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EDITORIALS |
From the Division of Surgical Oncology, John Wayne Cancer Institute at Saint John’s Health Center, Santa Monica, California.
Correspondence: Address correspondence to: Anton J. Bilchik, MD, John Wayne Cancer Institute, 2200 Santa Monica Boulevard, Santa Monica, CA 90404; Fax: 310-449-5261; E-mail: bilchika{at}jwci.org
In colorectal cancer, lymph node analysis is the most important factor for therapeutic decision-making because chemotherapy confers a significant survival benefit in node-positive patients.1 The role of postoperative adjuvant chemotherapy for patients without nodal metastasis is less clear; it should benefit the 30% of patients whose disease will recur but offers no apparent advantage for the 70% in whom resection is curative. Complicating the issue are the conflicting results of two large meta-analysis studies,2,3 which indicate substantial variability in the type of resection performed and hence the number of lymph nodes removed.4–7 The technique and the diligence of the pathologist also may vary. The result is that tumors may be understaged or overtreated, errors that directly impact a patient’s duration and quality of survival.
In a report to the World Congress of Gastroenterology in 1990, Fielding et al.8 recommended examination of at least 12 nodes per specimen. This recommendation was adopted by the American Joint Committee on Cancer (AJCC) and Tumor, Node, Metastasis Committee of the International Union Against Cancer.9 More recent studies have demonstrated that at least 14 lymph nodes are needed for accurate staging.10–12 The report by Joseph et al.13 in this issue of the Annals of Surgical Oncology is the largest US study to address the issue. Their analysis of 1585 patients with stage II and III colon cancer used a mathematical model to estimate the probability of correctly determining nodal status. The probability that T1/2 tumors were node negative was 25% when 18 lymph nodes were identified and 50% when 36 nodes were identified. The number of lymph nodes removed also impacted overall survival. In node-negative patients, the 5- and 8-year rates of overall survival were 100% and 92%, respectively, when more than 30 nodes were examined, compared with 80% and 72%, respectively, when fewer than 30 nodes were examined. The number of nodes needed for accurate prediction of nodal negativity was significantly higher than in other series. This provocative finding emphasizes the importance of surgical technique and suggests the limitations of current pathologic analysis.
The presentation of this article at the 2002 Annual Meeting of the Society of Surgical Oncology in Washington, DC, led to a heated debate because surgeons rarely obtain more than 35 lymph nodes in a specimen. In addition, Joseph’s group demonstrated the need to examine more lymph nodes draining T1/2 tumors than T3/4 tumors. Many surgeons do the opposite: limited resection of nodes associated with early-stage tumors and a more extensive clearance of nodes that drain advanced primaries because of the higher likelihood of nodal metastasis.
These findings raise several questions: (1) Does removing more lymph nodes impact survival or is it merely a way of identifying candidates for chemotherapy? (2) If standard colon resections are based on anatomic guidelines that provide both adequate margins and adequate regional lymph node clearance, why is there substantial variability between individual surgeons concerning the number of lymph nodes retrieved? (3) Are conventional pathologic methods adequate for evaluating lymph nodes or should alternative methods such as fat clearance and lymphatic mapping be routinely performed? (4) Is there adequate communication between the surgeon and the pathologist? It is not uncommon for a pathologist to identify several lymph nodes missed on the initial examination. (5) Is the retrieval of a small number of lymph nodes an indication for postoperative chemotherapy?
The Italian National Intergroup Study for Adjuvant Therapy on Colon Cancer14 reviewed survival data for 3648 patients with stage II and III colon cancer. Patients with fewer than seven lymph nodes retrieved from stage II colon cancer had a significantly worse survival. Although the authors recommended that these patients be considered for chemotherapy, this suggestion addresses the symptom rather than the problem, which is to increase the number of retrieved lymph nodes. One approach would be to abide more strictly by the National Cancer Institute guidelines, which state that an appropriate lymph node resection should extend to the level of the origin of the primary feeding vessel and be removed en bloc.15 The other is to develop new surgical or pathologic techniques to detect more lymph nodes.
The wide variation in lymph node retrieval clearly demonstrates that conventional methods for identifying lymph nodes are inadequate. The majority of lymph nodes containing metastatic disease are less than 5 mm in largest diameter and therefore easy to miss. Techniques such as fat clearance,16,17 cytokeratin immunohistochemistry, and multilevel step sectioning can increase the number of nodes identified and reduce sampling error. However, these techniques are too cumbersome and expensive for standard use.
Lymphatic mapping (LM) was developed to identify the sentinel lymph nodes (SNs) most likely to harbor metastases. Focused analysis of the SN has been shown to improve staging accuracy in melanoma, breast cancer, and more recently colon cancer. We recently compared nodal retrieval and nodal metastasis in patients who underwent colon resection alone (n = 370) or with LM of the SN (n = 120). All surgical procedures were performed during the same period at the same institution.18 Both the number of harvested lymph nodes and the rate of nodal metastasis were higher after LM. The sensitivity and specificity of LM have been reported by Wiese et al.,19 who documented the absence of tumor cells in multiple sections of nonsentinel nodes retrieved from specimens that contained tumor-negative SNs. Although this technique is being evaluated in a prospective trial, preliminary data suggest that it may be more practical and accurate to perform a focused analysis on the SN rather than expect the pathologist to do multiple sectioning and immunohistochemistry on more than 35 nodes.
Aside from the issue of lymph node retrieval is lymph node examination. The standard practice is to bisect a node and stain the face section with hematoxylin and eosin. Because this stained section represents less than 1% of the entire specimen, metastases, especially micrometastases, can be missed. These nodal micrometastases may have prognostic value.20 Although early retrospective studies failed to demonstrate the prognostic significance of single tumor cells by immunohistochemical methods,21 more recent reports suggest that molecular detection of tumor markers may be associated with increased recurrence and decreased overall survival.22 This suggests a need for more sophisticated analysis using immunohistochemistry and reverse transcriptase-polymerase chain reaction. The sixth edition of the AJCC Cancer Staging Manual has recently provided guidelines for the reporting of micrometastases found either by immunohistochemistry or molecular techniques.23
To maximize the number of nodes in a specimen, oncologic colon resections should be based on anatomical boundaries, margins, and vascular pedicle ligation. The surgeon should work closely with the pathologist to ensure that optimal methods are being used to identify even the smallest lymph nodes. Although this is still in the investigational stage, novel techniques such as lymphatic mapping may be extremely helpful to improve staging accuracy, identify more lymph nodes, and potentially change the margins of resection to encompass all tumor-draining lymph nodes. Ultimately, molecular markers of the primary tumor, such as K-ras, p53, and thymidylate synthase, may provide prognostic information that precludes assessment of the regional lymph nodes; however, at the present time the AJCC recommends that these markers be used only in the setting of clinical trials.23 Until multicenter prospective data demonstrate that molecular profiling of the primary tumor is prognostic, therapeutic decisions should be based on lymph node analysis.
Received for publication February 3, 2003. Accepted for publication February 7, 2003.
REFERENCES
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  V. Lemmens, I van Lijnschoten, M. Janssen-Heijnen, H. Rutten, C. Verheij, and J-W. Coebergh Pathology practice patterns affect lymph node evaluation and outcome of colon cancer: a population-based study Ann. Onc., December 1, 2006; 17(12): 1803 - 1809. [Abstract] [Full Text] [PDF]
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 N. N. Baxter, D. J. Virnig, D. A. Rothenberger, A. M. Morris, J. Jessurun, and B. A. Virnig Lymph Node Evaluation in Colorectal Cancer Patients: A Population-Based Study J Natl Cancer Inst, February 2, 2005; 97(3): 219 - 225. [Abstract] [Full Text] [PDF]
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 J. S. Spratt Prognosis With Colon Cancer Improves With Wide Resection of the Mesentery to Include Many Lymph Nodes Ann. Surg. Oncol., July 1, 2003; 10(6): 711 - 711. [Full Text] [PDF]
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