The efficacy of a machine learning algorithm for assessing tumour components as a prognostic marker of surgically resected stage IA lung adenocarcinoma.

BACKGROUND: The importance of the stromal components in tumour progression has been discussed widely, but their prognostic role in small size tumours with lepidic components is not fully understood. Applying digital tissue image analysis to whole-slide imaging may enhance the accuracy and reproducibility of pathological assessment. This study aimed to evaluate the prognostic value of tumour components of lung adenocarcinoma by measuring the dimensions of the tumour consisting elements separately, using a machine learning algorithm. METHODS: Between September 2002 and December 2016, 317 patients with surgically resected, pathological stage IA adenocarcinoma with lepidic components were analysed. We assessed the whole tumour area, including the lepidic components, and measured the epithelium, collagen, elastin areas and alveolar air space. We analysed the prognostic impact of each tumour component. RESULTS: The dimensions of the epithelium and collagen areas were independent significant risk factors for recurrence-free survival (hazard ratio, 8.38; 95% confidence interval, 1.14-61.88; P = 0.037, and hazard ratio, 2.58; 95% confidence interval, 1.14-5.83; P = 0.022, respectively). According to the subgroup analysis when combining the epithelium and collagen areas as risk factors, patients with tumours consisting of both large epithelium and collagen areas showed significantly poor prognoses (P = 0.002). CONCLUSIONS: We assessed tumour components using a machine learning algorithm to stratify the post-operative prognosis of surgically resected stage IA adenocarcinomas. This method might guide the selection of patients with a high risk of recurrence.

Continuation of aspirin perioperatively for lung resection: a propensity matched analysis.

PURPOSE: To clarify the safety and effectiveness of continuing aspirin during the perioperative period of lung resection. METHODS: We analyzed, retrospectively, consecutive patients who underwent lung resection between 2008 and 2017. To investigate the safety of aspirin continuation, patients who continued taking aspirin perioperatively (Group C) were matched to other patients (Group O), using a propensity score, and bleeding outcomes were compared. To assess the effect of aspirin interruption, Group C was matched to a group of patients whose aspirin regimen was interrupted (Group I), and the postoperative complications related to thromboembolism were compared. RESULTS: Among 3393 patients, 52 continued on aspirin (Group C) perioperatively, whereas 184 had their aspirin discontinued (Group I). Comparing the matched cohorts extracted from Group C and Group O (n = 45), there were no significant differences in bleeding outcomes. Comparing the matched cohorts extracted from Group C and Group I (n = 40), group C had fewer postoperative complications related to thromboembolism (0% vs. 7.5%, p = 0.039). CONCLUSION: Bleeding complications did not increase by continuing aspirin, but thromboembolic complications increased when the aspirin regimen was interrupted during the perioperative period of lung resection. Thus, in the absence of a prohibitive bleeding risk, the continuation of aspirin during the perioperative period of lung resection appears to be desirable.

Pathological features and prognostic implications of ground-glass opacity components on computed tomography for clinical stage I lung adenocarcinoma.

PURPOSE: To investigate the prognostic implications and pathological features of clinical stage I lung adenocarcinoma with ground-glass opacity (GGO) on computed tomography (CT). METHODS: The subjects of this retrospective study were 1228 patients with lung adenocarcinoma classified as clinical stage I, who underwent complete resection by lobectomy. The patients were divided into four groups based on the presence and proportion of GGO according to the consolidation-to-tumor ratio (CTR); A, CTR ≤ 0.5; B, 0.5 < CTR ≤ 0.75; C, 0.75 < CTR ≤ 1.0 with GGO; D, without GGO (pure-solid). We compared overall survival, pathological findings (N/ly/v/STAS), and histological subtypes within each clinical stage among the four groups. RESULTS: We found no significant differences among tumors with GGO (groups A, B and C) for prognosis or pathological findings in all the clinical stages. The prognoses of groups A, B and C were significantly better than that of group D for patients with clinical stages IA2-IB disease. Tumors without GGO on CT had a significantly larger number of positive N, ly, v and STAS in almost all stages than tumors with GGO on CT. Tumors without GGO on CT had significantly more solid predominant and less lepidic predominant adenocarcinoma. CONCLUSION: Not the proportion of GGO, but its presence on CT, as well as the size of the solid component, were correlated significantly with pathological characteristics and survival.

Supramolecular Photochirogenesis with a Higher-Order Complex: Highly Accelerated Exclusively Head-to-Head Photocyclodimerization of 2-Anthracenecarboxylic Acid via 2:2 Complexation with Prolinol.

An unprecedented 2:2 complex was shown to intervene in the enantiodifferentiating photocyclodimerization of 2-anthracenecarboxylic acid (A) mediated by a hydrogen-bonding template l-prolinol (P) to accelerate the formation of chiral anti-head-to-head and achiral syn-head-to-head cyclodimers in >99% combined yield with enhanced enantioselectivities of up to 72% ee for the former. The supramolecular complexation and photochirogenic behaviors, as well as the plausible structures, of intervening Am·Pn complexes (m, n = 1 or 2) were elucidated by combined theoretical and experimental spectroscopic, photophysical, and photochemical studies. Furthermore, the photochemical chiral amplification was achieved for the first time by utilizing the preferential 2:2 complexation of A with homochiral P to give normalized product enantioselectivities higher than those of the template used. The present strategy based on the higher-order hydrogen-bonding motif, which is potentially applicable to a variety of carboxylic acids and ß-aminoalcohols, is not only conceptually new and expandable to other (photo)chirogenic and sensing systems but also may serve as a versatile tool for achieving photochemical asymmetric amplification and constructing chiral functional supramolecular architectures.

Prediction of Pleural Lavage Cytology According to Thin-Section Computed Tomography in Non-Small-Cell Lung Cancer.

BACKGROUND: Although the positive rate of preresection pleural lavage cytology (PLC) is low, it is an important indicator of poor prognosis for non-small-cell lung cancer patients with frequent pleural dissemination (PD) recurrence. Thin-section computed tomography (TSCT) can reveal relationships between a primary tumor and the pleura at 1 to 2 mm intervals, and this is associated with visceral pleural invasion (VPI). However, its association with PLC remains unclear. Therefore, we aimed to improve PLC efficiency and predict PD recurrence by understanding the relationship between PLC and preoperative TSCT findings. PATIENTS AND METHODS: Between January 2014 and December 2018, we reviewed 978 patients with non-small-cell lung cancer who underwent PLC tests during complete resection surgery. Preoperative TSCT findings were evaluated, and factors with the highest specificity (proportion of patients with radiologically to pathologically diagnosed positive PLC) were investigated. We also evaluated their relationships with VPI and PD recurrence. RESULTS: PLC positive was identified in 55 (5.6%) of the 978 patients. The two TSCT findings predicting PLC results, "the absence of pleural findings," ie, tumor not attached to pleura or without pleural tag, and "consolidation-to-tumor ratio ≤0.5", had a specificity of 100% (95% confidence interval: 90.4%-100%); additionally, all cases with these findings were VPI negative and had no PD recurrence. And 24% of the cohort had either of these findings. CONCLUSION: The absence of pleural findings and/or consolidation-to-tumor ratio ≤0.5 of primary tumor on preoperative TSCT can predict PLC negativity with very high probability; therefore, PLC can be omitted for such patients.

Brain Metastasis of Non-small Cell Lung Cancer After Disease-Free Survival of 5 years: Case Series and Comprehensive Literature Review.

BACKGROUND: In the treatment of nonsmall cell lung cancer (NSCLC), a disease-free survival of 5 years is a criterion for cure. This study aimed to evaluate the characteristics and outcomes of patients with brain metastases of NSCLC after a disease-free survival of 5 years (late recurrent brain metastasis [LRBM]). METHODS: We reviewed 1281 consecutive patients with brain metastasis of lung cancer at a single institute between November 2014 and December 2022. Relevant articles were retrieved from PubMed. Only peer-reviewed journals published in English were included. RESULTS: Six patients (0.47%) showed LRBM. Three were male. The median age at lung cancer diagnosis was 45 years. The histological diagnosis of all patients was adenocarcinoma. Driver gene mutations were observed in five patients. The median latency period from lung cancer treatment to the development of brain metastasis was 13 years. All patients had no metastasis to any other organs and underwent craniotomies. The median follow-up duration after craniotomy was 3.5 years. No local intracranial recurrences were observed. Three patients had distant intracranial recurrences at 7, 2, and 0.6 years after craniotomy. Five patients survived for 8, 4, 3, 2, and 0.3 years after craniotomy. One patient experienced re-recurrence in the lung 4 years after craniotomy and died 3.7 years later. In our systematic review, only six studies described LRBM of NSCLC. CONCLUSIONS: LRBM is rare in patients with NSCLC. In our institution, many of these patients harbored driver gene mutations, and achieved long-term survival with aggressive local therapy. Multicenter analysis is mandatory.

Impact of central nervous system metastasis after complete resection of lung adenocarcinomas harboring common EGFR mutation - A real-world database study in Japan: The CReGYT-01 EGFR study.

OBJECTIVES: To clarify the impact of central nervous system (CNS) metastasis on performance status (PS) at relapse, on subsequent treatment(s), and on survival of patients with lung adenocarcinoma harboring common epidermal growth factor receptor (EGFR) mutation. METHODS: We conducted the multicenter real-world database study for patients with radical resections for lung adenocarcinomas between 2015 and 2018 at 21 centers in Japan. EGFR mutational status was examined at each center. RESULTS: Of 4181 patients enrolled, 1431 underwent complete anatomical resection for lung adenocarcinoma harboring common EGFR mutations. Three-hundred-and-twenty patients experienced disease relapse, and 78 (24%) had CNS metastasis. CNS metastasis was significantly more frequent in patients with conventional adjuvant chemotherapy than those without (30% vs. 20%, P = 0.036). Adjuvant chemotherapy did not significantly improve relapse-free survival at any pathological stage (adjusted hazard ratio for stage IA2-3, IB, and II-III was 1.363, 1.287, and 1.004, respectively). CNS metastasis did not affect PS at relapse. Subsequent treatment, mainly consisting of EGFR-tyrosine kinase inhibitors (TKIs), could be equally given in patients with or without CNS metastasis (96% vs. 94%). Overall survival after relapse was equivalent between patients with and without CNS metastasis. CONCLUSION: The efficacy of conventional adjuvant chemotherapy may be limited in patients with lung adenocarcinoma harboring EGFR mutations. CNS metastasis is likely to be found in practice before deterioration in PS, and may have little negative impact on compliance with subsequent EGFR-TKIs and survival after relapse. In this era of adjuvant TKI therapy, further prospective observational studies are desirable to elucidate the optimal management of CNS metastasis.

Long term outcomes beyond 5 years after pulmonary resection for non-small-cell lung cancer.

OBJECTIVES: We investigated the incidence of late recurrence beyond 5 years after pulmonary resection and aimed to identify candidates for long-term surveillance. METHODS: We retrospectively reviewed the medical records of 978 non-small-cell lung cancer patients who underwent pulmonary resection between 2002 and 2015 and survived without recurrence for 5 years. Clinicopathological factors associated with recurrence-free survival beyond 5 years after surgery were investigated using univariate and multivariate analyses. The development of late metachronous malignancies was also investigated. RESULTS: The median follow-up period from 5 years post-surgery was 27 months in the whole cohort. Late recurrence occurred in 37 (3.8%) patients. Late metachronous malignancies were diagnosed in 116 patients (11.9%), including 57 (5.8%) with lung cancer. One-, three-, and five-year recurrence-free survival rates beyond 5 years after surgery were 97.6%, 94.7%, and 94.7%, respectively. The recurrence-free survival of patients with pN1-2 was significantly poorer than that of patients with pN0 disease. Multivariate analysis revealed that adenocarcinoma and pN1-2 status were significantly associated with poor recurrence-free survival beyond 5 years post-surgery (P = 0.009 and 0.007, respectively). CONCLUSIONS: Non-adenocarcinoma histology and pN0 status were significant favorable factors for recurrence-free survival beyond 5 years post-surgery. The efficacies of long-term surveillance for the detection of late recurrence were considered limited for these populations. Twelve percent of the patients experienced late metachronous malignancies after pulmonary resection.

Diagnostic sensitivity of solid volume measurement for pathological invasion in non-solid lung adenocarcinoma.

Background: In the current tumor-node-metastasis (TNM) classification, the clinical T descriptor is defined by solid size (SS) on a computed tomography (CT) slice and the pathological one is done by invasive size (IS) in microscopic evaluations. We sometimes experience discrepancies in diagnosis of both descriptors. A volume analyzing application enables semi-automatic measurement of three-dimensional (3D) parameters in cases where there are discrepancies in diagnosing tumors' solid size and IS. In this study, we aimed to evaluate the association between 3D parameters and pathological invasion in non-solid small-sized lung adenocarcinomas. Methods: We enrolled 246 consecutive patients who underwent pulmonary resection at Shizuoka Cancer Center. Patients with lung adenocarcinomas that were radiologically non-solid, node-negative and sized ≤3 cm were eligible. We used a volume analyzing application to retrospectively measure 3D parameters of max and mean Hounsfield units (HUs) and solid volume (SV). The cut-off value of these parameters for diagnosing invasive adenocarcinoma (IAD) was set by describing receiver operating characteristic (ROC) curves. The correlation of IAD with these parameters was compared to its correlation with the SS. This study was not registered. Results: Of 246 patients with adenocarcinoma, 183 (74.4%) had IADs. In multivariate analyses, the total size (TS) and SS were significantly associated with IAD (P=0.006, 0.001, respectively), whereas 3D parameters including SV were not (P=0.80). In radiological adenocarcinoma (2.1-3.0 cm), SV >300 mm3 diagnosed IAD with a higher sensitivity than that of the SS (0.93 and 0.83, respectively). Conclusions: TS >20 mm and SS >5 mm were well-correlated with IAD. SV measurement may complement the current computed tomographic diagnosis of IAD based on the SS (2.1-3.0 cm).

Lobe-specific nodal dissection with intraoperative frozen section analysis for clinical stage-I non-small cell lung cancer: a validation study by propensity score matching.

OBJECTIVE: Lobe-specific nodal dissection (LND) is increasingly used for non-small cell lung cancer (NSCLC) in Japan; however, its treatment validity remains unclarified. Since 2013, LND has been used as a standard procedure for clinical stage-I (c-stage-I) NSCLC at our institution. We aimed to evaluate its validity using intraoperative frozen section analysis (FSA) for c-stage-I NSCLC. METHODS: The participants comprised patients with NSCLC who underwent LND between 2013 and 2016 (n = 307) or systematic nodal dissection (SND) between 2002 and 2013 (n = 367) for c-stage-I disease. FSA was routinely performed in LND to examine at least three stations. Outcomes were compared between the LND and SND groups. Patients in whom LND was converted to SND due to metastasis on FSA of the sampled lymph node were still categorized into the LND group, i.e., intention-to-treat analysis. The prognostic impact was compared using propensity score matching. RESULTS: The rate of conversion from LND to SND was 10.4%. Of the patients converted to SND, 12.5% had metastases outside the LND area. False-negative N2 results were detected in only 0.7% of the LND group patients after FSA. After matching, each group had 220 patients. There were no significant between-group differences in the lymph-node recurrence rate (7% vs. 6%), 5-year recurrence-free survival (80.1% vs. 79.0%), and overall survival (90.4% vs. 90.3%). CONCLUSIONS: LND with intraoperative FSA is a valid modality that could serve as a standard surgical procedure for c-stage-I NSCLC. Intraoperative FSA may lower the residual lymph-node metastasis risk in LND.

Prognostic impact of examined mediastinal lymph node count in clinical N0 non-small cell lung cancer.

OBJECTIVES: The number of examined mediastinal lymph nodes (mLNs) could represent the quality of mediastinal lymphadenectomy for non-small cell lung cancer (NSCLC). This study aimed to evaluate the prognostic impact of the number of examined individual mLNs in patients with resectable NSCLC. METHODS: We retrospectively evaluated 1420 patients with clinical stage IA-IIB, N0 NSCLC who underwent complete resection by lobectomy, which involved hilar and mLN dissection, between 2008 and 2016. We investigated the threshold number of examined mLNs that had prognostic significance and evaluated their effects on the risk of mLN recurrence. RESULTS: In a respective multivariable analysis according to the number of examined mLNs, examining ≥3 mLNs [reference (ref.) mLNs ≤2] achieved statistical significance and had the best prognosis (hazard ratio, 0.68; P = 0.013). In the multivariable analyses for each pathological N (pN) stage, ≥3 examined mLNs (ref. mLNs ≤2) were an independent prognostic factor in pN1 disease (hazard ratio, 0.32, P = 0.002), but not in pN0 or pN2 disease. The cumulative incidence of mLN recurrence was significantly lower in patients with ≥3 examined mLNs (ref. mLNs ≤2, hazard ratio, 0.27; P = 0.008) in pN1 disease. Patients with ≥3 examined mLNs had higher upstaging rates to pN2 than those with ≤2 examined mLNs. CONCLUSIONS: Examining ≥3 mLNs contributed to a favourable prognosis and low mLN recurrence risk in patients with clinical stage I-II, N0 NSCLC. Our findings can serve as a benchmark for the number of required mLNs to be examined.

Mediastinal lymph node dissection for the elderly with clinical stage I non-small cell lung cancer.

OBJECTIVES: We aimed to compare the differences in prognosis and perioperative complications between patients with and without mediastinal lymph node dissection (MLND) among elderly patients with clinical stage I non-small cell lung cancer (NSCLC). METHODS: We analysed 439 patients ≥ 75 years of age with NSCLC classified as clinical stage I who underwent complete resection with lobectomy. We divided the patients into two groups. Those with MLND were included in the MLND group (n = 365), and those without MLND or adequate systematic mediastinal lymph node sampling were included in the non-MLND group (n = 74). To reduce selection bias, a propensity score matching method (3:1) was implemented. We compared survival and the incidence of perioperative complications. RESULTS: After matching, we compared 171 patients in the MLND group to 57 patients in the non-MLND group. There were no significant differences in clinicopathological characteristics between the groups. The non-MLND group did not show a significantly better prognosis than the MLND group in overall survival and cancer-specific survival (p = 0.246 and 0.150, respectively). The cumulative incidence of recurrence was similar in the two groups. MLND did not affect chest drain duration or hospitalization. The numbers of patients with perioperative complications ≥ grade 2 or ≥ grade 3 did not differ between the groups (p = 0.312 and > 0.999, respectively). CONCLUSIONS: Anatomical pulmonary resection without MLND might be a treatment option for elderly patients with clinical stage I NSCLC. Further investigation is needed to clarify the value of MLND, especially for vulnerable elderly individuals.

Association between the mutational smoking signature and the immune microenvironment in lung adenocarcinoma.

OBJECTIVES: Mutational signatures associated with tobacco smoking (mutational smoking signatures: SS) are characterized mainly by C > A mutations. The aim of this study was to characterize the association between the tumor immune microenvironment and the SS in lung adenocarcinoma. METHODS: Lung adenocarcinomas surgically resected from 96 patients, for which whole exome sequencing data was available, were included in the study. We extracted the SS from whole exome sequencing data, calculated the weights of SS using deconstructSigs, and compared the clinicopathological features of SS positive (SS+) and negative (SS-) adenocarcinomas. We selected 18 tumor pairs from SS + and SS- adenocarcinomas (sex, EGFR mutation, and tumor size-matched) and examined the expression of five immune markers (CD20, CD8, FOXP3, CD204, and PD-L1) by immunohistochemistry. RESULTS: Of 96 specimens, there were 33 (34 %) SS + adenocarcinoma tumors. The smoking index significantly correlated with the weight of the SS (R = 0.43). Between SS + and SS- tumors, there was no significant difference in clinicopathological factors excluding smoking history. Immunohistochemistry revealed that the number of FOXP3 + T cells in SS + adenocarcinomas was significantly higher than that in the SS- adenocarcinomas (median number 58 vs. 36, p < 0.01). Also, the number of CD20 + B cells in SS + adenocarcinomas was significantly higher than that in the SS- adenocarcinomas (median number 77 vs. 29, p < 0.01); however; these phenomena could not be confirmed when stratified by smoking history. CONCLUSION: In lung adenocarcinoma, SS is associated with an immunosuppressive tumor microenvironment.

Ground-Glass Opacity Is a Strong Prognosticator for Pathologic Stage IA Lung Adenocarcinoma.

BACKGROUND: A ground-glass opacity (GGO) component on chest computed tomography (CT) pathologically corresponds to lepidic adenocarcinoma. However, the precise correspondence relation and the prognostic significance remains unclear in patients with pathologic stage IA lung adenocarcinoma. METHODS: We retrospectively reviewed the clinicopathologic features of 809 consecutive patients with pathologic stage IA lung adenocarcinoma who underwent complete resection between 2003 and 2014. We evaluated the prognostic impact of clinicopathologic variables including the radiologic appearance with a Cox proportional hazards model. RESULTS: Among the 809 patients, 465 (57%) were nodules with a GGO component, and 344 (43%) were solid nodules on chest CT. On final pathology, lepidic adenocarcinoma was identified in 445 (96%) of the GGO nodules and 239 (69%) of the solid nodules. The survival rate of the patients having a GGO nodule was significantly higher than that without GGO components (5-year overall survival, 97% versus 84%, p < 0.0001). In solid nodules, there was no significant prognostic difference between patients with and without a lepidic component (5-year overall survival, 87% versus 79%, p = 0.09). On multivariable analysis, solid appearance on chest CT was an independent prognostic factor (hazard ratio, 1.74; 95% confidence interval, 1.10 to 2.79; p = 0.019), but the pathologic invasive size and the pathologic lepidic growth component were not. CONCLUSIONS: In patients with pathologic stage IA lung adenocarcinoma, the radiologic appearance as a GGO nodule on chest CT is a better prognostic indicator than the presence of a lepidic component on pathology.

Prognostic Impact of the Number of Metastatic Lymph Nodes on the Eighth Edition of the TNM Classification of NSCLC.

INTRODUCTION: Current nodal staging of NSCLC is defined only by anatomical location of lymph nodes (LNs). The aim of this study is to investigate prognostic impacts of the number of metastatic LNs by stratifying the present N classification. METHODS: We analyzed 1989 patients with NSCLC who underwent complete resection by lobectomy or pneumonectomy involving dissection of the hilar and mediastinal LNs from 2003 to 2012. We classified patients according to the number of metastatic nodes and stations and their current category of metastatic LNs. We analyzed the overall survival in each group and assessed the survival impact of the combination of them. RESULTS: In the multivariate analyses of all patients, pathological N1 (pN1) (reference [ref.] pN2) and single-node metastasis (ref. multiple-node) were independent prognostic factors whereas single-station metastasis (ref. multiple-station) was not. In the respective multivariate analyses of pN1 and pN2 disease, multiple-node metastasis (ref. single-node) was an independent prognostic factor in pN1 disease (hazard ratio: 1.41, p = 0.04), but not in pN2 disease. Investigation for other boundaries of a number of metastatic LNs of three or more (ref. one to two), four or more (ref. one to three), and five or more (ref. one to four) found that all of them were independent prognostic factors in both pN1 and pN2 diseases. CONCLUSIONS: The number of metastatic LNs had a strong impact on survival in addition to the current pN classification. To clarify its prognostic impact, further study is needed in other datasets including patients treated by nonsurgical modalities.

Radiologic Criteria in Predicting Pathologic Less Invasive Lung Cancer According to TNM 8th Edition.

PURPOSE: The Japan Clinical Oncology Group Study 0201 has proposed radiologic criteria on thin-slice computed tomography to diagnose pathologic less invasive lung adenocarcinoma that could be a candidate for sublobar resection based on the previous tumor, node, metastasis classification system (TNM). The aim of this study was to propose the new radiologic criteria for predicting pathologic less invasive cancer according to the 8th edition TNM. PATIENTS AND METHODS: We analyzed 744 patients who had peripheral clinical Tis-T1cN0M0 non-small-cell lung cancer of 3 cm or less and underwent complete resection by lobectomy from 2003 to 2011. We defined lung cancer with no nodal involvement and no vessel invasion pathologically as a pathologic less invasive cancer and investigated the radiologic criteria on the basis of the solid component size and by the consolidation-to-tumor (C/T) ratio (calculated with the maximum solid component diameter divided by the maximum tumor diameter) by using preoperative thin-slice computed tomography to predict them with a specificity of 97% or more, and evaluated overall survival. RESULTS: Patients with clinical Tis/T1mi/T1a disease had no pathologic invasive cancer except for one patient (specificity, 99%). From the investigation with the C/T ratio, only the criterion of C/T ratio 0.5 or less met the standard (specificity, 100%). The final specificity after combining these criteria was 99.6%, and they showed excellent prognosis (5-year overall survival rate, 96.2%). CONCLUSION: Lung cancer with clinical Tis/T1mi/T1a or a C/T ratio of 0.5 or less can be completely cured by sublobar resection with sufficient margin because of its less invasive nature pathologically.

Growth patterns of small peripheral squamous cell carcinoma of the lung and their impacts on pathological and biological characteristics of tumor cells.

PURPOSE: The growth pattern of peripheral squamous cell carcinoma (SCC) of the lung is divided into two types: alveolar space-filling (ASF) growth and alveolar space-destructive (ASD) growth. The aim of this study was to investigate the clinicopathological differences between cancer cells displaying ASF and ASD growth. METHODS: We analyzed 155 patients with peripheral SCC measuring 30 mm or less in diameter. The proportion of ASF in the total tumor area (%ASF) was determined using digital image analysis. We examined the clinicopathological characteristics of the cancer cells and compared the immunophenotypes of high %ASF tumors (> 30%) and low %ASF tumors (0%). Finally, we analyzed the prognostic impact of ASD area with small SCC cases (≤ 2.0 cm, n = 72). RESULTS: Cases of high %ASF tumors showed significantly lower frequencies of lymphovascular invasion (p = 0.008). Immunohistochemical staining revealed that the expression score of laminin-5, invasive-related molecule, in cancer cells was significantly lower in high %ASF cases than in low %ASF cases (p = 0.001). Within the same tumor, laminin-5 expression in the ASF area was significantly lower than that in the ASD area (p = 0.001). The overall 5-year survival rate of patients with a larger ASD area (> 1.0 cm2) was significantly lower than that of patients with a smaller ASD area (≤ 1.0 cm2) (p = 0.017). CONCLUSIONS: In this study, we clearly showed that cancer cells presenting with ASF represents a "less invasive phenotype" in peripheral SCC.

Influence of Ground Glass Opacity and the Corresponding Pathological Findings on Survival in Patients with Clinical Stage I Non-Small Cell Lung Cancer.

INTRODUCTION: The aim was to clarify the influence on patient prognosis of ground glass opacity (GGO) component in each new TNM stage and propose grouping reflecting the prognosis more accurately. METHODS: We examined the data on 1290 patients who underwent lung cancer resection from 2003 to 2011. The demographics and overall survival of patients with adenocarcinoma with and without GGO, squamous cell carcinoma, and the others were compared according to clinical stage from 0 to IB. In adenocarcinoma, we examined the distribution of histological subtypes of adenocarcinoma with and without GGO in each clinical stage. RESULTS: Each clinical stage differentiated overall survival well. However, the prognosis of the patients with adenocarcinoma with GGO was considerably more favorable than that of the others in clinical stage IA2 and IA3 but not of those in clinical stage IB. In clinical stage 0 to IA3, patients showing adenocarcinoma in situ, minimally invasive adenocarcinoma, and invasive lepidic predominant adenocarcinoma accounted for about 50% of the total number of patients with adenocarcinoma with GGO (stage 0, 16 of 21; stage IA1, 113 of 143; stage IA2, 80 of 157; and stage IA3, 45 of 94). In clinical stage IB, 20% of adenocarcinomas with GGO showed invasive solid predominant adenocarcinoma (IB, seven of 38). Most of the adenocarcinomas without GGO were in clinical stage IA2 to IB, and the distribution of histological subtypes was similar at each clinical stage. Invasive acinar and solid predominant adenocarcinomas were more common in adenocarcinoma without GGO. CONCLUSIONS: Clinical T classification considering GGO component may offer more accurate prognosis for patients with lung cancer less than 3 cm in invasive diameter.

Differences of tumor microenvironment between stage I lepidic-positive and lepidic-negative lung adenocarcinomas.

OBJECTIVE: Lepidic growth is a noninvasive component of lung adenocarcinoma. Many adenocarcinoma cases contain coexistent lepidic and nonlepidic (invasive) components (lepidic-growth positive [Lep+] adenocarcinoma); however, some cases comprise only nonlepidic components (lepidic-growth negative [Lep-] adenocarcinoma). The aim of this study was to investigate the biological differences between the invasive components of Lep+ and Lep- adenocarcinoma. METHODS: We investigated the clinicopathologic characteristics of 232 adenocarcinomas (116 size-matched tumor pairs from Lep+ and Lep- adenocarcinomas). We then evaluated the cancer cell-specific expression levels of cancer stem cell, hypoxia, and invasion molecules in these lesions. The number of tumor-promoting stromal cells, including podoplanin-positive cancer-associated fibroblasts and CD204-positive tumor-associated macrophages, was also analyzed. RESULTS: Among cases with size-matched invasive components, significant differences were shown in total tumor size and predominant subtype in invasive component between Lep+ and Lep- adenocarcinomas. The expression levels of hypoxia-related molecules were significantly lower in Lep+ adenocarcinomas (glucose transporter 1: 0 vs 10, P < .01; carbonic anhydrase IX: 0 vs 0 [mean, 4.7 vs 14.1], P = .01). The number of podoplanin-positive cancer-associated fibroblasts and CD204-positive tumor-associated macrophages was significantly lower in Lep+ adenocarcinomas (podoplanin-positive cancer-associated fibroblasts: 0 vs 0 [mean: 1.6 vs 11.6], P < .01; CD204-positive tumor-associated macrophages: 8.7 vs 24.7, P < .01). CONCLUSIONS: Our results indicated that lower cancer cell-specific expression levels of hypoxia markers and a smaller number of tumor-promoting stromal cells in invasive component were characteristic features of Lep+ adenocarcinomas.

Long-term survival after complete resection of non-small-cell lung cancer in patients with interstitial lung disease.

OBJECTIVES: Patients with lung cancer and interstitial lung disease (ILD), usual interstitial pneumonia in particular, are known to have a poor outcome. The aim of this study was to evaluate the prognostic impact of ILD in patients with non-small-cell lung cancer. METHODS: A total of 2054 consecutive patients underwent complete resection of Stage IA-IIIA non-small-cell lung cancer in our institution between January 2002 and March 2013. The presence of ILD was diagnosed and categorized based on high-resolution computed tomography images. Multivariate analysis was performed to identify the prognostic factors. RESULTS: There were 106 (5%) patients with ILD. There were significantly more patients who developed severe complications (P < 0.01) in the ILD group, with 4 (4%) patients developing acute exacerbation. Although the difference in postoperative mortality rate was marginal between the groups (P = 0.07), the 5-year overall survival and cancer-specific survival rates of the ILD patients were significantly worse than those of the non-ILD group (overall survival: 40.4% vs 72.0%, P < 0.01; cancer-specific survival 55.4% vs 78.6%, P < 0.01). The results of multivariate analysis showed that coexistence of ILD (hazard ratio 1.45; P = 0.01) was an independent, unfavourable prognostic factor. CONCLUSIONS: The presence of ILD led to a much poorer survival after complete resection of non-small-cell lung cancer.