do not fall in this eligibility group include those with more than two positive nodes, gross (and >2 mm of microscopic) extranodal extension, palpable ("bulky") or matted axillary metastatic SLNs, women treated with mastectomy, and women treated with neoadjuvant chemotherapy.

Given the more limited clinical circumstances in which ALND is currently recommended, the rate of ALND has significantly decreased (by approximately 90%),[43,44] including the rate in mastectomy patients (by 56%).[43] In accordance, the prevalence of SLN frozen sections has also dropped dramatically,[45,46] down to 2% in one single-institution study.[45]