Miyako Hiramatsu

Pulmonary Ground-Glass Opacity (GGO) Lesions–Large Size and a History of Lung Cancer are Risk Factors for Growth

Objective: Ground-glass opacity (GGO) of the lung is being frequently detected by thin section computed tomography scan. However, the long term management of detected GGO is still unclear. To establish follow-up plans, we performed the clinical and radiological review to identify the factors that are closely associated with GGO growth. Methods: We retrospectively analyzed computed tomography images of 125 GGOs that were stable for 3 months between 1999 and 2006 at the Cancer Institute Hospital, Tokyo. To identify factors that affect the roentgenological growth, the time to GGO growth curve by Kaplan-Meyer method was evaluated in terms of gender, age, smoking, initial size, existence of a solid part, GGO density, location, multiplicity, and lung cancer history by univariate and multivariate analyses. Results: The median observation period was 1048 days (177–3269) and 26 of 125 GGOs (21%) grew. The estimated growth population for 5 years was 30%. The growth was more frequently seen in the elderly (p = 0.017), in part-solid GGO (p < 0.01) and in GGO of larger than 10 mm (p < 0.01, logrank test). By multivariate analysis, initial size (p < 0.01, Cox’s model) and history of lung cancer (p = 0.017, logistic model) were independent factors that were significantly associated with GGO growth. Fifty GGOs that were 10 mm or smaller and without a lung cancer history did not grow within 3.5 years. Conclusions: After initial management and 3 month follow-up, larger size (more than 10 mm) and a history of lung cancer are risk factors for GGO growth, and therefore should be considered when making a follow-up plan.

Correlation between morphology and EGFR mutations in lung adenocarcinomas Significance of the micropapillary pattern and the hobnail cell type.

The presence of epidermal growth factor receptor (EGFR) tyrosine kinase (TK) mutations significantly correlates with tumor sensitivity to TK inhibitors, particularly in lung adenocarcinomas, the predominant histological subtype in Japan and the United States. To clarify links between EGFR mutations and pathological findings in Japanese lung cancer, detailed pathological features of adenocarcinomas were examined using the WHO criteria as well as our cell type classification (hobnail, columnar and polygonal). Medical records were reviewed for a total of 107 surgically resected tumors. Clinicopathological factors were examined and correlations with EGFR status were evaluated. EGFR mutations were found in 63 patients (59%) distributed through all four exons examined (through exons 18-21). EGFR mutations were significantly associated with female gender (P=0.003), non-smoker status (P=0.008) and hobnail cell morphology (P<0.00001). In addition, detailed pathological examination showed significant associations with bronchioloalveolar carcinoma (BAC) component and a micropapillary pattern (MPP) (P=0.012 and 0.043, respectively). We conclude that characteristic histological features, i.e. the hobnail cell morphology and the presence of BAC component and MPP are good predictors of EGFR mutations in lung adenocarcinoma.

Unilateral thoracoscopic subtotal thymectomy for the treatment of stage I and II thymoma

OBJECTIVE The purpose of this study was to determine the feasibility of thoracoscopic thymectomy for the treatment of Masaoka stage I and II thymoma. METHODS We evaluated the short-term outcomes of 40 patients undergoing surgery for Masaoka stage I and II thymomas without myasthenia gravis between July 2000 and July 2008. Of these, 22 patients underwent complete thymoma resection using unilateral thoracoscopic subtotal thymectomy (UTST group), and 18 patients underwent trans-sternal thymectomy (TST group). RESULTS Intra-operative blood loss amounts did not differ significantly between the UTST and TST groups (100.6 ml and 208.1 ml, respectively, p=0.0513). The duration of the postoperative hospital stay was significantly shortened in the UTST group (4.6 days vs 11.2 days, p<0.0001). No patient in the UTST group underwent conversion to open surgery. No severe surgical complications, such as bleeding due to injury to the left brachiocephalic vein, and no postoperative complications, were detected in this series. CONCLUSIONS These preliminary results suggest that thoracoscopic thymectomy for Masaoka stage I and II thymoma is technically feasible and safe, and it is less invasive for the patient. Nevertheless, this procedure requires further investigation in a large series with a longer follow-up.

ASCL1-coexpression profiling but not single gene expression profiling defines lung adenocarcinomas of neuroendocrine nature with poor prognosis

BACKGROUND Lung adenocarcinoma is heterogeneous regarding histology, etiology and prognosis. Although there have been several attempts to find a subgroup with poor prognosis, it is unclear whether or not adenocarcinoma with neuroendocrine (NE) nature has unfavorable prognosis. MATERIALS AND METHODS To elucidate whether a subtype of adenocarcinoma with NE nature has poor prognosis, we performed gene expression profiling by cDNA microarray for 262 Japanese lung cancer and 30 normal lung samples, including 171 adenocarcinomas, 56 squamous cell carcinomas and 35 NE tumors. A co-expression gene set with ASCL1, an NE master gene, was utilized to classify tumors by non-negative matrix factorization, followed by validation using an ASCL1 knock-down gene set in DMS79 cells as well as an independent cohort (n=139) derived from public microarray databases as a test set. RESULTS The co-expression gene set classified the adenocarcinomas into alveolar cell (AL), squamoid, and NE subtypes. The NE subtype, which clustered together almost all the NE tumors, had significantly poorer prognosis than the AL subtype that clustered with normal lung samples (p=0.0075). The knock-down gene set also classified the 171 adenocarcinomas into three subtypes and this NE subtype also had the poorest prognosis. The co-expression gene set classified the independent database-derived American cohort into two subtypes, with the NE subtype having poorer prognosis. None of the single NE gene expression was found to be linked to survival difference. CONCLUSION Co-expression gene set with ASCL1, rather than single NE gene expression, successfully identifies an NE subtype of lung adenocarcinoma with poor prognosis.

Activation status of receptor tyrosine kinase downstream pathways in primary lung adenocarcinoma with reference of KRAS and EGFR mutations

The activation status of signal transduction pathways involving receptor tyrosine kinases and its association with EGFR or KRAS mutations have been widely studied using cancer cell lines, although it is still uncertain in primary tumors. To study the activation status of main components of growth factor-induced pathways, phosphorylated Akt (pAkt), extracellular signal-regulated kinases 1 and 2 (pERK) and other downstream proteins were immunohistochemically examined using surgical samples of 193 primary lung adenocarcinomas. Also, thyroid transcription factor-1 (TTF-1) expression and mutation status of EGFR and KRAS were examined. Advanced tumor stages (p<0.001), negative TTF-1 expression (p<0.001) and Akt activation (p=0.015) were independent and significant poor prognostic markers. Akt activation related to advanced stage (p=0.021), invasiveness (p=0.004), and not to mutations. TTF-1 expression associated with never-smoker (p=0.013), pre- or minimally invasiveness (p<0.001) and EGFR mutations (p=0.017) as well as with pERK (p=0.039) expression. EGFR mutations did not correlated with pAkt and pERK expression, which was different from the results based on cultured cells, while KRAS mutations were solely and significantly linked to ERK activation (p=0.009). In lung adenocarcinoma, tumors with TTF-1 expression have distinct characteristics regarding mutations, signal protein activation and clinical issues. Moreover, this property was revealed to be important in outcome estimation at any tumor stage, whereas Akt activation is abnormally affected according to the tumor stage regardless of their cell origin. The signal proteins were differently related to mutation status from cultured cells.

Risk Factors That Affect the Surgical Outcome in the Management of Focal Bronchiectasis in a Developed Country

BACKGROUND The purpose of this study was to demonstrate our surgical experience for focal bronchiectasis in the setting of modern diagnostic modalities and state-of-the-art medical treatment in a developed country. METHODS Thirty-one patients undergoing 33 lung resections for the treatment of focal bronchiectasis from 1991 to 2009 were reviewed. The mean age was 54 years. Twenty-nine patients (94%) were female; 21 patients (68%) had nontuberculous mycobacterial infection; and 22 patients (71%) received preoperative multiple-drug regimens containing clarithromycin. Five patients (16%) were in an immunocompromised status. All were diagnosed by chest computed tomography scan, and either the right middle lobe or left lingula were involved in 29 (94%). The curve for relapse-free interval was estimated by Kaplan-Meier methods. The factors that affected this curve were examined using Coxs regression analysis. RESULTS Operative morbidity and mortality were 18% and 0%, respectively. All patients became asymptomatic postoperatively. During the median follow-up of 48 months (11 to 216), 8 patients (26%) experienced recurrence, and the mean relapse-free interval was 34 months (3 to 216). By univariate analysis, an immunocompromised status (p=0.017), Pseudomonas aeruginosa infection (p=0.040), the preoperative extent of bronchiectatic lesion (p=0.013), and the extent of residual bronchiectasis after surgery (p=0.003) were significantly associated with the shorter relapse-free interval. By multivariate analysis, an immunocompromised status (p=0.039), Pseudomonas aeruginosa infection (p=0.033), and the extent of residual bronchiectasis (p=0.009) were independent and significant factors. CONCLUSIONS Complete resection of bronchiectasis while the disease is localized and is free from Pseudomonas aeruginosa infection is the key for a success. Also, immunocompromised status was suggested to be a risk factor.

HOXB2 as a Novel Prognostic Indicator for Stage I Lung Adenocarcinomas

Background: Outcomes of patients with lung adenocarcinomas can be predicted to some extent from the pathologic stage (p-stage). Although all attempts are made to fully remove cancer lesions, still a number of p-stage I patients without metastatic disease at the time of surgery develop recurrences and die of cancer. It is thus very important to identify p-stage I patients who are at risk of recurrence. Methods: Previously, using microdissected samples, we identified metastasis-related genes. Using real-time reverse-transcriptase polymerase chain reaction analysis, we investigated the transcriptional levels of the top metastasis-related genes using 96 independent test lung adenocarcinoma samples and investigated their correlations with the prognosis. Results and Conclusions: We document evidence that p-stage I patients with HOXB2 up-regulation have a worse prognosis than those with HOXB2 down-regulation (p = 0.0065), whereas the HOXB2 status has no prognostic significance for p-stage II–IV patients. Comparing tumors and corresponding normal lung tissue, we confirmed HOXB2 up-regulated lesions to have much higher HOXB2 expression than the corresponding normal tissue. Confirmation with a larger number of samples is needed, with further research to clarify the molecular functions of HOXB2.

Pulmonary adenocarcinoma in situ: analyses of a large series with reference to smoking, driver mutations, and receptor tyrosine kinase pathway activation.

Lung adenocarcinomas in situ (AISs) often occur in individuals who have never smoked, although smoking is one of the main causes of lung cancer. To characterize AIS and, in particular, determine how AIS might be related to smoking, we collected a large number of AIS cases and examined clinicopathologic features, EGFR and KRAS mutation status, and activation status of receptor tyrosine kinase downstream signal pathways, including pAkt, pERK, and pStat3, using immunohistochemistry. We identified 110 AISs (36 smokers and 74 nonsmokers) among 1549 adenocarcinomas resected surgically during 1995 to 2010. Between the AIS of smokers and nonsmokers, only the sex ratio was significantly different; all the other clinicopathologic factors including TTF-1 and driver mutations were not significantly different: EGFR and KRAS mutation rates (smokers:nonsmokers) were 61:58 (%) (P=0.7) and 6.1:1.4 (%) (P=0.2), respectively, whereas, in invasive adenocarcinomas, the rates were 41:69 (%) (P<0.001) and 9.4:2.3 (%) (P<0.04), respectively. For pAkt and pERK, around 40% to 50% of AISs were positive, and for pStat3, >80% were positive, with no significant differences between smokers and nonsmokers with AIS. Mucinous AIS (n=8) rarely harbored KRAS mutations and expressed significantly less pStat3 (P<0.001) than nonmucinous AIS. Taken together, AIS occurs predominantly in female individuals and nonsmokers. However, characteristics of AIS arising in smokers and nonsmokers were similar in terms of cell lineage, driver mutations, and receptor tyrosine kinase pathway activation. Our results suggest that smoking is not a major cause of AIS. Rather, smoking may play a role in progression of AIS to invasive adenocarcinoma with AIS features.

Anomalous Systemic Arterial Supply to Separate Lingular and Basal Segments of the Lung: An Anatomic Consideration

A 22-year-old man was referred for hemoptysis and general fatigue after exercise. Arteriography demonstrated an anomalous artery arising from the descending aorta supplying the lingular and all of the basal segments of the left lung. The feeding areas of the pulmonary and anomalous arteries were mutually exclusive. He underwent division of the anomalous artery and combined resection of the diseased segments. The upper division of the upper lobe and the superior segment of the lower lobe were spared. His symptoms were greatly improved postoperatively. The preoperative anatomic evaluation of anomalous vessels is crucial in surgical management.

Surgical management of non-cystic fibrosis bronchiectasis

Non-cystic fibrosis bronchiectasis (bronchiectasis) is an abnormal dilatation of the bronchi and bronchioles, resulting from a prolonged recurrent infectious process due to various causes and predisposing factors. This disease has several etiologies and affects a heterogeneous population of patients. The most important viewpoint for the surgical management of bronchiectasis is to select appropriate candidates for surgery and conduct suitable anatomic lung resections at the right time under appropriate conditions. The ideal candidates for lung resection are symptomatic patients with focal disease due to truly localized bronchial pathology regardless of optimal and absolute medical management.