Kazuya Uchino

Characteristics and prognosis of patients after resection of nonsmall cell lung carcinoma measuring 2 cm or less in greatest dimension

There remains ongoing controversy with regard to the optimal management strategy and the prognostic significance of small‐sized nonsmall cell lung carcinoma. Therefore, in the current study, the authors analyzed the clinical characteristics of patients who underwent complete resection of these lung tumors, the follow‐up data, and the significant prognostic factors.

Pleural lavage cytology in non-small cell lung cancer: Lessons from 1000 consecutive resections

OBJECTIVE Intraoperative pleural lavage cytology for lung cancer has not been widely accepted. The prognostic significance of this procedure has yet to be intensively analyzed because the reports published thus far have involved small patient populations. We therefore performed a large prospective trial of pleural lavage cytology to elucidate its importance. METHODS Cytologic status of pleural lavage fluid before any manipulation of the lung was examined in 1000 consecutive patients with non-small cell lung cancer but no pleural effusion who underwent tumor resection. RESULTS Forty-five (4.5%) of 1000 patients had positive cytologic findings. Positive cytologic findings were observed more frequently in patients with adenocarcinoma, advanced stage, higher involvement of lymph nodes, pleural involvement of the tumor, lymphatic permeation, vascular invasion, high level of serum carcinoembryonic antigen, and male sex. The survival rate for 5 years was 28% in patients with positive findings and 67% in patients with negative findings (P <.0001). Among 587 patients with stage I disease, 13 (2.2%) had positive findings, and their 5-year survival was 43%, which was significantly poor compared with that of patients with negative findings (81%, P =.0009). Multivariable analysis demonstrated that pleural lavage cytology was an independent prognostic determinant (P =.0290). Regarding the recurrence pattern in patients with positive findings, distant metastases (19/45 [42.2%]) were observed more frequently rather than local recurrences (19/45 [22.2%]). CONCLUSIONS Cytologic status of pleural lavage fluid immediately after thoracotomy, an independent significant prognostic factor, constitutes valuable information to detect patients at a high risk of recurrence. Therefore cytology should be performed at the time of curative resection for non-small cell lung cancer.

Expression of the TSLC1 adhesion molecule in pulmonary epithelium and its down-regulation in pulmonary adenocarcinoma other than bronchioloalveolar carcinoma

TSLC1 (tumor suppressor in lung cancer-1) is an adhesion molecule of the Ig superfamily that binds homophilically and mediates cell-cell interactions. Originally, TSLC1 was cloned as a candidate tumor suppressor from the genomic region that frequently exhibits loss of heterogeneity in human non–small-cell lung cancer (NSCLC). However, there have been no studies on TSLC1 expression in normal lungs or NSCLC. Here we show that pulmonary epithelial cells express TSLC1 and its expression levels are often decreased or lost in primary pulmonary adenocarcinoma, a major histologic type of NSCLC. Immunohistochemistry revealed that TSLC1 was localized at cell-cell boundaries of all columnar epithelial cells in mouse embryonic lungs of 10.5 and 13 days postcoitus. Similar staining patterns were observed in bronchiolar and alveolar epithelial cells of adult human lungs, suggesting a physiologic role for TSLC1 in interactions of these cells. Next we performed Western blot analyses of TSLC1 in 47 primary pulmonary adenocarcinomas and judged each tumor as either decreased or nondecreased by comparing TSLC1 expression levels of the tumor with the levels of normal lungs. The expression profiles had a significant relation to histologic subtypes but not to other clinicopathologic parameters. Sixteen bronchioloalveolar carcinomas (BACs) were all judged nondecreased, while 19 of 31 (63%) adenocarcinomas other than BAC were judged decreased (p < 0.0001). Immunohistochemistry of tumors judged nondecreased revealed that not only BAC cells but also tumor cells in lepidic growth components of adenocarcinomas other than BAC expressed TSLC1 on their lateral plasma membranes. These tumor cells are considered less invasive because they proliferate in a lepidic growth pattern along alveolar walls. Thus, the present results not only support the hypothesis that TSLC1 is a tumor suppressor of NSCLC but also suggest that preserved integrity of TSLC1 may contribute to less invasive phenotypes of lepidic growth tumor cells.

Discrepancy of computed tomographic image between lung and mediastinal windows as a prognostic implication in small lung adenocarcinoma

BACKGROUND There have been no proven preoperative indicators for postoperative survival of patients with an adenocarcinoma, the incidence of which has been increasing lately. METHODS Of 952 consecutive patients operated on for primary lung cancer between 1995 and 2002, 167 patients with a proven adenocarcinoma 3 cm or less in diameter underwent complete removal of the primary tumor. We examined their computed tomographic scans to estimate tumor shadow disappearance rate (TDR), which was defined as the ratio of the tumor area of the mediastinal window to that of the lung window, reviewed the clinical records, and evaluated their relation to prognosis. RESULTS On univariate analyses, size of the tumor (p = 0.0380), TDR (p = 0.0018), carcinoembryonic antigen (p = 0.0001) pathologic stage (p < 0.0001), nodal involvement (p < 0.0001), lymphatic invasion (p = 0.0001), and vascular invasion (p = 0.0017) were significantly associated with prognosis. Also, the outcomes of multivariate analyses for preoperative factors indicated that TDR (p = 0.0340) and carcinoembryonic antigen (p = 0.0047) are significant independent prognostic determinants. The 5-year survival was 48% in cases with a TDR of 0% to 25%, 87% in those with a TDR of 26% to 50%, 97% in those with a TDR of 51% to 75%, and 100% in those with a TDR of 76% to 100%. The incidence of lymphatic, vascular invasion, and nodal metastases was lower in patients with a higher TDR. CONCLUSIONS Small-sized adenocarcinomas with a higher TDR showed less lymphatic, vascular vessel invasion, or nodal involvement, and demonstrated longer survival, suggesting that TDR was associated with clinical-pathologic characteristics and tumor aggressiveness. Preoperative assessment of TDR may be useful to identify an appropriate candidate for a lesser pulmonary resection.

Long-term survival and prognostic factors of five-year survivors with complete resection of non-small cell lung carcinoma

OBJECTIVE We analyzed the long-term follow-up data on cancer-related death in 5-year survivors of complete resection of their non-small cell lung cancer and examined the prognostic factors having an impact on subsequent survival. METHODS Of 848 consecutive patients with proven primary non-small cell carcinoma who underwent complete removal of the primary tumor together with hilar and mediastinal lymph nodes, 421 patients (49.6%) survived 5 years or longer after the initial surgical treatment. Of all the data analyzed, only death related to cancer was treated as death. RESULTS The median follow-up of 5-year survivors was 84 months from the original treatment (range, 60 to 200 months). Their overall survival rate at 10 years was 91.0%. Multivariable Cox analysis demonstrated that although advanced surgical-pathological stage (P =.0001), nodal involvement (P =.0245), male gender (P =.0313), and non-squamous type of the tumor (P =.0034) were significant, independent, unfavorable prognostic determinants in all patients, none of the variables investigated significantly influenced the long-term survival of 5-year survivors. The rate of recurrence beyond 5 years was much lower compared with that within 5 years. In contrast, the rate of occurrence of new malignancies was unchanged throughout the long-term postoperative period. CONCLUSIONS Among 5-year survivors of complete resection of non-small cell lung cancer, neither stage, nodal status, sex, nor histologic condition further affected subsequent survival, suggesting that the 5-year interval might be sufficient to declare that a patient with lung cancer has been cured.

Immunohistochemical studies of pulmonary large cell neuroendocrine carcinoma: a possible association between staining patterns with neuroendocrine markers and tumor response to chemotherapy.

OBJECTIVE Pulmonary large cell neuroendocrine carcinoma is a rare high-grade malignant tumor. Because large cell neuroendocrine carcinoma is rare, the optimal treatment, including perioperative chemotherapy, has not been defined. We retrospectively analyzed the correlation among the effectiveness of perioperative chemotherapy in treating large cell neuroendocrine carcinoma, pathologic stage, and immunoreactivity to neuroendocrine markers. METHODS A total of 63 patients with pulmonary large cell neuroendocrine carcinoma undergoing surgical resection from 2001 to 2009 were included. The resected tumors were immunohistochemically stained with the 3 neuroendocrine markers synaptophysin, chromogranin A, and neural cell adhesion molecule. We categorized patients who were positive for all 3 markers as the triple-positive group and those who were negative for 1 or 2 markers as the non-triple-positive group. RESULTS Perioperative chemotherapy resulted in better overall survival than surgery alone (P = .042). Multivariate analysis of survival revealed that perioperative chemotherapy was a significant independent prognostic factor (hazard ratio, 0.323; 95% confidence interval, 0.112-0.934; P = .0371). Among the patients who received perioperative chemotherapy, the non-triple-positive group had a significantly greater 5-year survival rate than the triple-positive group (P = .0216). Moreover, among the non-triple-positive group, a significantly greater 5-year survival rate was observed for the patients who underwent surgery with chemotherapy than for those who underwent surgery without chemotherapy (P = .0081). In contrast, no difference was found in 5-year survival between patients with chemotherapy and those without chemotherapy when the tumors were triple positive. CONCLUSIONS Our results suggest that perioperative chemotherapy might benefit the survival of patients with pulmonary large cell neuroendocrine carcinoma, in particular when the tumors are not immunoreactive to all 3 neuroendocrine markers.

Significance of microscopic invasion into hilar peribronchovascular soft tissue in resection specimens of primary non-small cell lung cancer

INTRODUCTION The significance and handling of microscopic invasion of non-small cell lung cancer (NSCLC) into hilar peribronchovascular soft tissue (SHEATH+) have not been defined in the TNM classification by AJCC/UICC; nevertheless, SHEATH+ may be equivalent to spread into the mediastinum. Also, assessment of the margin of peribronchial resection is challenging because of the technical difficulty of inking, and intraoperative and postoperative artifacts. METHODS Records of 592 consecutive Asian patients with primary NSCLC (excluding adenocarcinoma in situ) who had, without any preoperative therapy, undergone lobectomy, sleeve lobectomy and pneumonectomy were examined. SHEATH+, simply defined as invasion of hilar peribronchovascular soft tissue, without categorizing any invasive patterns, and its significance were statistically analyzed. RESULTS Forty-four SHEATH+ cases demonstrated significantly advanced TNM stages, and were statistically associated with central occurrence, pN1-3, and vascular invasion, as assessed by logistic regression analysis. No statistically significant differences were observed between TNM stage-adjusted frequency of recurrence and recurrence-free intervals. Kaplan-Meiers estimates of the rate of overall and recurrence-free survival after surgery showed no statistically significant differences between SHEATH+ and SHEATH-. Coxs multivariate analysis suggested SHEATH was not a statistically independent prognostic factor under the TNM classification by AJCC/UICC (7th edition). CONCLUSIONS SHEATH+ in NSCLC was simply associated with central occurrence and advanced TNM stages. To the best of our knowledge, this is the first report on the significance of SHEATH+ in NSCLC.

Significant role of Psf3 expression in non-small-cell lung cancer

The GINS complex associates with cell division cycle (Cdc) protein 45 and mini‐chromosome maintenance (Mcm) proteins 2–7 to form the Cdc45–Mcm–GINS (CMG) complex, which is essential for DNA duplication. One member of the GINS complex is Psf3. We previously found that increased Psf3 expression was strongly associated with poor survival in lung adenocarcinoma. Here, we investigated the role of Psf3 expression in non‐small‐cell lung cancer (NSCLC). We verified Psf3 expression in human NSCLC tissues (180 patients) and cell lines. Immunohistochemical analysis revealed that the overexpression of Psf3 was significantly associated with vessel invasion (P = 0.016), lymphatic invasion (P = 0.002), and pleural invasion (P = 0.036). The overall survival rate in patients with Psf3 overexpression was significantly lower than that in patients without Psf3 overexpression (P = 0.006). Multivariate survival analysis revealed Psf3 expression to be an independent risk factor for an unfavorable outcome (P = 0.049). A proximal ligation assay showed interactions between Psf3 and other CMG components (such as Mcm2 and Cdc45) in both NSCLC specimens and cell lines, indicating that Psf3 acted as the CMG complex, which could lead to excessive proliferation. Knockdown of Psf3 inhibited the proliferation of both cell lines by delaying the S phase, which revealed that Psf3 played an important role in cancer proliferation. Thus, Psf3 acted as the CMG complex, promoting excessive proliferation. These results suggest that Psf3 inhibition might be a therapeutic target for NSCLC with Psf3 overexpression.

Efficacy of adjuvant chemotherapy for lung adenocarcinoma patients with positive pleural lavage cytology findings

OBJECTIVES Positive pleural lavage cytology (PLC) findings are considered to be predictive of a poor prognosis in patients with non-small-cell lung cancer (NSCLC). We investigated the clinical benefit of adjuvant chemotherapy for lung adenocarcinoma patients with positive PLC findings. METHODS We retrospectively reviewed the medical records of lung adenocarcinoma patients who underwent tumour resection and had positive PLC findings between January 2000 and December 2009. RESULTS Fifty-three patients (4.8%) of 1114 patients with lung adenocarcinoma had positive PLC findings. The median follow-up period was 33.6 months. Adjuvant chemotherapy was administered to 24 patients (adjuvant chemotherapy group); 7, 8 and 9 patients had pathological Stage I, II and III, respectively . The surgery-alone group comprised 29 patients; 12, 8 and 9 patients had pathological Stage I, II and III, respectively. The 5-year recurrence-free survival (RFS) rates were 34.6 and 15.7% (P < 0.01) in adjuvant chemotherapy and surgery-alone groups, respectively. The rate of distant recurrence was significantly reduced in the adjuvant chemotherapy group (25.0 and 58.6%; P = 0.01). Even for Stage I cases, adjuvant chemotherapy tended to improve the 5-year RFS rate compared with surgery alone (60.1 and 29%; P = 0.11). Multivariate analysis for RFS revealed that adjuvant chemotherapy [hazard ratio (HR), 0.45; P = 0.03], tumour size >30 mm (HR, 2.23; P = 0.02) and lymph node metastasis (HR, 2.67; P < 0.01) were significant independent prognostic factors for recurrence. CONCLUSIONS Adjuvant chemotherapy for lung adenocarcinoma patients with positive PLC findings significantly improved recurrence-free survival.

Outcomes of segmentectomy for cT1bN0M0 lung adenocarcinoma and squamous cell carcinoma: a possible association with pathological invasion

OBJECTIVES We evaluated the clinical benefit of segmentectomy for patients with cT1bN0M0 lung cancer. METHODS We retrospectively reviewed the medical records of 178 patients who underwent lobectomy or segmentectomy for cT1bN0M0 lung adenocarcinoma and squamous cell carcinoma from January 1995 to December 2005. We investigated the association of surgical outcomes with the presence of pathological invasion. RESULTS The median follow-up period was 93.4 months. Of 178 patients, 37 were scheduled for segmentectomy, but 6 of these patients were switched to receive lobectomy due to surgical N1 or N2 in 3 patients and insufficient surgical margins in 3 patients. In total, 31 patients underwent segmentectomy, and 147 underwent lobectomy. The 5-year overall survival (OS) was similar between the patients who underwent lobectomy (5-year OS, 81.6%) and segmentectomy (5-year OS, 77.4%, P = 0.73). Among pN0 patients without pathological invasion, there was no difference in OS between patients who underwent lobectomy (5-year OS, 89.9%) and segmentectomy (5-year OS, 88.9%, P = 0.80). In contrast, among pN0 patients with pathological invasion, OS was greater in patients who underwent lobectomy (5-year OS, 80.9%) than in those who underwent segmentectomy (5-year OS, 54.6%; P = 0.19). Moreover, a significantly higher rate of local and local + distant recurrence was observed in patients who underwent segmentectomy (45%) than in those who underwent lobectomy (15%) in this group (P = 0.02). CONCLUSIONS The results of our study suggest that segmentectomy may not be recommended for cT1b tumours if pathological invasion is suspected before surgery.