Is Axillary Dissection Always Indicated in Invasive Breast Cancer?

Introduction

In 1997, an estimated 181,600 new breast cancer cases will be diagnosed in the United States.[1] Between 1973 and 1993, there was a steady annual increase of more than 2% in the incidence of breast cancer.[2] This increment is predominantly due to the detection of early lesions by the widespread use of screening mammography in asymptomatic women.[3,4] As a result, an increasing number of women are candidates for breast conservation. The role of axillary dissection in the conservative management of breast cancer is well established. Surgery is performed to determine the pathologic staging of the lymph nodes. The node status serves as a guide for recommendations regarding systemic therapy, and the procedure has therapeutic value when the lymph nodes are positive for metastases.

Historically, axillary lymph nodes were viewed as the gateway to the spread of cancer. Halsted popularized the concept of an orderly spread of cancer from the breast to the regional lymph nodes and then to the rest of the body. A complete axillary dissection was considered a critical component of the surgical treatment of this disease. Halsted’s principles influenced breast cancer management until the introduction of alternative hypotheses, whereby axillary lymph node metastases were viewed as prognostic indicators, and not as governors of the complex host-tumor relationship in the development of distant metastases.[5] Based on an improved understanding of the natural history and biology of the disease, the technique and extent of axillary dissection has been modified. No stage-specific survival differences have been observed as a result of modifications in the technique of axillary dissection. It is the information from the procedure that guides the use of adjuvant systemic therapy, which influences patient survival.

In the conservative management of breast cancer, a level I/II axillary dissection is routinely performed. More recently, the concept of “sentinel node” biopsy has been studied. It is based on the assumption that the sentinel node[s] may be a reliable surrogate for any lymph node metastases in the regional drainage basin.[6] This approach can potentially lead to a recommendation for selective use of axillary dissection guided by the pathologic findings of the sentinel lymph node. Another area under investigation is the use of PET imaging as a screening modality for axillary metastases. It may have a role in selection of patients for axillary dissection. In a small study comparing 2-deoxy-2-fluoro-d-glucose (FDG) PET imaging to axillary dissection, PET had a specificity of 100% and a sensitivity of 90%.[7]

Morbidity of Axillary Dissection

Axillary dissection is a procedure with considerably greater morbidity than local excision of the primary alone. It is apparent that, although the morbidity from axillary dissection is not life-threatening, it has a significant bearing on a patient’s quality of life. The more commonly observed side effects include seroma, numbness in the distribution of the intercostobrachial nerve, pain, limitation in the range of shoulder mobility, and stiffness and edema of the arm. Ivens et al[8] reported numbness in 70% of patients, pain in 30%, and weakness in 25%. Long-term physical and psychological morbidity was studied through a series of questionnaires completed by patients seen at follow-up.[9] One-third of the patients noted consistent pain, 63% had impaired maximum arm/shoulder movement, 62% had numbness, and 17% experienced weakness in the arm more than 6 months after the procedure. Patients undergoing axillary dissection are also at risk for developing lymphedema of the arm with associated physical and functional limitations. Despite the trend toward a conservative approach, the incidence of lymphedema remains significant, ranging anywhere from 5% to 25%.[8,10-13]

When does an axillary dissection need to be done? In the contemporary management of breast cancer, the indications for an axillary dissection should be based on the relevance of the axillary node status to the individual patient’s overall treatment and outcome. For patients participating in clinical trials, axillary dissection is necessary to document the pathologic status of the nodes. Studies on trends of patient accrual in clinical trials show that only 3% to 4% of newly diagnosed breast cancer patients enroll in these studies.[14] For the significant majority of women who do not participate in clinical trials, the indication for axillary dissection should be individualized. The value of axillary dissection in the pathologic staging of disease is important. However, to do an invasive procedure predominantly to complete the pathologic staging is difficult to justify.

Axillary Dissection as a Guide for Adjuvant Systemic Therapy

Axillary lymph node metastases are important prognostic factors and have largely been used to guide adjuvant systemic therapy. There have, however, been changes in recommendations about adjuvant systemic therapy for N0 patients, and it has become necessary to use primary tumor characteristics for prognostic information. In early breast cancer, there are ongoing efforts to evaluate prognostic determinants other than lymph node status to trend patients' risk.[15]

Tumor size is known to be an important prognostic marker. The prognostic value of nuclear grade and histologic differentiation has been demonstrated, with high-grade lesions being associated with an inferior outcome. The presence of peritumoral lymphatic and blood vessel invasion has proven to negatively influence a patient’s risk of recurrence and disease-free survival. Hormone-receptor status, DNA flow cytometry measurements of ploidy, and S-phase fraction also have prognostic significance and are predictive of patient outcome both in node-negative and node-positive disease.

Angiogenesis, identified as an important factor in the metastatic process, has been shown to be an independent prognostic indicator in early breast cancer. Oncogenes, growth factors, and p53 expression are also being extensively investigated. Studies need to continue that further improve the predictive value of prognostic markers of the primary tumor and that identify reliable panels, either by combining already known factors or identifying new ones.

Cancer Cells in the Marrow

There are promising early results on the prognostic potential of breast cancer cells detected in the bone marrow.[16,17] Diel et al[17] studied the value of breast cancer cells detected in the bone marrow of 1,026 patients. The bone marrow interphase cells were stained with 2E11 monoclonal antibody that would react with the core protein of TAG-12, a tumor-associated glycoprotein expressed by more than 97% of all mammary carcinomas. The bone marrow was positive for tumor cells in 31% (171/546) of node-negative patients and in 32% (131/408) of those with T1 lesions. Eighty-two percent of patients with positive bone marrow assays developed metastases.

Multivariate analysis showed that, at a median follow-up of 40 months, the tumor cells detected in the marrow were superior as independent prognostic indicators of relapse than were axillary lymph nodes, stage, and tumor grade. Disease-free survival by stage showed that, for women with T1 disease, tumor cells detected in the marrow were the most powerful predictor of metastases, having a relative risk of 13.9, as compared to 1.9 for axillary lymph node metastases. These data suggest that, for women with small tumors, tumor cells detected in bone marrow are a more reliable prognostic guide than is axillary node status. Longer follow-up and additional studies are needed to confirm these observations.

Lin and colleagues[12] retrospectively studied 240 women with clinically node-negative tumors to determine the impact of axillary dissection on use of adjuvant therapy. In 152 patients, unfavorable characteristics of the primary tumor determined the recommendations for systemic adjuvant therapy. Of the remaining 88 patients thought not to require adjuvant therapy based on primary tumor characteristics, axillary node metastases were found in 11. Overall, the findings at axillary dissection influenced the recommendation for systemic therapy in only 5% of patients with clinical node-negative disease.

Treatment of the Axilla: Axillary Dissection or Axillary Irradiation?

One indication for axillary dissection is to treat the axilla. Axillary recurrence occurs in less than 2% in patients undergoing a complete dissection, compared to a 10% to 12% recurrence rate in patients who undergo a limited sampling.[18,19] Alternatively, in patients with clinically negative axillae treated with radiation alone, excellent local control rates are achieved. A number of studies on radiation alone for the axilla demonstrate axillary recurrence rates in the range ofless than 3% (Table 1).[5,20-23] In a review of 550 axillae treated with radiation therapy alone without axillary dissection in 537 patients, we observed only a 2% axillary recurrence rate in clinical N0 patients over the age of 50 years.[23a] In the National Surgical Adjuvant Breast Project (NSABP) B-04 randomized trial, there was no difference in the rate of isolated axillary failures noted for patients treated with simple mastectomy and 50 Gy radiation to regional nodes, as compared to those treated with a radical mastectomy. In clinical stage I/II disease, when the axilla was treated with radiation therapy only, Wazer et al reported 8-year breast cancer-specific survival to be as high as 93.8%.[24]