Contemporary Evaluation of Breast Lymph Nodes in Anatomic Pathology

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

Disclosures

Am J Clin Pathol. 2018;150(1):4-17. 

In This Article

Management of the Axilla in the Setting of a Positive SLN: Acosog Z0011 and IBCSG 23–01

Approximately 30% of women have positive SLNs, including 60% of women with palpable carcinomas and 15% of women with mammographically detected carcinomas.[3] Of these women, 50% to 60% will have no additional positive lymph nodes found on completion ALND.[32] Nomograms are traditionally used to calculate the likelihood of residual disease in the remaining lymph nodes.[2] Given the high frequency of negative completion ALND, the question of whether this procedure is really needed in all women with positive sentinel nodes has been addressed. Three trials published in the past 3 years have transformed management of the axilla: the ACOSOG Z0011 trial,[5] the International Breast Cancer Study Group (IBCSG) 23–01 trial,[6] and the European Organization for Research and Treatment of Cancer After Mapping of the Axilla: Radiotherapy or Surgery? (AMAROS) trial[33] Table 1.

ACOSOG Z0011 and IBCSG 23–01 addressed efficacy and adverse events in patients who had invasive breast cancer and positive SLNs and who were randomized to either completion ALND or no further surgery. ACOSOG Z0011 focused on women with metastatic disease of any size involving one or two SLNs (n = 813). Other eligibility criteria included successful SLN mapping, T1/T2 tumors, no palpable adenopathy, no gross extranodal extension, no neoadjuvant therapy, and breast-conserving therapy with the intention to treat with whole-breast radiotherapy.[5] IBCSG 23–01 also studied women who had one or two positive SLNs, but the deposits could not be any larger than a micrometastasis (≤0.2 cm) (n = 964). Similar to Z0011, additional criteria included T1/T2 tumors, no palpable adenopathy, no gross extranodal extension, and no neoadjuvant therapy. However, in 23–01, either breast-conserving therapy or mastectomy was allowed.[6]

The method of SLN mapping and pathologic evaluation was different in each of the trials. In Z0011, the suggested procedures were not compulsory. The number of H&E levels examined was not reported, but metastases detected by IHC only were not allowed.[5] In contrast, in 23–01, surgical and pathologic procedures were standardized. Ten H&E levels of a 2-mm-thick sliced lymph node(s) were examined, which is significantly more than routine evaluation and was designed to detect all micrometastases.[6]

The results of both trials were remarkably similar. For Z0011, additional positive nodes were identified in 27% of patients who had completion ALND, including 10% of those with micrometastases in the SLN. The local (in breast) recurrence at 5 years was 3.6% in the ALND group and 1.8% in the SLN biopsy (SLNB)–only group. Regional (axillary) tumor recurrence was 0.5% for ALND and 0.9% for SLNB only at 5 years, with similar 5-year DFS (82%-83%) and OS (91%-92%) in both groups.[5] For 23–01, 13% had additional positive nodes on completion ALND, similar to Z0011. The local (in breast) recurrence rate was 2% in both arms, with less than 1% regional (axilla) recurrence. Distant recurrence was 7% for the ALND group and 5% for the no ALND group. There was no significant difference in OS or DFS. There was significantly less lymphedema in the no ALND group (3% vs 13%; P ≤ .0026).[6]

Patient and tumor characteristics in the trials are also important for generalization purposes. In Z0011, most patients had tumors that were stage T1 (67%-70%), invasive ductal carcinoma (81%-84%), and ER positive (82%). Fifty-eight to 71.5% of patients had one positive node only, and 37% to 44% had micrometastases. The median number of nodes removed was two.[5] In 23–01, most patients had T1 (70%), grade 1 or 2 (68%), and ER-positive (90%) tumors and only one positive node (96%). In accordance with the study design, 97% of nodal tumor deposits were micrometastases or smaller. One (50%), two (30%), or three (11%) lymph nodes were most commonly removed.[6] In both trials, almost all patients (96%) got some form of adjuvant therapy, either chemotherapy or hormone therapy.[5,6] Although mastectomy was permitted for IBCSG 23–01, 91% of patients received breast-conserving therapy, almost all in combination with radiotherapy.[6]

There have been many criticisms of Z0011, and the results are controversial with good reason. There was a significant amount of missing data, including number of positive nodes (11%), size of nodal metastases (15%), tumor size (2%), grade (32%), and receptor status (9%). Macrometastases were identified in the SLN in 62% of the patients who underwent completion ALND compared with 55% of those who underwent no further surgery, raising the question whether the SLNB-only group had less tumor burden. A significant fraction of patients was lost to follow-up in both groups: 21% of patients in the ALND and 17% of patients in the SLNB-only group. When greater than 10% of patients are lost to follow-up, it is considered critical and compromises the conclusions that can be drawn.[34]

The radiation therapy that the women received has also received a lot of attention. The protocol required whole-breast irradiation, and a third field of directed nodal treatment (high tangential fields, or "high tangents") was not allowed. There were no dose, frequency, or field data specified in the original publications. Standard radiation fields treat the axilla, but if high tangents are used, the axilla receives higher doses. The radiation oncologists were not blinded to the surgical treatment. Given the low regional failure rates despite the additional nodal burden in 27% of patients in the completion ALND group, there was considerable speculation that patients with positive nodes received high tangents to the axilla.[34]

This was confirmed in a detailed review of the radiation fields applied to patients in Z0011, and in fact, approximately half of those with available records received high tangents in both arms of the study. Patients with a greater number of involved lymph nodes received high tangents preferentially.[35] Many believe that this accounts for the low risk of recurrence.[34] Thus, treatment recommendations based on Z0011 results should not be blindly extrapolated to patients who have mastectomy and forego radiation therapy or those who receive partial breast irradiation. Also, it can be argued that high tangents should be offered to those with positive nodes.

Gross extranodal extension (ENE) was an exclusion criterion in Z0011, but the significance of microscopic extranodal extension was not reported. A recent retrospective analysis of 11,730 patients (of whom 331 had ENE on SLNB) investigated the incidence of additional nodal disease in ALND following SLNB showing ENE. Patients with ENE had larger, multifocal tumors and more frequent lymphovascular invasion. Twenty percent of patients with ENE had four or more positive nodes in the ALND vs only 3% of patients without ENE. Thirty-three percent of patients with more than 2 mm of ENE had four or more positive nodes, whereas 9% of patients with 2 mm or less of ENE had four or more positive nodes. The conclusion is that with more than 2 mm of ENE, ALND is recommended.[36]

Others have tried to evaluate the significance of ENE in patients eligible for Z0011 and published superficially conflicting opinions. Choi and colleagues[37] initially published data that ENE is associated with increased overall axillary nodal burden, disease recurrence, and overall mortality (n = 655). They published a follow-up article recently specifically looking at the subset of patients eligible for Z0011 (n = 208) who did (n = 59) and did not (n = 149) have ENE and concluded that ENE did not significantly increase the risk of recurrence at 5 years.[38]

A recently published update of the Z0011 trial addressed the criticism of insufficient follow-up and confirmed that comparable outcomes in the two arms of the study persist at 10 years. The cumulative incidence of nodal recurrences was 0.5% in the ALND arm vs 1.5% in the SLNB alone arm at 10 years (P = .28). Overall 10-year locoregional recurrence was 6.2% with ALND and 5.3% with SLNB alone (P = .36).[39]

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