Annals of Surgical Oncology Cite Track
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10.1245/s10434-006-9189-3
Annals of Surgical Oncology 14:470-477 (2007)
© 2007 Society of Surgical Oncology
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Original Article

Prognostic Significance of Immunohistochemically Detected Blood and Lymphatic Vessel Invasion in Colorectal Carcinoma: Its Impact on Prognosis

Pin Liang, MD1,2, Ichiro Nakada, MD1, Jian-Wei Hong, MD3, Takanobu Tabuchi, MD1, Gyo Motohashi, MD1, Akira Takemura, MD1, Takeshi Nakachi, MD1, Teruhiko Kasuga, MD1 and Takafumi Tabuchi, MD1

1 Fourth Department of Surgery, Tokyo Medical University Kasumigaura Hospital, 3-20-1 Chuo, Ami, Inashiki, Ibaraki 300-0395, Japan
2 Department of General Surgery, First Affiliated Hospital of Dalian Medical University, Dalian, 116011, China
3 Department of Pathology, Tokyo Medical University Kasumigaura Hospital, 3-20-1 Chuo, Ami, Inashiki, Ibaraki 300-0395, Japan

Correspondence: Address correspondence and reprint requests to: Pin Liang, MD; Fourth Department of Surgery, Tokyo Medical University Kasumigaura Hospital, 3-20-1 Chuo, Ami, Inashiki, Ibaraki 300-0395, Japan; E-mail: lp212003{at}yahoo.com


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: The prognostic significance of blood vessel invasion (BVI) and lymphatic vessel invasion (LVI) is unclear. Because of the absence of specific markers for venous and lymphatic vessels, earlier studies could not reliably distinguish between BVI and LVI.

Methods: By immunostaining for podoplanin and CD34 antigen, we retrospectively investigated LVI and BVI in 419 tissue specimens of colorectal carcinoma. We performed univariate and multivariate analysis of the clinicopathologic features, frequency of recurrence, and outcome of patients with or without LVI and BVI.

Results: The use of hematoxylin and eosin (H&E) staining to identify BVI and LVI yielded a false positive rate of 9.1% and false negative rate of 12.6%. The incidence of BVI was significantly higher among tumors with LVI than tumors without LVI (P <.001). In logistic multivariate analysis, only LVI (P < .001) was associated with lymph node metastasis and BVI (P = .015) was associated with distant recurrence. Calculating the prognostic relevance, both two invasion types correlated with decreased survival in univariate analysis (both P <.001). In multivariate analysis, BVI (P =.024), lymph node status (P =.003) and tumor stage (P <.001) remained statistically significant factors for survival.

Conclusions: Our results suggest that immunohistologic evaluation of BVI and LVI could be useful in colorectal carcinoma indicating the risk of lymph node metastasis and recurrence, thereby contributing to prognostic evaluation.

Key Words: Colorectal carcinoma • Blood vessel invasion • Lymphatic vessel invasion • Prognosis • CD34 • Podoplanin


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The invasion of tumor cells into blood vessels or lymphatic vessels (intravasation) are critical steps for the establishment of metastasis. Both blood vessel invasion (BVI) and lymphatic vessel invasion (LVI) are crucial for tumor dissemination and they correlate with recurrence and survival in some types of cancer.1,2 Although some studies on colorectal carcinomas have been performed,3–5 both the identification of LVI and its distinction from BVI on conventional hematoxylin and eosin (H & E) stained sections are very difficult.6 As a result, the prognostic value of evaluating BVI and LVI in colorectal carcinoma is still unclear. Recently, podoplanin, a specific lymphatic microvessel marker, has enabled selective lymphatic microvessel immunostaining in paraffin-embedded sections.7,8 There has been no study of the prognostic significance of LVI and BVI in colorectal carcinoma using selective immunostaining. We therefore used podoplanin and CD34 immunostaining to retrospectively investigate the possible correlation between lymph node metastasis, recurrence, and BVI or LVI invasion, and we also examined the prognostic value of identifying LVI and BVI in specimens of colorectal carcinomas.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patients and Tissues
A total of 419 patients with primary colorectal carcinoma who had undergone curative surgical treatment from 1985 to 2000 at the Fourth Department of Surgery, Tokyo Medical University Kasumigaura Hospital were included in the study. Patients who had been lost to follow-up and patients with synchronous or metachronous multiple cancer were excluded from this study. The tumors were histopathologically classified according to the World Health Organization criteria proposed by Jass and Sobin in 1989.9 The extent of tumor invasion/metastasis was based on the Astler-Coller modification of the Dukes’ classification system.10 Focal dedifferentiation was defined as the presence of a polygonal (not columnar) cancer cell morphology with single or solitary trabecular form with indistinct polarity and an infiltrative pattern at the margin of invasion,11 which also has been referred to as "tumor budding".12 None of the patients had received chemotherapy or radiotherapy prior to surgery. Although only patients classified as Dukes’ Stage C had received 5-fluorourracil-based postoperatiove adjuvant chemotherapy, there was no significant difference in outcome among the patients given various chemotherapeutic agents (data not shown). The patients consisted of 267 men and 152 women and their mean age was 64.5 ± 18.3 years. The median follow-up time was 67.3 ± 38.7 months.

Immunohistochemistry Staining and Evaluation
Immunostaining procedures for podoplanin and CD34 were performed using the Envision+/HRP method with heat-induced antigen retrieval. Two representative blocks of each tumor were selected for immunostaining analysis of podoplanin, CD34, and consecutive 3 µm paraffin sections containing the tumor margin were dewaxed in xylene, then rehydrated in alcohol. For podoplanin staining, the sections were heated to 95°C in an oven (650W) for 45 min to reactivate the antigen. The endogenous peroxidase activity was suppressed by a solution of 3% hydrogen peroxide in methanol for 20 minutes. After being rinsed three times in phosphate-buffered saline (PBS), the sections were incubated for 90 min at room temperature with monoclonal antibody against podoplanin (11-003, AngioBio, Del Mar, CA, USA 1:50) and monoclonal antibody against CD34 (My10, Becton Dickinson, CA, USA 1:10). After washing in PBS, the sections were treated with goat antimouse immunoglobulins conjugated to peroxidase labeled-dextran polymer (K4001, Dako, Carpinteria, CA, USA) for 1 hour at room temperature. Then the sections were washed in PBS and developed in 0.05 M Tris-HCl buffer (pH = 7.5) containing 0.6 mg/ml 3,3'-diaminobenzidine tetrahydrochloride (DAB) for 10 min at room temperature. After washing in water, the nuclei were counterstained with Mayer’s hematoxylin. Negative control sections were stained by omitting the primary antibody.

The endothelial cells of all capillaries reacted with antibodies against CD34; the reactivity was usually stronger in blood vessels but nevertheless slightly present in a few lymphatic vessels. Only lymphatic vessels stained positive with podoplanin in this study, as in our previous report.13 Comparison of the consecutive sections yields reliable discrimination between lymphatic and blood vessel capillaries. Invasion was considered present if at least one tumor cell cluster was visible within a podoplanin and/or CD34-positive vessel. For comparison, lymphovascular space involvement was determined in routinely stained H & E sections. In this setting, differentiation between BVI and LVI was not attempted. All sections were simultaneously assessed by two independent investigators, who then compared their results and jointly reviewed questionable sections. Only cases on which they both agreed were listed as positive vessel invasion.

Documentation of Patterns of Recurrence and Survival
Recurrent sites were documented in 126 of the 155 patients (81.3%), being determined surgically in 39 and by clinical and/or radiographic procedures in 87. None were determined at autopsy or by reoperation in asymptomatic patients. Recurrence categories are expressed as the first site of recurrence rather than the cumulative (total) incidence of recurrence. There were 18 patients who had been discovered with combined local and distant recurrence on the first re-examanation and the recurrence site was categorized as distant or local. Among 155 patients with recurrent tumors, the exact site of treatment failure was unknown because of incomplete data or lack of confirmatory diagnosis in 29 patients. These 29 were excluded from the evaluation of patterns of recurrence, but were included in the calculation of survival rates. Local recurrence was defined as failure in the tumor bed, regional lymph nodes, anastomosis, drain site, and peritoneal seeding. Distant recurrence includes metastasis in the liver, lung, bone, or brain.

Overall survival was calculated from the date of diagnosis until the date of death or last follow-up. Patients who died from causes unrelated to carcinoma with no evidence of disease were censored at death.

Statistical Analysis
Pearson’s correlation coefficient was used to assess the correlation between the LVI and BVI. Association of LVI and/or BVI with clinical and histopathologic parameters was investigated using Kruskal-Wallis and Mann-Whitney tests as appropriate. Multiple logistic regression analysis was employed to determine the significant predictors for distant, local recurrence, and lymph node metastasis. Survival rate was calculated by the Kaplan-Meier method. Univariate influence of a given parameter on survival was assessed with the log-rank test, and the Cox proportional hazard regression model was used in multivariate analysis. A P value of 0.05 or less was considered as indicatating a statistically significant difference.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Correlation between BVI, LVI Assessed by Immunostaining and Stained H & E Specimens
The overall incidence of BVI and LVI was 41.2% (173 ) and 54.2% (227 ) respectively in immunostained specimens (Fig. 1a, bGo), Invasion of blood vessels only was seen in 27 specimens, invasion of lymphatic vessels only in 81, and both types of vessel invasion were observed in 146 specimens. In 239 cases, vessel invasion was already suspected based on the appearance of in conventionally stained H & E sections. In 38 specimens, results could not be verified by immunohistochemistry. In 53 additional cases, immunohistochemistry revealed vessel invasion that had not been found in stained H & E slides (Table 1Go). As a result, stained H & E slides were false positive in 9.1% and false negative in 12.6%.


Figure 1
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  		FIG. 1. Sample of colorectal carcinoma with both lymphatic and blood vessel invasion, podoplanin (A) and CD34 (B) stain on serial section of colorectal carcinoma, original magnification (x200. Only lymphatic vessels stain positive with podoplanin (arrow). Both lymphatic (arrow) and blood (double arrows) vessels stain with CD34.

 

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  		TABLE 1. Correlation between vessel invasion assessed by immunostaining and in stained H & E specimens
 
Distribution of BVI and LVI and their Correlation
By consecutive immunostaining with antibodies against podoplanin and CD34, numerous intratumoral and peritumoral vessels could be observed in each case. Intratumoral lymphatic vessels were extremely rare, most lymphatic vessels being located in the peritumoral areas, near the margin of tumor invasion. LVI in peritumoral areas were also significantly greater than that in intratumoral areas (226 cases vs 21 cases, P < .001 Mann-Whitney tests), which agrees with our previous study.14 However, no significant difference could be found between the frequency of peritumoral BVI and that of intratumoral BVI (93 cases vs 128 cases, P = .213 Mann-Whitney test). The frequency of BVI was significantly higher among LVI positive tumors than among LVI negative tumors (P < .001 r = 0.54, Pearson’s correlation coefficient analysis, Table 2Go).


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  		TABLE 2. Distribution of blood and lymphatic vessel invasion
 
Clinicopathologic Factors Associated with the Invasion of Lymphatic and Blood Vessels
Our analysis revealed both LVI and BVI to be significantly associated with deeper tumor invasion, and higher tumor stage. Tumors with LVI tend to have poor differentiation and a higher positive rate of tumor focal dedifferentiation than tumors with no LVI. However, a comparison of tumors with BVI and tumors without BVI revealed no statistically significant differences in different tumor differentiation and focal dedifferentiation (Table 3Go). There was no correlation between the frequency of BVI or LVI with age, sex, tumor site, and tumor size.


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  		TABLE 3. BVI and LVI according to tumor features
 
Lymph Node Metastasis in Relation to LVI and BVI
Logistic univariate analysis revealed that LVI, BVI, depth of invasion, and tumor focal dedifferentiation were related to lymph node metastasis. Among these factors, the presence of LVI (P < .001) was a significant independent risk factor for lymph node metastasis in logistic multivariate analysis (Table 4Go).


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  		TABLE 4. Logistic regression analysis of risk factors for lymph node metastasis
 
Recurrence and Survival
At the end of follow-up, 78 patients had distant recurrence and 66 patients had local recurrence (including 18 patients with combined distant and local recurrence). Logistic univariate analysis showed that the BVI and LVI were significantly associated with distant and local recurrence. However, LVI lost the association with both distant and local recurrence on multivariate analysis. BVI, lymph node metastasis, and tumor stage were associated with distant recurrence, and depth of invasion was associated with local recurrence (Table 5Go).


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  		TABLE 5. Logistic regression analysis of risk factors for local and distant recurrence
 
LVI and BVI were compared in terms of prognostic significance. The 5-year survival rate was 64.5% for all patients. In univariate survival analysis, a significant difference was found between patients with or without LVI, and between patients with or without BVI. In multivariate analysis, BVI, lymph node involvement and tumor stage remained statistically significant for survival (Table 6Go). Higher tumor stage, tumors with BVI or with lymph node involvement had a poorer clinical outcome. The 5-year survival rate of the patients with BVI and without BVI was shown in Fig. 2Go. Multivariate analyses which lymph node status was excluded were also performed; the LVI remained as not an independent predictor of recurrence and survival (P > 0.05).


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  		TABLE 6. Univariate and multivariate analysis of survival in 419 patients with colorectal carcinoma
 

Figure 2
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  		FIG. 2. Survival curves of patients with colorectal carcinoma with or without blood vessel invasion (BVI; P <.001, log-rank test). The 5-year survival rate of patients with BVI (36.4%) was significantly lower than that of patients without BVI (84.1%).

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
We sought to clarify the prognostic influence of BVI and LVI in colorectal cancer. While this topic has previously been investigated in some studies, results have been unclear.3,5,15,16 In various studies, the rate of BVI ranged from 10% to 89.5% and that of LVI varied from 8% to 73% on stained H & E specimens.17,18 One of the reasons for the wide range is that accurate microscopic identification of BVI and LVI is difficult on H & E-stained sections. Peritumoral edema, tissue shrinkage around infiltrating masses of tumor, and artifacts related to histologic processing can be mistaken for BVI or LVI. Interobserver variability may be substantial in the interpretation of H & E-stained specimens.19 Minsky et al. suggested that the use of elastic tissue staining could help identify BVI. Compared with the use of H & E-stains to identify BVI, it had a false positive rate of zero, but a false negative rate of 84 percent.19 However, Talbot et al. found elastic tissue staining to be rarely helpful because the rectal wall contains a large amount of background fiber with staining characteristics of elastic tissue.20 In the present study, we have for the first time been able to distinguish between lymphatic and blood vessels by using CD34 and podoplanin immunostaining in consecutive sections.

The incidence rate of blood and lymphatic vessel invasion in our study correlates well with the range of previous reports.13,15–17 A comparison of specimens with or without blood and lymphatic vessel invasion detection on stained H & E sections with findings on immunostaining revealed a false positive rate of 9.1% and a false negative rate of 12.6% among all cases in our study. This result showed that definitive identification of blood and lymphatic vessel invasion determined by stained H & E sections can be inadequate and that data based on stained H & E sections must be interpreted with care. Although the CD34 antigen was weakly expressed on a few lymphatic vessels compared with consecutive podinplanin stained sections on which only lymphatic vessels were stained, the blood vessels were accurately distinguished. Consecutive sections stained by CD34 and podoplanin are therefore useful to study the blood and lymphatic vessel invasion in paraffin sections.

BVI was observed both in the peritumoral and intratumoral areas. Tumors with BVI had a significantly higher incidence of LVI compared with cases with no BVI. Kim et al. and Brodsky et al. showed that LVI was associated with lymph node metastasis in colorectal cancer,21,22 and Saclarides et al. and Bayar et al. found that BVI may be a risk factor for lymph node metastasis in rectal cancer.23,24 However, these studies did not perform multivariate analysis. We found that although BVI was associated with lymph node metastasis in univariate analysis, multivariate analysis suggested that only LVI was an independent risk factor for lymph node metastasis in colorectal carcinoma. This implies that tumor cells might reach the lymph node mainly via the lymphatic system.

Lymphatic vessels and LVI were almost exclusively found at the invasion margin of tumor, not within the tumor, which agrees with recently published studies.1,2,14 Lymph node metastases were shown to occur in tumors that lack intratumoral functional lymphatics, suggesting that functional lymphatic vessels at the tumor margins are responsible for lymphatic dissemination. A close association of LVI and lymph node metastases was also reported in cervical cancer by Sakuragi et al.1 and in breast cancer by Schoppmann et al.25

In evaluating recurrence, some previous studies did not perform multivariate analysis.5,26 Using multivariate analysis, Meguerditchian et al. found that lymphovascular invasion was associated with recurrence, but they did not study BVI and LVI with regard to local and distant recurrence separately.27 Our data showed that there was a significant increase in local failures in patients with deeper tumor invasion, and a significant increase in distant failures in the patients with BVI and lymph node metastasis and higher tumor stage, which is in agreement with Horn et al. study which showed that BVI was an independent prognostic factor for distant metastasis in multivariate analysis.28 This result suggested that the patients with BVI might benefit the most from peri-operative adjuvant chemotherapy.

Univariate analysis in our study revealed that LVI and BVI were associated with significantly shorter survival. However, multivariate analysis revealed that tumors with BVI, lymph node metastasis, and higher tumor stage were significantly associated with poor prognosis. Because of the close correlation between LVI and lymph node metastasis, the pure prognostic effect of LVI could not be well assessed by considering lymph node status in multivariate statistical analysis; multivariate analyses which lymph node status was excluded were also performed, and the LVI remained as not an independent predictor of recurrence and survival.

A close correlation between LVI and lymph node metastasis, and lymph node metastasis association with poor prognosis were found in this study. However, LVI was not an independent prognostic factor for survival. The loss of prognostic significance of LVI in multivariate analysis could in part be explained by the possibility that multiple factors, steps, and molecular participants such as the increased in tumor expressing endothelial growth factors VEGF-C are probably involved and influence the process of tumor cells disseminating from the primary tumor through lymphatic system.29,30

In conclusion, our results suggest that immunohistologic evaluation of lymphovascular invasion might be important in colorectal carcinoma because blood and lymphatic vessel invasion are risk factors for lymph node metastasis, recurrence, and shorter survival.


   ACKNOWLEDGMENTS
 
The authors thank Tsutomu Kohda for technical assistance and are grateful to Prof. J. Patrick Barron of the International Medical Communications Center of Tokyo Medical University for his review of this manuscript. This work was supported by the Tokyo Medical University Cancer Foundation (200409).

Received for publication August 10, 2006. Accepted for publication August 10, 2006.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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