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10.1245/s10434-006-9120-y
Annals of Surgical Oncology 13:1386-1392 (2006)
© 2006 Society of Surgical Oncology
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Original Article

The Prognostic Effect of Micrometastases in Previously Staged Lymph Node Negative (N0) Colorectal Carcinoma: A Meta-analysis

Douglas Iddings, DO, Aziz Ahmad, MD, David Elashoff and Anton Bilchik, MD, PhD

Department of Surgical Oncology, John Wayne Cancer Institute at Saint John’s Health Center, Santa Monica, CA, USA

Correspondence: Address correspondence and reprint requests to: Anton Bilchik, MD, PhD; John Wayne Cancer Institute at Saint John’s Health Center, 2200 Santa Monica Boulevard, Santa Monica, CA 90404, USA; E-mail: bilchika{at}jwci.org


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 METHODS
 DISCUSSION
 REFERENCES
 
Background: The prognostic relevance of lymphatic micrometastases in colorectal carcinoma is unclear. To determine the prognostic significance of micrometastases in colorectal cancer, a meta-analysis was performed on all studies, which reported 3-year disease-free survival (DFS) and overall survival (OS).

Methods: Published studies selected for meta-analysis contained sufficient data from which to extrapolate estimates of 3-year DFS and/or OS. From 1991–2003, 25 studies re-examined N0 lymph nodes by serial sectioning and immunohistochemical (IHC) staining or reverse transcriptase-polymerase chain reaction (RT-PCR) assay. Eight studies (566 patients) with IHC detected micrometastases and three (173 patients) with RT-PCR micrometastases were used to determine DFS and OS. Weighted estimates of 3-year survival were combined across studies within each group, and the combined survival estimates were compared across groups using a binomial test.

Results: Micrometastases were identified in all IHC studies; upstaging, including N1, N1mi and N0(i+), was achieved in 32% (179/566 patients). All RT-PCR studies identified micro-metastases; upstaging to N0(mol+) was achieved in 37% (64/173 patients). There was a statistically significant difference in 3-year OS between RT-PCR positive N0(mol+) patients (77.8%) and those for whom micrometastases were not detected (96.6%) (P<.001).

Conclusion: The prognostic value of micrometastases detected retrospectively by RT-PCR is significant in AJCC stage II colorectal patients. Studies utilizing RT-PCR performed a more complete nodal analysis when compared to studies using IHC techniques. RT-PCR may also be more specific for the detection of clinically relevant micrometastases compared to IHC detected cytokeratins. Prospective studies are needed to evaluate the potential benefit of systemic chemotherapy in patients with molecular metastases.

Key Words: Colorectal micrometastases • Occult metastatic disease • Meta-analysis • Prognostic markers


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
METHODS
 DISCUSSION
 REFERENCES
 
Of the estimated 148,610 new cases of colorectal cancer to be diagnosed in the United States this year,1 approximately 58,000 (39%) will have histologically node-negative (N0) localized disease.2 Although patients with localized colorectal cancer [American Joint Committee on Cancer (AJCC) stage II] are potentially cured by surgical resection alone, up to 30% will develop recurrent disease and die from colon cancer.3 Since regional lymph node metastases is the most important prognostic factor in colon cancer, further pathologic investigation beyond routine histologic evaluation of the nodes may identify more patients at high risk of recurrence.

During the past 15 years, several studies have assessed the prevalence and prognostic value of lymphatic micrometastases in patients whose colorectal cancer had no evidence of nodal involvement by routine histologic assessment (N0). In all studies lymph nodes were upstaged when examined by immunohistochemistry (IHC) and serial sectioning and/or reverse transcriptase-polymerase chain reaction assay (RT-PCR). However, the influence of lymphatic micrometastases on prognosis has not been clearly established. While some studies have shown micrometastases can adversely affect outcomes, several other studies have been unable to show such a correlation.4–28 Most of these investigations were limited by small sample size and/or lack of standard technique, allowing for the possibility of under estimating micrometastases or false-positive staging based on the detection of common epithelial antigens.

To establish the prognostic value of micrometastatic lymphatic disease in patients with AJCC stage II colorectal cancer, we undertook a meta-analysis of all studies that reported survival data. Establishing prognostic factors for patients with stage II colorectal cancer is important because it can change adjuvant therapy. Currently, there is no direct evidence from randomized trials to support the routine use of adjuvant chemotherapy in stage II colon carcinoma patients. However, the significant impact of chemotherapy on stage III disease supports its consideration for use in high-risk stage II patients.29


   METHODS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
DISCUSSION
 REFERENCES
 
Data Collection
PubMed (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi) was searched for published studies (1989–2003) of nodal micrometastases and survival in patients whose colorectal cancer had been staged as N0. The search was conducted using combinations of the following key words: colorectal cancer, micrometastases, stage II, Duke’s B, immunohistochemistry (IHC), RT-PCR, disease-free survival and overall survival. Articles were obtained in full-text format and reviewed. Eligible articles were those with Kaplan–Meier survival curves or other data from which estimates of 3-year disease-free survival (DFS) and/or overall survival (OS) could be extrapolated. Exclusion criteria included lack of follow-up and/or survival data.

From articles the following data was acquired:

Total patients

Total and mean number of lymph nodes collected

Volume of lymph node analyzed

Method used to detect the micrometastases

Criteria used to define histologic micrometastases

Type of cytokeratin/antigen used for IHC or RT-PCR

Number of lymph nodes that were positive and negative for micrometastases

Number of patients found to have micrometastases

Duration of follow-up.

Statistical Analysis
Studies were grouped according to method for detection of micrometastases: histology using serial sectioning and IHC staining, or molecular techniques. Survival data was obtained either by the tumor surveillance program of the individual institution or death certificates after nodal analysis was complete. Most studies used the Kaplan–Meier method to estimate cancer-specific survival and the log-rank test to evaluate relapse-free survival rates and overall survival rates according to the presence of micrometastases.4–6,9,12,13,20,26 All studies used the Cox proportional hazards model to assess the risk ratio from several covariates. Associations between the discrete variables were commonly assessed using the {chi}2 test. Some studies assessed categorical and parametric data by the {chi}2 test and Wilcoxon’s rank-sum test, respectively.4,13,20,26 Other studies used Fisher’s exact test in combination with {chi}2 and the Wilcoxon’s test to assess categorical and parametric data. In all studies P values of <.05 were considered to indicate statistical significance.

Meta-analysis
For each type of micrometastases (IHC, RT-PCR) and each survival outcome (DFS, OS), we computed an aggregate estimate of the 3-year survival proportion based on the survival proportions in the relevant individual studies, weighted by their respective sample sizes. For example, the 3-year OS survival estimate for patients with RT-PCR evidence of nodal metastases was computed as:


Formula

where pi is the 3-year OS survival proportion in studyi and ni is the number of subjects with RT-PCR detected lymphatic micrometastases [N0(mol+)] in studyi.

Next, Fisher’s exact tests were used to compare the aggregate survival estimates between the positive and negative patients for each marker and each outcome. Since the meta-analysis format precluded access to original data, these comparisons were not adjusted for censoring.

Results
Of the 25 articles reviewed, 10 met the inclusion criteria. Fifteen articles were excluded because survival was not reported and/or data were categorized or grouped in a manner that prevented comparison with other studies. Of the 10 eligible studies, four used IHC and serial sectioning to evaluate the impact of nodal micrometastases on DFS in 236 patients, 5 used IHC with serial sectioning to evaluate OS in 372 patients (1 study contained data regarding DFS and OS with 42 patients).12 Three studies used RT-PCR to evaluate OS in 173 patients. One study evaluated 62 patients with both techniques: IHC and RT-PCR (26). All studies included a small sample size and contained ≤103 patients. Patients with stage II disease were analyzed separately when possible.

Prevalence of Colorectal Micrometastases in N0 Lymph Nodes
All studies were able to identify micrometastases after subjecting lymph nodes to greater pathologic scrutiny (Tables 1Go, 2Go). Prevalence of IHC-identified micrometastases averaged 32% (179/566 patients) and ranged between 21 and 53%, whereas the prevalence of molecular upstaging averaged 37% (64/173 patients) and ranged between 31 and 54%.


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  		TABLE 1. Individual IHC study summary
 

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  		TABLE 2. Individual RT-PCR study summary
 
Micrometastases Detected by Histology and IHC Staining
Among 236 patients from four studies (Table 3Go) mean 3-year DFS tended to be shorter when lymph nodes stained positive by IHC (76 vs. 80%), however this did not reach statistical significance. Similarly, among 372 patients from 5 studies (Table 4Go), mean 3-year OS tended to be shorter (81 vs. 83%) when IHC results were positive and also did not reach statistical significance.


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  		TABLE 3. IHC micrometastases 3-year DFS
 

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  		TABLE 4. IHC micrometastases 3-year OS
 
Although all IHC studies used serial sectioning to identify micrometastases, the sectioning technique varied. The most detailed evaluation of paraffin embedded (PE) lymph nodes examined three sections with three 4 µm slices per section, whereas other studies examined only a single 4 µm section from each lymph node. As shown in Table 1Go, the choice and number of monoclonal antibodies also varied considerably. Definitions of micrometastases ranged from "single cells or small clusters of cells with morphological appearance of epithelial cells"4 to "neoplastic (cytokeratin staining) cells alone or in clusters".13 The percentage of cases that were upstaged by the identification of isolated tumor cells only was not provided. When cell clusters were identified within the lymph nodes and used to upstage disease, the specific measurement of the cell clusters were not provided.

Micrometastases Detected by RT-PCR
Each molecular study concluded that micrometastases adversely affected outcome. A single study contained information on 3-year DFS.26 This study used RT-PCR with CEA to upstage nodal status from N0 to N0(mol+) in 19 (31%) of 62 patients. Three-year DFS was significantly shorter when patients had RT-PCR evidence of nodal metastases (78 vs. 90%; P = .027). Among 173 patients from three studies, 64 (37 %) had disease that was upstaged from N0 to N0(mol+) (Table 5Go). RT-PCR evidence of nodal micrometastases significantly decreased mean 3-year OS (78 vs. 97%; P < .001). Overall the three molecular studies examined a greater volume of the lymph nodes than did the IHC studies. Noura et al.26 extracted RNA from PE lymph node specimens. Specimens from each patient were trimmed of excess paraffin, pooled and then minced into 1 mm3 cubes.30,31 Liefers et al.27 extracted RNA from 50 µm-thick sections of the fresh frozen lymph node halves that remained after half was used for standard H&E staining.32,33 Rosenberg et al.28 used thirty 15 µm-thick cryostat sections of each fresh frozen lymph node half that remained after routine histopathology.34,35 The method of detecting micrometastases varied from using RT-PCR for amplifying CEA in two studies to using a combination of RT-PCR and IHC to evaluate cytokeratins in the third study. This study amplified CK-20 using RT-PCR and then employed histology with IHC (antibodies against CK-20) to increase the specificity and prognostic value of RT-PCR (28).


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  		TABLE 5. RT-PCR micrometastases 3-year OS
 
Limitations of Meta-Analysis
This meta-analysis and meta-analyses in general have inherent limitations.36 Several efforts were made to insure the quality of the end result. A systematic framework was used to select individual studies to minimize bias. No standard procurement, processing or reporting procedures had been established for micrometastases at the time the studies were performed; therefore, heterogeneity among trials was expected. To some extent, differences were accommodated by separating micrometastases detection techniques (IHC with serial sectioning versus RT-PCR).


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 DISCUSSION
REFERENCES
 
This is the first meta-analysis to evaluate the prognostic significance of lymph node micrometastases in patients with AJCC defined stage II (N0) colorectal cancer. Specifically, molecular techniques using RT-PCR upstaged 37% of patients from N0 to N0(mol+) and were associated with an absolute survival difference at 3 years of 18.7%. Patients with molecularly detected micrometastases (RT-PCR +) had a 78% 3-year OS while patients without molecularly detected micrometastases (RT-PCR) had a 97% 3-year survival (P<.001). Histologic techniques including serial sectioning with IHC staining were able to upstage 32% of patients from N0 to either N1, N1mi or N0(i+). Although micrometastases identified with IHC appeared to adversely affect DFS and OS the differences were not statistically significant.

Our data analysis shows that assessing previously staged N0 lymph nodes by molecular techniques can identify a subgroup of patients at greater risk for relapse. Although RT-PCR detected micrometastases clearly showed a clinically important and statistically significant difference in OS, micrometastases detected by histologic IHC methods did not. These findings are puzzling; if lymphatic micrometastases is a biologically important event that may effect prognosis, then both IHC and molecular techniques should be able to identify patients with high-risk N0 disease.

Limited nodal sampling might explain the non-significant survival impact of IHC-detected micrometastases in this meta-analysis. Inadequate lymph node sampling can underestimate lymphatic disease37–39 and may have limited the identification of clinically relevant micrometastases. Some studies evaluated a single lymph node to determine the presence or absence of micrometastases.4,13,20 One study reported that 63% of specimens contained 6 or fewer lymph nodes,20 whereas another study stated that the numbers of lymph nodes in the tissue blocks were unknown.5 Several of the studies averaged seven or fewer lymph nodes per patient.4,6,13,20 Only one study utilizing IHC to determine micrometastases averaged at least 12 lymph nodes per specimen, which is the recommended minimum to achieve adequate staging.12,40,41 By contrast, studies utilizing molecular techniques analyzed an average of 13.3 lymph nodes per specimen.26–28

Inadequate examination of individual lymph nodes might also have contributed to statistically non-significant IHC results. Criteria used to define IHC-detected micrometastases varied across histologic studies. One study examined only one 4 µm-thick section of each lymph node and considered a patient to harbor micrometastases if one positively staining cell could be identified in at least one lymph node.20 Another study defined micrometastases as "single cells or small clusters with morphological appearance of epithelial cells,"4 but not all epithelial cells that stain with anti-cytokeratin antibodies can be unequivocally defined as malignant. Only one study examined at least nine slices (3–4 µm) of each lymph node in specimens that contained on average 13 or more nodes.12 By contrast, studies that employed molecular techniques to evaluate micrometastases utilized a greater volume of the lymph node. One molecular study was able to pool all bisected nodes from each patient while the other two studies used 30 15-µm sections and multiple 50-µm sections of all the lymph nodes in each specimen to determine RT-PCR detected micrometastases.

A third potentially contributing factor might be the range of anti-cytokeratin antibodies used in IHC histology studies and that the majority of the RT-PCR studies did not use cytokeratins at all. The sensitivity and specificity of multiple cytokeratins have been discussed elsewhere, but there is no consensus regarding the optimal antigenic target for IHC staining of nodal specimens from patients with colorectal cancer. Moreover, IHC-detected cells within a node may not represent metastatic disease; hyperplastic mesothelial cells, benign epithelial cells, or tumor cells shed from the primary mass during surgical manipulation are also stained by IHC. The morphology of the epithelial cells identified must be critically evaluated for malignant features.

A final contributing factor might be the size of nodal micrometastases. If a portion of the IHC-detected micrometastases was determined to be non-malignant or isolated cells of small volume (<2 mm), this deposit could have been considered separately from larger deposits of malignant cells (i.e., N0(i+) vs. N1mi), a distinction that might improve the overall specificity. The importance of size of individual nodal metastases and the low sensitivity of H&E for identifying small metastases are underscored in the AJCC and UICC guidelines.40,41 The revised TNM guidelines define micrometastases and distinguish them from isolated tumor cells. Nodal tumor deposits are classified as macrometastases (N1: >2 mm), and micrometastases (N1mi: between 2 and 0.2 mm), whereas isolated tumor cells (N0(i+): <0.2 mm) are considered node negative. No IHC study in our analysis reported the measurement of the tumor deposit in the lymph nodes.

In summary, this meta-analysis supports the prognostic significance of micrometastases from colorectal cancer. Patients with RT-PCR evidence of micrometastases had markedly decreased survival as compared with patients without molecular micrometastases (P < .001); the variation within studies utilizing IHC methods might have masked a similar significant finding. Results from these studies underscore the need for increased standardization of lymph node harvesting and processing methodologies. It is important to recognize that lymphatic micrometastases is one potential facet of an individual patient’s multiple prognostic anatomic/pathologic parameters that could be used to determine risk of recurrence. Our analysis may help in determining whether outcome prediction and the need for adjuvant therapy can include the biologic event of lymphatic micrometastases in colorectal patients. For example, stage II patients who are truly node negative [N0(mol-)] with favorable primary tumor features may avoid chemotherapy entirely, decreasing toxicity and thus limiting over-treatment. To further determine the value of micrometastases in colorectal cancer, future prospective trials with hundreds of patients enrolled from centers with extensive experience, could examine adequate numbers (minimum of 12 lymph nodes per specimen) and adequate volumes of individual lymph nodes (5–10 4 µm sections). Perhaps molecular studies could examine larger pooled samples of all lymph nodes in a specimen when determining micrometastases. The markers utilized to identify micrometastases should ideally have a functional component (i.e.: CEA) that is specific to the malignancy. When functional markers cannot be utilized, pancytokeratin epithelial antigens (i.e.: AE1:AE3) need to be used in conjunction with close pathologic scrutiny to specifically identify micrometastases of tumor cells to avoid a false negative finding. Lymphatic mapping is an additional technique that could be used to further assist in detecting micrometastases. Although recent studies have shown there is a learning curve associated with lymphatic mapping of the colon that can limit its success,42,43 this technique can yield a single (sentinel) regional lymph node that is most likely to contain any lymphatic metastases and/or micrometastases from the primary tumor.44–46 Randomization of patients with micrometastases will then be able to establish the predictive (response to treatment) value. A large randomized multi-center controlled trial with standardized lymph node harvesting and processing methodologies would be pivotal in determining which N0 patients would benefit most from adjuvant chemotherapy.


   ACKNOWLEDGMENTS
 
Supported in part by grant CA090848 from the National Cancer Institute and by funding from the Rod Fasone Memorial Cancer Fund (Indianapolis, IN), the Henry L. Guenther Foundation (Los Angeles, CA), the William Randolph Hearst Foundation (San Francisco, CA) and the Davidow Charitable Fund (Los Angeles, CA), The Point Grey Charitable Trust, Gary Coull Trustee (Hong Kong, China), Mr. and Mrs. Sheldon E. Stunkel.


   FOOTNOTES
 
Oral presentation at the 2006 annual meeting of the Society of Surgical Oncology (SSO).

Received for publication June 4, 2006. Accepted for publication June 4, 2006.


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 INTRODUCTION
 METHODS
 DISCUSSION
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