Stage IA non-small cell lung cancer: Vessel invasion is a poor prognostic factor and a new target of adjuvant chemotherapy

doi:10.1016/j.lungcan.2007.01.019

Lung Cancer

Volume 56, Issue 3, June 2007, Pages 341-348

https://doi.org/10.1016/j.lungcan.2007.01.019 Get rights and content

Summary

This study reports the efficacy of adjuvant chemotherapy in stage IA non-small cell lung cancer (NSCLC) with vessel invasion (Vi). We sub-divided 322 patients with surgically resected pathological stage IA NSCLC into two groups according to Vi [non-Vi (n = 237) and Vi (n = 85)]. Both groups were compared with regard to age, gender, performance status, smoking habits, serum carcinoembryonic antigen level, extent of surgery, tumour size, histopathology, recurrence sites, and survival. The overall 5-year survival rates of non-Vi and Vi groups were 89.6% and 71.8% (P < 0.001), respectively. Distant metastasis was observed more frequently in the Vi group (P < 0.001, risk ratio: 9.06). Univariate and multivariable analyses identified poor performance status, squamous cell carcinoma, tumour size ≥15 mm and Vi as poor prognostic factors (P < 0.05). The overall 5-year survival rate of stage IA Vi group nearly overlapped with that of patients with stage IB NSCLC. Retrospectively, oral uracil-tegafur chemotherapy increased the overall 5-year survival rate of stage IA Vi group by more than 25% (P = 0.036). In conclusion, vessel invasion is a poor prognostic factor in patients with stage IA NSCLC. Prognosis of patients with Vi-stage IA NSCLC is similar to that of patients with stage IB NSCLC and is improved significantly by postoperative oral uracil-tegafur chemotherapy. Our preliminary study suggests that stage IA Vi group benefits from adjuvant chemotherapy.

Introduction

Recent advances in diagnostic imaging have increased the number of patients diagnosed with stage IA lung cancer. Histopathological and imaging studies of small size lung cancer strongly indicate the existence of good prognostic groups in stage IA non-small cell lung cancer (NSCLC) [1]. However, the overall 5-year survival of stage IA NSCLC still ranges from 66 to 85%, which indicates the existence of poor prognostic group [2], [3].

Stage IA NSCLC is sub-divided according to poor prognostic factors such as smoking history, serum level of carcinoembryonic antigen (CEA), extent of operation, tumour size, and vessel invasion (Vi) [4], [5], [6], [7], [8], [9]. Vi, which includes lymphatic or blood vessel invasion, is considered a useful predictor of survival in NSCLC. In a study of T1 N0 M0 adenocarcinomas and bronchioloalveolar carcinomas of the lung, Goldstain and colleagues demonstrated that the nonpulmonary metastasis-free survival advantage of patients without Vi was significant; 78% of patients were disease-free at 5 years when Vi was absent compared with only 35% when Vi was present [8].

Since 2004, clinical research studies have established the efficacy of adjuvant chemotherapy on post-operative patients with stage IB to IIIA NSCLC [10], [11], [12]. On the other hand, the trial of adjuvant chemotherapy on patients with stage IA NSCLC could not detect significant improvement of survival [11]. However, the seminal prospective study of Kato et al. [11] showed that treatment with uracil-tegafur, which has anti-vascular endothelial growth factor (VEGF) effect [13], tended to improve the survival rate of patients with a tumour measuring 2–3 cm in diameter. Because, Vi correlates with VEGF expression in lung cancer [14], we speculated that uracil-tegafur chemotherapy could improve survival of patients with surgically resected Vi-stage IA NSCLC.

The objectives of the present study were to assess whether Vi is a valuable prognostic criterion that can be used to sub-divide patients with surgically resected stage IA NSCLC, and to evaluate the effect of adjuvant chemotherapy of oral uracil-tegafur on stage IA Vi group.

Section snippets

Patients

This retrospective study included 322 patients (178 male and 144 female) with pathological stage IA NSCLC who underwent surgical resection at Oita Prefectural Hospital between February 1978 and March 2005. The age distribution ranged from 41 to 88 years (median, 67 years). None of the patients received radio- or chemotherapy preoperatively. The clinical records of these patients were reviewed to obtain routine demographic information and confirm accurate pathological staging. The records of

Results

Vi was identified in 85 patients (26.4%; Vi group) among 322 patients with stage IA NSCLC. The overall 5-year survival rates were 89.6% for the non-Vi group (n = 237) and 71.8% for the Vi group (Fig. 1). The difference between the two groups was significant (P < 0.001).

The associations between Vi and various clinicopathological prognostic factors are shown in Table 1. Chi-square analysis showed the proportion of patients with Vi was significantly higher in patients with high serum CEA level (>5

Discussion

The aim of the present study was to determine whether vessel invasion (Vi) is an independent prognostic factor in patients with surgically resected stage IA NSCLC, and whether adjuvant chemotherapy could improve the survival of the poor prognostic group.

Our results clearly showed that Vi is a poor prognostic factor in patients with surgically resected stage IA NSCLC. We showed that overall 5-year survival rate of Vi group was significantly lower than that of non-Vi group. Both lymphatic and

Conclusion

Our data point to the efficacy of adjuvant chemotherapy in the poor prognostic group of stage IA NSCLC. We focused on Vi as a profitable prognostic factor, which can be clearly used to sub-divide patients with stage IA NSCLC. The prognosis of patients with surgically resected Vi-stage IA NSCLC was similar to that of patients with stage IB NSCLC. Uracil-tegafur-based adjuvant chemotherapy significantly improved prognosis of patients with Vi-stage IA NSCLC possibly based on high sensitivity. A

Conflicts of interest

None declared.

Acknowledgements

We thank Drs. Yoshitaka Uchiyama and Norio Yamaoka for their effort in data assembly and invaluable assistance.

References (30)

P. Yang et al.
Clinical features of 5,628 primary lung cancer patients: experience at mayo clinic from 1997 to 2003
Chest
(2005)
T. Naruke et al.
Prognosis and survival in resected lung carcinoma based on the new international staging system
J Thorac Cardiovasc Surg
(1988)
H. Kawai et al.
Smoking history before surgery and prognosis in patients with stage IA non-small-cell lung cancer—a multicenter study
Lung Cancer
(2005)
A. Gajra et al.
Impact of tumor size on survival in stage IA non-small cell lung cancer: a case for subdividing stage IA disease
Lung Cancer
(2003)
K. Suzuki et al.
Predictors of lymph node and intrapulmonary metastasis in clinical stage IA non-small cell lung carcinoma
Ann Thorac Surg
(2001)
C.F. Mountain
Revisions in the international system for staging lung cancer
Chest
(1997)
T.T. Pechet et al.
Arterial invasion predicts early mortality in stage I non-small cell lung cancer
Ann Thorac Surg
(2004)
P. Micke et al.
Tumour-stroma interaction: cancer-associated fibroblasts as novel targets in anti-cancer therapy?
Lung Cancer
(2004)
S. Takeda et al.
Impact of large tumor size on survival after resection of pathologically node negative (pN0) non-small cell lung cancer
Ann Thorac Surg
(2005)
Y. Watanabe
Substaging of stage I—a commentary
Lung Cancer
(2003)

O. Birim et al.

Survival after pathological stage IA nonsmall cell lung cancer: tumor size matters

Ann Thorac Surg

(2005)

P. Macchiarini et al.

Most peripheral, node-negative, non-small-cell lung cancers have low proliferative rates and no intratumoral and peritumoral blood and lymphatic vessel invasion. Rationale for treatment with wedge resection alone

J Thorac Cardiovasc Surg

(1992)

M. Noguchi et al.

Small adenocarcinoma of the lung. Histologic characteristics and prognosis

Cancer

(1995)

Y. Sakao et al.

Carcinoembryonic antigen as a predictive factor for postoperative tumor relapse in early-stage lung adenocarcinoma

Eur J Cardiothorac Surg

(2004)

R.J. Ginsberg et al.

Randomized trial of lobectomy versus limited resection for T1 N0 non-small cell lung cancer. Lung Cancer Study Group

Ann Thorac Surg

(1995)

Cited by (109)

Artificial intelligence-based recurrence prediction outperforms classical histopathological methods in pulmonary adenocarcinoma biopsies
2023, Lung Cancer
Between 10 and 50% of early-stage lung adenocarcinoma patients experience local or distant recurrence. Histological parameters such as a solid or micropapillary growth pattern are well-described risk factors for recurrence. However, not every patient presenting with such a pattern will develop recurrence. Designing a model which can more accurately predict recurrence on small biopsy samples can aid the stratification of patients for surgery, (neo-)adjuvant therapy, and follow-up.
In this study, a statistical model on biopsies fed with histological data from early and advanced-stage lung adenocarcinomas was developed to predict recurrence after surgical resection. Additionally, a convolutional neural network (CNN)-based artificial intelligence (AI) classification model, named AI-based Lung Adenocarcinoma Recurrence Predictor (AILARP), was trained to predict recurrence, with an ImageNet pre-trained EfficientNet that was fine-tuned on lung adenocarcinoma biopsies using transfer learning. Both models were validated using the same biopsy dataset to ensure that an accurate comparison was demonstrated.
The statistical model had an accuracy of 0.49 for all patients when using histology data only. The AI classification model yielded a test accuracy of 0.70 and 0.82 and an area under the curve (AUC) of 0.74 and 0.87 on patch-wise and patient-wise hematoxylin and eosin (H&E) stained whole slide images (WSIs), respectively.
AI classification outperformed the traditional clinical approach for recurrence prediction on biopsies by a fair margin. The AI classifier may stratify patients according to their recurrence risk, based only on small biopsies. This model warrants validation in a larger lung biopsy cohort.
Prognostic significance of blood and lymphatic vessel invasion in pathological stage IA lung adenocarcinoma in the 8th edition of the TNM classification
2019, Lung Cancer
Citation Excerpt :
In addition, the lung cancer-specific survival outcomes differed significantly depending on the presence or absence of lymphatic or blood vessel invasion in patients with p-stage IA1 (Fig. B.1B) or IA2 (Fig. C.1B) tumors, respectively. Certain previous studies have also evaluated lymphatic and blood vessel invasion in combination [2,4,9], while others have analyzed these separately [3,5–8,10,11]. In previous studies that investigated lymphatic and blood vessel invasion separately, either lymphatic vessel invasion [5,10], blood vessel invasion [3,6,8,11], or both (TVI) [7] were reported to be prognostic factors.
The prognostic significance of blood and lymphatic vessel invasion in the 8th edition of the Tumor, Node, Metastasis (TNM) classification remains unclear. Therefore, this study aimed to evaluate the prognostic significance of blood and lymphatic vessel invasion in p-stage IA lung adenocarcinoma in the 8th edition of the TNM classification.
We retrospectively examined patients with p-Stage 0-IA lung adenocarcinoma, reclassified according to the 8th edition of the TNM classification. Blood and lymphatic vessel invasion were evaluated using hematoxylin-eosin and Elastica van Gieson and hematoxylin-eosin and anti-podoplanin antibody staining, respectively. Combined blood and lymphatic vessel invasion constituted tumor vessel invasion (TVI).
Overall, 306 patients were evaluated. The median follow-up period was 98.0 (range: 10–216) months. The 5-year recurrence-free survival differed significantly among patients with and without TVI in p-stage IA1 (TVI−: 100%, TVI+: 88.9%, P = 0.007) and IA2 (TVI−: 94.6%, TVI+: 80.8%, P = 0.012) but not in p-stage IA3 (TVI−: 66.7%, TVI+: 75.0%, P = 0.598). The 5-year lung cancer-specific survival also differed significantly among those with and without TVI in p-stage IA1 (TVI−: 100%, TVI+: 88.9%, P < 0.001) and IA2 (TVI−: 98.2%, TVI+: 88.7%, P = 0.043) but not in p-Stage IA3 (TVI−: 66.7%, TVI+: 75.0%, P = 0.858). No recurrence and lung cancer-specific deaths occurred in p-stage IA1 patients without TVI. On multivariate analysis, the presence of TVI was independently associated with recurrence and lung cancer-specific death in patients with p-stage IA1-2 lung adenocarcinoma. TVI did not affect the prognosis of those with p-stage IA3 adenocarcinoma.
TVI is a prognostic factor in patients with p-stage IA1-2 lung adenocarcinoma. P-stage IA1 lung adenocarcinoma without TVI may therefore be classified as minimally invasive.
Clinical significance of PD-L1-positive cancer-associated fibroblasts in pN0M0 non-small cell lung cancer
2019, Lung Cancer
Citation Excerpt :
From the viewpoint of tumor immunology, as a predictive biomarker for tumor recurrence in pN0M0 NSCLC, Takahashi et al. reported that high neutrophil–lymphocytes ratios in peripheral blood were associated with poor patient prognosis [35]. Another predictive biomarker of tumor recurrence in pN0M0 NSCLC is reported to be vessel invasion of tumor cells [36,37]. Ko et al. reported that overexpression of cyclin A2 on tumor cells was associated with poor relapse-free survival because cyclin A2 positively regulated the cell cycle of tumor cells [38].
Cancer-associated fibroblasts (CAFs) are a dominant cell type in tumor stroma and support the generation of pro-tumorigenic microenvironment. CAFs have frequent opportunities to interact with immune cells infiltrating the tumor stroma, but the process remains to be determined. In this study, we focused on immune checkpoint mechanism. We also examined the induction of programmed cell death-ligand 1 (PD-L1) on CAFs by immune cell, and the clinical significance of PD-L1-expressed CAFs in non-small cell lung cancer (NSCLC).
CAFs were isolated from human NSCLC tissues, and PD-L1 expression levels in CAFs were analyzed by real-time polymerase chain reaction and flow-cytometry. Following immunohistochemical analysis of PD-L1 in surgically resected pN0M0 NSCLC (n = 125, including 88 invasive adenocarcinomas and 37 squamous cell carcinomas), the correlation of PD-L1-positive CAFs with clinicopathological features was investigated.
PD-L1 mRNA and protein expression on CAFs was upregulated by exogenously supplemented interferon-gamma (IFN-γ) and downregulated through the depletion of IFN-γ. PD-L1 expression on CAFs was upregulated by co-culture with activated lymphocytes releasing IFN-γ. Immunohistochemistry revealed that PD-L1-positive CAFs were observed in 31 cases (24.8%). Postoperative relapse-free survival was significantly prolonged in patients with PD-L1-positive CAFs as compared with those with PD-L1-negative CAFs, with 5-year relapse-free probabilities of 84.5% and 66.3%, respectively (P = 0.031). Multivariate analysis revealed that PD-L1 expression on CAFs was an independent prognostic factor of longer relapse-free survival after surgery (hazard ratio: 3.225, P = 0.027).
PD-L1 expression on CAFs is reversibly regulated by environmental stimuli including IFN-γ from activated lymphocytes. In the non-metastatic NSCLC, PD-L1 expression on CAFs suggests the induction of anti-tumor immune responses, contributing to better prognosis after surgery.
Radiologic Criteria in Predicting Pathologic Less Invasive Lung Cancer According to TNM 8th Edition
2019, Clinical Lung Cancer
The Japan Clinical Oncology Group Study 0201 has proposed radiologic criteria on thin-slice computed tomography to diagnose pathologic less invasive lung adenocarcinoma that could be a candidate for sublobar resection based on the previous tumor, node, metastasis classification system (TNM). The aim of this study was to propose the new radiologic criteria for predicting pathologic less invasive cancer according to the 8th edition TNM.
We analyzed 744 patients who had peripheral clinical Tis-T1cN0M0 non–small-cell lung cancer of 3 cm or less and underwent complete resection by lobectomy from 2003 to 2011. We defined lung cancer with no nodal involvement and no vessel invasion pathologically as a pathologic less invasive cancer and investigated the radiologic criteria on the basis of the solid component size and by the consolidation-to-tumor (C/T) ratio (calculated with the maximum solid component diameter divided by the maximum tumor diameter) by using preoperative thin-slice computed tomography to predict them with a specificity of 97% or more, and evaluated overall survival.
Patients with clinical Tis/T1mi/T1a disease had no pathologic invasive cancer except for one patient (specificity, 99%). From the investigation with the C/T ratio, only the criterion of C/T ratio 0.5 or less met the standard (specificity, 100%). The final specificity after combining these criteria was 99.6%, and they showed excellent prognosis (5-year overall survival rate, 96.2%).
Lung cancer with clinical Tis/T1mi/T1a or a C/T ratio of 0.5 or less can be completely cured by sublobar resection with sufficient margin because of its less invasive nature pathologically.
Spread Through Air Spaces (STAS): A New Pathologic Morphology in Lung Cancer
2019, Clinical Lung Cancer
In 2015, the World Health Organization classification of lung cancer proposed the concept of spread through air spaces (STAS) as a new pattern of invasion in lung adenocarcinoma. The definition of STAS included one or more pathologic micropapillary clusters, solid nests or single cells beyond the edge of the tumor into air spaces in the surrounding lung parenchyma, and separation from the main tumor other than tumor islands. The roles of STAS has been investigated in many studies. The results indicated that STAS is associated with key clinical variables and the prognosis of patients both in lung adenocarcinoma, lung squamous cell carcinoma, small-cell lung cancer, and lung pleomorphic carcinoma. This mini review will be focused on the developments and perspectives of STAS in lung cancer.
Proposal on incorporating lymphovascular invasion as a T-descriptor for stage I lung cancer
2018, Lung Cancer
Lymphovascular invasion (LVI) and Visceral Pleural Invasion (VPI) have been reported to be risk factors for stage I Non-Small Cell Lung Cancer (NSCLC). However, only VPI was incorporated into the current 8th Tumor–Node–Metastasis (TNM) classification. This study aimed to explore the prognostic effect of LVI and VPI on TNM staging in pathological stage I NSCLC.
We retrospectively reviewed 2633 consecutive p-stage I NSCLC patients in the Shanghai Chest Hospital (2008–2012). By using the Kaplan–Meier method and Cox proportional hazard regression model, we identified the correlations between LVI, VPI, and clinical outcomes in p-stage 1 NSCLC.
Of all 2633 p-stage I NSCLC patients, 222 were pathologically diagnosed with LVI and 836 pathologically with VPI. The 5-year recurrence free survival (RFS) and overall survival (OS) rates of patients with LVI was significantly worse compared to those without LVI (61.2% vs 82.0%, p < 0.001; 73.3% vs 88.1%, p < 0.001). The same results emerged for patients with VPI (70.1% vs 85.9%, p < 0.001; 82.3% vs 90.0%, p < 0.001). Using the univariable and multivariable analysis, we found that when tumor diameter was 3 cm or smaller, LVI (RFS: hazard ratio [HR], 2.54; 95% confidence interval [CI], 1.86–3.50; p < .001; OS: HR, 2.53; 95% CI, 1.72–3.71; p < .001) and VPI (RFS: HR, 2.14; 95% CI, 1.71–2.67; p < .001; OS: HR, 1.56; 95% CI, 1.12–2.04; p = 0.01) were significant prognostic factors for RFS and OS. When tumor size was between 3–4 cm, LVI (HR, 1.84; 95% CI, 1.03–3.29; p = 0.039) and VPI (HR, 2.56; 95% CI, 1.61–4.07; p < .001) were associated with inferior OS.
The presence of LVI significantly affected OS and RFS in stage I NSCLC patients. Our results suggested that it might be better to incorporate LVI as a T descriptor as VPI in the further TNM classification.

View all citing articles on Scopus

View full text

Stage IA non-small cell lung cancer: Vessel invasion is a poor prognostic factor and a new target of adjuvant chemotherapy

Summary

Introduction

Section snippets

Patients

Results

Discussion

Conclusion

Conflicts of interest

Acknowledgements

Chest

J Thorac Cardiovasc Surg

Lung Cancer

Lung Cancer

Ann Thorac Surg

Chest

Ann Thorac Surg

Lung Cancer

Ann Thorac Surg

Lung Cancer

Ann Thorac Surg

J Thorac Cardiovasc Surg

Small adenocarcinoma of the lung. Histologic characteristics and prognosis

Cancer

Carcinoembryonic antigen as a predictive factor for postoperative tumor relapse in early-stage lung adenocarcinoma

Eur J Cardiothorac Surg

Randomized trial of lobectomy versus limited resection for T1 N0 non-small cell lung cancer. Lung Cancer Study Group

Ann Thorac Surg