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(Chest. 2003;124:1916-1923.)
© 2003 American College of Chest Physicians

Tumor Necrosis Correlates With Angiogenesis and Is a Predictor of Poor Prognosis in Malignant Mesothelioma*

John G. Edwards, FRCS; Daniel E. B. Swinson, BM BS; J. Louise Jones, FRCPath; Salli Muller, FRCPath; David A. Waller, FRCS (CTh), FCCP and Kenneth J. O’Byrne, MD

* From the Departments of Oncology (Drs. Edwards, Swinson, and O’Byrne) and Pathology (Dr. Jones), University of Leicester, Leicester; and Departments of Respiratory Medicine and Thoracic Surgery (Dr. Waller) and Pathology (Dr. Muller), University Hospitals Leicester NHS Trust, Leicester, UK.

Correspondence to: Kenneth J. O’Byrne, MD, Department of Oncology, Osborne Building, Leicester Royal Infirmary, Leicester, LE1 5WW, UK; e-mail: ken.obyrne{at}uhl-tr.nhs.uk


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Objectives: Malignant mesothelioma (MM) is a fatal tumor of increasing incidence related to asbestos exposure. Microscopic tumor necrosis (TN) is a poor prognostic factor in solid tumors, but it has not been characterized in MM. We wished to evaluate the incidence of TN in MM and its correlations with clinicopathologic factors, angiogenesis, and survival.

Methods: TN was graded in 171 routine formalin-fixed, paraffin-embedded hematoxylin-eosin–stained tumor sections by two independent observers. Angiogenesis was assessed by the microvessel count (MVC) of CD34 immunostained sections. TN was correlated with survival by Kaplan-Meier and log-rank analysis, and stepwise, multivariate Cox models were used to compare TN with angiogenesis and established prognostic factors and prognostic scoring systems.

Results: TN was identified in 39 cases (22.8%) and correlated with low hemoglobin (p = 0.01), thrombocytosis (p = 0.04), and high MVC (p = 0.02). TN was a poor prognostic factor in univariate analysis (p = 0.008). Patients with TN had a median survival of 5.3 months vs 8.3 months in negative cases. Independent indicators of poor prognosis in multivariate analysis were nonepithelioid cell type (p = 0.0001), performance status > 0 (p = 0.007), and increasing MVC (p = 0.004) but not TN. TN contributed independently to the European Organisation for Research and Treatment of Cancer (EORTC) [p = 0.03] and to the Cancer and Leukemia Group B (CALGB) [p = 0.03] prognostic groups in respective multivariate Cox analyses.

Conclusions: TN correlates with angiogenesis and is a poor prognostic factor in MM. TN contributes to the EORTC and CALGB prognostic scoring systems.

Key Words: angiogenesis • malignant mesothelioma • necrosis • prognosis


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Malignant mesothelioma (MM) is a fatal cancer of increasing incidence associated with asbestos exposure.1 MM responds poorly to surgery, chemotherapy, and radiotherapy,2 and has an appalling prognosis. The median survival is approximately 6 to 12 months.3 4 5 6 TNM staging7 is of limited value in the majority of patients, and did not predict survival in a large series of patients undergoing radical multimodality therapy.8 In contrast, prognostic scoring systems have been proposed based on the evaluation of clinicopathologic features of MM derived from patients in chemotherapy trials conducted by the European Organization for Research and Treatment of Cancer (EORTC)4 and the Cancer and Leukemia Group B (CALGB).5 We have previously validated these systems in a surgical series.3

Coagulative necrosis is a common feature of solid tumors. Tumor microvessels are fragile and susceptible to hypoxia,9 which suggests that the degree of tumor necrosis (TN) reflects the level of intratumoral hypoxia. Measured experimentally with a polarographic needle, intratumoral hypoxia correlates with poor prognosis and sensitivity to radiotherapy and chemotherapy in solid tumors.10 11 12 13 14 TN has been reported as an indicator of a poor prognosis in a number of solid tumors, including non-small cell lung cancer (NSCLC),15 16 17 18 GI stromal tumors,19 and Ewing sarcoma.20 In breast cancer, TN has been shown to correlate with increased tumor size, high-grade disease, negative estrogen receptor status, high microvessel density, and infiltrates of macrophages that express vascular endothelial growth factor (VEGF).21 22 23 24 These findings suggest that, in rapidly growing tumors, a hypoxic environment that results in TN stimulates angiogenesis due to the release of angiogenic growth factors from infiltrating macrophages.

We have demonstrated previously that angiogenesis, as assessed by microvessel count (MVC), is an independent prognostic factor in MM.25 Although TN has been noted in MM,26 it has not been characterized in terms of relations to clinical and pathologic features and prognosis. The purpose of this study was to evaluate the incidence of TN in MM and explore correlations with known clinicopathologic factors, the EORTC and CALGB prognostic scoring systems, and angiogenesis.


   Materials and Methods
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 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Patients
All cases of MM presenting to our institution from 1988 to 2001 were identified and case notes reviewed. Demographic and clinicopathologic data were retrieved. CALGB5 and EORTC4 prognostic groups were derived, as described previously.3 These patients were referred to the regional Department of Cardiothoracic Surgery for surgical biopsy, management of pleural effusion or empyema, palliative debulking surgery,27 or for radical surgery. Each histopathologic report was obtained and the diagnostic slides reviewed by a pathologist to confirm the diagnosis. The routinely processed, formalin-fixed, paraffin-embedded, hematoxylin-eosin–stained tumor sections, which had been used for the original diagnostic purposes, were retrieved. For each case, hematoxylin-eosin sections were reviewed from all the diagnostic tissue blocks, and the section displaying the most prominent TN (if present) was selected for scoring and interpretation. Survival was calculated from the date of the diagnostic biopsy. The prediagnostic variables, such as performance status and hematologic indexes, were taken as those recorded from those immediately before this time. The pathologic TNM stage was recorded only when either the patient had undergone radical surgery or staging surgical biopsy. It was believed that deriving the TNM stage retrospectively from clinical and radiologic data alone may not be sufficiently accurate.

Interpretation
Sections were inspected at low power (x 40) using light microscopy by two independent observers (J.G.E. and D.E.B.S.) blinded to clinicopathologic data and outcome. A consensus was determined using a dual-headed microscope where the observers differed in the allocated TN score. A pathologist (J.L.J. and/or S.M.) assisted in the derivation of the scoring system, the assessment of indeterminate cases, and adjudicated unresolved differences. The degree of TN on the section was scored subjectively as follows: grade 0, no necrosis; grade 1, one focus of necrosis per low-power field (LPF), occupying < 10% per LPF; grade 2, more than one foci, each occupying < 10%, or one focus occupying 10 to 30% per LPF; grade 3, single or multiple foci > 30% per LPF (Fig 1 ).



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  		Figure 1.. Hematoxylin-eosin–stained sections of epithelioid MM demonstrating grade 1 TN (top, A), grade 2 TN (center, B), and grade 3 TN (bottom, C) [arrow = 200 µm].

 
Assessment of Angiogenesis
Angiogenesis had been assessed previously in the majority of this cohort by Chalkley counting of intratumoral microvessels, as we have reported.25 Briefly, 4-µm sections of tumor were mounted on 2% 3-aminopropylethoxysilane coated glass slides. After rehydration through graded alcohols, sections were incubated overnight at 4°C with CD34 antibody (NCL-END; Novocastra; Newcastle, UK). A biotinylated secondary antibody (E0354; Dako; Ely, UK) and the streptavidin-biotin peroxidase complex (K0377; Dako), with the chromogen diaminobenzidine tetrahydrochloride, were used for visualization. Intratumoral hot spots were identified under lower-power light microscopy and microvessels counted at x 250 with a Chalkley graticule.28 The MVC was defined as the sum of the microvessels thus counted from the three hot spots of greatest individual counts. The most intense hot spots of immunostaining were examined first and counted; further hot spots were counted until no change occurred in the MVC.

Statistical Analysis
Statistical analysis was performed using the SPSS software system (SPSS for Windows Version 9.0; SPSS; Chicago, IL). The level of agreement between observers was assessed by calculating the Cohen statistic. The {chi}2 test was used to analyze the correlation of TN with categorical variables and Student t test for continuous variables. Hematologic indexes were analyzed as both continuous and categorical variables, the cut-points for the latter were based on the CALGB and EORTC series. Cancer-specific survival curves were estimated using the Kaplan-Meier method, and the log-rank test was used to assess the statistical significance of differences between groups. A Cox proportional hazards regression model was used to identify statistically significant differences in survival and to estimate hazard ratios and 95% confidence intervals (CIs).29 The assumption of proportional hazards was assessed graphically by plotting log[-log(survivor)] against log(time) for each of the prognostic groups. Prognostic variables identified by univariate analysis, with p < 0.1, were analyzed in a multivariate Cox model. A forward, stepwise selection procedure was used, with variables being added to the model according to a partial likelihood ratio test, using an entry criterion of p < 0.05.


   Results
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 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
TN was identified in 39 of 171 cases (22.8%). TN was grade 1, 2, and 3 in 14, 14, and 11 cases, respectively. Agreement between observers, before obtaining a consensus, was reached in 161 patients (94.2%; Cohen statistic, 0.85). Due to the lack of difference in survival between the TN grades (p = 0.2), the following statistical analyses were performed comparing two groups (TN present or absent). MVCs were available for 107 cases. The median MVC was 23 microvessels.

Correlation With Clinicopathologic Factors and Angiogenesis
The relationships of TN and clinicopathologic variables are seen in Tables 1 and 2 . TN positively correlated with a platelet count > 400 x 109/L (p = 0.04) and hemoglobin < 14 g/dL (p = 0.01); when analyzed as continuous variables, these trends remained but statistical significance was lost (Table 2) . High MVCs were associated with TN when expressed both as a continuous variable (p = 0.02) and when greater than the median value (p = 0.04). No relationships were seen with the other clinicopathologic variables, such as cell type, performance status, and the presence of weight loss or pleuritic chest pain. It was possible to derive a pathologic TNM stage in 53 patients (31%). TN was not associated with high TNM stage in these patients (p = 0.41). There was no significant difference in the incidence of TN in patients undergoing surgical biopsy only, compared to those who had resection of tumor by palliative debulking surgery or radical surgery (p = 0.6). The grade of TN had no significant impact on any of the above relationships.


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  		Table 1.. Correlations Between TN and Categorical Clinicopathologic and Biological Variables*

 

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  		Table 2.. Correlations Between TN and Continuous Clinicopathologic and Biological Variables: Linear Regression*

 
Survival Analysis
The median survival for all 171 cases was 186 days. However, 17 patients died within 30 days of the date of diagnostic biopsy and these were excluded from further survival analyses to avoid bias from postoperative deaths. There was not a greater proportion of TN in these patients (p = 0.5). TN was associated with a worse survival (p = 0.008, log-rank; Fig 2 ). However, there was no difference in survival between the three grades of TN (p = 0.2). The overall median survival for the 120 included cases without TN was 248 days, whereas for the 34 included cases with TN it was 158 days (p = 0.008, log-rank). Six-month and 12-month survival rates were 62.1% (95% CI, 53.4 to 70.9%) and 34.5% (95% CI, 25.8 to 43.3%), respectively, for patients without TN, but 47.1% (95% CI, 30.3 to 63.8%) and 15.9% (95% CI, 3.3 to 28.6%) for those with TN. Similarly, those with MVCs greater than the median were associated with poor outcome.



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  		Figure 2.. Kaplan-Meier plot showing that TN was associated with a worse survival (p = 0.008, log-rank). Cum = cumulative.

 
In addition to TN, nonepithelioid cell type, the presence of weight loss > 5%, Eastern Cooperative Oncology Group performance status > 0, hemoglobin < 14 g/dL, and platelet count > 400 x 109/L were poor prognostic factors in univariate analysis (Table 3 ). Furthermore, both the CALGB and EORTC prognostic scoring systems stratified each prognostic group to survival accordingly.


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  		Table 3.. Prognostic Significance of Clinicopathologic and Biological Parameters

 
In multivariate analysis, cell type, performance status, and MVC were the independent predictors of poor survival (Table 4 ). TN was not an independent factor in univariate analysis, even when the MVC was not analyzed in the model. When analyzing the epithelioid cases alone with the log-rank test, there was a significant difference in survival between those with and without TN (p = 0.0004). The median survival in the 70 epithelioid cases without TN surviving > 30 days was 384 days; it was 158 days in the 22 epithelioid cases with TN. The presence of TN contributed to both the CALGB and EORTC prognostic scoring systems, when analyzed with each, in turn, in Cox multivariate analysis (Table 5 ).


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  		Table 4.. Independent Poor Prognostic Factors Identified in Multivariate Cox Proportional Hazards Analysis*

 

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  		Table 5.. Multivariate Cox Proportional Hazards Models of Prognostic Scoring Systems*

 

   Discussion
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
This study has characterized, for the first time, TN in a large series of MM and demonstrates that the presence of TN is associated with poor survival. The correlation between TN and survival is particularly marked in the epithelioid cases. This implies a relationship where increased tumor cell death indicates a more aggressive cancer. It is possible to explain this apparently paradoxical relationship by rapid tumor growth outstripping the vascular supply, causing ischemic damage to the microvasculature and thereby increased TN.9 30

The association of TN and MVC is consistent with studies in breast cancer.21 22 TN, and the surrounding zone of hypoxia, results in the attraction of an inflammatory infiltrate, in which macrophages are prominent.21 23 31 Macrophages may play a central role in angiogenesis through the secretion of pro-angiogenic factors such as VEGF, tumor necrosis factor-{alpha}, interleukin (IL)-8, and basic fibroblast growth factor.32 These factors, following macrophage recruitment, stimulate angiogenesis in the remaining viable tumor. In breast cancer, microvessel hot spots were situated away from areas of TN,21 as was found in this study. In keeping with this, in a further study22 in breast cancer, MVC increased from the central though the intermediate to the peripheral zone of the tumor.

There were also associations with high platelet counts and low hemoglobin concentrations, both of which were poor prognostic factors in univariate analysis. Thrombocytosis is associated with poor outcome in other solid tumors, such as NSCLC,33 34 in which we have also found a correlation between TN and platelet count.18 The association between platelet count and TN may simply reflect the fact that both are seen in tumors with an aggressive phenotype. It is possible, however, to hypothesize that thrombocytosis, angiogenesis, and TN are linked mechanistically. Vascular stasis, exposure of the subendothelial collagen and increased expression of platelet-binding factors may each lead to increased platelet adhesion and activation in malignant disease. Platelet adhesion and activation may result in the release of angiogenic growth factors, such as VEGF and platelet-derived endothelial cell growth factor, but also the formation of platelet plugs that cause coagulative necrosis. This sequence of events may be more likely to occur if the platelet count is elevated.35 36 TN may also result in thrombocytosis through the release of cytokines such as IL-6 from activated infiltrating inflammatory cells. IL-6 is a potent stimulator of platelet synthesis, is up-regulated by hypoxia,37 is angiogenic,38 39 and is expressed in MM.40 41

TN was not an independent prognostic factor when compared with the clinicopathologic factors, which may be due to the relatively low proportion of cases with TN, when compared to the incidences of the other factors. However, TN did contribute to both the CALGB and EORTC prognostic scoring systems in multivariate analysis.

A possible confounding association between necrosis and tumor mass could not be assessed in this study. Increased tumor volumes are associated with worse survival in MM.42 More bulky tumors might be expected to demonstrate more extensive TN, but we observed no correlation between TN and TNM stage in the 48 cases where the latter could accurately be derived. It should be noted, however, that the International Mesothelioma Interest Group7 T stage does not take account of tumor bulk, but is based on invasion of intrathoracic tissues and structures. In NSCLC, we found that TN correlated with increasing T stage.18 However, TN remained a prognostic factor in a large series of stage IA NSCLC cases.43 In breast cancer, TN correlated with increasing tumor size,21 whereas in other tumors, an association between T stage and necrosis remains unclear. Increasing mass was associated with hypoxia in an experimental murine allograft model.44

The subjective assessment of TN used resulted in a high agreement between the observers and expert adjudication was required only for a few cases. Similar subjective methods of TN assessment have been described and validated.18 21 In the study presented here, the grade of TN was not significant with respect to either clinicopathologic correlations or survival. We therefore propose that assessment of the presence of any TN is sufficient for prognostic purposes, rather than evaluation of the extent of TN in the tumor. It is difficult in a study of this type to rule out completely possible sample bias, particularly with regard to the smaller biopsy specimens used. However, we found that the proportion of patients with TN detected from biopsy specimens was similar to that from those who had underwent palliative or radical tumor resection (which had a larger amount of sample for review). It is important to note that the biopsy specimens were not from closed (needle) procedures but were large surgical biopsies from either open or video-assisted thoracoscopic surgery. Slides from all the pathologic diagnostic tissue blocks for each tumor were reviewed. These observations suggest that sampling error in our assessment of TN is unlikely to be relevant.

In conclusion, we have demonstrated that the presence of TN is a poor prognostic factor in MM. The methodology we adopted does not require immunohistochemistry and is reproducible between observers. The positive correlations of TN with angiogenesis and thrombocytosis support evidence that these processes are related and confirms that TN is part of an aggressive tumor phenotype in MM. The presence of TN in patients with MM who are resistant to radiotherapy and chemotherapy deserves investigation.


   Acknowledgements
 
We thank the Institutes of Cancer Studies and Lung Health, and Medisearch, Leicester, UK.


   Footnotes
 
Abbreviations: CALGB = Cancer and Leukemia Group B; CI = confidence interval; EORTC = European Organisation for Research and Treatment of Cancer; IL = interleukin; LPF = low-power field; MM = malignant mesothelioma; MVC = microvessel count; NSCLC = non-small cell lung cancer; TN = tumor necrosis; VEGF = vascular endothelial growth factor

Financial support was provided by a Leicester Royal Infirmary Research Fellowship, and the June Hancock Mesothelioma Research Fund and the Sir Samuel Scott of Yews Trust.

Received for publication August 22, 2002. Accepted for publication May 13, 2003.


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 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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