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Eur J Cardiothorac Surg 2004;25:439-442
© 2004 Elsevier Science NL

Invasion of blood vessels as significant prognostic factor in radically resected T1-3N0M0 non-small-cell lung cancer

^a Department of Thoracic and Hyperbaric Surgery, University Medical School of Graz, Auenbruggerplatz 29, A-8036 Graz, Austria
^b Institute of Pathology, University Medical School of Graz, Graz, Austria

Received 17 November 2003; accepted 24 November 2003.

^* Corresponding author. Tel.: +43-316-385-3302; fax: +44-316-385-4679
e-mail: sabine.gabor{at}kfunigraz.ac.at

	Abstract

Top Abstract 1. Introduction 2. Material and methods 3. Results 4. Discussion 5. Conclusion References

 
Objectives: Radical resection is the therapy of choice in non-small-cell lung cancer (NSCLC). However, even in early stages (T1N0, T2N0) up to 35% of patients will experience recurrence. The aim of this retrospective study was to evaluate the prognostic influence of lymph vessel or blood vessel invasion in N0 patients. Methods: A total of 72 patients (male, 49; female, 23; median age 59; range 40–72) with NSCLC entered the study. The stages were T1–3N0 (T1, 25; T2, 41; T3, 6). Thirteen pneumonectomies and 59 lobectomies or bilobectomies with systematic lymphadenectomy and R0 resection were performed. Histologically, 24 adenocarcinomas, 31 squamous cell carcinomas and 14 subtypes of large cell carcinoma were found. In 22 cases microscopic invasion of the lymphatic vessels and in 11 invasions of blood vessels were found. Six patients showed invasion of either structure. Results: The patients were followed up for at least 5 years or until death. During the follow-up period 27 patients died (21 because of recurrence and 6 because of diagnosis not related to NSCLC). The 5 years overall survival amounted to 62.5%. In cases with invasion of the blood vessels the survival rate was 23.5%, in cases without invasion 74.5% (P0.01), whereas lymph vessel invasion had no significant impact on survival. Multivariate analysis covering T stages, histological subtypes, location of the tumor, grading, age, sex, and invasion of the lymphatic or the blood vessels showed invasion of the blood vessels as the only factor with significant prognostic impact in the study population. Conclusions: In resectable N0 patients with NSCLC the microscopic invasion of blood vessels should be considered as an additional prognostic parameter.

Key Words: Prognosis • Non-small-cell lung cancer • Blood vessel invasion • Lymph vessel invasion

	1. Introduction

Top Abstract 1. Introduction 2. Material and methods 3. Results 4. Discussion 5. Conclusion References

 
Lung cancer is the most common cause of mortality due to cancer worldwide. Non-small-cell lung cancer (NSCLC) accounts for approximately 80% of lung cancer [1]. Radical resection is still the therapy of choice in NSCLC. However, though nodal negative stages have a better prognosis than nodal positive ones, even in stage I (T1–2N0) up to 35% of patients will experience distant or local recurrence.

Among the numerous prognostic factors that have been identified in NSCLC, simple patho- or pathohistologic features have been little studied except for T and N categories. However, even the clear-cut pathologic findings as documented by light microscopy on H and E stain are the global results of multiple steps on the biologic and cellular level in tumor growth. Blood vessel invasion (BVI), for example, requires tumor growth around the vessels, destruction of vascular walls, and propagation of the tumor into the vascular lumen.

Up to this time, the prognostic impact of blood vessel invasion had been studied only in small series of NSCLC and in selected subgroups of patients [2].

The aim of our work was to establish the impact of blood vessel and/or lymph vessel invasion on prognosis in a series of radically resected T1–3 nodal negative NSCLC.

	2. Material and methods

Top Abstract 1. Introduction 2. Material and methods 3. Results 4. Discussion 5. Conclusion References

 
A total of 72 consecutive patients with pT1-3N0M0 NSCLC, who had undergone radical resection and lymph node dissection (male, 49; female, 23; median age 59; range 40–72) were retrospectively reviewed. For patients' characteristics see Table 1.

2.2. Histopathological workup
The surgical specimens were immediately fixed in 10% formalin and underwent routine histopathological workup with paraffin embedding. Each lymph node was investigated for metastasis by using three slices as a routine. In case of doubt, serial cuttings were added. Representative areas of the tumor were processed by serial cutting in each case. Routine hematoxylin–eosin stain was used for all slices.

Blood vessel invasion was defined as the presence of neoplastic structures inside the lumen of a vessel. In most cases it was characterized by neoplastic cells, embedded in organized vascular thrombosis. Lymph vessel invasion was diagnosed by the presence of clear-cut tumor cells within the lumen of a lymph vessel. If there was any doubt whether the neoplastic cells could represent artifacts, the specimen underwent serial cutting, documenting the presence or absence of infiltration of the vascular wall.

2.3. Follow-up
No adjuvant therapy either pre- or post-operatively was administered. The patients were followed up for at least 5 years or until death. Follow-up investigations included physical investigation and chest roentgenograms every 6 months throughout the first 3 years as well as routine laboratory investigations, CT scan and bronchoscopy at yearly intervals. In case of clinically suspect metastasis cerebral CT scan, abdominal ultrasound or bone scan was performed.

2.4. Statistical analysis
Survival time was defined as the interval from the date of operation to the last follow-up or until death. Recurrence-free survival was defined as the period ranging from the date of surgery to diagnosis of relapse. Deaths related to causes other than NSCLC were not excluded from the analysis. Statistical analysis was performed using the SPSS software system. The post-operative survival rate was analyzed by the Kaplan–Meier method, and the differences in survival rates were assessed by the log-rank test (Fig. 1)

Fig. 1. Kaplan–Meier curve. , Survival rate without blood vessel invasion; , survival rate with blood vessel invasion.

. Multivariate analyses were performed using stepwise Cox proportional hazards model to identify independent prognostic factors. The criterion for significance was P<0.05.

	3. Results

Top Abstract 1. Introduction 2. Material and methods 3. Results 4. Discussion 5. Conclusion References

 
The pathological stages according to UICC 93 were T1, 25; T2, 41; T3, 6 (see Table 1). Histologically, 27 adenocarcinomas, 31 squamous cell carcinomas and 14 subtypes of large cell carcinoma were found. In 22 cases microscopic invasion of the lymphatic vessels, in 11 invasions of blood vessels and in six cases invasion of both was present.

During the follow-up period 29 patients developed tumor recurrence (four locoregional, 25 distant). Twenty-seven patients died (21 because of recurrence and six because of diagnosis not related to NSCLC). The recurrence-free survival was 19 months for the total collective, 15 months for patients with lymph vessel invasion, and 16 months for those with blood vessel invasion (P>0.05).

The 5 years survival amounted to 62.5%. In cases with invasion of the blood vessels the survival rate was 23.5%; in cases without invasion 74.5%. Multivariate analysis documented that T stage, histological subtype, location of the tumor, lymph vessel invasion, grading, age and sex had no significant influence on survival.

The only factor significantly influencing survival was the invasion of the blood vessels (P0.01).

	4. Discussion

Top Abstract 1. Introduction 2. Material and methods 3. Results 4. Discussion 5. Conclusion References

 
The most important factor predicting the outcome in patients with lung cancer is whether the tumor has spread locally, regionally, and/or systemically. The TNM classification describes the local, regional and systemical extent of the tumor. Multivariate analysis in our study shows that considering the T classification, the histological subtypes, the location of the tumor, grading, sex, age, lymphatic vessel invasion and blood vessel invasion, only blood vessel invasion is an important prognostic factor in completely resected T1–3N0M0 NSCLC.

Similar to our results, other investigators have found that both disease-free survival and overall survival in completely resected T1N0M0 was influenced by blood vessel invasion [2–4]. It was even suggested that vascular invasion should be considered as a prognostic factor superior to the T-stage (Kessler). It has been observed that in tumors with a high degree of angiogenesis, blood vessel invasion was significantly more frequent (Macchiarini). During the early stages of tumor growth, angiogenesis is required to permit further growth of the tumor. New intratumoral capillaries are generated from pre-existing vessels. Tumor cells may then penetrate these vessels and escape from the primary site to distant organs. So blood vessel invasion is one of the steps leading to metastasis [2,5].

In consequence, it has already been suggested to consider the presence of blood vessel invasion in the tumor as an indicator for the presence of occult metastases in stages currently regarded as amenable to curative surgery. Based upon the current data, these very patients might be scheduled for post-operative adjuvant systemic therapy [6].

Except Macchiarini all other investigators included nodal negative and positive patients with NSCLC in their studies. The ‘N’ factor is one of the essential prognostic factors [7,8]. It was even suggested that among patients with nodal micro metastasis and vascular endothelial growth factor over-expression the risk of systemic disease should be considered [9,10]. In our study we investigated patients with N0 and blood and lymphatic vessel invasion. In these cases no adjuvant chemo- or radiotherapy is determined. We had a recurrence rate of 36.4% in radically resected N1–3 N0 NSCLC. In cases of blood vessel invasion we had a significantly different recurrence rate of 74.3% (P<0.05). In consequence we should consider if an adjuvant treatment in cases with an N0 situation and blood vessel invasion might lower the recurrence rate.

In contrast to other studies, we found no significant difference in survival between cases with or without invasion of the lymphatic vessels (Brechot).

	5. Conclusion

Top Abstract 1. Introduction 2. Material and methods 3. Results 4. Discussion 5. Conclusion References

 
In resectable N0M0 patients with NSCLC the microscopic invasion of blood vessels should be considered as additional prognostic factor identifying patients with a higher risk for recurrence. Further studies are required to evaluate potential benefits from post-operative chemotherapy in this very subgroup.

	Footnotes

 
Presented at the joint 17th Annual Meeting of the European Association for Cardio-thoracic Surgery and the 11th Annual Meeting of the European Society of Thoracic Surgeons, Vienna, Austria, October 12–15, 2003.

	References

Top Abstract 1. Introduction 2. Material and methods 3. Results 4. Discussion 5. Conclusion References

 

1. Poleri C., Morero J.L., Nieva B., Vazquez M.F., Rodriguez C., de Titto E., Rosenberg M. Risk of recurrence in patients with surgically resected stage I non small cell lung cancer. Chest 2003;123:1858-1867.[Abstract/Free Full Text]
2. Kessler R., Gasser B., Massard G., Roeslin N., Meyer P., Wihlm J., Morand G. Blood vessel invasion is a major prognostic factor in resected non small cell lung cancer. Ann Thorac Surg 1996;62:1489-1493.[Abstract/Free Full Text]
3. Macchiarini P., Fontanini G., Hardin M.J., Chuanchieh H., Bigini D., Vignati S., Pingitore R., Angeletti C.A. Blood vessel invasion by tumor cells predicts recurrence in completely resected T1N0M0 non small cell lung cancer. J Thorac Cardiovasc Surg 1993;106(1):80-89.[Abstract]
4. Ichinose Y., Yano T., Asoh H., Yokoyama H., Yoshino I., Katsuda Y. Prognostic factors obtained by a pathologic examination in completely resected non small cell lung cancer: an analysis in each pathologic stage. J Thorac Cardiovasc Surg 1995;110(3):723-730.[Abstract/Free Full Text]
5. Fontanini G., Bigini D., Vignati S., Basolo F., Mussi A., Lucchi A., Chino S., Angeletti C.A., Harris A.L., Bevilacqua G. Microvessel count predicts metastatic disease and survival in non small cell lung cancer. J Pathol 1995;177(1):57-63.[CrossRef][Medline]
6. Cote R.J. Occult metastases: real harm or false alarm?. J Thorac Cardiovasc Surg 2003;126(2):10-15.
7. Brechot J.M., Chevret S., Charpentier M.C., Appere de Vecchi C., Capron F., Prudent J., Rochemaure J., Chastang C. Blood vessel and lymphatic vessel invasion in resected non small cell lung carcinoma. Correlation with TNM stage and disease free and overall survival. Cancer 1996;78(10):2111-2118.[CrossRef][Medline]
8. Brundage M.D., Davies D., Mackillop J. Prognostic factors in non small cell lung cancer. A decade of progress. Chest 2002;122:1037-1057.[Abstract/Free Full Text]
9. Drings P., Dienemann H., Wannenmacher M. Management des Lungenkarzinoms. . Berlin: Springer, 2002.
10. Ohta Y., Oda M., Wu J., Tsunezuka Y., Hiroshi M., Nonomura A., Watanabe G. Can tumor size be a guide for limited surgical intervention in patients with peripheral non-small cell lung cancer? Assessment from the point of view of nodal micrometastasis. J Thorac Cardiovasc Surg 2001;122(5):678-681.

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Gabor, S. Articles by Smolle Jüttner, F.M. Search for Related Content PubMed PubMed Citation Articles by Gabor, S. Articles by Smolle Jüttner, F.M. Related Collections Lung - basic science Lung - cancer Lung - other