Safety of Sentinel Lymph Node Dissection and Significance of Cytokeratin Micrometastases
Authors: Robert J. Rosser, Armando Giuliano, Kelly McMasters
Journal: Journal of Clinical Oncology (2001)

Article Tools SPECIAL DEPARTMENTS Article Tools OPTIONS & TOOLS Export Citation Track Citation Add To Favorites Rights & Permissions COMPANION ARTICLES No companion articles ARTICLE CITATION DOI: 10.1200/JCO.2001.19.6.1882 Journal of Clinical Oncology - published online before print September 21, 2016 PMID: 11251022 Safety of Sentinel Lymph Node Dissection and Significance of Cytokeratin Micrometastases Robert J. RosserxRobert J. RosserSearch for articles by this author Armando GiulianoxArmando GiulianoSearch for articles by this author Kelly McMastersxKelly McMastersSearch for articles by this author Show More Desert Regional Medical Center, Desert Hospital–Salick Comprehensive Cancer Center, Palm Springs, CAJohn Wayne Cancer CenterUniversity of Louisville, J. Graham Brown Cancer Center, Louisville, KY 40202 https://doi.org/10.1200/JCO.2001.19.6.1882 First Page Full Text PDF Figures and Tables © 2001 by American Society of Clinical OncologyjcoJ Clin OncolJournal of Clinical OncologyJCO0732-183X1527-7755American Society of Clinical OncologyjcoJ Clin OncolJournal of Clinical OncologyJCO0732-183X1527-7755American Society of Clinical OncologyResponse15032001Response15032001Reply 1:The letter from Dr Rosser makes an excellent point concerning the uncertain significance of small numbers of malignant cells detected only by immunohistochemical (IHC) examination of sentinel nodes. Quite likely, breast cells, benign and malignant, may be dislodged by manipulation. Such cells could be taken up by the lymphatic system and could be detectable by highly sensitive assays such as IHC or reverse transcriptase polymerase chain reaction. When we undertook our prospective study in 1995,1 the concept of the sentinel node biopsy was not well recognized. Using this technique without axillary dissection had not been attempted. We were concerned about the safety of not removing lymph nodes that may have micrometastases. Consequently, our study was designed in the most cautious manner so that patients who had IHC-detectable tumor cells in the lymph nodes were subject to completion axillary dissection to assure removal of any other involved nodes. I agree with Rosser that if these dislodged epithelial cells are of no significance, axillary dissection is unnecessary and also more aggressive adjuvant therapy may be unwarranted. Unfortunately, it is not clear that we can establish which breast cancer cells in the sentinel node are dislodged “traumets” of no significance and which cells have metastatic potential. The current trial of the American College of Surgeons (Z0010) mentioned in our article is designed to determine the clinical significance of metastases detected by IHC. Once this trial is completed, we hope to understand the biologic significance of such tumor cells in sentinel nodes.The real point is not that sentinel lymph node dissection should be done without massage, but that we should complete the research necessary to understand the significance of isolated tumor cells. The occurrence of these cells was recognized long before sentinel node dissection was performed. The breast with a malignancy is inevitably subject to external pressure, such as mammography, needle biopsies, surgical biopsies, and even an incidental bump or hug. Cells may be dislodged. It will take large studies to determine the clinical relevance of these dislodged cells and more work to learn how to distinguish a “traumet” from a “real met.”Reply 2:Dr Rosser takes issue with the safety of sentinel lymph node biopsy for breast cancer, citing evidence that he believes breast cancer cells or clusters of cells detected by analysis of sentinel nodes by cytokeratin immunohistochemistry (CK-IHC) are related to traumatic dislodgment of tumor cells into the lymphatic system. Such cells in the sentinel node are referred to as “traumets.” While this phenomenon is controversial and by no means universally accepted, we too are troubled by the finding of sentinel node metastases in as high as 12% of patients with ductal carcinoma-in-situ (DCIS) (without microinvasion) when CK-IHC is used.1 In many cases, these patients are then subjected to axillary lymph node dissection and even chemotherapy. This simply does not match the clinical reality of this disease, with a 98% or better long-term disease-specific survival rate when treated by simple mastectomy or breast-conserving therapy. Therefore, CK-IHC seems to detect the presence of cells in the sentinel nodes that may not have clinical significance.Because the significance of breast cancer micrometastases detected by CK-IHC is very controversial, a consensus panel involving pathologists and surgeons has recently agreed that CK-IHC should not be performed routinely for identification of nodal micrometastases. We agree wholeheartedly with this position and have recently ceased to perform CK-IHC at our center. We also corresponded with the more than 250 surgeons involved in our multi-institutional study of breast cancer sentinel lymph node biopsy2 encouraging them to discontinue the use of CK-IHC for clinical decision making. However, we continue to participate in the American College of Surgeons Oncology Group Trial Z0010, in which CK-IHC of sentinel nodes is performed at a central site, the investigators are blinded to the results, and the prognostic significance of CK-IHC–positive sentinel nodes will be prospectively evaluated in a large cohort of patients. A similar investigation is underway in the National Surgical Adjuvant Breast and Bowel Project B-32 trial as well. We believe that these important studies will answer the question of the significance of CK-IHC–detected micrometastases once and for all.Rosser implies that because CK-IHC may find evidence of breast cancer cells that are not prognostically significant, sentinel lymph node biopsy is not safe. The logic behind this contention, however, is flawed. First, there is no evidence that patients who undergo sentinel lymph node biopsy are at any greater risk of locoregional or systemic recurrence compared with patients who undergo standard axillary dissection. In fact, there is some evidence that cancer cells can be detected in the peripheral blood of early-stage breast cancer patients routinely.3,4 The development of metastases is a complex multistep process that involves more than just escape of cells from the primary tumor. Furthermore, Rosser implies that the sentinel lymph node biopsy procedure is responsible for the presence of so-called “traumets.” There are many other interventions that could result in breast cancer cells being traumatically dislodged (assuming this theory is correct), including mammography, breast examination, and breast biopsy by a variety of techniques. Surely Dr Rosser does not suggest that we forego any of these potentially traumatic, but important, diagnostic maneuvers. Therefore, sentinel lymph node biopsy is yet another diagnostic test that necessarily involves manipulation of the breast, and it should be no less dangerous than other procedures for diagnosis and treatment of breast cancer. Therefore, we believe that sentinel lymph node biopsy, when performed properly and in experienced hands, is a safe and accurate alternative to routine axillary dissection for breast cancer.REFERENCE1. Giuliano AE, Haigh PI, Brennan MB, et al: Prospective observational study of sentinel lymphadenectomy without further axillary dissection in patients with sentinel node negative breast cancer. J Clin Oncol 18:: 2553,2000-2559, Link, Google Scholar1. Klauber-DeMore N, Tan LK, Liberman L, et al: Sentinel lymph node biopsy: Is it indicated in patients with high-risk ductal carcinoma-in-situ and ductal carcinoma-in-situ with microinvasion? Ann Surg Oncol 7:: 636,2000-642, Crossref, Medline, Google Scholar2. McMasters KM, Tuttle TM, Carlson DJ, et al: Sentinel lymph node biopsy for breast cancer: A suitable alternative to routine axillary dissection in multi-institutional practice when optimal technique is used. J Clin Oncol 18:: 2560,2000-2566, Link, Google Scholar3. Racila E, Enhus D, Weiss AJ, et al: Detection and characterization of carcinoma cells in the blood. Proc Natl Acad Sci U S A 95:: 4589,1998-4594, Crossref, Medline, Google Scholar4. Krag DN, Ashikaga T, Moss TJ, et al: Breast cancer cells in the blood: A pilot study. Breast J 5:: 354,1999-358, Crossref, Medline, Google Scholar