Yasuhiro Tsutani

Histopathologic evaluation of stepwise progression of pancreatic carcinoma with immunohistochemical analysis of gastric epithelial transcription factor SOX2: comparison of expression patterns between invasive components and cancerous or nonneoplastic intraductal components.

Objectives: The purpose of this study was to perform histopathologic and immunohistochemical analyses of gastric transcription factor SOX2 and gastric mucin MUC5AC to better understand the stepwise progression of pancreatic carcinoma. Methods: Twenty-eight representative sections from 14 surgically resected pancreatic carcinomas were assessed microscopically. Sites of pancreatic intraepithelial neoplasia (PanIN) were counted, and histologic subtypes of invasive ductal carcinoma (IDC) were determined. The expression of SOX2 and MUC5AC in PanIN and IDC was examined immunohistochemically. Results: One hundred thirty-eight PanINs were identified. In 4 of the 14 cases, gradual transition from PanIN-1A to PanIN-3 was observed in a single duct, suggesting stepwise progression. The expression of MUC5AC increased with the progression of lesions from PanIN-1A to PanIN-3. SOX2 was expressed in only 6 of 107 early PanINs (5.8%). Out of 31 PanIN-3s, 7 were positive (22.6%), and SOX2 protein was localized in the nuclei of cells of the basal epithelium or in the vicinity of luminal necrosis. In addition, SOX2 was frequently and strongly expressed in poorly differentiated (57.1%) and neurally invasive (63.6%) components. Conclusions: The results of our histopathologic examinations suggest that PanIN progresses stepwise to IDC. Immunohistochemistry results suggest that SOX2 is involved in later events of carcinogenesis.

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.

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.

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.

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.

Role of FDG-PET/CT in evaluating surgical outcomes of operable breast cancer – Usefulness for malignant grade of triple-negative breast cancer

BACKGROUND The aim of this study was to evaluate the significance of (18)F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) for speculating the malignant level and prognostic value of operable breast cancers. METHODS Of 578 consecutive patients with primary invasive breast cancer who underwent curative surgery between 2005 and 2010, 311 patients (53.8%) who received FDG-PET/CT before initial therapy were examined. RESULTS Receiver operating characteristics (ROC) curve analysis showed the cutoff value of the maximum standardized uptake value (SUVmax) to predict cancer recurrence was 3.8 in all patients and 8.6 in patients with the triple-negative subtype, respectively. In all patients, 3-year DFS rates were 98.8% for patients with a tumor of SUVmax ≤ 3.8 and 91.6% for patients with a tumor of SUVmax > 3.8 (p < 0.001). High value of SUVmax was significantly associated with large tumor size (p < 0.001), lymph node metastasis (p = 0.040), high nuclear grade (p < 0.001), lymphovascular invasion (p = 0.032), negative hormone receptor status (p < 0.001), and positive HER2 status (p = 0.014). Based on the results of multivariate Cox analysis in all patients, high SUVmax (p = 0.001) and negative hormone receptor status (p = 0.005) were significantly associated with poor prognosis. In patients with triple-negative subtype, 3-year DFS rates were 90.9% for patients with a tumor of SUVmax ≤ 8.6 and 42.9% for patients with a tumor of SUVmax > 8.6 (p = 0.002), and high SUVmax was the only significant independent prognostic factor (p = 0.047). CONCLUSION FDG-PET/CT is useful for predicting malignant behavior and prognosis in patients with operable breast cancer, especially the triple-negative subtype.

Solid tumor size on high-resolution computed tomography and maximum standardized uptake on positron emission tomography for new clinical T descriptors with T1 lung adenocarcinoma

BACKGROUND To better describe clinical T descriptors using solid tumor size (the maximum dimension of the solid component of the tumor) on high-resolution computed tomography (HRCT) and maximum standardized uptake value (SUVmax) on F-18-fluorodeoxyglucose positron emission tomography/CT (FDG-PET/CT). PATIENTS AND METHODS We examined 610 consecutive patients with clinical stage IA lung adenocarcinoma who underwent complete resection. Recurrence-free survival (RFS) was assessed on the basis of whole tumor size (maximum dimension of the tumor), solid tumor size, or a combination of solid tumor size and SUVmax. RESULTS RFS based on whole tumor size was not significantly different between patients with tumors measuring ≤2 cm and 2-3 cm (P = 0.089), whereas RFS based on solid tumor size was significantly different (P < 0.0001). We divided patients into four groups on the basis of solid tumor size and SUVmax: group 1: solid tumor size ≤2 cm, SUVmax ≤1.8; group 2: solid tumor size ≤2 cm, SUVmax >1.8; group 3: solid tumor size 2-3 cm, SUVmax ≤3.6; and group 4: solid tumor size 2-3 cm, SUVmax >3.6. Groups 2 and 3 were combined because they showed similar RFS each other. RFS was significantly different among these groups: group 1 versus groups 2 + 3, P < 0.0001; groups 2 + 3 versus group 4, P = 0.019. CONCLUSIONS Both solid tumor size on HRCT and SUVmax on FDG-PET/CT reflect prognosis well in patients with clinical stage IA lung adenocarcinoma and may support new clinical T descriptors.