Molecular Analysis Evaluation of Axillary Nodal Micrometastasis in Patients with Breast Cancer
SB Bokhari, AH Uihlein, KM Jasnosz, SD Finkelstein, JF Silverman. Allegheny General Hospital, Pittsburgh, PA; RedPath Integrated Pathology, Pittsburgh, PA
Background: The significance of micrometastasis (MiM) versus macrometastasis (MaM) in breast carcinoma (BC) impacts pathology staging and management. Currently, axillary lymph node (LN) deposits less than 2 mm are disregarded however such a finding could represent early spread of tumor. Two different mechanisms can account for this occurrence: 1) passive dislodgement of cancers cells from the primary site in breast to draining LN or 2) lymphatic invasion by aggressive tumor with active growth and dissemination. Ideally, pathology diagnosis and staging should reflect the true status of the cancer cell biology in the individual patient. To address this we performed comparative mutational profiling of primary BC and corresponding MiM and MaM LN deposits.
Design: 14 cases of breast ductal carcinoma with nodal MiM and 9 control cases consisting of breast ductal carcinoma with nodal MaM (total 23 cases) were retrieved from the hospital computer system. All cases were confirmed by histology and immunohistochemistry (IHC) and were microdissected using unstained formalin fixed, paraffin embedded standard tissue sections. Microdissection targets consisted of one non-neoplastic site, 2-3 sites of primary BC and LN metastatic deposits. Each microdissected sample was quantitatively genotyped and time course of mutation acquisition determined using a broad panel of 17 mutational markers including k-ras-2 point mutation and loss of heterozygosity (LOH) for 1p, 3p, 5q, 9p, 10q, 17p, 17q, 21q, 22q.
Results: All control cases of MaM disease showed the same number or greater cumulative mutations in LN deposits and this was used to define two states: active growth (MaM disease) versus passive spread (LN deposit showed fewer cumulative mutations than primary tumor). Of the 14 cases with MiM, 9/14 (64.3%) showed fewer mutations in the nodal MiM versus the primary BC, supporting passive displacement rather than true metastasis. 5/14 cases (35.7%) showed biologically active disease with more mutations in the nodal MiM versus the primary BC, supporting true biological metastases.
Conclusions: Our results support the need for individualizing pathologic staging of BC with respect to the biological nature of MiM disease. We believe molecular analysis is a useful technique to better evaluate the significance of MiM in axillary lymph nodes. The methods used here support its implementation in correlative studies with outcome analysis.
Tuesday, March 23, 2010 9:30 AM
Poster Session III # 38, Tuesday Morning