Colorectal carcinoma is the most common cancer of the gastrointestinal tract, with over 148,000 cases diagnosed and 56,000 deaths occurring annually in the United States. For carcinomas of the colon and rectum, one of the most important prognostic factors is tumor stage. Management of colon carcinoma in patients with resectable disease involves surgery. Patients with stage I and II histologic node-negative disease have 5-year survival rates ranging from 80% to 90%. The involvement of regional mesenteric lymph nodes indicates stage III disease, for which the 5-year survival rate drops dramatically to 50% or 40%.
In a randomized controlled trial, adjuvant chemotherapy with fluorouracil(Drug information on fluorouracil) (5-FU) and leucovorin in stage III and high-risk stage II colon cancer patients resulted in a 5-year survival rate of 74% vs 63% for patients treated only with surgery. Improved survival in stage III colon cancer patients receiving adjuvant treatment has been confirmed by other studies.[4,5] Therefore, accurate pathologic staging is of the utmost importance.
A key problem in pathologic nodal evaluation is that small lymph nodes may be missed on gross inspection.[6,7] In addition, microscopic cancerous deposits may be overlooked on routine hematoxylin and eosin (H&E) staining. Either of these problems can result in understaging,[8,9] which may leave a significant portion of patients without the potential benefit of adjuvant chemotherapy. More sensitive methods of tissue analysis, including polymerase chain reaction (PCR) and immunohistochemistry, could potentially increase the accuracy of tumor staging.
Regional lymph nodes are routinely removed in the surgical management of epithelioid neoplasms in order to stage the disease and assess prognosis. These resections are also helpful in deciding on appropriate adjuvant therapy. However, regional lymphadenectomy for breast cancer and melanoma is associated with well-known morbidities such as lymphedema and nerve injury. Early-stage cancer tends to present with a low incidence of regional lymph node metastasis; thus, regional lymphadenectomy for staging often reveals lymph nodes without histologic evidence of metastasis. A new method of accurately staging the regional nodes without removing the entire lymph node basin was therefore developed.
The sentinel lymph nodes are defined as the first node or nodes in the initial drainage pathway of a tumor, where metastases are most likely to occur. This concept originated with the lymphangiogram studies conducted in the 1960s and 1970s in an attempt to select patients who would benefit from an extended lymph node dissection.[10,11] The strategy was popularized by Morton and colleagues, who used isosulfan blue dye injections to track the drainage pattern of early-stage melanomas and find the sentinel nodes. The procedure was later applied successfully to breast cancer by Giuliano and colleagues.
Another approach has been to use radioactive-labeled substances such as technetium (Tc)-99m-labeled sulfur(Drug information on sulfur) colloid with preoperative gamma camera imaging and intraoperative gamma probes to aid in localizing sentinel nodes.[14,15] A recently completed multicenter trial supports routine use of sentinel node mapping and biopsy in melanoma. Other trials such as the American College of Surgeons Oncology Group Z0010 Breast Sentinel Node Trial and the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-32 Breast Sentinel Node Trial are exploring the clinical importance of this technique in carcinoma of the breast. In addition, the sentinel node concept has been extended to tumors in a variety of other sites including the head and neck, thyroid, female organs, and gastrointestinal tract.
Sentinel Node in Colorectal Cancer
Investigators recently began applying the sentinel node concept to colorectal cancer, for which a unique form of this technique is used. Removal of mesenteric lymph nodes is a routine component of colorectal cancer resection because regional lymph nodes provide staging information and define adjuvant treatment. However, among patients with stage II histologic node-negative disease, 5-year survival may be as low as 45%. Perhaps in a portion of these cases, micrometastases were present at the time of surgical resection and were simply missed. This may occur because the average number of nodes found by standard node dissection varies, ranging from 8 to 17 nodes in several reports.[18,19]
Multiple factors account for this variability, including the techniques used for gross inspection of lymph nodes, a history of prior radiation therapy, and the amount of tissue obtained for assessment. Extensive pathologic evaluations of every single node would be too time-consuming and generally not feasible. Such evaluations would be more appropriate if only a single node or a small number of nodesfor example, the sentinel nodes in colorectal cancerwere identified and evaluated for micrometastases.
Attempts to improve tumor staging in colorectal carcinoma have included the use of monoclonal antibodies targeted to antigens expressed by tumor cells such as carcinoembryonic antigen (CEA). These antibodies are labeled with radioactive compounds and injected intravenously several days prior to surgery. An intraoperative gamma probe then scans the pre- and postresection areas that are suspicious for tumor, including the regional and periaortic lymph nodes.
This method, called radioimmunoguided surgery, may be helpful in detecting regional metastatic disease that is not obvious by imaging methods and intraoperative inspection. It may also aid in assessing the presence of residual disease after surgical resection, thus providing prognostic information regarding risk of tumor recurrence. Drawbacks associated with this technique include its ineffectiveness in detecting neoplastic cells that do not express the antigen selected, imprecise localization of tumors with extensive necrosis, and uptake of the radioactive compound by organs without tumor.
Localization of sentinel nodes in colorectal carcinoma is achieved using a colored dye such as isosulfan blue (Lymphazurin), which was used by Morton and colleagues in their elegant study in melanoma patients.[10,12] The colorectal tumor is located intraoperatively, and 1 to 2 mL of the dye is injected subserosally into the peritumoral area so that it can reach the draining lymphatics (Figure 1). These lymphatic channels and pericolonic nodes are often visualized within minutes with blue stain (Figure 2). Nodes near the tumor vicinity that first absorb the blue color are marked with sutures on the mesentery because the dye could "wash out" after several minutes. The entire resected specimen is sent for pathologic examination.[22,23] Occasionally, the pathologist may identify a second set of blue nodes that was not initially visualized by the surgeon.
Isosulfan blue dye has also been injected subserosally at the tumor site after resection of the colorectal tumor and mesentery (ex vivo). This technique can only be used with visceral malignancies such as colorectal cancers because the bowel segment containing the primary tumor and the mesenteric nodes is resected en bloc.