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Originally published as JCO Early Release 10.1200/JCO.2005.04.5757 on January 17 2006 © 2006 American Society of Clinical Oncology.
Is There Clinical Value to Sentinel Lymph Node Sampling in Colon Cancer?Department of Surgery, University of North Dakota School of Medicine and Health Sciences, Grand Forks, ND The well-established concept of sentinel lymph node (SLN) sampling for malignancies is based on the orderly and sequential flow of lymphatic fluid from the site of the primary tumor through the lymphatic vessels and lymph nodes within the draining lymphatic basin. It is accepted that the lymphatic dissemination of tumor cells follows this pattern, with the additional supposition that the tumor cells will be effectively filtered out in the lymph nodes in the drainage basin. When this concept applies, localization, removal, and pathologic analysis of SLNs provides important staging and prognostic information regarding lymphatic dissemination of the primary tumor. The accuracy and advantages of SLN sampling for malignancies of the integumentary system (principally melanoma and breast cancer) have been well documented in multiple trials since Morton's original report on SLN biopsy for malignant melanoma in 1992.1 The principal advantages of SLN biopsy include less radical surgery for node-negative patients and increased accuracy in determining the nodal status of the draining lymph node basin because pathologic analysis can be concentrated on one or a few lymph nodes most likely to contain micrometastases instead of all the nodes in the basin. When SLN sampling gives an accurate representation of the nodal status of the draining lymph node basin, full lymph node dissection is not necessary in patients with negative SLNs. This reduces or eliminates postoperative morbidity such as lymphedema, neuropathic pain, and wound complications. While this advantage is important for tumors of the breast and skin, it is not significant in colon cancer, as regional lymphadenectomy has long been the standard of care for surgical resection in colorectal cancer. In addition, there is little or no increased morbidity with wide lymphadenectomy in a standard colon resection as the anatomy of the colon is well suited to removing adjacent regional lymph nodes at the time of resection. For colorectal cancer, the principal advantage of SLN sampling is in improving the accuracy and ease of determination of lymph node status after resection. Approximately one third of patients who are node-negative (stage I and II) eventually recur, suggesting that the accuracy of current techniques in assessing the nodal status of colorectal cancer is poor. Although a portion of these patients may recur due to hematogenous metastases, it is also probable that understaging due to the lack of detecting lymph node metastases plays a role in a significant portion of these recurrences. When accurate determination of clinically significant lymph node status leads to a change in therapy, a substantial benefit will be achieved for patients who might avoid unnecessary therapy (node-negative disease) or receive a survival advantage from adjuvant therapy (node-positive disease). The article by Redston et al2 in this issue of Journal of Clinical Oncology prospectively analyzes SLN sampling in characterizing lymph node micrometastatic disease (MMD) for curable colon cancer in a multi-institutional setting. A previous report from this study showed a high false-negative rate of 54% when using standard staining techniques in examining SLN.3 This study reports the addition of immunohistochemistry (IHC) analysis of the lymph nodes with an improved false-negative rate of 12% and accuracy of 88%. Other reports using IHC for SLN analysis in colorectal cancer have shown variable results with false-negative rates of 3% to 45% and accuracy of 55% to 98%.4-7 A recently reported study, also prospective and multi-institutional with a larger sample size (132 patients), demonstrated a false-negative rate of 7% and a sensitivity of 88%.8 Possible explanations for the wide range of results include technical experience of surgeons as well as pathologists, different techniques in identifying SLN, lymph node sectioning techniques, antibody used for IHC, different criteria for definition of IHC positivity, small sample sizes, and skip lesions. Several of these factors are apparent in this study as well as many of the other reported studies. Larger prospective studies that are not subject to these criticisms will provide more definitive answers to the questions regarding accuracy and false-negative rates for SLN sampling in colorectal cancer. Although the accuracy of SLN sampling in colon cancer may continue to be debated until further prospective trials give more definitive evidence, the more important question is the clinical significance of MMD in lymph nodes with each of the methods of detection. MMD may be detected on standard histopathologic staining, by IHC techniques, or on a molecular level with real-time polymerase chain reaction (RT-PCR). The clinical significance of each of these methods must await the correlation of survival with positive SLN, preferably in prospective studies. Retrospective studies have demonstrated poorer prognosis in colon cancer patients whose regional lymph nodes were positive for MMD when examined by IHC techniques,9,10 but other studies have failed to correlate these results.11 If detection of MMD by any technique demonstrates prognostic significance, the use of SLN sampling will become all the more important as it is impractical and expensive to perform IHC or RT-PCR on all lymph nodes in a colorectal cancer resection specimen. There are no universally accepted criteria for the characteristics of IHC-positive cells identified in lymph nodes that constitute a clinically significant lymph node metastasis. Individual IHC-positive cells can be found in lymph nodes of patients who have colon resections for benign disease, and may be due to reactive mesothelial cells passing through or trapped in these nodes. The study by Redston et al2 did analyze lymph nodes from patients with benign disease and found that 20% of patients with benign disease would have been classified as node-positive by the criteria that was used. Clearly, the criteria that determine whether IHC-positive cells in lymph nodes should be considered as metastatic tumor cells or other benign cells need to be defined better. In some studies, single IHC-positive cells that do not have morphologic characteristics of malignant cells are not included as positive, while in other studies they are. As in breast cancer, the ultimate test will be the effect that these cells have in predicting recurrence, long-term survival, and whether the results impact treatment options. As the treatment gap between node-negative and node-positive patients narrows, whether or not a lymph node is positive or negative by current standards may lose its significance. In addition, the emergence of microarray gene expression patterns in guiding treatment options and predicting prognosis could make the determination of lymph node status obsolete for many solid tumors in the near future. There are still many questions that must be answered before SLN sampling in colon cancer can be dismissed or added to the standard of care. Whether the concepts of SLN sampling apply to nonintegumentary solid tumors has been the subject of much debate and controversy in the surgical and oncologic literature in recent years. The need for accurate and scientifically validated resolution of this controversy is important as the results may influence the management of many cancer patients for years to come. Author's Disclosures of Potential Conflicts of Interest The author indicated no potential conflicts of interest. Author Contributions
REFERENCES
1. Morton DL, Wen DR, Wong JH, et al: Technical details of intraoperative lymphatic mapping for early stage melanoma. Arch Surg 127:392-399, 1992 2. Redston M, Compton CC, Miedema BW, et al: Analysis of micrometastatic disease in sentinel lymph nodes from resectable colon cancer: Results of Cancer and Leukemia Group B trial 80001. J Clin Oncol 24:878-883, 2006 3. Bertagnolli M, Miedema B, Redston M, et al: Sentinel node staging of resectable colon cancer: Results of a multicenter study. Ann Surg 240:624-630, 2004[Medline] 4. Paramo JC, Summerall J, Poppiti R, et al: Validation of sentinel lymph node mapping in patients with colon cancer. Ann Surg Oncol 9:550-554, 2002[CrossRef][Medline] 5. Saha S, Wiese D, Badin J, et al: Technical details of sentinel node mapping in colorectal cancer and its impact in staging. Ann Surg Oncol 7:120-124, 2000[CrossRef][Medline] 6. Merrie AE, van Rij AM, Phillips LV, et al: Diagnostic use of sentinel node in colon cancer. Dis Colon Rectum 44:410-417, 2001[CrossRef][Medline] 7. Saha S, Dan AG, Beutler T, et al: Sentinel lymph node mapping technique in colon cancer. Semin Oncol 31:374-381, 2004[CrossRef][Medline] 8. Bilchik A, Dinome M, Saha S, et al: A prospective phase II multi-center trial evaluating staging adequacy in colon cancer: Preliminary results. 2005 Annual Scientific Session of the Western Surgical Association. 17, 2005 (abstr 1) 9. Broll R, Schauer V, Schimmelpenning H, et al: Prognostic relevance of occult tumor cells in lymph nodes of colorectal carcinomas: An immunohistochemical study. Dis Colon Rectum 40:1465-1471, 1997[CrossRef][Medline] 10. Greenson JK, Isenhart CE, Rice R, et al: Identification of occult micrometastases in pericolic lymph nodes of Duke's B colorectal cancer patients using monoclonal antibodies against cytokeratin and CC49: Correlation with long-term survival. Cancer 73:563-569, 1994[CrossRef][Medline] 11. Tschmelitsch J, Klimstra DS, Cohen AM: Lymph node micrometastases do not predict relapse in stage II colon cancer. Ann Surg Oncol 7:601-608, 2000
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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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