Kouzo Yamada

Performance evaluation of 4 measuring methods of ground-glass opacities for predicting the 5-year relapse-free survival of patients with peripheral nonsmall cell lung cancer: a multicenter study.

Objective: To evaluate the performance of 4 methods of measuring the extent of ground-glass opacities as a means of predicting the 5-year relapse-free survival of patients with peripheral nonsmall cell lung cancer (NSLC). Methods: Ground-glass opacities on thin-section computed tomographic images of 120 peripheral NSLCs were measured at 7 medical institutions by the length, area, modified length, and vanishing ratio (VR) methods. The performance (Az) of each method in predicting the 5-year relapse-free survival was evaluated using receiver operating characteristic analysis. Results: The mean Az value obtained by the length, area, modified length, and VR methods in the receiver operating characteristic analyses was 0.683, 0.702, 0.728, and 0.784, respectively. The differences between the mean Az value obtained by the VR method and by the other 3 methods were significant. Conclusions: Vanishing ratio method was the most accurate predictor of the 5-year relapse-free survival of patients with peripheral NSLC.

Initial findings and progression of lung adenocarcinoma on serial computed tomography scans.

To study the initial findings of lung adenocarcinoma revealed by computed tomography (CT) scanning and observe tumor progression and elucidate appropriate follow-up schedule of tumor diagnosis via CT findings of suspected lung adenocarcinoma. Method: We studied 59 patients who had undergone CT scanning twice or more at intervals of 3 months or longer before surgery. We evaluated the initial CT findings as well as all subsequent changes. The rate of tumor growth was estimated by tumor volume doubling time, using the original method of Schwartz. The histological classifications were evaluated according to the criteria of Noguchi et al (Cancer 1995;75:2844-2852). Result: The initial appearances of lung adenocarcinoma were divided into 4 types: (1) ground-glass opacity-like lesions, (2) bubble-like appearance, (3) small nodules, and (4) scar-like lesions. Ground-glass opacity-like lesions tended to increase in size over the years, with solid parts appearing in some lesions during follow-up examinations. Bubble-like appearance displayed characteristic CT findings and tended to increase over the years from the time of initial diagnosis, and we therefore tended to consider them as old inflammatory lesions. Small nodules tended to increase in size over the months more rapidly than in other types. Scar-like lesions tended to exist mainly in the lungs already damaged by lung fibrosis and/or emphysema and therefore were difficult to detect on initial CT scans. Conclusion: We categorized 4 types of initial findings of lung adenocarcinomas detected by CT. We determined that each type of lesion had its own unique characteristic growth patterns and required varying follow-up periods.

Natural History of Pulmonary Subsolid Nodules: A Prospective Multicenter Study

Introduction: The purpose of this study was to evaluate the natural course of the progression of pulmonary subsolid nodules (SSNs). Materials and Methods: Eight facilities participated in this study. A total of 795 patients with 1229 SSNs were assessed for the frequency of invasive adenocarcinomas. SSNs were classified into three categories: pure ground‐glass nodules (PGGNs), heterogeneous GGNs (HGGNs) (solid component detected only in lung windows), and part‐solid nodules. Results: The mean prospective follow‐up period was 4.3 ± 2.5 years. SSNs were classified at baseline as follows: 1046 PGGNs, 81 HGGNs, and 102 part‐solid nodules. Among the 1046 PGGNs, 13 (1.2%) developed into HGGNs and 56 (5.4%) developed into part‐solid nodules. Among the 81 HGGNs, 16 (19.8%) developed into part‐solid nodules. Thus, the SSNs at the final follow‐up were classified as follows: 977 PGGNs, 78 HGGNs, and 174 part‐solid nodules. Of the 977 PGGNs, 35 were resected (nine minimally invasive adenocarcinomas [MIAs], 21 adenocarcinomas in situ [AIS], and five atypical adenomatous hyperplasias). Of the 78 HGGNs, seven were resected (five MIAs and two AIS). Of the 174 part‐solid nodules, 49 were resected (12 invasive adenocarcinomas, 26 MIAs, 10 AIS, and one adenomatous hyperplasia). For the PGGNs, the mean period until their development into part‐solid nodules was 3.8 ± 2.0 years, whereas the mean period for the HGGNs was 2.1 ± 2.3 years (p = 0.0004). Conclusion: This study revealed the frequencies and periods of development from PGGNs and HGGNs into part‐solid nodules. Invasive adenocarcinomas were diagnosed only among the part‐solid nodules, corresponding to 1% of all 1229 SSNs.

Early monocytopenia after chemotherapy as a risk factor for neutropenia.

Neutropenia is a major adverse effect of cancer chemotherapy and sometimes causes life-threatening events. The present study was therefore conducted to identify risk factors for such neutropenia. Forty patients who had received chemotherapy at 3- or 4-week intervals for advanced lung cancer from May 1991 through February 1997 were analyzed retrospectively. Thirty-seven of the patients had received cisplatin-based chemotherapy. The mean neutrophil count on days 6 to 8 in 32 patients who developed grade 3 or 4 neutropenia during chemotherapy was not significantly different from that in eight patients who developed grade 1 or 2 neutropenia during chemotherapy. However, the mean leukocyte and monocyte counts on days 6 to 8 in the 32 patients with grade 3 or 4 neutropenia (5,181 +/- 1,830/microl and 87 +/- 84/microl, respectively) were significantly lower than those in the eight patients with grade 1 or 2 neutropenia (7175 +/- 1671/microl and 248 +/- 127/microl, respectively; p = 0.008 and p = 0.0001). Moreover, all 30 patients with a monocyte count of less than 150/microl on days 6 to 8 had grade 3 or 4 neutropenia and 8 of 10 patients with a monocyte count of 150/microl or higher on days 6 to 8 had grade 1 or 2 neutropenia, despite the absence of a correlation between the leukocyte count on days 6 to 8 and the neutrophil nadir. We conclude that a monocyte count of less than 150/microl on days 6 to 8 may be a predictor of grade 3 or 4 neutropenia during cancer chemotherapy at 3- or 4-week intervals (sensitivity 94%, specificity 100%).

Comparison of thin-section CT and pathological findings in small solid-density type pulmonary adenocarcinoma: Prognostic factors from CT findings

OBJECTIVE We divided pulmonary adenocarcinoma of ≤ 20 mm into air-containing and solid-density types based on a percentage reduction of the maximum tumor diameter in the mediastinal window image compared to the area in the lung window image on thin-section (TS) CT of ≥ 50% (air-containing type) and <50% (solid-density type). No relapse occurred in patients with air-containing type. The prognosis of solid-density type may be poor even when the tumor size is 20mm or smaller. We investigated whether CT findings for these tumors could serve as prognostic factors. METHODS The subjects were 105 patients with solid-density type pulmonary adenocarcinoma that was identified on TSCT and found to have a diameter of 20mm or smaller after surgical resection during the period from April 1997 to November 2004. Notches, air bronchogram, pleural retraction, spiculation, venous involvement, and ground glass opacity were examined on TSCT, and their associations with pathological findings (i.e., pleural invasion, lymphatic permeation, vascular invasion, lymph node metastasis, and Noguchis classification) and relapse were investigated using chi-square test and Cox proportional hazards model. RESULTS The incidence of relapse was significantly higher in cases with notches. The incidence of notches increased with tumor growth and notches were frequent in Noguchi type D tumors, reflecting poorly differentiated adenocarcinoma. Lymphatic permeation and type D cases were independent factors associated with a poor prognosis using Cox proportional hazards model. CONCLUSIONS TSCT findings may be useful for prediction of the prognosis of solid-density type pulmonary adenocarcinoma.

Prognostic impact of survivin, cyclin D1, integrin β1, and VEGF in patients with small adenocarcinoma of stage I lung cancer

The purpose of this study was to investigate the impact of survivin, cyclin D1, integrin β1, and vascular endothelial growth factor (VEGF) in tumor on survival of patients with small adenocarcinoma of the lung. Seventy-two patients with pathologic stage I resected tumors <2 cm in diameter were entered into the study. Each patient underwent curative surgical resection for lung cancer between July 1992 and November 1999. The resected tumors were subjected to immunostaining for each gene. Thirty-five, 26, 6, and 16 patients had tumors with >10% survivin-, >20% cyclin D1-, >10% integrin β1-, and >10% VEGF-positive cells, respectively. When the survival of 72 patients was compared according to each gene expression, the overall survival of patients with positive expression of survivin, cyclin D1, and integrin β1 was significantly worse than that of individuals whose tumors had negative expression of each gene. By multivariate analysis controlling for each gene expression, no gene expression was an independent marker of poor prognosis, however, the overall survival of the complex gene expression (2 or more gene-positive) group (n = 35) was significantly worse than that of 0 or 1 gene-positive group (n = 37; log-rank test, P = 0.0011; Wilcoxon test, P = 0.0011). When the association between survival and pathologic factors, including lymphatic invasion, venous invasion, type of bronchioalveolar carcinoma, and complex gene positive expression was analyzed, only complex gene-positive expression was found to be a significant independent factor (hazard ratio = 0.085, P = 0.0299). It can be concluded that multiple increased expression of oncogene is a poor prognostic factor in patients with small adenocarcinoma of the lung.

Correlation of 18F-fluorodeoxyglucose uptake on positron emission tomography with Ki-67 index and pathological invasive area in lung adenocarcinomas 30 mm or less in size

BACKGROUND (18)F-fluorodeoxyglucose positron emission tomography (FDG-PET) is commonly used to distinguish benign from malignant lesion. Recently, maximum standardized uptake value (SUVmax) on FDG-PET has found to have prognostic value. We examined the relationship between SUVmax and proliferative activities as indicated by maximum diameter of tumor opacity on mediastinal-window images (TOM), Ki-67 index, and diameter of the pathological invasive area in lung adenocarcinomas <or=30 mm. METHODS Thin-section computed tomography (TS-CT) and FDG-PET were performed on 140 patients with resectable lung adenocarcinomas <or=30 mm between March 2006 and May 2008. Tumors were classified as air-type or solid-type based on TS-CT findings. In all resected specimens, diameter of the pathological invasive area and Ki-67 index were assessed. RESULTS SUVmax was significantly lower for air-type than for solid-type tumors (0.97 vs. 3.96, p<0.0001). In solid-type tumors, SUVmax correlated with diameter of TOM (r=0.450, p<0.0001), Ki-67 index (r=0.567, p<0.0001), and diameter of the pathological invasive area (r=0.672, p<0.0001). In multiple regression analysis, SUVmax correlated significantly with Ki-67 index and diameter of the pathological invasive area but not with diameter of TOM. The cut-off value of SUVmax for predicting invasive area >5mm was determined as 2.15 by ROC analysis, with sensitivity of 88.3% and specificity of 84.6%. CONCLUSIONS SUVmax correlated significantly with Ki-67 index and diameter of the pathological invasive area. The present results suggest the potential role of FDG-PET in predicting adenocarcinomas with invasive characteristics.

Comparison between CT tumor size and pathological tumor size in frozen section examinations of lung adenocarcinoma

OBJECTIVE We examined the appropriate measurement for pathological tumor size by comparing radiological and pathological tumor size of resected lung adenocarcinoma in FSE. MATERIALS AND METHODS We reviewed records of 59 resected specimens of lung adenocarcinoma for FSE from January to December 2008. Specimens were well-inflated with saline by using an injector before cutting into segments. After selecting the tumor segment of maximal diameter, we compared three ways of measuring pathological tumor size by using paired t-test: (I) macroscopic tumor size (MTS), measured with a metal straight ruler, (II) microscopic frozen section tumor size (FSTS), and (III) microscopic paraffin section tumor size (PSTS). We compared each discrepancy rate (DR) [DR=(CT tumor size-pathological tumor size)/CT tumor size×100] (%) between tumors that were air-containing type and solid-density type on CT scans, and also compared the tumors with lepidic component rates (LCR) ≥50% and LCR <50%, by using Mann-Whitney U-tests. RESULTS FSE could diagnose malignancy with 100% accuracy. The mean CT tumor size was 18.36mm, and the mean pathological tumor sizes (MTS, FSTS, and PSTS) were 17.81, 14.29, and 14.23mm, respectively. FSTS and PSTS were significantly smaller than CT tumor size (p<0.001). The DR calculated with PSTS was significantly larger in air-containing than in solid-density tumors, and also larger in LCR ≥50% than in LCR <50% tumors. CONCLUSION FSE with the inflation method diagnosed malignancy with 100% accuracy. The lung specimen must be sufficiently inflated to prevent tissue shrinking, and we propose MTS as the definition for pathological tumor size in FSE. The greater discordance observed between CT tumor size and microscopic tumor size was assumed to be due to shrinkage of the lepidic component in the tumor.

Prognosis of small adenocarcinoma of the lung based on thin-section computed tomography and pathological preparations.

Objective: We investigated the relationship between findings from tumor opacity in the mediastinal window image and solid lesions in pathological preparations and related the results to tumor recurrence. Methods: The subjects were 115 patients with a lung adenocarcinoma of 20 mm or smaller who underwent surgical resection. The proportion of the reduction in the tumor opacity in the mediastinal window image maximum diameter to the maximum diameter of the tumor opacity was calculated as the reduction percentage, and the proportion of the maximum solid lesions in pathological preparation diameter to the maximum tumor diameter was calculated as the pathological ratio. Results: The incidence of relapse was significantly higher in patients with a reduction percentage of less than 50% and in patients with a pathological ratio of less than 50%. Conclusions: Measurement of the reduction percentage and the pathological ratio may allow prediction of prognosis of small adenocarcinoma of the lung.

Limited resection trial for pulmonary ground-glass opacity nodules: case selection based on high-resolution computed tomography—interim results

OBJECTIVE Our previous trial for small ground-glass opacity nodule on high-resolution computed tomography suggested all these cancers might have been radically managed with limited resection. Good correlation between radiologic and pathologic findings in early lung adenocarcinomas has been reported. We aimed to confirm limited resection efficacy as radical surgery in patients with high-resolution computed tomography-indicated minimally invasive lung cancer. The purpose of this interim analysis is to report the details of the patient and nodule characteristics, intraoperative cytology capability as a negative margin indicator, and patient outcome with the median follow-up period of 7 years and 4 months. METHODS Enrollment required patients with a tumor ≤2 cm, diagnosed or suspected as a cT1N0M0 carcinoma in the lung periphery and depicted on high-resolution computed tomography as a sub-solid nodule with tumor disappearance ratio ≥0.5. We performed a wedge or segmental resection as appropriate. The primary endpoint is 10 year local recurrence-free survival rate. RESULTS This study started in November 2003, and 101 patients were enrolled as of November 2009. Of them, 95 were eligible for analysis. There were 38 men and 57 women, aged 30-75, averaging 62 years. Tumor sizes ranged from 7 to 20 mm on computed tomography, averaging 15 mm. There were 11 Noguchi type A tumors, 54 type B tumors, 24 type C tumors, one malignant lymphoma and 5 non-cancerous lesions. All cancers showed no vessel invasion. With a median follow-up period of 88 months, there have been no recurrences. CONCLUSION So far, high-resolution computed tomography appears to predict non- or minimally invasive ground-glass opacity lung cancers with high reliability, warranting limited resection as curative surgery in this cohort.