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The Sentinel Node in Colorectal Carcinoma

The Sentinel Node in Colorectal Carcinoma

ABSTRACT: One of the most important prognostic factors in colorectal cancer is the presence or absence of regional lymph node metastases. In many instances, micrometastatic disease may not be found on routine pathologic analysis using hematoxylin and eosin staining, but may be discovered only with immunohistochemical methods or polymerase chain reaction assay. Lymphoscintigraphy with biopsy of the sentinel nodes, defined as the first nodal basin in the drainage pathway of a tumor, was developed to provide accurate staging without the morbidity associated with the classic lymph node dissections performed for melanoma or breast cancer. This concept has recently been applied to colorectal cancers, but the method used is unique because oncologic principles of resection are still adhered to for the primary tumor along with en bloc resection of the locoregional mesenteric nodes, some of which are sentinel nodes. Sentinel nodes are ideal for sensitive pathologic techniques of detecting micrometastatic disease, as they often reflect the status of the entire locoregional nodal basin. Gross metastatic nodes reveal significant prognostic information and guide the use of adjuvant therapy in affected patients. However, the detection of micrometastatic disease in sentinel nodes by sensitive pathologic methods has not been proven to result in poor prognosis or benefit from adjuvant therapy for colorectal cancer. [ONCOLOGY 16:567-585, 2002]

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.[1] 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%.[2] The involvement of regional
mesenteric lymph nodes indicates stage III disease, for which the 5-year
survival rate drops dramatically to 50% or 40%.[2]

In a randomized controlled trial, adjuvant chemotherapy with 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.[3] 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.

The Sentinel Node

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.[10] 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,[12] 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.[13]

Another approach has been to use radioactive-labeled substances such as
technetium (Tc)-99m-labeled 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.[16] 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.[17]

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%.[6] 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 nodes—for example, the sentinel nodes in colorectal cancer—were
identified and evaluated for micrometastases.

Intraoperative Techniques

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.[20] 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.[21]

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.[24]

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