Prognostic Importance of Nodal Microenvironment beyond Extracapsular Extension in Breast Cancer Outcomes

Abstract

<h3>Purpose/Objective(s)</h3> Lymph node (LN) involvement and extracapsular extension (ECE) play important roles in breast cancer risk stratification, management, and outcome. Involvement of other axillary tissues (AXT) excised during surgery is often omitted in pathology reports and its prognostic significance is yet to be elucidated. <h3>Materials/Methods</h3> Medical records of 1,919 breast cancer patients with pathologic lymph nodes treated at our institution from 2000-2019 was retrospectively reviewed. Extensive details of LN involvement are reported by pathologists at our institution and were divided into 4 groups: LN+ only, LN+ECE, LN+AXT without ECE, and LN+ECE+AXT. AXT was defined as the involvement of lymphatic vessels, blood vessels, soft tissue metastasis, matted unspecified masses and combination of any of those forms. The primary endpoint was the impact of AXT on locoregional failure (LRF) defined as recurrence in either breast/chest wall/axilla/supraclavicular fossa, on axillary failure (AF) defined as recurrence in the axilla only and on distant failure (DF) defined as metastasis. Subgroup analysis explored the differences between types of AXT and Cox Hazard models were used. <h3>Results</h3> Among 1,919 patients analyzed, 995 had LN+ only involvement, 534 had LN+ECE, 81 had LN+AXT without ECE, and 309 had LN+ECE+AXT. The overall median follow-up was 6.5 years. The 10 years cumulative incidence of LRF was 5.9%, 6.4%, 11.8% and 10.9% in LN only, LN+ECE, LN+AXT without ECE and LN+ECE+AXT groups, respectively. The 10 years cumulative incidence of AF was 0.92%, 0.83%, 4.1% and 4.4% in LN+ only, LN+ECE, LN+AXT without ECE and LN+ECE+AXT groups, respectively. The 10 years cumulative incidence of DF was 15.7%, 23%, 23.5% and 42.1% in LN+ only, LN+ECE, LN+AXT without ECE and LN+ECE+AXT groups, respectively. On multivariable analysis controlling for number of malignant LN, ECE, tumor biology, grade and size, type of axillary surgery and radiation dose delivered to the draining lymphatics, the presence of other AXT was significantly associated with LRF (HR:2.3, P<0.01), AF (HR:4.7, P<0.01) and DF (HR: 1.4, P=0.02). ECE and number of malignant LN were not associated with LRF and AF, but rather associated with DF (HR:1.4, P=0.009 and HR:1.03, P=0.002, respectively). Delivery of 50 Gy or more to draining lymphatics was associated with better axillary control (HR:0.3, P=0.01) compared to 45 Gy. No significant difference between 45 Gy and 50 Gy to the lymphatics was observed for LRF and DF. Subgroup analysis did not show a difference between the described forms of AXT on LRF and DF. <h3>Conclusion</h3> Pathologic evaluation of the axilla's microenvironment beyond tumor deposits in lymph nodes and ECE is important to ensure adequate local control in the axilla. Given the higher risk of recurrence posed by tumor infiltration into surrounding axillary tissues, delivery of at least 50Gy to lymphatics should be considered. Our findings demonstrate the need for pathology reports to include assessment of the axilla's microenvironment.