Shiaki Oh

The size of consolidation on thin-section computed tomography is a better predictor of survival than the maximum tumour dimension in resectable lung cancer

OBJECTIVES Ground-glass opacity (GGO) is a preoperative prognostic factor in resectable lung cancer. However, the impact of GGO on the T factor in the TNM staging system remains unclear and the maximum tumour dimension is also an uncertain measurement for assessing the prognosis of early lung cancer with a mixture of consolidation and GGO. Thus, we sought to determine which the better prognostic factor was, the size of the consolidation on computed tomography scan or the conventional maximum tumour dimension. METHODS Between January 2004 and January 2011, 398 consecutive clinical stage IA lung cancer patients underwent surgical resection at our hospital. Univariate and multivariate analyses were performed by the logistic regression procedure to determine the relationship between pathological lymph node metastasis-positive status and clinical or radiological findings such as the maximum dimensions of consolidation and the tumour, the presence of air bronchogram, pleural indentation and the preoperative serum carcinoembryonic antigen (CEA) level. RESULTS Of the 398 patients, 59 (14.8%) had pathological lymph node metastasis. Univariate analysis revealed four significant predictors of pathological nodal involvement: the presence of air bronchogram, the size of consolidation, the maximum tumour dimension and the preoperative CEA level (P < 0.01, respectively). In a multivariate analysis, the size of consolidation and the presence of air a bronchogram were significant predictors of nodal metastasis (P < 0.01, respectively). CONCLUSIONS The maximum dimension of the consolidation was an independent unfavourable prognostic factor, regardless of the maximum tumour dimension. This could lead to the more accurate prediction of pathological lymph node metastasis with both GGO and consolidation.

The importance of intraoperative fluid balance for the prevention of postoperative acute exacerbation of idiopathic pulmonary fibrosis after pulmonary resection for primary lung cancer.

OBJECTIVES Postoperative acute exacerbation (PAE) of idiopathic pulmonary fibrosis (IPF) is a serious complication that is hard to treat. Therefore, it is important to manage IPF patients in such a way as to avoid PAE. Conversely, the relationship between postoperative acute lung injury and perioperative fluid administration has been reported. Herein, we analyse the perioperative risk factors of PAE of IPF, including fluid management. METHODS Fifty-two patients diagnosed as having clinical IPF who underwent pulmonary resection (segmentectomy, lobectomy or bilobectomy) for primary lung cancer were analysed retrospectively. Preoperative predictive factors and perioperative management items, especially fluid management, were evaluated. RESULTS The incidence of PAE of IPF was 13.5% (7 of 52 patients). Six patients (85.7%) died of respiratory failure induced by uncontrollable PAE of IPF. Upon univariate analysis, the amount of the intraoperative fluid infused (ml/kg/h), the intraoperative fluid balance (ml/kg/h) and the preoperative C-reactive protein (CRP) level were found to be significantly higher in IPF patients who developed PAE than in those who did not. A multivariate logistic regression analysis showed that the intraoperative fluid balance and the preoperative CRP were prognostic factors for PAE of IPF [P = 0.026, odds ratio (OR) = 1.312 and P = 0.048, OR = 1.280, respectively]. CONCLUSIONS To prevent PAE of IPF, intraoperative management that minimizes intravenous fluid administration is essential. Moreover, caution is particularly important in patients with preoperative evidence of inflammation.

A Rational Diagnostic Algorithm for the Identification of ALK Rearrangement in Lung Cancer: A Comprehensive Study of Surgically Treated Japanese Patients

Background EML4-ALK fusion gene is found in only a small subset (2–6%) of non-small cell lung cancer. There is an urgent need to establish a rational diagnostic algorithm to identify this rare but important fusion in lung cancer. Methods We performed a comprehensive analysis of EGFR/KRAS mutation and ALK rearrangement in a total of 360 surgically resected lung cancers. ALK rearrangement was examined by 3 analyses: multiplex reverse transcription-PCR, fluorescent in situ hybridization (FISH), and immunohistochemistry (IHC) with the intercalated antibody-enhanced polymer method. A scoring system was used for IHC (iScore). A test set (202 patients with unselected lung cancer) was used for proposing a diagnostic algorithm. This diagnostic algorithm was validated in 158 patients with EGFR and KRAS mutation-negative adenocarcinoma. Results ALK rearrangement was identified in 2 patients (1.0%) from the test set and both adenocarcinomas were negative for EGFR and KRAS mutations. The results of FISH and RT-PCR were completely matched. The highest iScore 3 was found only in the 2 positive cases. A diagnostic algorithm was proposed: IHC screening for ALK rearrangement followed by confirmatory FISH. In the validation set, 8 cases (5.1%) had iScore 3 and were positive for FISH, while the other cases had iScore 0 and were negative for FISH. Conclusions Screening for ALK rearrangement by IHC followed by confirmatory FISH is a rational diagnostic algorithm. If needed, patients may be selected for screening ALK rearrangement by their EGFR and KRAS mutation status.

Clonality status of multifocal lung adenocarcinomas based on the mutation patterns of EGFR and K-ras

PURPOSE The purpose of this study is to clarify the clonality status of multifocal lung adenocarcinomas based on the mutation patterns of epidermal growth factor receptor (EGFR) and K-ras. METHODS We analyzed 82 multifocal lung adenocarcinomas from 36 patients who underwent surgical resection. Genomic DNA was extracted from formalin-fixed, paraffin-embedded tissue and analyzed for EGFR and K-ras mutations. We determined the clonality status of multifocal lung adenocarcinomas based on the mutation patterns of EGFR and K-ras. The actuarial survival time was estimated and the prognostic factors were evaluated for 31 patients with synchronous multifocal lung adenocarcinomas. RESULTS EGFR and K-ras mutations were detected in 36 (44%) and 19 (23%) of the 82 tumors, respectively. EGFR mutations had occurred randomly in 20 (91%) of the 22 patients with at least one EGFR mutated tumor. K-ras mutations had occurred randomly in 14 (93%) of the 15 patients with at least one K-ras mutated tumor. Combining the results for the EGFR and K-ras mutation patterns, the clonality status of multifocal lung adenocarcinomas could be determined in 30 (83%) of the 36 patients. No statistically significant difference in the actuarial survival of the patient subgroups stratified according to the clonality status, which was based on the presence of EGFR and K-ras mutations, was observed. CONCLUSIONS Both EGFR and K-ras mutations frequently occur randomly in multifocal lung adenocarcinomas. Combined mutation pattern analyses of EGFR and K-ras may be useful for making decisions regarding treatment strategies for patients with multifocal lung adenocarcinomas.

Risk factors for morbidity after pulmonary resection for lung cancer in younger and elderly patients.

The aim of this study was to evaluate the perioperative morbidity, mortality, and risk factors for morbidity after lung cancer resection in younger and elderly patients. This study retrospectively reviewed 1073 patients with non-small cell lung cancers (NSCLC) who underwent pulmonary resection. The risk factors for morbidity were analyzed independently in groups of 664 younger (<70 years) patients and 409 elderly (≥ 70 years) patients. Co-morbidities, such as hypertension, ischemic heart disease, and renal insufficiency were more frequently observed in the elderly group in comparison to the younger group. However, there were no statistical differences in the rates of overall morbidity and 30-day mortality between the younger and elderly groups (36% vs. 42% and 0.3% vs. 0.5%, respectively). Multivariate analyses revealed the risk factors for morbidity to be % forced expiratory volume in 1 s (FEV(1)), the extent of pulmonary resection and tumor histology in the younger group, and smoking, hypertension, renal insufficiency and % diffusing capacity of the lung to carbon monoxide (DLCO) in the elderly group, respectively. In conclusion, the rate of morbidity and mortality in elderly patients were similar to those observed in younger patients. However, perioperative management should be cautiously performed while taking into account the risk factors for morbidity especially in elderly patients because they frequently have various co-morbidities.

Galectin-4, a Novel Predictor for Lymph Node Metastasis in Lung Adenocarcinoma

Metastasis is still a major issue in cancer, and the discovery of biomarkers predicting metastatic capacity is essential for the development of better therapeutic strategies for treating lung adenocarcinoma. By using a proteomic approach, we aimed to identify novel predictors for lymph node metastasis in lung adenocarcinoma. Two-dimensional sodium dodecyl sulfate polyacrylamide gel electrophoresis showed 6 spots differentially expressed between lymph node metastasis-positive and lymph node metastasis-negative groups in a discovery set. Subsequent mass spectrometry showed that 2 of these spots were derived from galectin-4, and western blot analysis confirmed the overexpression of galectin-4 in metastatic samples. The predictive value of galectin-4 was confirmed by immunohistochemical analysis for a validation set consisting of 707 surgically resected specimens of lung adenocarcinomas (stages I to IV). We observed that 148 lung adenocarcinomas (20.9%) expressed galectin-4, which was significantly associated with variables of disease progression such as tumor size (p<0.0001), pleural invasion (p = 0.0071), venous invasion (p = 0.0178), nodal status (p = 0.0007), and TNM stage (p<0.0001). By the multivariate analysis, Galectin-4 expression was revealed as one of the independent predictor for lymph node metastasis, together with solid predominant and micropapillary histologic pattern. Furthermore, galectin-4 expression was revealed to be an independent predictor for lymph node metastasis and an adverse survival factor in patients with lung adenocarcinoma of acinar predominant type. Galectin-4 plays an important role in metastatic process of lung adenocarcinoma. Immunohistochemical testing for galectin-4 expression may be useful together with the detection of specific histology to predict the metastatic potential of lung adenocarcinoma.

Clinicopathologic features in resected subcentimeter lung cancer – status of lymph node metastases

Widely used low dose helical thoracic computed tomography (CT) scan in screening results is detecting more and more small-sized lung cancers. Whether systematic lymph node (LN) dissection should be done or not on subcentimeter lung cancers still remains controversial. From June 2000 to December 2008, the records of all patients who underwent resection of primary non-small cell lung cancer (NSCLC) 1 cm or less in diameter were reviewed. LN metastases and lymphatic vessel invasion (LVI) were studied between different subgroups to determine the predictors of metastases. Of all 41 patients, there were 35 (85%) cases of adenocarcinoma, 3 (7%) cases of squamous cell carcinoma, 3 (7%) cases of other types. There were 6 (15%) cases with nodal metastases. Lymphatic invasion was found in 11 (27%) patients. Tumor differentiation, visceral pleural involvement, preoperative serum carcinoembryonic antigen (CEA), ground-glass opacity content on CT and blood vessel invasion (BVI) were significant predictors for both LN metastases and LVI. Systematic LN dissection is recommended for subcentimeter patients with good risk, however, if the patient is female, or with normal CEA, or with ground-glass opacity, or with Noguchi A or B type, surgeons might omit the procedure.

The maximum standardized uptake value of fluorodeoxyglucose positron emission tomography of the primary tumour is a good predictor of pathological nodal involvement in clinical N0 non-small-cell lung cancer

OBJECTIVES Fluorodeoxyglucose positron emission tomography (FDG-PET) plays an important role in the evaluation of resectable non-small-cell lung cancer (NSCLC). However, this modality cannot be used to detect histological nodal involvement, which can result in stage-migration for resectable lung cancer. In this study, we tried to evaluate the possibility of predicting histological nodal involvement in patients with NSCLC using the maximum standardized uptake value (SUVmax) of FDG-PET of the primary tumour instead of that of the lymph nodes. METHODS Between February 2008 and September 2011, 898 patients underwent lung cancer surgery at our institute. Among them, we retrospectively analysed 265 patients with clinical N0 NSCLC, who underwent preoperative FDG-PET. The relationships between clinicopathological features, including the findings of FDG-PET and pathological nodal involvement, were investigated. The factors investigated were age, gender, preoperative carcinoembryonic antigen titre, maximum tumour dimension, consolidation/tumour dimension ratio (C/T ratio), SUVmax in the primary tumour and smoking history. RESULTS Of the 265 clinical N0 NSCLC patients, 214 (80.8%) had pathological N0 status and 27 (10.2%) and 24 (9.0%) had pathological N1 and N2 disease. In a multivariate analysis, the C/T ratio (P = 0.046) and SUVmax of the primary tumour (P = 0.016) were significant predictors of pathological nodal involvement. With regard to pathological N1-2 disease, the sensitivity, specificity, accuracy and positive and negative predictive values of mediastinal node involvement in patients with NSCLC with an SUVmax for FDG-PET of 10 or more were 49.0, 83.2, 76.6, 41.0 and 87.3%, respectively. Of the 61 patients with NSCLC with an SUVmax for FDG-PET of 10 or more, 25 (41.0%) had pathological N1-2 disease, while only 26 (12.7%) of the remaining 204 patients with an SUVmax for FDG-PET of <10 had nodal disease (P < 0.0001). CONCLUSIONS Postoperative nodal status was significantly predicted by the SUVmax of FDG-PET of the primary tumour instead of the lymph nodes themselves. The patients with NSCLC in particular who show strong uptake values of SUVmax in the primary tumour could have occult nodal metastases, and may be indicated for a further preoperative modality for an accurate staging.

Tumour standardized uptake value on positron emission tomography is a novel predictor of adenocarcinoma in situ for c-Stage IA lung cancer patients with a part-solid nodule on thin-section computed tomography scan†

OBJECTIVES Adenocarcinoma in situ (AIS), which is considered to be pathologically non-invasive in the new International Association for the Study of Lung Cancer/the American Thoracic Society/the European Respiratory Society classification, might be present in patients who show a part-solid nodule on thin-section computed tomography (CT) scan. METHODS Between 2008 and 2011, 556 clinical Stage IA (c-Stage IA) lung cancer patients underwent pulmonary resection. For all the patients, the findings obtained by preoperative thin-section CT were reviewed and categorized as pure ground-glass nodule (GGN), part-solid nodule or pure-solid nodule based on the findings on thin-section CT, i.e. based on the consolidation/tumour ratio (CTR). A part-solid nodule was defined as a tumour with 0 < CTR < 1.0, which indicated focal nodular opacity that contained both solid and GGN components. All the patients were evaluated by positron emission tomography (PET), and the maximum standardized uptake value (SUVmax) was recorded. Several clinicopathological features were investigated to identify predictors of AIS in clinical Stage IA lung cancer patients with a part-solid nodule radiologically, using multivariate analyses. RESULTS One-hundred and twelve c-Stage IA lung cancer patients showed a part-solid appearance on thin-section CT. Among them, AIS was found in 10 (32%) of the tumours with 0 < CTR ≤ 0.5, in contrast to 3 (5%) with 0.5 < CTR < 1.0. According to multivariate analyses, SUVmax and CTR significantly predicted AIS in patients with a part-solid nodule (P = 0.04, 0.02). The mean SUVmax of the patients with AIS was 0.57 (0-1.6). Moreover, in the subgroup of part-solid nodule with a SUVmax of ≤1.0 and a CTR of ≤0.40, which were calculated as cut-off values for AIS based on the results for a receiver operating characteristic curve, 6 (40%) patients with these criteria showed a pathological non-invasive nature, even patients with a part-solid nodule. CONCLUSIONS Among c-Stage IA adenocarcinoma with a part-solid nodule on thin-section CT scan, an extremely low level of SUVmax could reflect a pure GGN equivalent radiologically and AIS pathologically. The preoperative tumour SUVmax on PET could yield important information for predicting non-invasiveness in patients with a part-solid nodule.

What is the appropriate operative strategy for radiologically solid tumours in subcentimetre lung cancer patients

OBJECTIVES Solid lung cancers, even subcentimetre lesions, are considered to be invasive pathologically. However, the clinicopathological features and appropriate operative strategies in patients with these small lesions are still controversial, especially for those with a radiologically solid appearance. METHODS Between 2004 and 2011, 135 patients underwent pulmonary resection for subcentimetre lung cancer with clinical-N0 (c-N0) status. The findings of preoperative thin-section computed tomography (CT) were reviewed, and subcentimetre lung cancer was divided into three groups: pure ground-glass nodule, part-solid and pure-solid lesions. RESULTS Among the 135 subcentimetre lung cancer patients with c-N0 status, 71 showed a solid appearance on thin-section CT scan. Furthermore, pathological nodal examinations were performed in 49 patients, and nodal involvement was found pathologically in 6 (12.2%) patients. All of them had pure-solid tumours (P = 0.0010). Among the patients with solid subcentimetre lung cancers, the maximum standardized uptake value (SUVmax) was the only significant predictor of nodal involvement by a multivariate analysis (P = 0.0205). With regard to the surgical outcomes, the overall 5-year survival and disease-free survival rates were 100 and 97.8% for part-solid lesions, and 87.3 and 74.8% for pure-solid lesions, respectively. Moreover, there was a significant difference in disease-free survival between a high SUVmax group (60.0%) and a low SUVmax group (94.9%) (P = 0.0013). CONCLUSIONS There might be a possibility of lymph node metastasis despite subcentimetre lung cancer, especially for radiological pure-solid nodules that show a high SUVmax. If limited surgery is indicated for solid subcentimetre lung cancer, a thorough intraoperative evaluation of lymph nodes is needed to prevent loco-regional failure.