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Annals of Surgical Oncology 8:300-304 (2001)
© 2001 Society of Surgical Oncology

ORIGINAL ARTICLES

Pattern of Lymph Node Micrometastasis and Prognosis of Patients with Colorectal Cancer

Kazuhiro Yasuda, MD, Yosuke Adachi, MD, Norio Shiraishi, MD, Kimio Yamaguchi, MD, Yasuhiro Hirabayashi, MD and Seigo Kitano, MD

From the Department of Surgery I, Oita Medical University,Oita, Japan.

Correspondence: Address correspondence and reprint requests to: Kazuhiro Yasuda, MD, Department of Surgery I, Oita Medical University, 1-1 Idaigaoka, Hasama-machi, Oita 879-5593, Japan; Fax: 81-97-549-6039.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: Studies of lymph node micrometastases in patients with colorectal cancer have ignored the prognostic significance of the number and level of lymph node micrometastases. The aim of this study was to clarify the prognostic significance of the status of lymph node micrometastases in histologically node-negative colorectal cancer.

Methods: We used immunohistochemistry with anti-cytokeratin antibody CAM5.2 to examine 1013 lymph nodes in 42 patients (12 recurrent and 30 nonrecurrent) with histologically determined Dukes’ B colorectal cancer. Five serial 6-µm sections were used for immunohistochemical staining. The frequency, tumor cell pattern, and number and level of lymph node micrometastases were compared between the recurrent and nonrecurrent groups.

Results: Micrometastasis was confirmed in 16% (59/373) of lymph nodes in the recurrent group and 12% (77/640) of lymph nodes in the nonrecurrent group, and the frequency of lymph node micrometastases was 92% (11/12) in the recurrent group and 70% (21/30) in the nonrecurrent group. The tumor cell pattern in the metastatic lymph nodes was similar in the recurrent and nonrecurrent groups. Micrometastasis in four or more lymph nodes occurred more frequently in the recurrent group than in the nonrecurrent group (58% vs. 20%, P < .05), and micrometastasis to N2 or higher nodes occurred more frequently in the recurrent group than in the nonrecurrent group (92% vs. 47%, P < .01).

Conclusions: The number and level of positive micrometastatic lymph nodes was significantly correlated with postoperative recurrence of histologically determined Dukes’ B colorectal cancer. This parameter is a useful prognostic indicator in histologically node-negative colorectal cancer and is helpful in planning adjuvant chemotherapy.

Key Words: Colorectal cancer • Lymph node micrometastasis • Micrometastasis • Immunohistochemistry • Cytokeratin • Prognosis


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Among clinicopathologic parameters related to the prognosis of patients with colorectal cancer, histologically determined depth of tumor invasion and status of lymph node metastasis are the most important.1–4 Some patients without lymph node metastasis have postoperative recurrences or develop metastases.4–6 Lymph node micrometastasis is associated with these recurrences and metastases.

Lymph node micrometastases, characterized by single cells and small clusters of tumor cells, are easily detected using immunohistochemical techniques.7–9 Most studies of lymph node micrometastasis in colorectal cancer report that lymph node micrometastasis has no prognostic significance for patients with histologically node-negative colorectal cancer.10–14 The relation between lymph node micrometastases patterns and the prognosis of patients has not been investigated.

To explain the clinical significance of micrometastasis in the lymph nodes of patients with colorectal cancer, we investigated the frequency, tumor cell pattern, and number and level of micrometastasis. The prognostic value of lymph node micrometastasis was assessed in patients with histologically determined Dukes’ B colorectal cancer.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Forty-four patients with histologically node-negative, Dukes’ B, colorectal cancer were studied. Patients had no liver metastasis and no invasion to the adjacent organ, and they underwent curative resection in the Department of Surgery I, Oita Medical University, between 1984 and 1992.

The age and sex of patients, tumor size, histologic type, lymphatic and venous invasions, and depth of wall invasion were obtained from histopathology reports. Clinicopathological findings were determined with the general rules for clinical and pathological cancer studies of the colon, rectum, and anus outlined by the Japanese Society for Cancer of the Colon and Rectum.15 The levels of lymph node metastasis were divided into four groups according to anatomical distribution: N1 included paracolic nodes within 5 cm of a colon cancer margin and pararectal nodes within 2 cm of a rectal cancer margin; N2 included paracolic nodes between 5 cm and 10 cm of a colon cancer margin, pararectal nodes between 2 cm and 4 cm of a rectal cancer margin, and intermediate nodes along the main vessels; N3 included nodes at the root of main vessels; and N4 included paraaortic lymph nodes.15

Immunohistochemical Staining
Primary tumors and lymph nodes were fixed in 10% formalin solution and embedded in paraffin. One 3-µm section was cut for hematoxylin and eosin staining, and five serial 6-µm sections were cut for immunohistochemical staining with mouse monoclonal antihuman cytokeratin antibody (CAM 5.2; Becton Dickinson, San Jose, CA). CAM 5.2 specifically recognizes cytokeratins 8 and 18.16 Immunohistochemical staining was performed with the streptavidin-biotin immunoperoxidase procedure (Histofine SAB-PO kit; Nichirei Corporation, Tokyo, Japan). After deparaffinization and rehydration, sections were trypsinized with 0.1% calcium chloride solution at 37°C for 20 minutes, and 10% normal rabbit serum was applied for 20 minutes to block nonspecific reactions. Sections were first incubated overnight in CAM 5.2 diluted 1:5 at 4°C, then in biotinylated rabbit anti-mouse immunoglobulin for 30 minutes, and finally in streptavidin-peroxidase for 10 minutes. Each step was separated by careful washing in phosphate-buffered saline. Hematoxylin and eosin staining showed that two patients had lymph node metastasis, and they were excluded.

Follow-up and Statistics
For follow-up study, death due to recurrence was confirmed by medical charts and death certificates. Statistical analyses were performed with the {chi}2 test and Student’s t-test. P values < .05 were considered statistically significant. Survival rates were calculated with the Kaplan-Meier method, and the difference was evaluated by the generalized Wilcoxon test.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
We examined 1013 lymph nodes from 42 patients with Dukes’ B colorectal cancer. The number of lymph nodes per patient ranged from 3 to 94 with a median of 18 and a mean of 24. CAM 5.2-positive tumor cells were found as single cells and small clusters of cells and were detected mostly in the peripheral sinuses of the lymph nodes (Figs. 1 and 2). Of 12 patients with recurrences, 7 had liver metastasis, 2 had lymph node metastasis, 2 had local recurrence, and 1 had lung metastasis. Thirty patients had no recurrences for over 5 years.



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  		FIG. 1. A single tumor cell stained with CAM5.2 in the peripheral sinus of a lymph node (original magnification, x50).

 


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  		FIG. 2. Small cluster of tumor cells in the peripheral sinus of a lymph node. (A) hematoxylin and eosin stain, and (B) CAM5.2 stain (original magnification, x50).

 
Table 1 shows the clinicopathologic findings of the recurrent and nonrecurrent groups. No significant differences existed in tumor size, histologic type, lymphatic and venous invasions, and depth of wall invasion.


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  		TABLE 1. Clinicopathologic parameters
 
Micrometastasis was found in 59 of 373 lymph nodes in the recurrent group (16%) and in 77 of 640 lymph nodes in the nonrecurrent group (12%). The frequency of lymph node micrometastases was 92% (11/12) in the recurrent group and 70% (21/30) in the nonrecurrent group (Table 2). The tumor cell pattern in the micrometastatic lymph nodes was similar in the recurrent and nonrecurrent groups. The frequency of micrometastasis found in four or more lymph nodes was significantly greater for the recurrent group (58%) than for the nonrecurrent group (20%) (P < .05), and the frequency of micrometastasis found in the N2 and higher nodes was significantly greater for the recurrent group (92%) than for the nonrecurrent group (47%) (P < .01).


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  		TABLE 2. Micrometastases in the lymph nodes
 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
In the present study, we explored the prognostic significance of the status of micrometastasis in the lymph nodes of histologically node-negative colorectal cancer. In patients with Dukes’ B colorectal cancer, recurrence was predicted by the number and level of micrometastases in the regional lymph nodes. The prognostic value of the number and level of metastases histologically determined by hematoxylin and eosin stains is well established.17–21 In previous studies, the 5-year survival rate significantly decreased when the number of positive lymph nodes exceeded 3.17–20 The level of lymph node metastasis was closely correlated with 5-year survival rate; 72–85% for N1, 51–67% for N2, and 30–56% for N3.17,20,21 In our present study, the micrometastasis of four or more lymph nodes and that of N2 and higher level of lymph nodes were significantly correlated with postoperative recurrence and prognosis of histologically node-negative colorectal cancer (Figs. 3 and 4). A multivariate analysis based on nine clinicopathologic factors including the status of micrometastasis revealed that the level of micrometastasis in the lymph nodes was the strongest parameter correlating with the survival (P = .0999).



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  		FIG. 3. Survival curves for 42 patients with Dukes’ B colorectal cancer according to the number of positive micrometastatic lymph nodes. The 5-year survival rate was significantly higher for patients with 0–3 micrometastases than for those with 4 or more micrometastases (90% vs. 50%, P < .01).

 


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  		FIG. 4. Survival curves for 42 patients with Dukes’ B colorectal cancer according to the level of positive micrometastatic lymph nodes. The 5-year survival rate was significantly higher for patients with N0 or N1 micrometastasis than for those with N2–N4 micrometastasis (94% vs. 68%, P < .05).

 
Previous studies demonstrated that the presence of lymph node micrometastasis in patients with colorectal cancer did not influence patient prognosis.10–14 Broll et al.14 showed that there were no significant differences in disease-free survival rates between micrometastatic tumor-cell negative and positive groups for stage I/II colorectal cancer patients. Another report did not find a significant relation between 10-year survival rates and number/pattern of lymph node micrometastasis in Dukes’ B colorectal cancer.11 In contrast, Greenson et al.22 found that lymph node micrometastasis was correlated with a poor prognosis for patients with Dukes’ B colorectal cancer. In similar findings from another report, patients with micrometastasis in N3 or N4 lymph nodes had a high risk for recurrence.23 The micrometastasis detection frequency increases in proportion to the total thickness and number of cut sections examined. In previous studies, the total thickness of examined sections was from 4 to 9 µm.10–14,22 Sasaki et al.24 found that the detection frequency of lymph node micrometastasis was maximal when examining a total thickness of 27 µm. We examined five sections with a total thickness of 30 µm, and the frequency of lymph node micrometastasis was high in both the recurrent and nonrecurrent groups.

A small quantity of micrometastatic tumor cells presumably can be destroyed by host immunoreaction and can not develop metastatic foci.10,11 Adell et al.13 demonstrated that an increasing number of micrometastatic cancer cells was associated with increased degree of poor prognosis. The number of lymph nodes with micrometastasis is important for estimating patient outcomes.

In our study, there was no significant relation between the presence of recurrence and clinicopathologic features, including tumor size, histological type, and lymphatic and venous invasions. We recommend immunohistochemical examination with antibodies against cytokeratins for the detection of micrometastasis in the dissected lymph nodes of Dukes’ B colorectal cancer. When extended micrometastasis is detected by immunohistochemical study, adjuvant chemotherapy should be administered even after radical surgery.

In conclusion, the micrometastatic involvement of four or more lymph nodes and that of N2 and higher lymph nodes are useful indicators of recurrence in patients with histologically Dukes’ B colorectal cancer. Further prospective studies, including a larger number of patients, are needed to confirm the prognostic significance.

Received for publication September 20, 2000. Accepted for publication November 1, 2000.


   REFERENCES
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 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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