Akira Haro

Never-smoking Nonsmall Cell Lung Cancer as a Separate Entity : Clinicopathologic Features and Survival

To propose ‘never‐smoking nonsmall cell lung cancer (NSCLC)’ as a separate entity, the clinicopathologic differences of operable NSCLC between never‐smoking patients and patients with a history of smoking were investigated.

Non-small cell lung cancer in never smokers as a representative ‘non-smoking-associated lung cancer’: epidemiology and clinical features

Recent interest in lung cancer without a history of tobacco smoking has led to the classification of a distinct disease entity of ‘non-smoking-associated lung cancer’. In this review article, we have made an overview of the recent literature concerning both the epidemiology and clinical features of lung cancer in never smokers, and have brought ‘non-smoking-associated lung cancer’ into relief. The etiology of lung cancer in never smokers remains indefinite although many putative risk factors have been described including secondhand smoking, occupational exposures, pre-existing lung diseases, diet, estrogen exposure, etc. Non-small cell lung cancer (NSCLC) in never smokers is clinically characterized by an increased incidence in females and a higher occurrence of adenocarcinoma in comparison to NSCLC in ever smokers in both surgical patients and non-resectable advanced-stage patients. Furthermore, the prognosis of never-smoking NSCLC is better than that of smoking-related NSCLC in both surgical patients and non-resectable advanced-stage patients. Recently recognized novel gene mutations such as EGFR (epidermal growth factor receptor) mutations are largely limited to never smokers or light smokers, and the expression of this gene is responsible for the clinical efficacy of gefitinib, an epidermal growth factor receptor-tyrosine kinase inhibitor. NSCLC with the EML4 (echinoderm microtubule-associated protein-like 4)-ALK (anaplastic lymphoma kinase) fusion gene is also more likely to occur in never smokers and in those with adenocarcinoma histology, and is expected to benefit from ALK inhibitors. In consideration of the future increase in never-smoking NSCLC or ‘non-smoking-associated lung cancer’, both clinical trials and investigations are needed.

Prognostic significance of intratumoral blood vessel invasion in pathologic stage IA non-small cell lung cancer.

BACKGROUND The 5-year survival rate of pathologic stage IA non-small cell lung cancer (NSCLC) is excellent; however, up to 10% of patients with pathologic stage IA NSCLC still relapse postoperatively and die. This study retrospectively analyzed the clinicopathologic features of patients with pathologic stage IA NSCLC to identify the prognostic factors and investigate the effect of a combination of intratumoral vessel invasion and tumor size. METHODS From December 1991 to December 2003, 217 consecutive patients with stage IA NSCLC were selected, and disease-free survival (DFS) was analyzed. RESULTS Intratumoral blood vessel invasion (BVI) was identified as an independent poor prognostic factor (p = 0.0006). The relative risk for patients with BVI was 4.599 times higher than that for patients without BVI (95% confidence interval, 1.913 to 11.056). According to the new T N M system, the difference in DFS between the patients with and without BVI was statistically significant, not only in tumors exceeding 2 cm (T1b with BVI vs T1b without BVI, p = 0.0020) but also in tumors smaller than 2 cm (T1a with BVI vs T1a without BVI, p < 0.0001). The survival curve of T1b patients without BVI was similar to that of T1a patients without BVI (p = 0.0892). Distant recurrence was frequently observed in both T1a and T1b patients with BVI. CONCLUSIONS BVI is an independent poor prognostic factor in patients with pathologic stage IA NSCLC. These T1a and T1b patients with BVI both might benefit from adjuvant chemotherapy.

Verification of the Newly Proposed T Category (Seventh Edition of the Tumor, Node, and Metastasis Classification) from a Clinicopathological Viewpoint in Non-small Cell Lung Cancer—Special Reference to Tumor Size

Introduction: This study first verified the T classification, which is the major point of the revision regarding the seventh Tumor, Node, and Metastasis classification, from a viewpoint of the clinicopathological findings at the primary tumor site in non-small cell lung cancer. Methods: The medical records of 1393 patients with non-small cell lung cancer who underwent a complete resection at this hospital from 1974 to 2003 were thoroughly reviewed for pathologic findings and survival. Results: According to greatest dimension of the primary tumors, the 5-year postoperative survival was 77.8% for T1a (≤2 cm), 63.3% for T1b (≤3 cm), 46.4% for T2a (≤5 cm), 38.8% for T2b (<7 cm), and 21.4% for T3 (>7 cm). The differences among those new T categories were all statistically significant. The incidence of lymphatic permeation within the primary tumor was 17.2% for T1b and 29.8% for T2a (T1b versus T2a, p < 0.05). The incidence of vascular invasion within the primary tumor was 24.9% for T1b, 35.3% for T2a, and 54.2% for T2b (T1b versus T2a and T2a versus T2b, p < 0.05). On the other hand, the incidence of pleural invasion of the primary tumor was 18.1% for T1a, 29.4% for T1b, 49.3% for T2a, 47.3% for T2b, and 87.5% for T3 (T1a versus T1b, T1b versus T2a, T2b versus T3, p < 0.05). Significant differences were observed among the newly revised T subsets in at least one incidence of lymphatic, vascular, or pleural invasion. Conclusion: The new T classification, which is based mainly on the tumor size, is therefore considered to be appropriate for the pathologic findings of the primary tumor.

Results of a surgical resection of pulmonary metastasis from malignant head and neck tumor

There have been only a few reports about a surgical resection of pulmonary metastasis from malignant head and neck tumor. Here we investigate the survival after a pulmonary metastasectomy, and discuss the prognostic factors. We retrospectively reviewed 25 patients who underwent a pulmonary metastasectomy from malignant head and neck tumor at Kyushu University Hospital from 1981 through 2008. We assessed the five year overall survival by the Kaplan-Meier method and the log-rank (Mantel-Cox) test using the Stat View software program. The three- or five-year overall survival after a metastasectomy was 53.3% and 50.0%, respectively. We investigated the clinico-pathological prognostic factors including gender, age, histology, disease free interval, number or size of pulmonary metastatic tumors, and the operative procedure. Both age (older than 60 years) (P=0.0189) and pulmonary metastases from squamous cell carcinomas in either oral cavity or pharyngeal region (P=0.0002) were identified to be adverse prognostic factors. To obtain a long survival, a positive surgical resection is considered to be an effective and standard treatment for pulmonary metastasis from malignant head and neck tumor. It is also necessary, however, to elucidate fully the primary site and histology of such pulmonary metastasis.

Differences in the expression of epithelial–mesenchymal transition related molecules between primary tumors and pulmonary metastatic tumors in colorectal cancer

PurposeEpithelial–mesenchymal transition (EMT) is a key event in cancer metastasis. This study immunohistochemically examined the expression of EMT-related molecules in both primary colorectal cancer and pulmonary metastases, and analyzed the expression pattern.MethodsTen patients with colorectal cancer that underwent surgical resections for both the primary tumor and metastatic pulmonary tumors were included. The expression status of EMT-related molecules was examined using immunohistochemical staining.ResultsNine of the 10 cases maintained the expression of both E-cadherin and β-catenin in the primary site. The expression of E-cadherin and β-catenin in the pulmonary metastatic site was preserved in 10 and 12 out of 15 metastatic lesions, respectively. The EMT-related transcription factor, Twist, was positively expressed in all 10 cases, Smad interacting protein 1 (Sip1) in 9, Snail in 4 and Slug in 3 of the primary sites. On the other hand, staining for Twist, Sip1 and Snail at the metastatic pulmonary site, was negative in all 10 cases.ConclusionThe expression of EMT-related transcription factors in metastatic pulmonary tumors from colorectal cancer decreased in comparison to the primary tumors. These findings suggested that the expression status of EMT-related transcription factors might play an important role in the implantation of metastatic foci.

Aspergilloma mimicking a lung cancer

INTRODUCTION Pulmonary aspergillosis occurs in the parenchymal cavities or ectatic airways. It rarely affects healthy people with an intact immune response. There have been few reports describing an aspergilloma mimicking a lung cancer. PRESENTATION OF CASE We experienced the case of an asymptomatic healthy 71-year-old female who was admitted with an abnormal lung shadow. Chest CT revealed an irregularly shaped solid lung nodule in the left upper lobe, which increased in size during the follow-up at a regional hospital. The pathology of the bronchial biopsy was negative for malignant cells, and the cultures were negative. Because a lung cancer was strongly suspected, video-assisted thoracic surgery was performed. Aspergillus was detected by a pathological study of the excised specimen, with no evidence of lung cancer. DISCUSSION It is difficult to make an accurate diagnosis of aspergilloma by imaging findings in healthy people with an intact immune response, and therefore a surgical resection allows both the pathological diagnosis and treatment to be performed concurrently. CONCLUSION An aspergilloma presenting a mass shadow on imaging may mimic a lung cancer in healthy people with intact immune response.

Assessing a clinical pathway to improve the quality of care in pulmonary resections

PurposeTo evaluate the efficacy of the current clinical pathway for pulmonary resections.MethodsThis study examined variances from expected clinical pathway outcomes for pulmonary resections performed between 2005 and 2009. Data on a total of 383 patients were retrospectively analyzed.ResultsThe median length of hospital stay (LOS) using the clinical pathway was 12 days (range: 1–188 days); the mean LOS was 15.5 days. The cost per day with use of the clinical pathway was 102 726 yen. Poor control of pain from intercostal neuralgia was the most frequently observed variance from expected outcomes. It affected 119 of 168 electronic clinical pathway patients (70.8%). The clinical pathway was terminated in 3.9% of patients (15/383) due to serious or life-threatening complications.ConclusionsThis study showed the single institutional experience of the clinical pathway for pulmonary resections. These findings indicate a need to revise certain aspects of the pathway, based on data from our analysis of variances.

Ground-glass opacity lesions on computed tomography during postoperative surveillance for primary non-small cell lung cancer

Improvement in chest high-resolution computed tomography (CT) has increased the detection of ground-glass opacity (GGO) lesions. However, there is no clear therapeutic consensus about concurrent GGO lesions detected during postoperative follow-up chest CT after treatment for primary lung cancer. This study retrospectively and prospectively investigated 21 patients in whom 53 GGO lesions were detected during postoperative follow-up CT of non-small cell lung cancer at Kyushu University Hospital from April 2009 to February 2010. We investigated clinicopathological factors, such as age, gender, lesion number, size, laterality, time of identification, and enlargement or emergence of the inner solid component. The malignancy rate of the concurrent GGO lesions was assessed by log-rank test in the Kaplan-Meier curves. Twenty percent of the 53 GGO lesions had malignant radiological findings during the 5-year follow-up after they were first identified by CT. The newly emerging GGO lesions at postoperative CT had significantly more malignant radiological findings (39.5%) than other GGO lesions (9.5%). Three potentially malignant GGO lesions were treated by surgical resection and three were treated by stereotactic radiotherapy. These six treated GGO lesions showed a good clinical course without recurrence after treatment. Special attention should be paid to newly emerging GGO lesions after resection of primary non-small cell lung cancer. It is necessary to select an appropriate treatment, taking account of various factors such as the laterality and number of GGO lesions or the pathological stage of the postoperative lung cancer.

The influence of intracellular epidermal growth factor receptor (EGFR) signal activation on the outcome of EGFR tyrosine kinase inhibitor treatment for pulmonary adenocarcinoma

PurposeThe epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), such as gefitinib, exhibit up to a 70% response rate against non-small cell lung cancer (NSCLC) harboring somatic activating mutations of the EGFR gene (EGFR). The mechanism of intrinsic resistance of EGFR mutation-positive NSCLC against EGFR-TKIs is not known. The current study assesses the relationship between the molecular expression of EGFR signals and the response to gefitinib treatment in patients with pulmonary adenocarcinoma to elucidate the mechanism of intrinsic resistance to gefitinib.MethodsThe present study included 30 patients with pulmonary adenocarcinoma who were treated with gefitinib for a postoperative recurrence. The correlation between the response to gefitinib treatment and various clinical and molecular features was evaluated.ResultsEGFR mutations were detected in 20 (66.7%) of the 30 patients. The response to gefitinib treatment was a complete response in 1 case, partial response in 12 cases, stable disease in 4 cases, and progressive disease in 13 cases. Both univariate and multivariate analyses showed the presence of an EGFR mutation, and the expression of phospho-EGFR (p-EGFR) significantly correlated with a better response to gefitinib treatment. Ten of the 16 p-EGFR positive patients were disease controlled, but all 4 p-EGFR negative patients were intrinsically resistant to EGFR-TKIs (P = 0.025). Other factors including sex, smoking status, serum carcinoembryonic antigen and cytokeratin-19 fragment levels, EGFR, Met proto-oncogene, phospho-Met, and hepatocyte growth factor expression were not associated with the response to gefitinib treatment.ConclusionThese results suggest that, even if EGFR mutations were observed, a p-EGFR negative state might be a cause of intrinsic resistance to EGFR-TKIs.