Yoshihiro Miyata

Appropriate Sublobar Resection Choice for Ground Glass Opacity-Dominant Clinical Stage IA Lung Adenocarcinoma: Wedge Resection or Segmentectomy

BACKGROUND The purpose of this multicenter study was to characterize ground glass opacity (GGO)-dominant clinical stage IA lung adenocarcinomas and evaluate prognosis of these tumors after sublobar resection, such as segmentectomy and wedge resection. METHODS We evaluated 610 consecutive patients with clinical stage IA lung adenocarcinoma who underwent complete resection after preoperative high-resolution CT scanning and 18 F-fl uorodeoxyglucose PET/CT scanning and revealed 239 (39.2%) that had a . 50% GGO component. RESULTS GGO-dominant tumors rarely exhibited pathologic invasiveness, including lymphatic, vascular, or pleural invasion and lymph node metastasis. There was no significant difference in 3-year recurrence-free survival (RFS) among patients who underwent lobectomy (96.4%), segmentectomy (96.1%), and wedge resection (98.7%) of GGO-dominant tumors ( P = .44). Furthermore, for GGO-dominant T1b tumors, 3-year RFS was similar in patients who underwent lobectomy (93.7%), segmentectomy (92.9%), and wedge resection (100%, P = .66). Two of 84 patients (2.4%) with GGO-dominant T1b tumors had lymph node metastasis. Multivariate Cox analysis showed that tumor size, maximum standardized uptake value on 18 F-fl uorodeoxyglucose PET/CT scan, and surgical procedure did not affect RFS in GGO-dominant tumors. CONCLUSIONS GGO-dominant clinical stage IA lung adenocarcinomas are a uniform group of tumors that exhibit low-grade malignancy and have an extremely favorable prognosis. Patients with GGOdominant clinical stage IA adenocarcinomas can be successfully treated with wedge resection of a T1a tumor and segmentectomy of a T1b tumor.

Multicenter analysis of high-resolution computed tomography and positron emission tomography/computed tomography findings to choose therapeutic strategies for clinical stage IA lung adenocarcinoma.

OBJECTIVE The detection rates of small lung cancers, especially adenocarcinoma, have recently increased. An understanding of malignant aggressiveness is critical for the selection of suitable therapeutic strategies, such as sublobar resection. The objective of this study was to examine the malignant biological behavior of clinical stage IA adenocarcinoma and to select therapeutic strategies using high-resolution computed tomography, fluorodeoxyglucose-positron emission tomography/computed tomography, and a pathologic analysis in the setting of a multicenter study. METHODS We performed high-resolution computed tomography and fluorodeoxyglucose-positron emission tomography/computed tomography in 502 patients with clinical T1N0M0 adenocarcinoma before they underwent surgery with curative intent. We evaluated the relationships between clinicopathologic characteristics and maximum standardized uptake values on fluorodeoxyglucose-positron emission tomography/computed tomography, ground-glass opacity ratio, and tumor disappearance rate on high-resolution computed tomography and component of bronchioloalveolar carcinoma on surgical specimens, as well as between these and surgical findings. We used a phantom study to correct the serious limitation of any multi-institution study using positron emission tomography/computed tomography, namely, a discrepancy in maximum standardized uptake values among institutions. RESULTS Analyses of receiver operating characteristic curves identified an optimal cutoff value to predict high-grade malignancy of 2.5 for revised maximum standardized uptake values, 20% for ground-glass opacity ratio, 30% for tumor disappearance rate, and 30% for bronchioloalveolar carcinoma ratio. Maximum standardized uptake values and bronchioloalveolar carcinoma ratio, tumor disappearance rate, and ground-glass opacity ratio mirrored the pathologic aggressiveness of tumor malignancy, nodal metastasis, recurrence, and prognosis, including disease-free and overall survival. CONCLUSIONS Maximum standardized uptake value is a significant preoperative predictor for surgical outcomes. High-resolution computed tomography and fluorodeoxyglucose-positron emission tomography/computed tomography findings are important to determine the appropriateness of sublobar resection for treating clinical stage IA adenocarcinoma of the lung.

Original ResearchLung CancerAppropriate Sublobar Resection Choice for Ground Glass Opacity-Dominant Clinical Stage IA Lung Adenocarcinoma: Wedge Resection or Segmentectomy

BACKGROUND The purpose of this multicenter study was to characterize ground glass opacity (GGO)-dominant clinical stage IA lung adenocarcinomas and evaluate prognosis of these tumors after sublobar resection, such as segmentectomy and wedge resection. METHODS We evaluated 610 consecutive patients with clinical stage IA lung adenocarcinoma who underwent complete resection after preoperative high-resolution CT scanning and 18 F-fl uorodeoxyglucose PET/CT scanning and revealed 239 (39.2%) that had a . 50% GGO component. RESULTS GGO-dominant tumors rarely exhibited pathologic invasiveness, including lymphatic, vascular, or pleural invasion and lymph node metastasis. There was no significant difference in 3-year recurrence-free survival (RFS) among patients who underwent lobectomy (96.4%), segmentectomy (96.1%), and wedge resection (98.7%) of GGO-dominant tumors ( P = .44). Furthermore, for GGO-dominant T1b tumors, 3-year RFS was similar in patients who underwent lobectomy (93.7%), segmentectomy (92.9%), and wedge resection (100%, P = .66). Two of 84 patients (2.4%) with GGO-dominant T1b tumors had lymph node metastasis. Multivariate Cox analysis showed that tumor size, maximum standardized uptake value on 18 F-fl uorodeoxyglucose PET/CT scan, and surgical procedure did not affect RFS in GGO-dominant tumors. CONCLUSIONS GGO-dominant clinical stage IA lung adenocarcinomas are a uniform group of tumors that exhibit low-grade malignancy and have an extremely favorable prognosis. Patients with GGOdominant clinical stage IA adenocarcinomas can be successfully treated with wedge resection of a T1a tumor and segmentectomy of a T1b tumor.

Oncologic outcomes of segmentectomy compared with lobectomy for clinical stage IA lung adenocarcinoma: propensity score-matched analysis in a multicenter study.

OBJECTIVE Our objective was to compare the oncologic outcomes of lobectomy and segmentectomy for clinical stage IA lung adenocarcinoma. METHODS We examined 481 of 618 consecutive patients with clinical stage IA lung adenocarcinoma who underwent lobectomy or segmentectomy after preoperative high-resolution computed tomography and F-18-fluorodeoxyglucose positron emission tomography/computed tomography. Patients (n = 137) who underwent wedge resection were excluded. Lobectomy (n = 383) and segmentectomy (n = 98) as well as surgical results were analyzed for all patients and their propensity score-matched pairs. RESULTS Recurrence-free survival (RFS) and overall survival (OS) were not significantly different between patients undergoing lobectomy (3-year RFS, 87.3%; 3-year OS, 94.1%) and segmentectomy (3-year RFS, 91.4%; hazard ratio [HR], 0.57; 95% confidence interval [CI], 0.27-1.20; P = .14; 3-year OS, 96.9%; HR, 0.49; 95% CI, 0.17-1.38; P = .18). Significant differences in clinical factors such as solid tumor size (P < .001), maximum standardized uptake value (SUVmax) (P < .001), and tumor location (side, P = .005; lobe, P = .001) were observed between both treatment groups. In 81 propensity score-matched pairs including variables such as age, gender, solid tumor size, SUVmax, side, and lobe, RFS and OS were similar between patients undergoing lobectomy (3-year RFS, 92.9%, 3-year OS, 93.2%) and segmentectomy (3-year RFS, 90.9%; 3-year OS, 95.7%). CONCLUSIONS Segmentectomy is suitable for clinical stage IA lung adenocarcinoma, with survivals equivalent to those of standard lobectomy.

Prediction of pathologic node-negative clinical stage IA lung adenocarcinoma for optimal candidates undergoing sublobar resection

OBJECTIVE Patients with pathologic node-negative early lung cancer may be optimal candidates for sublobar resection. We aimed to identify predictors of pathologic lymph node involvement in clinical stage IA lung adenocarcinoma. METHODS The data from a multicenter database of 502 patients with completely resected clinical stage IA lung adenocarcinoma were retrospectively analyzed to determine the relationship between the lymph node metastasis status and tumor size on high-resolution computed tomography (HRCT) or maximum standardized uptake value (SUVmax) on [18F]-fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography (FDG-PET/CT). Revised SUVmax was used to correct interinstitutional discrepancies. RESULTS In multivariate analyses, either a solid tumor size on HRCT (P = .001) or an SUVmax on FDG-PET/CT (P = .049) was an independent predictor of lymph node metastasis. The predictive criteria of pathologic node-negative early lung cancer were a solid tumor size of less than 0.8 cm or an SUVmax of less than 1.5. Patients who met the predictive criteria of pathologic node-negative disease had less pathologic invasiveness, such as lymphatic, vascular, or pleural invasion (P < .001), and better disease-free survival (P < .0001) than those who did not, and 86 (40.4%) of the 213 patients with T1b (2-3 cm) tumors met the predictive criteria. CONCLUSIONS Either a solid tumor size or an SUVmax was a significant independent predictor of nodal involvement in clinical stage IA lung adenocarcinoma. The pathologic node-negative status criteria of a solid tumor size of less than 0.8 cm on HRCT or an SUVmax of less than 1.5 on FDG-PET/CT may be helpful for avoiding systematic lymphadenectomy for clinical stage IA lung adenocarcinoma, even in cases of T1b (2-3 cm) tumor.

Difference in Prognostic Significance of Maximum Standardized Uptake Value on [18F]-Fluoro-2-Deoxyglucose Positron Emission Tomography Between Adenocarcinoma and Squamous Cell Carcinoma of the Lung

OBJECTIVE This study evaluates the prognostic significance of [18F]-fluoro-2-deoxyglucose positron emission tomography/computed tomography findings according to histological subtypes in patients with completely resected non-small cell lung cancer. METHODS We examined 176 consecutive patients who had undergone preoperative [18F]-fluoro-2-deoxyglucose-positron emission tomography/computed tomography imaging and curative surgical resection for adenocarcinoma (n = 132) or squamous cell carcinoma (n = 44). Maximum standardized uptake values for the primary lesions in all patients were calculated as the [18F]-fluoro-2-deoxyglucose uptake and the surgical results were analyzed. RESULTS The median values of maximum standardized uptake value for the primary tumors were 2.60 in patients with adenocarcinoma and 6.95 in patients with squamous cell carcinoma (P< 0.001). Analyses of receiver operating characteristic curves identified an optimal maximum standardized uptake value cutoff value to predict recurrence of 3.7 for adenocarcinoma, whereas such an indicator could not be identified for squamous cell carcinoma. Although 2-year disease-free survival rates were 70.2% for maximum standardized uptake value ≤6.95 and 59.3% for maximum standardized uptake value >6.95 (P = 0.83) among patients with squamous cell carcinoma, 2-year disease-free survival rates were 93.9% for maximum standardized uptake value ≤3.7 and 52.4% for maximum standardized uptake value >3.7 (P < 0.0001) among those with adenocarcinoma, and notably, 100 and 57.2%, respectively, in patients with Stage I adenocarcinoma (P < 0.0001). On the basis of the multivariate Cox analyses of patients with adenocarcinoma, maximum standardized uptake value (P = 0.008) was a significantly independent factor for disease-free survival as well as nodal metastasis (P = 0.001). CONCLUSIONS Maximum standardized uptake value of the primary tumor was a powerful prognostic determinant for patients with adenocarcinoma, but not with squamous cell carcinoma of the lung.

Combined immunohistochemistry of β-catenin, cytokeratin 7, and cytokeratin 20 is useful in discriminating primary lung adenocarcinomas from metastatic colorectal cancer

BackgroundIt is important to discriminate between primary and secondary lung cancer. However, often, the discriminating diagnosis of primary lung acinar adenocarcinoma and lung metastasis of colorectal cancer based on morphological and pathological findings is difficult. The purpose of this study was to evaluate the clinical usefulness of immunohistochemistry of β-catenin, cytokeratin (CK) 7, and CK20 for the discriminating diagnosis of lung cancer.MethodsWe performed immunohistochemistry of β-catenin, CK7, and CK20 in 19 lung metastasis of colorectal cancer samples, 10 corresponding primary colorectal cancer samples and 11 primary lung acinar adenocarcinoma samples and compared the levels of accuracy of the discriminating diagnosis by using antibodies against these antigens.ResultsPositive staining of β-catenin was observed in all the lung metastasis of colorectal cancer samples as well as in the primary colorectal cancer samples but in none of the primary lung acinar adenocarcinoma samples. Positive staining of CK7 was observed in 90.9% of the primary lung acinar adenocarcinoma samples and in 5.3% of the lung metastasis of colorectal cancer samples, but in none of the primary colorectal cancer samples. Positive staining of CK20 was observed in all the primary colorectal cancer samples and in 84.2% of the lung metastasis of colorectal cancer samples, but in none of the primary lung acinar adenocarcinoma samples.ConclusionCombined immunohistochemistry of β-catenin, CK7, and CK20 is useful for making a discriminating diagnosis between lung metastasis of colorectal cancer and primary lung acinar adenocarcinoma. This method will enable accurate diagnosis of a lung tumor and will be useful for selecting appropriate therapeutic strategies, including chemotherapeutic agents and operation methods.

The prognostic role of pathologic invasive component size, excluding lepidic growth, in stage I lung adenocarcinoma

OBJECTIVES We performed an investigation of the prognostic significance of the invasive component size, excluding lepidic growth, in lung adenocarcinoma patients. METHODS The data from 603 patients with completely resected pathologic stage I lung adenocarcinomas were analyzed retrospectively to determine the relationship between pathologic tumor size and surgical results. RESULTS The median tumor size of the total growth and the invasive component were 2.2 cm and 1.3 cm, respectively. There were significant differences in recurrence-free survival between patients classified on the basis of invasive component sizes (≤ 0.5 cm vs 0.5-2.0 cm, P < .001; and 0.5-2.0 cm vs > 2.0 cm; P = .026). A multivariate Cox regression analysis showed that invasive component size (P = .002), age, sex, and lymphatic invasion were independent prognostic factors for recurrence-free survival, whereas total tumor size was not (P = .068). There were no significant differences in recurrence-free survival between patients who received adjuvant chemotherapy and those who did not in the group with invasive component size of 0.5 cm or less (P = .29) and in the group with invasive component size of 0.5 to 2.0 cm (P = .50). However, the recurrence-free survival of patients who received adjuvant chemotherapy was significantly better than that of those who did not in the group with invasive component size greater than 2.0 cm (P = .009). CONCLUSIONS Pathologic invasive component size, as opposed to total tumor size, is associated more significantly with malignant behavior and prognosis and specifically should be considered before choosing candidates for adjuvant chemotherapy in pathologic stage I lung adenocarcinoma.

Objective assessment of endoscopic surgical skills by analyzing direction-dependent dexterity using the Hiroshima University Endoscopic Surgical Assessment Device (HUESAD)

PurposeWe evaluated our system of objectively assessing endoscopic surgical skills.MethodsWe developed the Hiroshima University Endoscopic Surgical Assessment Device (HUESAD), which records the movement of the tip of an endoscopic instrument precisely. The orbits of experienced surgeons (expert group) and those of medical students (novice group) were evaluated by measuring the deviation from the ideal course on horizontal and vertical planes. These data were integrated with the time taken to move the tip of an endoscopic instrument between a distal side pole (A) and a proximal side pole (C) (Task 1), and between a left side pole (D) and a right side pole (B) (Task 2).ResultsThe integrated deviation of the expert group was significantly lower than that of the novice group on both the horizontal and vertical planes in Task 1 (P = 0.0004, P = 0.009) and Task 2 (P < 0.0001, P = 0.0002). Thus, the spatial perception of experts was significantly better than that of novices. We also found that the direction of the scope and the movement of the endoscopic instrument were related to difficulties in spatial perception for both experts and novices. HUESAD detected and resolved these differences based on the directions of the scope and movement of the endoscopic instruments.ConclusionsThe HUESAD is a reliable system for assessing a surgeon’s dexterity, based on direction and movement. It helps us to attain a higher degree of accuracy and to create an ideal setting for optimal endoscopic surgery.

Upregulation of Notch2 and Six1 is associated with Progression of Early-Stage Lung Adenocarcinoma and a More Aggressive Phenotype at Advanced Stages

Purpose: Lung adenocarcinoma often manifests as tumors with mainly lepidic growth. The size of invasive foci determines a diagnosis of in situ, minimally invasive adenocarcinoma, or invasive types and suggests that some adenocarcinomas undergo malignant progression in that order. This study investigates how transcriptional aberrations in adenocarcinoma cells at the early stage define the clinical phenotypes of adenocarcinoma tumors at the advanced stage. Experimental Design: We comprehensively searched for differentially expressed genes between preinvasive and invasive cancer cells in one minimally invasive adenocarcinoma using laser capture microdissection and DNA microarrays. We screened expression of candidate genes in 11 minimally invasive adenocarcinomas by reverse transcriptase PCR and examined their involvement in preinvasive-to-invasive progression by transfection studies. We then immunohistochemically investigated the presence of candidate molecules in 64 samples of advanced adenocarcinoma and statistically analyzed the findings, together with clinicopathologic variables. Results: The transcription factors Notch2 and Six1 were upregulated in invasive cancer cells in all 11 minimally invasive adenocarcinomas. Exogenous Notch2 transactivated Six1 followed by Smad3, Smad4, and vimentin, and enlarged the nuclei of NCI-H441 lung epithelial cells. Immunochemical staining for the transcription factors was double positive in the invasive, but not in the lepidic growth component of a third of advanced Ads, and the disease-free survival rates were lower in such tumors. Conclusions: Paired upregulation of Notch2 and Six1 is a transcriptional aberration that contributes to preinvasive-to-invasive adenocarcinoma progression by inducing epithelial–mesenchymal transition and nuclear atypia. This aberration persisted in a considerable subset of advanced adenocarcinoma and conferred a more malignant phenotype on the subset. Clin Cancer Res; 18(4); 945–55. ©2011 AACR.