Sentinel node biopsy in colorectal cancer: Must we believe it?

Abstract

Lymph node metastasis predicts survival and recurrence in colon cancer (CC), so decisions regarding adjuvant therapy are largely based on nodal status. Chemotherapy is not a routine treatment for node-negative CC because its toxicity and expense exceed its limited benefit in patients without evidence of nodal involvement. The sentinel lymph node (SLN) procedure is a selective sampling technique that can be used to ultrastage regional nodes. The real problem of SLN biopsy in CC is the procedure sensitivity rate. In future, studies concerning SLNs will have to consider issues such as the role of laparoscopy in colorectal resection (which cause technical difficulties in identification of SLNs) and the risk of overstaging of illness as well as the need to exclude T4 CC and, probably, rectal cancer from the studies. Is this the future of correct staging of colorectal cancer? Lymphadenectomy is at the present an integral part of colorectal surgery and surgeons must perform it correctly to improve their results. Nevertheless, for the future another “staging system” is necessary in colorectal cancer which takes into account biologic aspects of the tumor to identify patients with aggresive illness in order to treat them with more effective and less toxic therapies.

The sentinel lymph node (SLN) procedure is a selective sampling technique that can be used to ultrastage regional nodes. We analyse the feasibility of this technique and its clinical impact for improving the accuracy of staging and selecting patients eligible for adiuvant treatment.

The well-established concept of 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]. For colorectal cancer, the principal advantage of SLN sampling is improvement in the accuracy and ease of determination of lymph node status after resection.

Lymph node metastasis predicts survival and recurrence in colon cancer (CC)[2], so decisions regarding adjuvant therapy are largely based on nodal status. Chemotherapy is not a routine treatment for node-negative CC because its toxicity and expense exceed its limited benefit in patients without evidence of nodal involvement. However, 25% of patients with node-negative CC will develop disease recurrence after surgical resection alone. This suggests the inadequacy of the tumor staging system or the staging technique. The SLN procedure is a selective sampling technique that can be used to ultrastage regional nodes. The SLNs are the first nodes to receive lymphatic drainage from a primary tumor and thus the most likely nodal site of metastasis. Mapping, dissection, and focused examination of SLNs can identify occult nodal metastases that may increase the risk of recurrence. The tumor status of the SLN does not change the extent of resection because en bloc resection of the primary CC includes regional lymph nodes. However, results of SLN-based nodal ultrastaging can improve identification of candidates for adjuvant therapy of CC, a treatment that is highly effective for metastatic disease but too toxic and expensive for routine use in node-negative CC[3].

Nodes in a resected specimen have traditionally been identified by a combination of visualization and palpation on gross pathologic examination. However, simply removing and examining all palpable lymph nodes[4] is an inadequate method because metastasis frequently targets nodes < 0.5 cm in diameter[5]. The thoroughness of the lymph node harvest from the resection specimen and the number of nodes examined have been stressed by most authors. Joseph et al[6] suggested 40 nodes as a minimum for accurate assessment. At the other end of the spectrum is an increasingly popular selective sampling approach based on identification of the SN. Thus, the SN can be identified either before (in vivo mapping) or after (ex vivo mapping) the tumor has been resected. As in melanoma and breast cancer, blue dyes and/or radioactive colloids are used as mapping agents.

However, even when a node is selectively targeted for assessment, metastases may go undetected. Indeed, standard assessment based on hematoxylin and eosin staining of one level of a paraffin-embedded block reportedly can miss as many as 33% of metastases[7]. Techniques such as multilevel sectioning, cytokeratin immunohistochemistry (IHC), and reverse transcription-polymerase chain reaction can identify missed tumor cells in nodes[8], although their impact on staging is unclear[9].

The real problem of SLN biopsy in CC is the procedure sensitivity rate. However, some surgeons have shown the SLN technique to be nearly as sensitive for CC as it is for melanoma and breast cancer[10]. Failure to identify tumor-containing SLNs can be attributed to a surgeon’s lack of experience with the procedure, lack of standardized tissue processing in the pathology department, variations in surgical technique, and aberrant lymphatic drainage because of occlusion of the lymph channel by the tumor. Bembenek et al[11] recently reported that the accuracy of SLN recovery increases with experience in the procedure. This learning curve is similar to that described for SLN biopsy in breast cancer and melanoma, where 20 to 30 SLN procedures are required for adequate sensitivity and accuracy[12,13]. In the prospective randomized trial reported by Stojadinovic et al [14] participating surgeons demonstrated technical proficiency with the SLN procedure by completing 6 to 12 learning cases before enrolling patients.

Standardization of the SLN procedure through surgical experience should be accompanied by standardization of the pathologic analysis; this includes standardized processing of SLNs marked by the surgeon and routine assessment of the en bloc specimen for any additional SLNs. The number of SLNs and non-SLNs should be recorded. All SLNs should be permanently fixed and embedded in paraffin; multiple thin sections of each SLN found to be negative by HE should be examined by IHC[15].

Even though the SLNs-procedure has rarely been adopted by surgeons, lymphatic mapping and focused analysis of the SLN in CC should not be abandoned. Although the natural history of micrometastases and isolated tumor cells in CC is not defined, SLN biopsy and analysis provide the most effective means of identifying micrometastases so that the clinical significance of these tumor foci can be further studied. The importance of further investigation is indicated by a paradox in the current CC staging guidelines from the American Joint Committee on Cancer (AJCC): patients classified as stage IIb disease with conventional staging have a poorer prognosis than patients with stage IIIa disease[16]. This paradox reflects the fact that chemotherapy is not routine for stage II disease. If the 25% rate of recurrence for stage I and II CC corresponds to a 25% rate of understaging, then many of these patients might benefit from adjuvant therapy if they can be accurately identified. The SLN procedure has a role in improving the identification of candidates for chemotherapy by identifying patients whose SLNs contain IHC evidence of micrometastasis. Although the importance of these micrometastases has yet to be fully understood, they are included in the current AJCC staging classification[17].

Although the SLN procedure remains investigational in CC, its potential for improving the accuracy of staging merits a concerted effort to standardize its surgical and pathologic aspects. It is quite possible that widespread application of a standardized SLN procedure for CC will eventually improve the prognostic classification of patients with stage II disease and micrometastases.

In the future, studies concerning SLNs will have to consider issues such as the role of laparoscopy in colorectal resection (which cause technical difficulties in identification of SLNs), the risk of overstaging of illness as well as the need to exclude T4 CC and, probably, rectal cancer from the studies.

Is this the future of correct staging of colorectal cancer? The lymphadenectomy is at the present an integral part of colorectal surgery and surgeons must perform it correctly to improve their results. Nevertheless for the future another “staging system” is necessary in colorectal cancer, which takes into account biologic aspects of the tumor to identify patients with aggresive illness in order to treat with more effective and less toxic therapies.