Yujin Kudo

Impact of visceral pleural invasion on the survival of patients with non-small cell lung cancer.

BACKGROUND In this study, we investigated visceral pleural invasion (VPI) as a poor prognostic factor in patients with non-small cell lung cancer (NSCLC) according to the 7th edition of the TNM classification. METHODS Between January 2000 and December 2007, 886 consecutive patients with pathological T1a-T2b NSCLC underwent complete resection with systematic lymph node dissection in Tokyo Medical University. We statistically analyzed the association between VPI and clinicopathologic factors, or clinical outcomes. RESULTS The 5-year overall survival (OS) rates of the pl0, pl1, and pl2 patients were 80.8%, 63.7%, and 49.6%, respectively, with significant differences between pl0 and pl1 (p=0.002), pl1 and pl2 (p=0.03). Thus, the pl1 and pl2 patient groups were defined as patients with VPI. VPI was found to be a significant independent prognostic factor by multivariate survival analysis (p=0.0002). In patients with tumors ≤3 cm, especially with tumors ≤2 cm, VPI was significantly associated with an increased rate of lymph node metastasis, compared with non-VPI (p=0.0003 and p=0.015, respectively). Analysis of the OS of patients stratified by tumor size (≤3 cm, 3.1-5 cm, 5.1-7 cm) and VPI status showed that in any nodal status, patients with 3.1-5 cm/VPI tumors had significantly worse survival than patients with ≤3 cm/VPI tumors (p=0.019) and patients with 3.1-5 cm/non-VPI tumors (p=0.001). On the other hand, there was no significant difference in the OS between patients with 3.1-5 cm/VPI tumors and patients with 5.1-7 cm tumors regardless of lymph node metastasis (T2b tumors). Similar relationships were observed among these groups with N0 disease. CONCLUSION We identified the presence of VPI as an independent poor prognostic factor in patients with NSCLC of ≤7 cm. Tumors 3.1-5cm with VPI should be upstaged to T2b tumors in the future in the TNM classification of the Union of International Cancer Control staging system. In addition, the surgical strategy involving more extensive lymph node dissection for patients with ≤3 cm/VPI tumors, especially ≤2 cm/VPI, is warranted owing to more frequent lymph node metastasis.

Association between high-resolution computed tomography findings and the IASLC/ATS/ERS classification of small lung adenocarcinomas in Japanese patients

OBJECTIVES The detection rate of small pulmonary nodules has recently increased and new techniques have been developed to improve diagnostic yield. The IASLC/ATS/ERS classification demonstrated a difference in prognosis depending on the histological subtypes of lung adenocarcinoma. We evaluated the association between high-resolution computed tomography (HRCT) findings and the classification of these tumors. METHODS We reviewed the data of 220 lung adenocarcinoma (≤3 cm) patients who received complete resection with lymph node dissection in our hospital. From the HRCT findings, the tumors were classified into the following 3 categories: pure-solid nodules, part-solid nodules, or pure ground-glass opacity (GGO) nodules. Pathological invasion factor (PIF) was evaluated by the degree of blood vessel invasion, lymphatic permeation, and visceral pleural invasion. RESULTS The tumors were classified as pure GGO nodules in 16 patients, part-solid nodules in 91, and pure-solid nodules in 113 from the HRCT findings. Tumors were diagnosed as noninvasive or minimally invasive adenocarcinomas (NMIADs) in 44 patients, and invasive adenocarcinomas (IADs) in 176. Lymph node metastasis was present in 31 patients (14.1%) and PIF in 101 (45.9%). All pure-solid nodules were IADs with a high PIF frequency (75.2%) or with lymph node metastasis (26.5%). All pure GGO nodules were NMIADs or lepidic-predominant adenocarcinomas. Among the part-solid nodules, IAD was detected in 67.0% of the patients and PIF in 16.5%. The consolidation/tumor (C/T) ratio and consolidation size were associated with IAD (optimal cut-off values: 0.4 and 8mm, respectively) and PIF (0.8 and 15 mm, respectively). CONCLUSIONS The HRCT findings correlated with the IASLC/ATS/ERS classification and were useful for evaluating the histological nature of the tumors. Most pure-solid tumors had the potential for high-grade malignancy, including PIF and lymph node metastasis. For part-solid tumors, the C/T ratio and consolidation size were important for predicting PIF and for diagnosing IAD according to this classification.

Virtual segmentectomy based on high-quality three-dimensional lung modelling from computed tomography images

OBJECTIVES The aim of this study was to demonstrate the feasibility and efficacy of a novel simulation software called, virtual segmentectomy. METHODS We developed the segmentectomy simulation system, which was programmed to analyse the detailed 3D bronchovascular structure and to predict the appropriate segmental surface and surgical margin, based on lung modelling from CT images. RESULTS We have attempted this novel technique for 3 cases of pulmonary metastases and 1 case of multiple lung cancer. For validation, the predicted resection margin was compared with the actual resected specimen. The surgical surface, as estimated by the simulation, was compared with the surface of the specimen and a surgical video. To test its feasibility, the operation time, blood loss, durations of chest tube placement and hospitalization as well as pathological findings were assessed. CONCLUSIONS Preoperative simulation and intraoperative guidance by virtual segmentectomy could contribute significantly to determining the most appropriate anatomical segmentectomy and curative resection.

Proposal on incorporating blood vessel invasion into the T classification parts as a practical staging system for stage I non-small cell lung cancer

BACKGROUND We investigated blood vessel invasion (BVI) as a possible negative prognostic factor in patients with stage I non-small cell lung cancer (NSCLC) according to the 7th edition of the TNM classification. METHODS Between 1999 and 2007, a total of 694 consecutive patients with pathological stage I NSCLC underwent complete resection with systematic lymph node dissection at Tokyo Medical University Hospital. All sections of the specimens were stained by Elastica van Gieson to visualize elastic fibers and were examined to determine the prognostic symptoms of BVI. We statistically analyzed the association between BVI and clinicopathologic factors, as well as clinical outcomes. RESULTS BVI was detected in 201 patients with stage I NSCLC (29.0%). The 5-year overall survival (OS) rates of the non-BVI and BVI patients were 90.5% and 66.0%, respectively (p < 0.0001). BVI was found to be a significant independent prognostic factor by multivariate survival analysis in stage IA and stage IB NSCLC (HR 2.591, p < 0.001; HR 2.347, p = 0.009, respectively). The 5-year OS rate of patients with BVI was significantly worse than that of patients without BVI in the T1a (94.5% vs 87.5%, p < 0.0001), T1b (82.7% vs 65.9%, p < 0.0001), and T2a (90.9% vs 61.8%, p < 0.0001) subgroups. CONCLUSION We identified the presence of BVI as an independent poor prognostic factor in patients with stage I NSCLC. In the future revision of the TNM staging system, the routine use of elastic fiber stains in pathological evaluations of lung cancer for BVI determination might be recommended, and tumors with BVI should be upstaged to the higher current T staging.

Correlation between whole tumor size and solid component size on high-resolution computed tomography in the prediction of the degree of pathologic malignancy and the prognostic outcome in primary lung adenocarcinoma.

Background The presence of ground glass opacity (GGO) on high-resolution computed tomography (HRCT) is well known to be pathologically closely associated with adenocarcinoma in situ. Purpose To determine whether it is more useful to evaluate the whole tumor size or only the solid component size to predict the pathologic high-grade malignancy and the prognostic outcome in lung adenocarcinoma. Material and Methods Using HRCT data of 232 patients with adenocarcinoma who underwent curative resection, we retrospectively measured the whole tumor and solid component sizes with lung window setting (WTLW and SCLW) and whole tumor sizes with a mediastinal window setting (WTMW). Results There was significant correlation between the WTLW and the measurements of pathological whole tumor (pWT) (r = 0.792, P < 0.0001). The SCLW and WTLW values significantly correlated with the area of pathological invasive component (pIVS) (r = 0.762, P < 0.0001 and r = 0.771, P < 0.0001, respectively). The receiver operating characteristics area under the curve for WTLW, SCLW, and WTMW used to identify lymph node metastasis or lymphatic or vascular invasion were 0.693, 0.817, and 0.824, respectively. Kaplan-Meier curves of disease-free survival (DFS) and overall survival (OS) were better divided according to SCLW and WTMW, compared with WTLW. Multivariate analysis of DFS and OS revealed that WTMW was an independent prognostic factor (HR = 0.72, 95% confidence interval [CI] = 0.58–0.90, P = 0.004 and HR = 0.74, 95% CI = 0.57–0.96, P = 0.022, respectively). Conclusion The predictive values of the solid tumor size visualized on HRCT especially in the mediastinal window for pathologic high-grade malignancy and prognosis in lung adenocarcinoma were greater than those of whole tumor size.

Do tumours located in the left lower lobe have worse outcomes in lymph node-positive non-small cell lung cancer than tumours in other lobes?

OBJECTIVES Although an association between prognosis and lobar location of lung cancer, particularly the left lower lobe (LLL), has been suggested, the certainty of such association remains controversial. The purpose of this study was to evaluate the impact of tumour lobar location on surgical outcomes as an independent prognostic factor for survival in our non-small cell lung cancer (NSCLC) patient series. METHODS We retrospectively reviewed 978 NSCLC patients who underwent complete resection in our hospital between 2000 and 2007. We statistically analysed the association between clinicopathological factors and clinical outcomes. RESULTS Among the 978 patients reviewed, the NSCLC was located in the LLL in 143 (14.6%) patients, and lymph node involvement was identified in 210 patients (21.5%). The 5-year overall survival rates of patients whose NSCLC was located in the LLL and in other lobes (non-LLL) were 73.1 and 74.3%, respectively, and showed no significant association (P = 0.86). On the other hand, the 5-year survival rates of patients whose NSCLC occurred in the LLL (n = 33) and non-LLL (n = 177) and with lymph node metastasis were 32.7 and 57.7%, respectively, and showed a significant association (P = 0.01). Therefore, we performed a more detailed analysis on the 210 NSCLC patients with lymph node metastasis. On multivariate analysis, we found that LLL tumour (P = 0.02), tumour size >3 cm (P = 0.02) and N status (P < 0.001) were significant independent predictors for survival. CONCLUSIONS LLL tumours with lymph node metastasis are strongly associated with mortality in NSCLC patients. The location of the primary tumour may contribute in determining the optimal management strategy and accurate prediction of prognosis.

The Frequency and Prognostic Impact of Pathological Microscopic Vascular Invasion According to Tumor Size in Non-Small Cell Lung Cancer

BACKGROUND Microscopic vascular invasion (MVI) in patients with non-small cell lung cancer (NSCLC) has been reported to be a strong predictor of poor outcomes but it has not been a descriptor of the TNM classification. The purposes of this study were to determine whether the presence of MVI is related to a predictor of poor outcomes and to explore the degree of MVI according to tumor size. METHODS A total of 1,884 patients with stage pT1-4N0-2 NSCLC who underwent complete resection comprised the study sample. Overall survival (OS) and recurrence-free proportion were estimated using the Kaplan-Meier method. The Cox proportional hazards model was used to assess independent predictors of poor outcomes. RESULTS Of 1,884 patients, 1,097 (58.2%) had MVI. Multivariate analysis showed MVI was a significant independent predictor of unfavorable OS (hazard ratio, 1.666; P < .001) and recurrence (hazard ratio, 2.268; P < .001). The frequency of MVI varied according to tumor size, and in each cohort of tumor sizes ≤ 2 cm, > 2 to 3 cm, and > 3 to 5 cm, there were significant differences in survival outcome by MVI status. The proportions of patients with a 5-year recurrence-free period with tumor sizes ≤ 2 cm, > 2 to 3 cm, and > 3 to 5 cm between MVI (+) and MVI (-) were 93.0% and 72.5% (P < .001), 90.8% and 63.3% (P < .001), and 86.4% and 59.9% (P < .001), respectively. CONCLUSIONS This study demonstrated that MVI was a strong predictor of poor outcomes and that the effect is more prominent in patients with tumor sizes ≤ 5 cm. Further analysis of survival and MVI should be collected for future revision of the TNM system.

Gene expression profiling and molecular pathway analysis for the identification of early-stage lung adenocarcinoma patients at risk for early recurrence

Clinicohistopathological staging is insufficient to predict disease progression and clinical outcome in lung carcinoma. Based on the results of the principal component analysis of 24 samples of early-stage lung adenocarcinoma, two subgroups were identified within the early-relapse group. The histological classification of all samples of group A was poorly differentiated, whereas one out of three in group B was poorly differentiated. DAVID functional annotation analysis revealed that the molecular pathways enriched in group A included those associated with cell adhesion molecules (CAMs), cell cycle and antigen processing and presentation, whereas those in group B included CAMs, T cell receptor signaling, cytokine-cytokine receptor interaction, toll-like receptor signaling, chemokine signaling, primary immunodeficiency and natural killer cell-mediated cytotoxicity. The CAM pathway was enriched in both groups. This comprehensive gene expression and functional pathway analysis identified a distinct molecular pathway, CAMs, that correlated with the early relapse of patients with early-stage lung adenocarcinoma.

Prognostic Factors for Survival After Recurrence in Patients With Completely Resected Lung Adenocarcinoma: Important Roles of Epidermal Growth Factor Receptor Mutation Status and the Current Staging System

UNLABELLED Epidermal growth factor receptor (EGFR) status and pathological stage (p-stage) were shown to be essential prognostic factors for estimating survival after recurrence of lung adenocarcinoma. In patients with EGFR mutations, those with early p-stage tumors showed better survival after disease recurrence than those with advanced p-stage tumors. The EGFR mutation status and p-stage could also prompt the design of clinical trials on adjuvant therapy for patients after complete surgical resection. BACKGROUND The current staging system and epidermal growth factor receptor (EGFR) mutation status are key factors for predicting survival. However, the significance of these factors as predictors of survival after disease recurrence (PRS) has not been sufficiently elucidated. The objective of this study was to investigate the clinicopathological factors, particularly the EGFR mutation status and pathological stage (p-stage), which affect PRS in patients with completely resected lung adenocarcinoma. PATIENTS AND METHODS We retrospectively reviewed the data of 198 consecutive lung adenocarcinoma patients with disease recurrence who previously underwent complete surgical resection in our hospital. RESULTS Of the 198 patients, 117 were examined for EGFR mutations (mutants). Mutants were detected in 57 patients (28.7%). The patients with mutants had a significantly better 3-year PRS (3y-PRS) rate (68.6%) than those with an EGFR wild type (WT) status (51.7%) or an unknown (UN) status (27.0%). The 3y-PRS rates for p-stage I to II (p-I-II) and p-stage III (p-III) were 52.5% and 29.3%, respectively. Multivariate survival analysis showed that the EGFR mutation status and p-stage had significant associations with favorable PRS. The 3y-PRS rate for mutants/p-I-II (81.4%) was significantly better than that for mutants/p-III (48.0%). Conversely, there was no significant difference between mutants/p-III and WT/UN/p-I-II (3y-PRS: 40.7%) or between mutants/p-III and WT/UN/p-III (3y-PRS: 24.4%). CONCLUSION EGFR status and p-stage were shown to be essential prognostic factors for estimating PRS. In patients with mutants, those with early p-stage tumors showed better PRS than those with advanced p-stage tumors.

Three-dimensional multidetector computed tomography may aid preoperative planning of the transmanubrial osteomuscular-sparing approach to completely resect superior sulcus tumor.

The anterior transcervical-thoracic approach clearly exposes the subclavian vessels and brachial plexus. We believe that this approach is optimal when a superior sulcus tumor (SST) invades the anterior part of the thoracic inlet. However, this approach is not yet widely applied because anatomical relationships in this procedure are difficult to visualize. Three-dimensional tomography can considerably improve preoperative planning, enhance the surgeon’s skill and simplify the approach to complex surgical procedures. We applied preoperative 3-dimensional multidetector computed tomography to a case where an SST had invaded the anterior part of the thoracic inlet including the clavicle, sternoclavicular joint, first rib, subclavian vessels and brachial plexus. After the patient underwent induction chemotherapy, we performed the transmanubrial osteomuscular-sparing approach and added a third anterolateral thoracotomy with a hemi-clamshell incision and completely resected the tumor.