Serum VEGF and bFGF adds prognostic information in patients with normal platelet counts when sampled before, during and after treatment for locally advanced non-small cell lung cancer

Vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) have both been implicated to have roles in tumour angiogenesis. In the present retrospective study, serum VEGF and bFGF from patients with locally advanced non-small cell lung cancer (NSCLC) were analysed before, during and after treatment. Seventy-three patients and a total of 460 serum samples were analysed for VEGF and 443 serum samples were analysed for bFGF. Pre-treatment bFGF levels in patients with normal platelet counts, were correlated to poorer survival, P-value = 0.047. During chemotherapy, each rise of one unit bFGF corresponded to a hazard ratio of 4.06 (P=0.022). In patients with normal platelet counts, VEGF levels after radiotherapy significantly correlated to good prognosis (P=0.023), during radiotherapy VEGF levels indicated the same correlation (P=0.085). We conclude that serum VEGF and especially bFGF are of clinical interest as prognostic factors, especially in patients presenting with normal platelet counts.     

晚期非小细胞肺癌患者外周血VEGF和bFGF及MMP-9水平与预后的关系

目的 检测晚期非小细胞肺癌（NSCLC）患者化疗前后外周血血管内皮生长因子（VEGF）、碱性成纤维细胞生长因子（bFGF）和基质金属蛋白酶-9（MMP-9）的水平,探讨其与疗效、预后的关系。方法 酶联免疫吸附试验（ELISA）检测46例晚期NSCLC患者化疗前后血浆VEGF、bFGF和MMP-9水平,并对随访资料进行生存分析,应用COX回归模型分析预后影响因素。结果 化疗前血浆VEGF、bFGF和MMP-9中位值分别为275pg／ml、69pg／ml和122ng／ml,均高于健康对照组（P〈0．05）。化疗前血浆VEGF与bFGF水平正相关,Spearman’S相关系数为0．329。化疗前血浆VEGF、bFGF和MMP-9水平与白细胞、血色素、血小板计数无相关性,与年龄、性别、病理类型、分化程度、TNM分期等亦无关。Ⅳ期广泛转移者（包括骨转移）化疗前血浆MMP-9水平显著高于仅有骨转移者（P=0．013）。化疗后血浆bFGF下降为预后的独立保护因素,RR=11．737（P=0．02）。结论 检测晚期NSCLC患者外周血的某些血管生成相关因子,可能有利于协助预测转移倾向及评价预后。     

Angiogenesis in non-small cell lung cancer: the prognostic impact of neoangiogenesis and the cytokines VEGF and bFGF in tumours and blood

BACKGROUND: Due to a dismal prognosis of advanced lung cancer, novel screening tools and more effective treatments are clearly needed. Lately, an increasing number of tumour-released angiogenic cytokines which affect vessel formation, tumour growth, invasion, and metastasis have been identified. Vascular endothelial growth factors (VEGFs) and basic fibroblast growth factor (bFGF) are among the most important angiogenic factors. Based on available literature, we have explored the mechanisms of angiogenesis and its prognostic significance in non-small cell lung cancer, estimated by microvessel density (MVD) and the presence of VEGF and bFGF in the tumour and blood from NSCLC patients. METHODS: Several comprehensive Pubmed searches for the period January 1993 to May 2005 were performed using strategic combinations of the terms non-small cell lung cancer, angiogenesis, vascular endothelial growth factor, basic fibroblast growth factor, tumour expression, microvessel density, circulating, and serum. RESULTS: NSCLC neoangiogenesis, as measured by MVD, and tumour expression of VEGF are poor prognostic factors for survival (MVD, HR 1.8-2.0; VEGF, HR 1.5). bFGF tumour expression is also associated with poor survival and more aggressive disease. When evaluating the prognostic impact of elevated VEGF levels in blood, 10 of 16 studies (63%) indicated a negative prognostic impact. Of five studies on the prognostic value of circulating bFGF, three studies reported a negative prognostic impact, while one indicated bFGF as a good prognostic factor and one was inconclusive. CONCLUSION: Angiogenic factors are poor prognostic indicators for tumour aggressiveness and survival in NSCLC. Assessments of circulating levels of VEGF and possibly bFGF may be valuable future tools for treatment planning and monitoring of treatment effect and relapse. First, however, these blood tests need to be standardised and validated in large-scale prospective clinical trials.     

Vascular endothelial growth factor, platelet-derived endothelial cell growth factor and angiogenesis in non-small-cell lung cancer

High microvessel density, an indirect measure of angiogenesis, has been shown to correlate with increased tumour size, lymph node involvement and poor prognosis in non-small-cell lung cancer (NSCLC). Tumour cell vascular endothelial growth factor (VEGF) and platelet-derived endothelial cell growth factor (PD-ECGF) expression correlate with angiogenesis and a poor outcome in this disease. In a retrospective study VEGF and PD-ECGF expression and microvessel density were evaluated immunohistochemically in surgically resected specimens (T1-3, N0-2) from 223 patients with operable NSCLC using the VG1, P-GF.44C and JC70 monoclonal antibodies respectively. High VEGF immunoreactivity was seen in 104 (46.6%) and PD-ECGF in 72 (32.3%) cases and both were associated with high vascular grade tumours (P= 0.009 and P= 0.05 respectively). Linear regression analysis revealed a weak positive correlation between VEGF and PD-ECGF expression in cancer cells (r= 0.21; P = 0.002). Co-expression of VEGF and PD-ECGF was not associated with a higher microvessel density than VEGF or PD-ECGF only expressing tumours. Furthermore a proportion of high vascular grade tumours expressed neither growth factor. Univariate analysis revealed tumour size, nodal status, microvessel density and VEGF and PD-ECGF expression as significant prognostic factors. Tumour size (P < 0.02) and microvessel density (P < 0.04) remained significant on multivariate analysis. In conclusion, VEGF and PD-ECGF are important angiogenic growth factors and have prognostic significance in NSCLC. Furthermore the study underlines the prognostic significance of microvessel density in operable NSCLC.     

Plasma vascular endothelial but not fibroblast growth factor levels correlate with colorectal liver mestastasis vascularity and volume

The extent to which plasma levels of angiogenic factors in healthy individuals and tumour volume-related variations in colorectal cancer affect the accuracy of circulating angiogenic factors as predictors of colorectal cancer vascularity is unknown. We used enzyme-linked immunosorbant assay to measure plasma vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) levels in colorectal liver metastasis (CLM) patients, and 'no cancer' controls. CLM volume was determined from computerized tomography scans, and tumour vessel count and vessel volume from anti-endothelial antibody-stained biopsies. There was a significant (P= 0.03) increase in plasma VEGF level in 29 CLM patients (median 180.3 pg/ml(-1), iqr 132.5-284.8 pg/ml(-1) compared with 19 controls (median 125.8 pg/ml(-1), iqr 58.2-235.9 pg/ml(-1). There were significant correlations between plasma VEGF and tumour vessel count (r = 0.66, P = 0.03), tumour vessel volume (r= 0.59, P = 0.03), and CLM volume (r= 0.53, P = 0.03). A VEGF level in the upper quartile of the plasma VEGF distribution had a 70% sensitivity and 75% specificity in predicting an upper quartile liver metastasis tumour vessel count. No relation was identified between CLM and plasma bFGF levels. Plasma VEGF level predicted CLM vascularity, despite an overlap with normal levels and tumour volume-related variations.     

非小细胞肺癌血管生成因子与耐药相关基因关系的研究

目的:探讨血管生成因子(VEGF、bFGF)和耐药相关基因(MDR1、MRP、LRP)在非小细胞肺癌(non-smallcelllungcancer,NSCLC)中的表达及相互关系。方法:应用免疫组化技术检测96例NSCLC组织中VEGF、bFGF、MDR1、MRP、LRP蛋白表达,其中36例应用RT-PCR技术检测上述基因mRNA表达。结果:VEGF、bFGF、MDR1、MRP、LRPmRNA表达率分别为69.5%(25/36)、52.8%(19/36)、33.3%(12/36)、52.8%(19/36)、50.0%(18/36);蛋白表达率分别为51.0%(49/96)、58.3%(56/96)、45.8%(44/96)、59.4%(57/96)、64.6%(62/96),各基因mRNA表达与蛋白表达基本一致。统计分析表明:VEGF表达与MDR1、LRP表达相关(P=0.025,P=0.022),与MRP表达无关(P=0.428);bFGF表达与MDR1、LRP表达相关(P=0.001,P=0.012),并与MRP+LRP共表达相关(P=0.001)。结论:在非小细胞肺癌中血管生成因子与耐药相关基因具有一定的相关性。     

可手术非小细胞肺癌患者术前血浆中VEGF/sVEGFR-1比值与长期生存关系的初步探索

目的:检测可手术非小细胞肺癌患者术前血浆中VEGF、sVEGFR-1的表达水平,并分析其与临床病理资料和长期生存的关系。方法:收集98例可手术非小细胞肺癌患者术前静脉血,用ELISA方法检测血浆中VEGF和sVEGFR-1的表达水平,并分析其表达水平与患者临床病理资料和长期生存之间的关系。结果:可手术非小细胞肺癌患者术前血浆中VEGF、sVEGFR-1的表达水平与患者的临床病理资料没有相关性,但是多因素生存分析中,年龄、TNM分期和VEGF/sVEGFR-1比值是可手术非小细胞肺癌患者长期生存的独立预后因子。结论:血浆VEGF/sVEGFR-1比值与可手术非小细胞肺癌患者的长期生存相关,该比值在非小细胞肺癌的意义值得进一步深入研究。     

Prognostic significance of platelet and microvessel counts in operable non-small cell lung cancer

BACKGROUND: Microvessel density, an indirect measure of angiogenesis, has been shown to be an independent prognostic marker in many solid tumours including non-small cell lung cancer (NSCLC). Platelets transport and release angiogenic growth factors. Platelets are increasingly likely to adhere to tumour microvessels due to raised expression of platelet-binding proteins and stasis in blood-flow. Increased vascular permeability in tumour microvessels facilitates platelet extravasation into the extracellular matrix. Adherence and extravasation both lead to platelet activation and release of growth factors capable of instigating the angiogenic process. METHODS: A total of 181 patients were identified who underwent resection of stage I-IIIa NSCLC with a post-operative survival >60 days. Patients were followed-up for a minimum of 24 months. Sections from the tumour periphery were stained for the endothelial marker CD34 (Novocastra NCL-END) using standard ABC immunohistochemistry. Chalkley counting was used to assess microvessel density. RESULTS: A pre-operative platelet count greater than the median and above the normal range (>400) was associated with a poor outcome (P=0.01 and P=0.04, respectively). Tumours with an above median and high Chalkley count (upper tertile) had a worse prognosis (P=0.007 and P=0.0006, respectively). There was no association between platelet count and Chalkley count. CONCLUSIONS: Platelet and microvessel counts are both potential prognostic markers for NSCLC. The role of platelets in the angiogenic process needs to be further investigated.     

Prognostic importance of serum vascular endothelial growth factor in relation to platelet and leukocyte counts in human renal cell carcinoma.

It has been shown that both serum vascular endothelial growth factor (VEGF) and also platelet counts are associated with survival in renal cell carcinoma (RCC). It is not known, however, whether VEGF in serum relates to the angiogenic activity of the tumour or is derived from circulating blood components. Therefore, the interrelation between serum VEGF, platelet and leukocyte counts compared with health history, clinicopathological findings and outcome was evaluated in patients with RCC. Blood samples were collected before nephrectomy in 161 patients. Serum VEGF165 was assessed by a quantitative ELISA method. Platelet and leukocyte counts were analysed routinely and obtained from medical records. The variables were compared using univariate and multivariate analysis. There were significant correlations between VEGF levels, and platelet (P < 0.001) and leukocyte counts (P < 0.001). Serum VEGF levels, platelet counts, as well as leukocyte counts correlated significantly to stage and grade. Platelet counts were significantly lower in men with medication (P = 0.042), and decreased with age particularly in women (P = 0.001). Age or medication did not affect VEGF levels or leukocyte counts. Both VEGF and platelets gave significant prognostic information in univariate analysis. Using Cox multivariate analysis, VEGF was the last variable to be excluded. Only stage and grade remained as independent prognostic factors. Both VEGF levels and platelet counts gave prognostic information but VEGF was more reliable as predictor of survival in patients with RCC.     

EXPRESSION OF VASCULAR ENDOTHELIAL GROWTH FACTOR AND BASIC FIBROBLAST GROWTH FACTOR IN HUMAN NON-SMALL CELL LUNG CANCER AND THEIR CLINICAL SIGNIFICANCE

Solid tumors contain tumor cells and vascular systems[1]. The growth and metastasis of solid tumors beyond 1-2mm in diameter depends on neovascularization. So the study of neovascularization helps to explain the biologic behavior of tumor. Angiogenesis is a complicated process mediated by a variety of angiogenic factors, which include vascular endothelial growth factor(VEGF) and basic fibroblast growth factor(bFGF). VEGF is an endothelial cell-specific mitogen with a pivotal role and may a…     

初治非小细胞肺癌患者血小板增高与临床病理及预后的关系

[目的]探讨初治非小细胞肺癌患者血小板增高与临床病理参数及预后的关系。[方法]检测初治非小细胞肺癌治疗前血小板计数,其中血小板增高组103例（血小板计数≥400×109/L）,随机选择同期收治的血小板正常组100例作为对照,分析血小板增高与患者临床病理参数及预后的关系。[结果]两组患者肿瘤分化程度、临床分期、淋巴结转移情况差异有统计学意义,血小板增高患者分化程度相对差（χ2=4.140,P=0.042）,临床分期晚（χ2=4.656,P=0.031）,淋巴结转移患者比例高（χ2=11.226,P=0.001）。单因素分析显示病理类型、分化程度、淋巴结转移、临床分期、治疗方式、血小板计数是影响非小细胞肺癌预后的因素,其中血小板增高患者3年生存率为18.2%,明显低于血小板正常患者的39.1%（χ2=10.684,P=0.001）。多因素分析显示分化程度、血小板计数、临床分期是初治非小细胞肺癌患者预后的独立影响因素。[结论]血小板增高是初治非小细胞肺癌患者预后不良的独立影响因素。临床医师应特别关注治疗前血小板增高肿瘤患者。     

Platelet number and interleukin-6 correlate with VEGF but not with bFGF serum levels of advanced cancer patients.

We have compared the platelet number and the serum concentration of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF) and interleukin-6 (IL-6) in 80 blood samples of 50 patients with advanced cancer. We have also measured the mitogenic effect of patient sera on endothelial cells in vitro in order to estimate the biological activity of serum VEGF. Serum VEGF concentration correlated with platelet number (r = 0.61; P < 10(-4)). Serum IL-6 levels correlated with platelet count (r = 0.36; P < 10(-3)), with serum VEGF levels (r = 0.55; P < 10(-4)) and with the calculated load of VEGF per platelet (r = 0.4; P = 3 x 10(-4)). Patients with thrombocytosis had a median VEGF serum concentration which was 3.2 times higher (P < 10(-4)) and a median IL-6 serum level which was 5.8 times higher (P = 0.03) than in other patients. Serum bFGF did not show an association with any of the other parameters. Patient sera with high VEGF and bFGF content stimulated endothelial cell proliferation significantly more than other sera (P = 4 x 10(-3)). These results support the role of platelets in the storage of biologically active VEGF. Platelets seem to prevent circulating VEGF from inducing the development of new blood vessels except at sites where coagulation takes place. IL-6, besides its thrombopoietic effect, also seems to affect the amount of VEGF stored in the platelets. This is in accordance with the indirect angiogenic action of IL-6 reported previously. The interaction of IL-6 with the angiogenic pathways in cancer might explain the stimulation of tumour growth occasionally observed during IL-6 administration. It also conforms to the worse outcome associated with high IL-6 levels and with thrombocytosis in several tumour types and benign angiogenic diseases.     

血管内皮生长因子、碱性成纤维细胞生长因子在非小细胞肺癌中的表达及临床意义

目的：探讨血管内皮生长因子（VEGF）、碱性成纤维细胞生长因子（bFGF)在非小细胞肺癌（Non-small cell lung cancer,NSCLC)中的表达及临床意义。方法：应用免疫组织化学方法检测96例NSCLC组织中VEGF、bFGF蛋白水平的表达，其中36例应用RT－PCR技术检测上述基因mRNA表达。结果：NSCLC中VEGF mRNA主要表达分泌性VEGF121和VEGF165，阳性率分别为69．5％（25／36）和41．7％（15／36），bFGF mRNA阳性率为52．8％（19／36）；免疫组化显示VEGF、bFGF阳性表达率分别为55．6％（20／36）和58．3％（21／36），二者之间呈正相关（P＝0．002）；VEGF、bFGF表达与患者年龄、性别、病理类型、分化程度、TNM分期、肿瘤转移、生存期等临床资料之间无统计学意义。结论：VEGF、bFGF在NSCLC血管形成中起重要作用，且二者具有协同作用。     

Pet birds and risk of lung cancer in North-Western Germany

The relationship between non-small cell lung cancer and platelet counts, serum levels of vascular endothelial growth factor (VEGF) and endostatin, is unclear. Platelet counts and serum VEGF and endostatin levels were measured preoperatively in 99 patients with non-small cell lung cancer, and the relationship between these factors and clinicopathological features, including prognosis, was examined. Mean serum VEGF level was slightly higher in patients than in healthy subjects (P=0.23). Mean serum endostatin level was 42.4+/-40.4 ng/ml in patients compared to 16.3+/-10.3 ng/ml in healthy subjects (P=0.0003). Serum endostatin levels were significantly higher in patients with involvement greater than T2 or stage IB, compared to other patients. Platelet count and serum endostatin level greater than the median were associated with poor prognosis. Our results suggested that platelet count and serum endostatin level may be useful markers for non-small cell lung cancer.     

Serum vascular endothelial growth factor per platelet count in hepatocellular carcinoma: correlations with clinical parameters and survival

BACKGROUND: Platelets have been reported to act as transporters of tumor-originated vascular endothelial growth factor (VEGF), contributing to tumor angiogenesis and progression. Serum VEGF per platelet count, as an indirect theoretical estimate of VEGF in platelets, may predict the malignant potential of tumors. However, its prognostic significance is still unclear in hepatocellular carcinoma (HCC), a highly vascular tumor. METHODS: Serum VEGF was measured by enzyme-linked immunosorbent assay. We compared serum VEGF, platelet count and serum VEGF per platelet count in 52 HCC patients, 26 liver cirrhosis patients and 30 healthy controls. The relation of serum VEGF per platelet count with clinicopathologic variables of HCC patients and the prognostic significance were investigated. RESULTS: Serum VEGF per platelet count in HCC patients was higher than in liver cirrhosis patients and healthy controls (P < 0.01). There was a statistically significant correlation between serum VEGF and platelet count in HCC patients (r = 0.751, P < 0.01). Serum VEGF per platelet count was higher in patients with advanced stage and portal vein thrombosis (P < 0.01). Patients with high serum VEGF per platelet count (>1.4 pg/10(6)) showed poor response to treatment and shorter overall survival (P < 0.01). Serum VEGF per platelet count was an independent prognostic factor with the presence of portal vein thrombosis (P < 0.01). CONCLUSIONS: Serum VEGF per platelet count could be a feasible prognostic indicator during the follow-up of patients with HCC.     

High plasma fibrinogen concentration and platelet count unfavorably impact survival in non–small cell lung cancer patients with brain metastases

High expression of fibrinogen and platelets are often observed in non-small cell lung cancer （NSCLC） patients with local regional or distant metastasis. However, the role of these factors remains unclear. The aims of this study were to evaluate the prognostic significance of plasma fibrinogen concentration and platelet count, as well as to determine the overall survival of NSCLC patients with brain metastases. A total of 275 NSCLC patients with brain metastasis were enrolled into this study. Univariate analysis showed that high plasma fibrinogen concentration was associated with age 〉 65 years （P = 0.011）, smoking status （P = 0.009）, intracranial symptoms （P = 0.022）, clinical T category （P = 0.010）, clinical N category （P = 0.003）, increased partial thromboplastin time （P 〈 0,001）, and platelet count （P 〈 0.001）. Patients with low plasma fibrinogen concentration demonstrated longer overall survival compared with those with high plasma fibrinogen concentration （median, 17.3 months versus 11.1 months; P 〈 0.001）. A similar result was observed for platelet counts （median, 16.3 months versus 11.4 months; P = 0.004）. Multivariate analysis showed that both plasma fibrinogen concentration and platelet count were independent prognostic factors for NSCLC with brain metastases （R2 = 1.698, P 〈 0.001 and R2 = 1.699, P 〈 0.001, respectively）. Our results suggest that high plasma fibrinogen concentration and platelet count indicate poor prognosis for NSCLC patients with brain metastases. Thus, these two biomarkers might be independent prognostic predictors for this subgroup of NSCLC patients.     

The prognostic significance of a previous malignancy in operable non-small cell lung cancer

There is little data in literature on survival of patients with lung cancer as a second primary (SP) malignancy. This retrospective study was undertaken to investigate whether a previous malignancy has prognostic significance in operable non-small cell lung cancer (NSCLC). Sixty-six patients with SP NSCLC were compared with 75 'first primary' (FP) NSCLC patients without a previous malignancy. All the 141 patients had been surgically treated with curative intent at The Netherlands Cancer Institute (NKI) between 1977 and 1996. Patients who had undergone resections for lung metastases were excluded. Clinical and pathological characteristics were collected and a multivariate analysis on all the 141 patients was carried out. All the previous malignancies were invasive cancers associated with metastatic potential and predominantly located in the aerodigestive tract. Female-male ratio was higher in the SP group (29 vs. 15%, P = 0.06). Tumour diameter was smaller in the SP group (3.0 vs. 4.7 cm, P < 0.0001). Pneumonectomy was performed less frequently in the SP group. Five-year survival rate was higher in the SP group (61 vs. 34%, P = 0.04). Univariate favourable prognostic factors were; small tumour diameter, female gender, favourable pTNM-stage, favourable pT-stage, favourable cTNM-stage, no post-operative radiotherapy and a history of previous malignancy. Multivariate analysis showed tumour diameter, female gender and pTNM-stage to be the major potential confounders. When adjustments were made for these three variables, the prognostic advantage of the SP group disappeared. It was concluded that SP NSCLC has a similar prognosis when compared with FP NSCLC. NSCLC diagnosed during the follow-up of a previous malignancy, and deemed operable, therefore, warrants the same diagnostic and therapeutic approach as NSCLC as first malignancy.     

化疗前后 NLR、血小板计数对评估晚期非小细胞肺癌患者预后的价值

目的：探讨化疗前后中性粒细胞／淋巴细胞比值（NLR）、血小板计数对晚期非小细胞肺癌（NSCLC）患者预后的判断价值。方法选取河南省安阳市肿瘤医院2011年10月—2012年12月收治的70例晚期 NSCLC 患者为研究对象,收集化疗前及化疗2周期后 NLR 及血小板水平。NLR 以中位数3．43为界,分低 NLR 及高 NLR 组;血小板≥300×109／L 为血小板升高组,100×109／L ＜血小板＜300×109／L为正常组。化疗2周期后根据 NLR 变化,分为3组：①化疗前低 NLR 组;②化疗前高 NLR化疗后降为低 NLR 组;③化疗前高 NLR 化疗后仍为高 NLR 组。根据化疗前后血小板计数的变化分为3组：①化疗前血小板正常组;②化疗前血小板升高化疗后降至正常组;③化疗前血小板升高化疗后仍为升高组。对比不同组患者的临床病理特征和远期生存。结果低 NLR 组、高 NLR 组患者中位生存时间分别为16．0、12．5个月,差异有统计学意义（χ2＝3．654,P ＝0．041）。血小板正常组、升高组中位生存时间分别为14．3、10．0个月,差异有统计学意义（χ2＝5．358,P ＝0．021）。化疗前后 NLR 变化3组患者的中位生存时间分别为14．5、12．1、9．0个月,差异有统计学意义（χ2＝7．701,P ＝0．021）。血小板计数变化3组患者中位生存时间分别为14．3、13．1、10．4个月,差异有统计学意义（χ2＝12．775,P ＝0．002）。COX 多因素分析显示 NLR（RR ＝1．467,95％CI 为1．014～2．124,χ2＝4．130,P ＝0．042）、血小板（RR ＝1．631,95％CI 为1．108～2．402,χ2＝6．137,P ＝0．013）和 TNM分期（RR ＝1．380,95％CI 为1．052～1．809,χ2＝5．420,P ＝0．020）均是影响晚期 NSCLC 患者预后的独立预后因素。结论化疗前 NLR 和血小板计数与患者不良预后有关,NLR 和血小板升高,患者生存期缩短。     

Tumour necrosis is an independent prognostic marker in non-small cell lung cancer: correlation with biological variables

BACKGROUND: Tumour necrosis (TN) is recognized to be a consequence of chronic cellular hypoxia. TN and hypoxia correlate with poor prognosis in solid tumours. METHODS: In a retrospective study the prognostic implications of the extent of TN was evaluated in non-small cell lung cancer (NSCLC) and correlated with clinicopathological variables and expression of epidermal growth factor receptor, Bcl-2, p53 and matrix metalloproteinase-9 (MMP-9). Tissue specimens from 178 surgically resected cases of stage I-IIIA NSCLC with curative intent were studied. The specimens were routinely processed, formalin-fixed and paraffin-embedded. TN was graded as extensive or either limited or absent by two independent observers; disagreements were resolved using a double-headed microscope. The degree of reproducibility was estimated by re-interpreting 40 randomly selected cases after a 4 month interval. RESULTS: Reproducibility was attained in 36/40 cases, Kappa score = 0.8 P < 0.001. TN correlated with T-stage (P = 0.001), platelet count (P = 0.004) and p53 expression (P = 0.031). Near significant associations of TN with N-stage (P = 0.063) and MMP-9 expression (P = 0.058) were seen. No association was found with angiogenesis (P = 0.98). On univariate (P = 0.0016) and multivariate analysis (P = 0.023) TN was prognostic. CONCLUSION: These results indicate that extensive TN reflects an aggressive tumour phenotype in NSCLC and may improve the predictive power of the TMN staging system. The lack of association between TN and angiogenesis may be important although these variables were not evaluated on serial sections.