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Originally published as JCO Early Release 10.1200/JCO.2006.05.6036 on April 10 2006 © 2006 American Society of Clinical Oncology.
Sentinel Lymph Node Histopathology in Breast Cancer: Minimal Disease Versus ArtifactSt Clare's Mercy Hospital, St John's, Newfoundland, Canada
Vanderbilt University, Nashville, TN The presence or absence of tumor deposits in axillary lymph nodes in patients with breast carcinoma remains central to staging and prognosis as well as guidance of treatment decisions. Sentinel lymph node biopsy can be reliably performed by experienced teams to avoid axillary dissection and its resultant morbidities in recognized subsets of breast cancer patients.1 With general acceptance of sentinel lymph node examination has come the increasing awareness that positivity is not a dichotomous variable. Some sentinel lymph nodes are indeed more positive than others. And not all cytokeratin-positive cells are tumor. The optimal histologic examination of sentinel lymph node remains controversial; however, there is generalized use of multiple sections that are cut to maximize exposure of the subcapsular sinus.2,3 Many perform immunohistochemical stains, whereas others do not.4 The use of sentinel methodology increased the number of patients with supposed positive lymph nodes and micrometastatic disease. Conversion rates range from 10% to 50% when the protocol for pathologic examination of lymph nodes changes from a single section to multiple levels and immunohistochemical stains. The majority of these converters have minimal microscopic deposits. The efforts of Greene et al,5 Singletary and Greene,6 and Singletary et al7 clearly classify most cases of minimal involvement as isolated tumor cells and micrometastases in the hope that significant clinical and prognostic information may someday be made from these categories. A 2003 publication7 from the American Joint Committee on Cancer and the International Union Against Cancer removed the primacy of staining by immunohistochemistry and recognized that it is the size of the tumor deposit and not the method of detection that is important. The European Working Group for Breast Screening Pathology has concluded that one should apply this classification by choosing the lower category as the best option when in doubt.8 Some bias toward upstaging is largely kept in check by the rule that separate clumps are measured by the size of the largest clump. Contrary to the measuring of tumor clumps in lymph channels, it is our approach to measure intracapsular lymphatic tumor as lymphatic involvement, probably analogous to peritumoral lymphatic invasion. Certainly, this easily identifiable pattern may have more local implication than the prognostic implication of viable tumor growing in nodal substance. There are two other patterns of cancer in and near lymph nodes that should be specifically recognized. The first is the occasional solitary growth centered in the capsule, with limited local growth outward from the node and into the adjacent soft tissue. This finding is seen in low-grade, tubular variant carcinomas and may have little implication for local or distant disease. On the other end of the malicious spectrum is the presence of lobular-pattern carcinoma within the adjacent axillary soft tissue; this pattern should be specially recognized because it implicates extensive local disease in the axilla, and some patterns of minimal involvement may have more importance because they implicate the involvement of other lymph nodes.9 As we refine our understanding of minimal nodal involvement and mimickers of nodal involvement, we will come to understand in what relationship to other measures of a patient's disease these findings may add or detract. The examination of axillary lymph nodes, including sentinel nodes in patients who have had a previous minimally invasive biopsy procedure (tissue core biopsy or fine-needle aspiration biopsy), has resulted in a relatively new diagnostic category of benign transport of small groups of epithelial cells, both benign and malignant, into draining, usually axillary, lymph nodes. Needling procedures (cytologic and tissue core) have been shown to displace carcinomatous epithelial cells within the breast.10,11 In a prior study, we have shown that needling procedures can transport both benign and carcinomatous epithelial cells into breast lymphatic channels and into axillary nodes.12 Other authors have subsequently supported these findings.13 This phenomenon does seem to occur more commonly if the primary lesion contains papillary elements and may be a reflection of the more mechanically fragile nature of these lesions or their greater likelihood of surviving transport to the nodes intact.11,14 Many pathologists have been interpreting the presence of any epithelial cells in the lymph node as positive for metastases. With the standard use of needling procedures and the increasing use of in-depth comprehensive examination of lymph nodes, especially those designated as sentinel, there is no doubt that the rate of false-positive diagnoses will increase. Pathologists and clinicians must be aware of this phenomenon and interpret it correctly and with confidence. Other presentations, such as tumor in lymphatic channels of the capsule, may also have special implications. Other causes of false-positive sentinel lymph nodes subjected to immunohistochemical staining must also be considered. It is well recognized that macrophages, which are common inhabitants of the draining lymph node, will phagocytose keratinic debris. These cells will than appear positive when an immunohistochemical stain against cytokeratins is applied to them. Simultaneous staining with CD68, a microphage marker, will clarify those cases not diagnosed correctly on review of hematoxylin and eosin–stained slides. Breast epithelial inclusions of presumed embryologic histogenesis will also stain with immunohistochemical stains against cytokeratin. The benign nature of the epithelium usually, but not always, prevents these elements from falsely being diagnosed as micrometastatic disease. Fibroblastic reticulum cells stain positively for certain cytokeratins and can sometimes be mistaken for carcinoma on morphologic grounds. Finally, contamination within the laboratory can result in an overlay of epithelial cells (from another patient or from the keratinocytes on the hands of laboratory personnel) that may be misdiagnosed as positive for metastases. Vigilant examination, knowledge of potential pitfalls, and artifacts and cautious interpretation must all be used when examining lymph nodes. The article in this issue of the Journal of Clinical Oncology by Bleiweiss et al15 describing falsely positive axillary lymph nodes as a result of iatrogenic displacement and transport of benign epithelial elements in patients with breast carcinoma adds to the substantive and increasing literature advising caution in overinterpreting the presence of epithelial cells in exhaustively examined sentinel lymph nodes when their presence can be reasonably explained by benign transport. It is interesting that many of their samples are carcinoma arising in a papillomatous lesion. We agree with many of the authors' suggestions on the cautious interpretation of such findings with respect to their metastatic capability. True metastasis, implicating the likelihood of distant metastatic capacity, is not a simple event; instead, it is a multistep process using cellular and molecular alterations that have taken place in the native cells and the target organ. The mere physical presence in the draining lymph node of groups of cells from the primary lesion must not be interpreted as established metastases with all its implications. As many authors, including Bleiweiss et al,15 have pointed out, we need answers from prospective clinical trails. We look forward to the future development of laboratory assays that will correctly differentiate small lymph node deposits that are truly metastatic (implicating greater likelihood of distant metastases than already indicated by size, grade, and other measures of the primary tumor) from those minimal deposits that are unlikely to have any significant impact on the patient and those deposits that have been benignly transported to the lymph node as a clean-up mechanism by the lymphatic system. Authors' Disclosures of Potential Conflicts of Interest The authors indicated no potential conflicts of interest. Author Contributions
REFERENCES
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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