4 Author Study Bulte et al. [18] 7 hospitals in Netherlands 3.8 years 503 pN0 38 pNmi Hainsworth et al. [19] St Vincent’s Hospital, Australia 31/343 occult node metastases found on IHC, plus 10 found on H&E Truong et al. [20] Colleoni et al. [29] de Boer et al. [21] Houvenaeghel et al. [33] Surveillance Epidemiology and End Results database Italian medical oncology department Dutch cohort study of all centers in Netherlands (MIRROR study) A French center 6.6 years 7.3 years 4.2 years 5.1 years — 62,551 pT1–2pN0-: 57,980 pN0, 1818 pNmi, 2753 pNmac >2 mm but <2 cm 1959 pT1-3, pN0, pN1mi or pN0i+), or pN1a (single positive node) and M0 (a) 856 Nmi/ITC without adjuvant therapy, (b) 995 Nmi/ITC with adjuvant therapy, (c) 856 node-negative SN involvement in 388 times (55.4%) by H&E, 312 times by IHC Table 2: Important studies on micrometastatic nodes in breast cancer. Median FU Patient number ALND: axilllary lymph node dissection; DFS: disease-free survival; FU: followup; n.s.: statistically nonsigniﬁcant; OS: overall survival; SNB: sentinel node biopsy; s.s.: statistically nonsigniﬁcant. from January 1st, 2000 to December 31st, 2006 [40]. All SNs were assessed by serial H&E and IHC sections. Patients with micrometastases (0.2–2 mm) underwent completion ALND. Patients with ITC (<0.2 mm) were individually discussed and an ALND was performed selectively based on additional clinicopathological criteria and patient preference. Patients were followed for a median of 27 months (range 12–72 months). 1076 patients who underwent SN were included for analysis. The experience is unique as it demonstrates the breakdown of cases into each category: 211 (20%) had a positive SN biopsy using H&E. Forty-nine patients (5%) had a negative SN on H&E which was positive on IHC. Of these, 15 had micrometastases and underwent an ALND. Two had further axillary nodal disease. ITC were found in the remaining 34 patients. Sixteen of these patients underwent an ALND. Five of this group had further nodal disease. Therefore, micrometastases and ITCs, detected only by IHC analysis of SNs, are associated with further positive nodes in the axilla in up to 15% of patients. However, more research is needed and IHC is not yet the standard procedure in most pathology departments. 3.3. Eﬀect on Survival of Completion ALND. Completion ALND remains the gold standard for patients with a tumor- involved SN. ALND achieves regional control, but its eﬀect on survival remains controversial. The American College of Surgeons Oncology Group (ACOSOG) Z0011 study random- ized clinically node-negative patients who underwent SN biopsy and had 1 or 2 SN with metastases detected by H&E to ALND or no further axillary surgery [41]. Ineligibility criteria were SN metastasis detected by IHC, 3 or more SN positive, third ﬁeld RT for nodal RT or accelerated partial breast irradiation (APBI). Both groups have tangent breast RT plus systemic therapy (which can be hormone or chemotherapy). The 446 patients with SN biopsy alone and 445 patients with SN biopsy plus ALND were similar Pathology Research International Conclusion Local relapse—5(1.0%) versus 1(2.6%) Regional relapse—0% versus 0% Distant relapse—17(3.4%) versus 3(7.9%) Combined locoregional relapse—1(0.2%) versus 0% Combined regional and distant relapse—3(0.6%) versus 0% (n.s., see text for details) Among the 31 patients, presence of occult metastases in 2 or more nodes was associated with decreased DFS and OS (P < .05) 10-year BCSS (82.3% versus 91.9%) and OS (68.1% versus 75.7%) in pNmi compared to pN0. (s.s.) pN1mi/pN0i+ versus pN0 disease: HR = 1.58; 95% CI, 1.01 to 2.47; P = .047 for DFS; HR = 1.94; 95% CI, 1.04 to 3.64; P = .037 for distant metastases. Disease events: (a) for Nmi: HR 1.56 (95% CI:1.15-2.13; for ITC:HR 1.50 (95% CI:1.15-1.94) (b) HR 0.57 (95% CI:0.45-0.73) May omit additional ALND for pT1a and pT1b tumors, and pT1a-c tumors corresponding to tubular, colloidal or medullary cancers