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© 2002 American Society for Clinical Oncology Volume of Lymphatic Metastases Does Not Independently Influence Prognosis in Colorectal CancerByFrom the Departments of Surgery and Pathology, University of Hawaii School of Medicine, Honolulu, HI; and Department of Surgery, Harbor–University of California Los Angeles Medical Center, Torrance, CA. Address reprint requests to Jan H. Wong, MD, Department of Surgery, 1356 Lusitana St, 6th Floor, Honolulu, HI 96813; email: wongj{at}hawaii.edu
PURPOSE: To evaluate the prognostic relevance of the volume of nodal metastatic disease in colorectal cancer patients. PATIENTS AND METHODS: One hundred node-positive patients with T2 or T3 carcinoma of the colon or rectum after routine histologic examination of the regional nodes were studied. The metastatic tumor was measured with an ocular micrometer, and the tumor volume was determined. RESULTS: The mean lymph node metastatic tumor volume was 5.1 ± 4.99 mm3 (range, 0.05 to 83,434 mm3). There was only a weak positive correlation with number of nodes involved with metastatic disease and tumor volume in nodes (r = .45). Median follow-up was 39 months (range, 1 to 87 months). The number of nodes was highly predictive of outcome. Individuals with one to three positive nodes had a substantially better survival than individuals with four or more positive nodes (P < .001). The volume of nodal metastatic disease correlated with outcome (P = .019). Patients dying as a result of disease had substantially greater mean metastatic nodal volume than those who were alive (3,705 v 1,783 mm3; P = .036). However, the total metastatic nodal volume did not, independent of positive nodes or number of positive nodes, predict outcome. Individuals with micrometastatic nodal volume did not have improved survival when compared with individuals with macrometastatic nodal volume (P = .79). CONCLUSION: The number of nodes involved with metastatic tumor, rather the volume of metastatic involvement of the regional lymph nodes, predicts outcome. These results suggest that micrometastatic disease may have a similar prognosis as macrometastatic disease when the same number of lymph nodes are involved with metastatic tumor.
THE MOST IMPORTANT prognotic factor in apparently localized carcinoma of the colon and rectum is the presence or absence of metastatic disease in the regional lymph nodes. Patients with nodal metastases have a significantly worse outcome than individuals whose disease is confined to the bowel wall. However, node-positive colorectal cancer represents a spectrum of disease. Individuals with minimal nodal involvement, as determined by the number of regional nodes involved with metastatic disease, do better than individuals with more extensive regional node disease.1 A novel approach to identifying regional nodes at greatest risk for harboring metastatic disease in cutaneous melanoma2,3 and breast cancer4 has been described. This operative approach, termed selective lymphadenectomy, is proving to be a cost-effective approach to more thoroughly analyze regional lymph nodes at the greatest risk for harboring metastatic disease.5 This approach has resulted in the identification of occult micrometastatic disease in a substantial number of individuals who otherwise might not have been identified by routine histologic analysis.6 However, the identification of occult micrometastatic disease has raised the issue of the biologic and clinical relevance of these findings. A number of retrospective studies in melanoma,7 breast cancer,8 and colorectal cancer9,10 have suggested that the detection of occult micrometastases in regional lymph nodes is prognostically relevant. In colorectal cancer, this remains controversial.11-13 It might be reasonable to assume that micrometastatic deposits of tumor cells identified in regional lymph nodes represent a metastatic phenotype that is identical to the metastatic phenotype of macrometastatic nodal involvement, and, therefore, the extent of metastatic involvement may not be relevant. However, it is apparent that the metastatic tumor burden, as reflected by the number of tumor-positive nodes, correlates with outcome. Patients with more tumor positive nodes have a worse prognosis than individuals with fewer tumor-positive nodes.1 Although the number of nodes involved with metastatic tumor is directly related to the extent of metastatic disease identified, some patients may have extensive nodal involvement of only a few nodes, whereas others might have multiple nodes involved with only minimal replacement of the node with metastatic disease. We sought to address whether direct measurement of tumor involvement might add to the prognostic value of regional node staging. This article examines whether the volume of tumor present in regional lymph nodes improves the prognostic value of identifying tumor dissemination in regional lymph nodes.
Patients From January 1992 to December 1996, 239 patients with T2 or T3 carcinoma of the colon and rectum underwent curative resection. Of these 239 patients, 100 individuals were found to be node-positive by routine hematoxylin and eosin staining, and these form the study group. These patients had a mean age of 65 years (range, 37 to 93 years). There were 45 men and 55 women. In our institution, all node-positive patients, unless this was contraindicated by comorbidities, have been routinely treated with adjuvant systemic therapy, usually fluorouracil with levamisole14 or leucovorin. Patients with rectal cancer routinely receive postoperative radiation if the tumor is T3 and or has nodal disease. Patient follow-up was obtained through the institutional tumor registry.
Pathologic Examination and Determination of Tumor Volume Lymph nodes were collected as follows: the peritoneum overlying the remainder of the mesentery was incised and then examined by careful palpation for the presence of lymph nodes. The mesenteric and adventitial fat was carefully displaced by manual pressure, visually inspected for lymph nodes, and palpated for the presence of firm tissue that was indicative of a lymph node. Any firm tissue remaining after gentle pressure on the mesenteric fat was isolated from the surrounding mesenteric fat and sent as a lymph node specimen for histologic examination by routine hematoxylin and eosin staining. The following standard sections were submitted for microscopic examination: proximal, distal, and closes radial margins; tumor, including the area of deepest invasion and junction with adjacent normal mucosa; and representative uninvolved mucosa and lymph nodes. Representative sections were examined in all grossly involved lymph nodes. All grossly uninvolved lymph nodes, when larger than 3 mm, were bivalved in the longitudinal axis and embedded in paraffin. Lymph nodes smaller than 3 mm in diameter were embedded whole. A single section was routinely performed (two faces in bivalved lymph nodes and a single face in lymph nodes < 3 mm in diameter). Histologic sections were processed in the usual manner, cut at 4 µm, and stained with hematoxylin and eosin. No special nonhistologic techniques were used to identify nodal metastases. The T status of the tumor was determined after pathologic examination of the resected specimen and was defined according the American Joint Committee on Cancer Staging criteria.15 Tumor grading was determined according to the degree of differentiation of the glands, the degree of nuclear and cellular pleomorphism, and the mitotic activity and was reported in a standard synoptic format for colorectal carcinoma in accordance with recommendations from the College of American Pathologists. All specimens with node-positive pathology were reviewed by one pathologist (P.T.), and the metastatic tumor was measured with an ocular micrometer in the short axis (a = short axis) and the long axis (b = long axis). Because the tumor measurements were obtained only from a two-dimensional single pathologic section, tumor volume was estimated by the following formula:
Micrometastatic nodal volume disease was defined as
Statistical Analysis
The majority of patients had tumors located in the ascending or sigmoid colon (68%). Table 1 summarizes the location of the primary tumor and number of positive nodes at each site. Although more nodes were examined in tumors located in the ascending colon and in sites not otherwise specified, these were not statistically significant differences. There was no difference in the number of positive nodes identified in the various anatomic sites. The majority of patients had T3 tumors (81%). As might be anticipated, the T status was not associated with overall (P = .19) or disease-free survival (P = .42) in node-positive patients.
The mean metastatic nodal tumor volume was 5.1 ± 4.99 mm3 (range, 0.05 to 83,434 mm3). As was anticipated, metastatic nodal tumor volume increased with the number of involved nodes. However, there was only a weak positive correlation with the number of nodes involved with metastatic disease and metastatic nodal tumor volume (Fig 1; r = .45). Although individuals with extensive numbers of nodes involved with metastatic tumor often have significant tumor volumes, this was not uniformly the case. If the single patient who had an extensive volume of disease (83,434 mm3) associated with 18 nodes being positive was excluded from the analysis, the association of tumor volume with number of nodes was even weaker.
The median follow-up of the study population was 39 months (range, 1 to 87 months). The number of nodes involved with metastatic disease significantly affected the actuarial 5-year survival. The median survival of patients with one to three positive nodes had not been reached. In contrast, those with four or more positive nodes had a median survival of only 23 months. Individuals with one to three positive nodes had a substantially better survival than individuals with four or more positive nodes (Fig 2; P < .001). Furthermore, the mean number of nodes involved with metastatic disease in patients free of disease was significant less than in those who had died as a result of disease (3.1 ± 2.5 v 6.7 ± 5.6; P < .001).
The total nodal volume of metastatic disease correlated with prognosis. Patients with an increasing volume of metastatic disease were at substantially increased risk of dying as a result of recurrent disease (P = .019). Patients dying as a result of disease had a substantially greater nodal tumor volume at diagnosis than those who had not died as a result of disease (3,705 ± 8,077 mm3 v 1,783 ± 5,239 mm3; P = .036). However, by a stepwise logistic regression analysis, the total nodal volume of metastatic disease (hazard ratio [HR], 0.999; 95% confidence interval [CI], 0.999 to 0.999) did not, independent of positive nodes (HR, 1.41; 95% CI, 1.17 to 1.70) or number of positive nodes (HR, 1.50; 95% CI, 1.22 to 1.86), predict outcome. Twelve of 62 patients with one to three positive nodes had only micrometastatic involvement of the regional lymph nodes, as defined in Patients and Methods. There was no difference in survival between those with micrometastatic volume disease involvement and macrometastatic volume disease involvement (Fig 3; P = .79). Only two patients with four or more positive nodes had a nodal volume that was micrometastatic. To address whether metastatic disease volume might affect survival, we stratified patients with four or more positive nodes on the basis of median volume of metastatic involvement. Again there was no difference in survival between those with high metastatic nodal volume and low metastatic nodal volume (Fig 4; P < .001).
It is well recognized that the greater the number of lymph nodes involved with metastatic colorectal cancer, the higher the risk of developing recurrent disease.1 For this reason, the American Joint Committee on Cancer distinguishes between patients with one to three positive nodes and those with four or more positive nodes.15 However, it is not an uncommon observation that some individuals may have only a single large metastatic focus, whereas other individuals are found to have multiple positive nodes with only minimal replacement of the node by metastatic disease. These observations raised the question of whether individuals with minimal metastatic disease involving multiple nodes have a similar prognosis as their counterparts with a similar number of nodes that are more extensively involved with metastatic disease. This article demonstrates that nodal tumor volume correlates poorly with the number of nodes involved with metastatic disease and suggests that the number of nodes, rather than the extent of nodal involvement as determined by nodal tumor volume, is the critical variable in determining prognosis. Tumor burden is a well-accepted prognostic variable. Patients with a total tumor burden exceeding 1 kg are considered to have a life-threatening volume of disease. In apparently localized colorectal cancer, tumor burden is routinely assessed by indirect methods. Primary colorectal cancer tumor burden is characterized by depth of penetration through the bowel wall, whereas regional nodal tumor burden is characterized by the number of tumor-involved nodes. Although primary tumor characteristics are important, the presence or absence, as well as the extent, of metastatic disease in the regional lymphatics is the most important prognostic factor in apparently localized colorectal cancer. It has been suggested that undetected metastatic disease may contribute to the failure of the surgical primary therapy of colorectal cancer. To address this concern, a number of investigators have sought to determine the number of nodes that need to be collected and examined to accurately reflect the histology of the regional lymphatic basin.18-21 Inadequate examination of the regional lymph nodes can lead to substantial differences in outcome.22 An alternative approach to improved staging of the regional lymphatics has used more sensitive techniques to identify smaller deposits of disease. Serial sectioning and hematoxylin and eosin staining have been used to increase the detection of metastatic disease. Some investigators have used immunohistochemical examination,9,11-13 and others have used reverse transcriptase–polymerase chain reaction technology10,23 to identify metastatic disease in regional lymph nodes in colorectal cancer patients. It has been demonstrated that immunohistochemical examination can identify additional tumor deposits in approximately 20% of nodes that were normal by routine hematoxylin and eosin staining.5
The term micrometastatic disease is commonly used and refers to small deposits of metastatic disease in the regional lymph nodes, identified not only by routine hematoxylin and eosin staining, but also by more sensitive assays. In an effort to standardize nomenclature, the College of American Pathologists, in a consensus statement, defined micrometastatic nodal disease as histologically confirmed metastatic tumor that measures The biologic relevance of micrometastatic nodal disease in colorectal cancer remains controversial. Some investigators have suggested that the finding of micrometastatic disease imparts a worse prognosis. Liefers et al,10 who used reverse transcriptase–polymerase chain reaction technology, suggest that the presence of micrometastatic disease adversely influences outcome, whereas Greenson et al,9 who used immunohistochemical staining techniques, found patients with micrometastatic disease to have a significantly poorer prognosis. Other investigators, however, have not demonstrated that the survival of patients with micrometastatic disease in the regional nodes is adversely affected,11-13,24 raising the question of whether or not these more sensitive techniques should be routinely used in staging colorectal cancer patients. Recently, novel approaches to identifying nodes at risk for harboring micrometastatic disease have been developed.25,26 With these techniques, individuals with micrometastatic disease can routinely be identified in a potentially cost- and time-effective fashion. For this reason, gaining insight into the biologic relevance of micrometastatic disease is becoming increasingly important. The results of this study demonstrate that as the number of nodes involved with metastatic disease increases, the survival of patient decreases. This finding is consistent with that previously reported by others.27 We sought to gain insight into whether the volume of tumor present might give additional information regarding the prognosis of patients. It would seem reasonable to assume that as the number of nodes involved with metastatic disease increases, there would be a linear correlation with the tumor volume. However, there was only a weak positive correlation between the nodal tumor volume and the number of nodes involved with metastatic disease (r = .45). As we had observed, it is not uncommon to observe only minimal replacement of multiple nodes with metastatic disease.28 In contrast, occasionally, large volumes of tumor are found in only a few nodes, leading to only the weak positive correlation we observed. However, micrometastatic node volume, when calculated directly from hematoxylin and eosin slides, seems to be as prognostically relevant as macrometastatic node volume. Increasing nodal tumor volume was associated with an increased risk of developing recurrent disease. Furthermore, patients who died as a result of recurrent colorectal cancer had a significantly higher nodal tumor burden than those who remained alive. However, when controlled for the number of nodes involved with metastatic tumor, nodal tumor volume did not independently predict outcome. The metastatic process is clearly a complex series of events.29 Sentinel node staging suggests an orderly progression of metastatic disease in the regional lymphatics, initially to a sentinel lymph node and then to the remainder of the regional node basin.30 It may be that even within the regional lymphatic system, the ability to metastasize from the sentinel node to subsequent nodes represents a more advanced progression through the metastatic process. The finding of a few large nodes with extensive replacement and growth of metastatic disease within the node would seem to represent a different metastatic phenotype than the metastatic phenotype in which multiple normally sized nodes are partially replaced with metastatic disease. In our analysis, the former phenotype is relatively uncommon, however, and does not seem to add to or replace the prognostic value of the number of regional nodes involved with metastatic disease. Lymph node collection from colorectal cancer specimens represents a critical aspect of staging of colorectal cancer. The ease of identification of tumor-involved lymph nodes is not related to the nodal size,21 because nodes with metastatic disease are not statistically different in size from those without metastatic disease. The presence or absence of nodal metastases represents the most important prognostic factor in localized colorectal cancer. The number of nodes, rather than the volume of tumor involvement of the regional lymphatics, determines outcome. These results would suggest that micrometastatic disease is biologically relevant.
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Morton DL, Duan-Ren W, Wong JH, et al: Technical details of intraoperative lymphatic mapping for early stage melanoma. Arch Surg 127: 392-399, 1992 4. Giuliano AE, Kirgan DM, Guenther JM, et al: Lymphatic mapping and sentinel lymphadenectomy for breast cancer. Ann Surg 220: 391-401, 1994[Medline] 5. Turner RR, Ollila DW, Krasne DL, et al: Histopathologic validation of the sentinel lymph node hypothesis for breast carcinoma. Ann Surg 226: 271-278, 1997[CrossRef][Medline] 6. Gusterson B, Ott R: Occult axillary lymph-node micrometastases in breast cancer. Lancet 336: 434-435, 1990 (letter)[CrossRef][Medline] 7. Cochran AJ, Wen DR, Morton DL: Occult tumor cells in the lymph nodes of patients with pathological stage I malignant melanoma: An immunohistological study. Am J Pathol 12: 612-618, 1988 8. Group IBCS: Prognostic importance of occult axillary lymph node micrometastases from breast cancers. Lancet 335: 1565-1568, 1990[CrossRef][Medline] 9. Greenson JK, Isenhart CE, Rice R, et al: Identification of occult micrometastases in pericolic lymph nodes of Dukes’ B colorectal cancer patients using monoclonal antibodies against cytokeratin and CC49. Cancer 73: 563-569, 1994[CrossRef][Medline]
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Liefers G-J, Cleton-Jansen A-M, van de Velde CJH, et al: Micrometastases and survival in stage II colorectal cancer. N Engl J Med 339: 223-228, 1998 11. Cutait R, Alves VAF, Lopes LC, et al: Restaging of colorectal cancer based on the identification of lymph node micrometastases through immunoperoxidase staining of CEA and cytokeratins. Dis Colon Rectum 34: 917-920, 1991[CrossRef][Medline] 12. Adell G, Boeryd B, Franlund B, et al: Occurrence and prognostic importance of micrometastases in regional lymphnodes in Dukes’ B colorectal carcinoma: An immunohistochemical study. Eur J Surg 162: 637-642, 1996[Medline] 13. Jeffers MD, O’Dowd GM, Mulcahy H, et al: The prognostic significance of immunohistochemically detected lymph node micrometastases in colorectal carcinoma. J Pathol 172: 183-187, 1994[CrossRef][Medline]
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Moertel CG, Flemming TR, Macdonald JS, et al: Fluorouracil plus levamisole as effective adjuvant therapy after resection of stage III colon carcinoma: A final report. Ann Intern Med 122: 321-326, 1995 15. Beahrs OH, Henson DE, Hutter RVP, et al (eds): Manual for Staging of Cancer (ed 4). Philadelphia, PA, Lippincott, 1992 16. Compton CC, Fielding LP, Bugart LJ, et al: Prognostic factors in colorectal cancer: College of American Pathologists consensus statement 1999. Arch Pathol Lab Med 124: 979-994, 1999 17. Kaplan E, Meier P: Nonparametric estimation from incomplete observation. J Am Stat Assoc 53: 457-481, 1958[CrossRef] 18. Fielding LP, Aresnault PA, Chapuis PH, et al: Clinicopathological staging for colorectal cancer: An International Documentation System (IDS) and an International Comprehensive Anatomical Terminology (ICAT). J Gastroenterol Hepatol 6: 325-344, 1991[Medline] 19. Goldstein NS, Weldon S, Coffey M, et al: Lymph node recovery from colorectal resection specimens removed for adenocarcinoma: Trends over time and a recommendation for a minimum number of lymph nodes to be recovered. Am J Clin Pathol 106: 209-216, 1996[Medline] 20. Scott KWM, Grace RH: Detection of lymph node metastases in colorectal carcinoma before and after fat clearance. Br J Surg 76: 1165-1167, 1986[CrossRef]
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Copyright © 2002 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2 mm in size on a single section
2 tests were used to test for differences between study groups by using SPSS 10.0.7 for Windows (SPSS, Inc, Chicago, IL). 
