Ryo Maeda

Prognostic Impact of Cancer-Associated Stromal Cells in Patients With Stage I Lung Adenocarcinoma

BACKGROUND The tumor microenvironment, of which cancer-associated fibroblasts (CAFs) and tumor-associated macrophages (TAMs) are the major cellular components, plays an important role in tumor progression. This study evaluated the significance of podoplanin-positive CAFs and CD204-positive TAMs, which may reflect tumor-promoting CAFs and TAMs, as risk factors for recurrence in patients with stage I lung adenocarcinoma. METHODS The expression of podoplanin in CAFs and CD204 in TAMs was analyzed by immunohistochemistry in 304 patients with stage I lung adenocarcinoma who underwent surgical resection between September 1992 and July 2004. The recurrence-free proportion (RFP) was estimated using the Kaplan-Meier method. RESULTS The presence of podoplanin-positive CAFs and the higher number of CD204-positive TAMs were associated with a lower 5-year RFP (P < .001 and P = .001, respectively). Podoplanin-positive CAFs were an independently statistically significant risk factor for recurrence with the highest hazard ratio (3.474, P = .029, by multivariate Cox proportional hazards model). According to subgroup analyses combining podoplanin-positive CAFs and other independent risk factors (visceral pleural invasion and intratumoral vascular invasion), the 5-year RFPs were 95.6%, 92.3%, 80.5%, and 30.3% (P = .294, P = .067, and P < .001) for patients with zero, one, two, or three risk factors, respectively. CONCLUSIONS Podoplanin-positive CAFs were the most powerful independent risk factor for recurrence in patients with stage I lung adenocarcinoma. Podoplanin-positive CAFs may be useful for identifying patients with a high risk of recurrence who might benefit from adjuvant chemotherapy.

Late Recurrence of Non-Small Cell Lung Cancer More Than 5 Years After Complete Resection: Incidence and Clinical Implications in Patient Follow-up

BACKGROUND The purpose of this study was to evaluate the risk of late recurrence in patients who had undergone complete resection for non-small cell lung cancer (NSCLC) and remained recurrence-free for > or = 5 years. METHODS Between 1993 and 2002, 1,358 patients with NSCLC underwent complete primary tumor resection and systematic lymph node dissection. Of these, 819 patients remained recurrence-free for 5 years. Recurrence-free probability was estimated from the benchmark of 5 years after primary tumor resection to the date of first recurrence or last follow-up, using the Kaplan-Meier method. Multivariate Cox regression was used to test the relationship of recurrence-free probability to various clinicopathologic factors. RESULTS Of the 819 patients who were free of recurrence at 5 years, 87 (11%) developed a subsequent recurrence. The recurrence-free probabilities at 3 years and 5 years from the point of 5 years after primary tumor resection were 92% and 87%, respectively. The 5-year recurrence-free probabilities from the point of 5 years after primary tumor resection were 81% for patients with intratumoral vascular invasion (P < .001), and 89%, 84%, and 65% for patients with N0, N1, and N2 cancers, respectively (P < .001). Multivariate Cox analysis demonstrated that intratumoral vascular invasion and nodal involvement significantly influenced recurrence 5 years after complete resection (P = .030, P = .022, respectively). CONCLUSIONS Patients with NSCLC with selected tumor characteristics have a significant risk of late recurrence. Therefore, 5 years might not be a sufficient amount of time to declare that NSCLC has been cured.

Risk Factors for Tumor Recurrence in Patients With Early-Stage (Stage I and II) Non-small Cell Lung Cancer: Patient Selection Criteria for Adjuvant Chemotherapy According to the Seventh Edition TNM Classification

OBJECTIVES The purpose of this study was to evaluate risk factors for tumor recurrence in patients with completely resected early-stage non-small cell lung cancer (NSCLC). METHODS Between July 1992 and December 2007, 1,967 consecutive patients with stage I and II NSCLC with diagnoses based on the seventh edition TNM classification underwent complete resection. All patients were divided into three groups according to the stage and presence of lymph node metastasis: stage I, patients with stage I, T1-T2aN0M0 disease; stage IIN0, patients with stage II, T2b-T3N0M0, node-negative disease; and stage IIN1, patients with stage II, T1-2N1M0, node-positive disease. Freedom from recurrence rate was estimated using the Kaplan-Meier method, and recurrence risk factors were identified by univariate and multivariate analyses. RESULTS The 5-year freedom from recurrence rates for stage I, stage IIN0, and stage IIN1 patients were 84%, 61%, and 54%, respectively. By multivariate analyses, three variables (histologic differentiation, vessel invasion, and visceral pleural invasion) in stage I and two variables (adenocarcinoma histology and visceral pleural invasion) in stage IIN0 and stage IIN1 were shown to be independently significant risk factors for recurrence. According to subgroup analyses that combined these risk factors in each group, the 5-year freedom from recurrence rate was 63% for stage I with three risk factors, whereas those for stage IIN0 and stage IIN1 without risk factors were 83% and 78%, respectively. CONCLUSION In patients with stage I and II NSCLC, we identified risk factors for recurrence. When these factors are combined, high- and low-risk subgroups can be identified within each group.

Long-term survival and risk factors for recurrence in stage I non-small cell lung cancer patients with tumors up to 3 cm in maximum dimension.

BACKGROUND The purpose of this study was to evaluate patients with stage I non-small cell lung cancer (NSCLC) and tumors up to 3 cm in maximum dimension who underwent surgical resection on the revised TNM classification and to investigate the risk factors for recurrence. METHODS Between 1994 and 2003, 713 consecutive stage I NSCLC patients with tumors up to 3 cm in maximum dimension underwent complete resection. Recurrence-free probability was estimated from the date of the primary tumor resection to the date of the first recurrence or the last follow-up using the Kaplan-Meier method. RESULTS The recurrence-free probability of stage I NSCLC patients with tumors up to 3 cm in maximum dimension was 87% at 5 years. On multivariate analyses, three variables were shown to be independently significant recurrence risk factors: histologic differentiation (hazard ratio, 2.3), intratumoral vessel invasion (hazard ratio, 2.9), and visceral pleural invasion (VPI) (hazard ratio, 1.8). According to subgroup analyses combining these three risk factors, the 5-year recurrence-free probability was 94% for patients with zero or one factor (n = 492) and 71% for patients with two or three factors (n = 221), respectively (P < .001). CONCLUSION In stage I NSCLC patients with tumors up to 3 cm in maximum dimension, we identified three risk factors for recurrence that independently increase their risk of recurrence. In addition to VPI, histologic differentiation and intratumoral vessel invasion should be examined and their data collected for the next revision of the TNM staging system.

Poor Prognostic Factors in Patients With Stage IB Non-small Cell Lung Cancer According to the Seventh Edition TNM Classification

BACKGROUND This study investigated poor prognostic factors in patients with stage IB non-small cell lung cancer (NSCLC) according to the seventh edition of the TNM classification. METHODS Between July 1992 and December 2004, 1,204 consecutive patients with stage I NSCLC diagnosed based on the sixth edition TNM classification underwent complete resection with systematic node dissection. Of these patients, 434 were reclassified as stage IB according to the seventh edition TNM classification. Univariate analyses were performed using the log-rank test to select prognostic factors. The Cox proportional hazards regression model was used for multivariate analyses to identify independent factors indicating an unfavorable prognosis. RESULTS On multivariate analyses, two variables were independent significant factors indicating an unfavorable prognosis: presence of intratumoral vascular invasion and presence of visceral pleural invasion. According to subgroup analyses combining these two risk factors, 5-year disease-specific survival probabilities were 93%, 83%, and 73% for patients with zero, one, or two risk factors, respectively. The 5-year disease-specific survival of patients without risk factors was not statistically different from that of patients with stage IA cancer. In addition, the 5-year disease-specific survival curve of patients with two risk factors lay beneath that of patients with T2b or T3N0M0, stage II cancer, and there were no statistically significant differences between them. CONCLUSIONS We identified the presence of intratumoral vascular invasion and the presence of visceral pleural invasion as independent poor prognostic factors in patients with stage IB NSCLC. When these two factors are combined, higher- and lower-risk subgroups can be identified, which will help to personalize adjuvant chemotherapy.

Original ResearchLung CancerRisk Factors for Tumor Recurrence in Patients With Early-Stage (Stage I and II) Non-small Cell Lung Cancer: Patient Selection Criteria for Adjuvant Chemotherapy According to the Seventh Edition TNM Classification

OBJECTIVES The purpose of this study was to evaluate risk factors for tumor recurrence in patients with completely resected early-stage non-small cell lung cancer (NSCLC). METHODS Between July 1992 and December 2007, 1,967 consecutive patients with stage I and II NSCLC with diagnoses based on the seventh edition TNM classification underwent complete resection. All patients were divided into three groups according to the stage and presence of lymph node metastasis: stage I, patients with stage I, T1-T2aN0M0 disease; stage IIN0, patients with stage II, T2b-T3N0M0, node-negative disease; and stage IIN1, patients with stage II, T1-2N1M0, node-positive disease. Freedom from recurrence rate was estimated using the Kaplan-Meier method, and recurrence risk factors were identified by univariate and multivariate analyses. RESULTS The 5-year freedom from recurrence rates for stage I, stage IIN0, and stage IIN1 patients were 84%, 61%, and 54%, respectively. By multivariate analyses, three variables (histologic differentiation, vessel invasion, and visceral pleural invasion) in stage I and two variables (adenocarcinoma histology and visceral pleural invasion) in stage IIN0 and stage IIN1 were shown to be independently significant risk factors for recurrence. According to subgroup analyses that combined these risk factors in each group, the 5-year freedom from recurrence rate was 63% for stage I with three risk factors, whereas those for stage IIN0 and stage IIN1 without risk factors were 83% and 78%, respectively. CONCLUSION In patients with stage I and II NSCLC, we identified risk factors for recurrence. When these factors are combined, high- and low-risk subgroups can be identified within each group.

Lung adenocarcinomas with micropapillary components

PurposeMicropapillary adenocarcinoma is becoming increasingly recognized as a prognostically important histological subtype of carcinoma in various organs. This report presents the clinicopathological findings of lung adenocarcinomas with micropapillary components.MethodsA total of 15 patients with micropapillary components were selected between April 2005 and December 2008. The results of their clinical presentation, metastasis to lymph nodes, pleural invasion, pathological stage, and clinical outcomes were evaluated.ResultsIn all, 12 patients underwent a lobectomy or bilobectomy with a regional lymph node dissection; 8 showed metastases to the regional lymph nodes at the time of the operation. Altogether, 14 of 15 cases showed lymphovascular invasion; 10 cases were up-staged after the operation because of lymph node metastases or pleural invasion. The duration of follow-up ranged from 1 to 42 months (median 16 months). Seven patients are alive without disease, whereas seven are alive with disease and one patient died of disease.ConclusionThese results suggest that the micropapillary components are a manifestation of aggressive behavior, as shown by the frequent lymph node metastases and pleural invasion. Surgeons should search more carefully for metastases and conduct a closer follow-up on these patients when this feature is present with lung adenocarcinoma.

The Prognostic Impact of Cigarette Smoking on Patients with Non-small Cell Lung Cancer

Introduction: The purposes of this study are to investigate the association between cigarette smoking and clinicopathological characteristics of patients with non-small cell lung cancer (NSCLC) and to evaluate its significance as a predictor of recurrence after resection. Methods: A total of 2295 consecutive patients with NSCLC underwent complete resection with systematic node dissection between August 1992 and December 2006 at the National Cancer Center Hospital East. Results: A statistically significant difference in the 5-year overall survival rate was observed between never and ever smokers in patients with stage I (92% and 76%, respectively, p < 0.001) NSCLC, whereas no difference was observed in stage II (57% and 52%, respectively, p = 0.739) and stage III (30% and 33%, respectively, p = 0.897). In patients with stage I NSCLC, 5-year recurrence-free proportions (RFPs) for never and ever smokers were 89% and 80%, respectively (p < 0.001). In contrast, the 5-year RFPs for never smokers were lower than those for ever smokers in stage II (44% and 60%, respectively, p = 0.049) and stage III (17% and 31%, respectively, p = 0.004). In stage I patients, significant difference in 5-year RFP was observed between never and ever smokers (89% and 83%, respectively) in patients with adenocarcinoma, but not in patients with nonadenocarcinoma (82% and 76%, respectively). Conclusions: Smoking history showed different impact on postoperative recurrence in patients with NSCLC between stage I and stages II and III, and depending on histology in stage I patients. Disease stages should be considered while evaluating smoking history as a predictor of recurrence.

Long-Term Outcome and Late Recurrence in Patients with Completely Resected Stage IA Non-small Cell Lung Cancer

Background: The purpose of this study was to quantify the risk of late recurrence in patients with stage IA non-small cell lung cancer (NSCLC) who remained recurrence-free for more than 5 years after resection. Methods: Between August 1992 and December 2002, a total of 519 patients with stage IA NSCLC underwent complete resection at our institution. Recurrence-free probability was measured from the benchmark of 5 years after primary tumor resection to the date of first recurrence or last follow-up using the Kaplan-Meier method. Results: Of a total of 519 patients, 434 remained recurrence-free for 5 years. Among these, 21 (4.8%) developed late recurrence more than 5 years after resection. Recurrence-free interval ranged from 1 to 53 months, and the median recurrence-free interval was 14 months from the benchmark of 5 years after primary tumor resection. The 5-year recurrence-free probability from the benchmark was 93%. Multivariate Cox analysis demonstrated that vascular invasion significantly influenced late recurrence (p = 0.038). The 5-year recurrence-free probability from the benchmark was 84% for patients with vascular invasion and 95% for patients without vascular invasion (p < 0.001). Conclusions: Patients with stage IA NSCLC with vascular invasion harbor a significant risk of late recurrence more than 5 years after complete resection. In patients with stage IA NSCLC with vascular invasion, 5 years without recurrence is not sufficient to conclude that NSCLC is cured. In contrast, patients without vascular invasion may be declared to be cured at 5 years after resection if they are recurrence-free.

Influence of Cigarette Smoking on Histological Subtypes of Stage I Lung Adenocarcinoma

Background: The purpose of this study was to examine the association between cigarette smoking and histological subtypes of lung adenocarcinoma. Methods: We reviewed a total of 320 consecutive patients with stage I adenocarcinoma who underwent complete resections with systematic node dissections from January 2004 to December 2006 at the National Cancer Center Hospital East. Results: A statistically significant difference was observed in recurrence-free probabilities between never smokers and ever smokers (3-year recurrence-free probabilities of 95.6% and 88.6%, respectively, p = 0.034). Among adenocarcinoma histological subtypes, only a solid component was significantly more frequent in ever smokers than in never smokers (p < 0.001). Among patients with solid components, significantly more cases had lymphatic permeation (p = 0.007), intratumoral vascular invasion (p < 0.001), and visceral pleural invasion (p < 0.001). Multivariate analysis revealed that ever-smoking history was the only statistically significant independent clinical predictor for a solid component (p < 0.001). Among ever smokers, smoking extent in pack-years of patients with solid components was significantly greater than that of those without solid components (p < 0.001). With respect to predominant subtypes, smoking extent in pack-years of patients with predominantly solid adenocarcinomas was significantly greater than that of patients with predominantly bronchioloalveolar carcinoma, papillary, or acinar adenocarcinomas (all p < 0.001). Conclusion: A greater smoking extent was associated with the presence of adenocarcinoma solid components, which may have more aggressive biological features resulting in poorer outcomes.