The terms "micrometastasis" and "macrometastasis" were originally defined to be metastatic deposits of breast carcinoma cells that measured less than or greater than 2 mm, respectively (14
). However, the 6th edition of the AJCC (American Joint Committee on Cancer) Cancer Staging Manual has recently recommended that minute amounts of metastatic tumor cells should be classified as micrometastases or isolated tumor cells (ITCs) based on their dimensions, i.e., ITCs are classified as single tumor cells or cell clusters measuring <0.2 mm, and micrometastases are classified as clusters of cells measuring >0.2 mm, but <2.0 mm (15
). Moreover, although the presence of LN micrometastases in CRC patients has previously been investigated, no consensus has been reached regarding its prognostic significance. The previously reported results are barely comparable because they differ with regard to the clinicopathologic parameters and the methodologies that were used, and the previous studies usually included both colon and rectal cancer, which do not have the same prognosis.
Special techniques such as IHC or reverse transcriptase polymerase chain reaction (RT-PCR) can be used to identify the micrometastases within LNs that are not detectable by conventional H-E staining. Several studies have employed IHC with using monoclonal antibodies directed against carcinoembryonic antigen (CEA), epithelial membrane antigen (EMA) or cytokeratin (CK). O'Brien et al. (16
) reported that although LN micrometastases may be more easily detected by performing IHC for CEA, the screening of H-E stained sections by a competent pathologist appeared to be equally sensitive. Davidson et al. (6
) found that among 200 LNs reported as being free of tumor deposits by H-E, micrometastasis was only found in one LN by performing IHC for CEA and EMA, and these researchers suggested that performing routine IHC of the LN sections in conjunction with H-E was unhelpful. Adell et al. (4
) re-examined regional LNs with using monoclonal antibodies against CK, and they detected micrometastases in 39% of the patients, but these patients' outcomes were not significantly different from those patients with negative LNs. In contrast, Greenson et al. (7
) reported that CK staining revealed occult metastases in 5.8% of the examined nodes, and they found that CK-positive cells within the LNs were correlated with a significantly poorer prognosis. Consequently, they recommended CK staining of the pericolic LNs in patients with Dukes' B colorectal carcinoma. Moreover, Sasaki et al. (17
) detected LN micrometastases in 38% of the Dukes' A and B patients with recurrent disease, which was significantly greater than in those patients without recurrent disease (13%).
In the present study, occult cancer cells in the previously considered negative LNs were detected by H-E staining in 5.0% of the patients, and these patients were consequently restaged as pN1. However, the disease-free and overall survival rates of the restaged pN1 patients on univariate analysis were not significantly different from those of the pN0 patients. Significant correlations between the presence of occult tumor cells and survival have been reported by some studies (7
), whereas others have failed to demonstrate this correlation (4
). However, the previous studies that used only 1 section per lymph node detected micrometastases at rates ranging from 4% to 31% (5
), whereas other studies that used 2 or more sections per lymph node showed higher rates that ranged from 76% to 100% (17
). Noura et al. (11
) demonstrated that the rate of detecting LN micrometastases increases as the slice number is increased from 1 to 2 to 5.
However, the prognostic significance of the LN micrometastases that are detected by IHC in colorectal cancer patients is controversial. In contrast, based on the findings obtained with using molecular genetic techniques, some investigators have suggested there is a positive correlation between the presence of micrometastases and a poor prognosis in patients with nodenegative colorectal cancer (19
). RT-PCR has the advantage of allowing large numbers of LNs to be processed. However, it is unclear whether RT-PCR is more useful for detecting of micrometastases than IHC, and furthermore, its prognostic significance has not been established (22
In the present study, all the occult tumor cells detected on IHC were confirmed by performing examinations of the corresponding H-E re-stained sections. As many as 70% of the tumor-positive LNs have been reported to contain metastases of <0.5 cm in diameter (23
), and these metastases can not be seen or felt by a surgeon or a pathologist, and they might also be missed during conventional pathologic dissection and H-E staining. Using multiple step sections for IHC can improve the staging accuracy, but this process is labor intensive and the cost of examining the slides corresponding to a whole LN is prohibitive.
However, the microscopic examinations involving only one histologic section of a LN are clearly inadequate for the detection of micrometastases and also possibly for the detection of macrometastases. In the present study, macrometastases were detected in 5 of the LNs with occult tumor cells.
It is also important to recognize that patients may be at a high risk of recurrence regardless of micrometastatic involvement. A poorly differentiated tumor, lymphatic and venous invasion, extension to adjacent organs and inadequate regional LN retrieval all have adverse effects, and those patients with such features should be recommended for adjuvant treatment (24
). The National Cancer Institute recommends that a minimum of 12 LNs should be assessed when staging a patient with colorectal cancer (25
). In the present study, 20 (12.5%) patients developed disease recurrence and 14 (8.8%) patients finally succumbed to colon cancer. Retrieval of less than 12 LNs and the presence of lymphatic invasion were significantly associated with poor overall survival. Furthermore, retrieval of fewer than 12 LNs was found to be significantly associated with shorter disease-free survival.