Small-sized Lung Adenocarcinoma Research Articles

AI-driven Characterization of Solid Pulmonary Nodules on CT Imaging for Enhanced Malignancy Prediction in Small-sized Lung Adenocarcinoma

ObjectivesDistinguishing solid nodules from nodules with ground-glass lesions in lung cancer is a critical diagnostic challenge, especially for tumors ≤2 cm. Human assessment of these nodules is associated with high inter-observer variability, which is why an objective and reliable diagnostic tool is necessary. This study focuses on artificial intelligence (AI) to automatically analyze such tumors and to develop prospective AI systems that can independently differentiate highly malignant nodules. Materials and methodsOur retrospective study analyzed 246 patients who were diagnosed with negative clinical lymph node metastases (cN0) using positron emission tomography-computed tomography (PET/CT) imaging and underwent surgical resection for lung adenocarcinoma. AI detected tumor sizes ≤2 cm in these patients. By utilizing AI to classify these nodules as solid (AI_solid) or non-solid (non-AI_solid) based on confidence scores, we aim to correlate AI determinations with pathological findings, thereby advancing the precision of preoperative assessments. ResultsSolid nodules identified by AI with a confidence score ≥0.87 showed significantly higher solid component volumes and proportions in patients with AI_solid than in those with non-AI_solid, with no differences in overall diameter or total volume of the tumors. Among patients with AI_solid, 16% demonstrated lymph node metastasis, and a significant 94% harbored invasive adenocarcinoma. Additionally, 44% were upstaging postoperatively. These AI_solid nodules represented high-grade malignancies. ConclusionIn small-sized lung cancer diagnosed as cN0, AI automatically identifies tumors as solid nodules ≤2 cm and evaluates their malignancy preoperatively. The AI classification can inform lymph node assessment necessity in sublobar resections, reflecting metastatic potential.

Predictive value of systemic immune-inflammation index in the high-grade subtypes components of small-sized lung adenocarcinoma

BackgroundIdentification of micropapillary and solid subtypes components in small-sized (≤ 2 cm) lung adenocarcinoma plays a crucial role in determining optimal surgical procedures. This study aims to propose a straightforward prediction method utilizing preoperative available indicators.MethodsFrom January 2019 to July 2022, 341 consecutive patients with small-sized lung adenocarcinoma who underwent curative resection in thoracic surgery department of Xuanwu Hospital, Capital Medical University were retrospectively analyzed. The patients were divided into two groups based on whether solid or micropapillary components ≥ 5% or not (S/MP5+ and S/MP5-). Univariate analysis and multivariate logistic regression analysis were utilized to identify independent predictors of S/MP5+. Then a nomogram was constructed to intuitively show the results. Finally, the calibration curve with a 1000 bootstrap resampling and the receiver operating characteristic (ROC) curve were depicted to evaluate its performance.ResultsAccording to postoperative pathological results, 79 (23.2%) patients were confirmed as S/MP5+ while 262 (76.8%) patients were S/MP5-. Based on multivariate analysis, maximum diameter (p = 0.010), consolidation tumor ratio (CTR) (p < 0.001) and systemic immune-inflammation index (SII) (p < 0.001) were identified as three independent risk factors and incorporated into the nomogram. The calibration curve showed good concordance between the predicted and actual probability of S/MP5+. Besides, the model showed certain discrimination, with an area under ROC curve of 0.893.ConclusionsThe model constructed based on SII is a practical tool to predict high-grade subtypes components of small-sized lung adenocarcinoma preoperatively and contribute to determine the optimal surgical approach.

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

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. 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. 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). 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).

FP06.01 Unexpected Aggressive Histological Component in Subsolid Lung Adenocarcinoma: Priority for Resection Without Delay

Ground glass opacity (GGO)-containing small-sized adenocarcinoma of the lung can generally be expected to have a fair prognosis after resection. However, some of such tumors might contain a histological aggressive component that is related to poor prognosis. This study aimed to identify the predictors for the aggressive histological component in GGO-containing small-sized lung adenocarcinoma to screen the patients who should undergo resection without delay in the era of COVID-19.

Predictors of CT Morphologic Features to Identify Spread Through Air Spaces Preoperatively in Small-Sized Lung Adenocarcinoma

ObjectivesThis study aimed to explore the predictive CT features of spread through air spaces (STAS) in patients with small-sized lung adenocarcinoma.MethodsFrom January 2017 to May 2019, patients with confirmed pathology of small-sized lung adenocarcinoma (less than or equal to 2 cm) and who underwent surgery were retrospectively analyzed. The clinical, pathological, and surgical information and CT features were analyzed.ResultsA total of 47 patients with STAS (males, 61.7%; mean age, 56 ± 8years) and 143 patients without STAS (males, 58%; mean age, 53 ± 11 years) were included. Pathologically, papillary, micropapillary, solid predominant subtypes, and vascular and pleural invasion were most commonly observed features in the STAS group. Radiologically, higher consolidation tumor ratio (CTR), presence of spiculation, satellites, ground glass ribbon sign, pleural attachment, and unclear tumor–lung interface were more commonly observed features in the STAS group. CTR, presence of ground glass ribbons and pleural connection, and absence of cystic airspaces were considered as stable predictors of STAS in multivariate logistic models. The receiver operating characteristic curve (ROC) analysis for predicting STAS demonstrated higher area under the curve (AUC) in the model that used CTR (0.760, 95% confidence interval, 0.69–0.83) for predicting STAS than in the model that used long diameter of entire lesion (0.640).ConclusionsCTR is the best CT sign for predicting STAS in small-sized lung adenocarcinoma. The ground glass ribbon is a newly found indicator and has the potential for predicting STAS.

Segmentectomy vs Lobectomy for Clinical Stage IA Lung Adenocarcinoma With Spread Through Air Spaces

This study aimed to investigate the prognosis after segmentectomy as compared with lobectomy for small-sized lung adenocarcinoma with spread through air spaces (STAS). This retrospective study included 609 patients who underwent lobectomy or segmentectomy with lymph node dissection for clinical stage IA lung adenocarcinoma between April 2011 and March 2020 at Hiroshima University Hospital. Patient characteristics and prognosis after segmentectomy and lobectomy were investigated. STAS was detected in 293 patients (48.1%). The recurrence-free survival (RFS) rate was significantly worse with STAS-positive adenocarcinoma than with STAS-negative adenocarcinoma both in patients who underwent lobectomy (5-year RFS, 68.2% vs 90.2%; P<.001) and in patients who underwent segmentectomy (5-year RFS, 81.3% vs 93.0%; P= .003). Among thepatients with STAS, there was no significant difference in RFS between patients who underwent lobectomy (5-year RFS, 68.2%) and those who underwent segmentectomy (5-year RFS, 81.3%; P= .225). In a multivariable analysis using propensity score to adjust clinical patient characteristics, segmentectomy was not found to be an independent prognostic factor of RFS (hazard ratio 0.732, P= .326) among patients with STAS. Among the patients with STAS, only 1 patient (1%) with insufficient resection margin (0.5 mm) had local recurrence and 1 patient (1%) with invasive mucinous adenocarcinoma had recurrence in preserved lobe after segmentectomy. Spread through air spaces was a poor prognostic factor in patients with clinical stage IA lung adenocarcinoma. Prognosis after segmentectomy was comparable with that of lobectomy in lung adenocarcinoma with STAS without increasing locoregional recurrence.

How long is cessation of preoperative smoking required to improve postoperative survival of patients with pathological stage I non-small cell lung cancer?

BackgroundSmoking can cause non-small cell lung cancer (NSCLC). However, the effects of preoperative smoking on tumor progression are not well-known. In addition, the duration of smoking cessation that can provide NSCLC patients with smoking history similar postoperative prognosis as that of nonsmokers remains unknown. This study aimed to investigate the period of smoking cessation that may “compensate” for past smoking history regarding postoperative survival in cases of resected pathological stage I NSCLC by examining the relationship between clinicopathological factors and preoperative smoking.MethodsWe retrospectively examined clinicopathological factors including preoperative smoking status and postoperative survival in 453 patients with pathologically proven stage I NSCLC at our Institute. Smoking status was evaluated using the following four parameters: cigarettes per day, number of years of smoking, pack-years, and number of years since smoking cessation.ResultsPathological factors that reflect tumor invasiveness including vascular invasion (VI) and pleural invasion (PL) were associated with the degree of preoperative smoking in adenocarcinomas, particularly invasive diameters of 2–3 cm. Such a relationship was not identified for non-adenocarcinomas. Heavy smoking status was significantly related to PL in lepidic or papillary predominant adenocarcinomas and to VI in acinar or solid predominant adenocarcinomas. Former smokers who quit smoking for ≥10 years had similar postoperative survival as non-smokers for adenocarcinoma ≤3 cm.ConclusionsAccumulative smoking habit correlated with VI and PL, particularly in 2–3 cm adenocarcinoma, whereas larger adenocarcinomas and non-adenocarcinomas of any size appear to grow and become invasive independent of preoperative smoking status. Longer smoking cessation ≥10 years can result in postoperative survival similar to that of non-smokers with adenocarcinomas ≤3 cm. Current smokers should quit smoking immediately to ensure longer survival even though they suffer from small-sized lung adenocarcinomas in the future.

Novel imprint cytological classification is correlated with tumor spread through air spaces in lung adenocarcinoma

ObjectivesSpread through air spaces (STAS) is a risk factor for local recurrence after sublobar resection in lung cancer patients. We recently proposed the novel Nakayama-Higashiyama imprint cytological classification (N-H classification) based on small-sized lung adenocarcinoma surgical specimens, which correlated with histological patterns and nodal involvement. This study aimed to evaluate the correlation between STAS and the N-H classification and to validate the N-H classification as an intraoperative predictor of the presence of STAS. Materials and methodsWe retrospectively analyzed 164 intraoperative imprint cytologies and their paired histologic specimens from patients undergoing surgical resection for lung adenocarcinoma in our institute in 2017–2019. Using the NH classification, imprint cytological findings were classified into 5 groups (Groups I to V) based on cell cluster shape, cell and nucleus size, and the existence of necrosis. We examined the characteristics of imprint cytology and STAS in the resected tissues and analyzed the relationship between them. ResultsTumor STAS was observed in 29 (17.7 %) cases. The presence of STAS was significantly associated with the NH classification (P < 0.0001). STAS was present in 6 of 57 cases (10.5 %) in NH classification Group II, 11 of 42 cases (26.2 %) in Group III, and 12 of 28 cases (42.9 %) in Group IV/V; STAS was not observed in any case in Group I. Logistic regression analysis revealed that tumors with a ground glass opacity rate of <50 % on computed tomography (P = 0.00867) and Groups III–V of the NH classification (P = 0.00201) were significant independent predictors for STAS. ConclusionIntraoperative imprint cytology with the N-H classification for lung adenocarcinoma is well correlated with the STAS status of the tumor and might have applications as an intraoperative predictive marker of STAS. This classification may be useful for intraoperative detection of STAS and in the decision-making process for the surgical procedure.

Novel Imprint Cytological Classification for Small Pulmonary Adenocarcinoma Using Surgical Specimens: Comparison with the 8th Lung Cancer Staging System and Histopathological Classification.

Objectives: Small-size lung lesions suspected of being cancer are now often being identified on computed tomography. Correspondingly, a new lung cancer staging system has been proposed by the International Association for the Study of Lung Cancer (IASLC), in which the T1 factor and adenocarcinoma are re-subclassified. Previously, we proposed an intraoperative cytological diagnosis and its classification of small-size lung adenocarcinoma, which correlated significantly with clinical malignancy, to be used for selecting the surgical strategy. In the current study, the correlation of our intraoperative cytological classification with the new 8th IASLC classification was investigated.Materials and Methods: A total of 139 consecutive small-size lung adenocarcinoma cases were surgically resected from 2000 to 2006 and included in this study. Intraoperative stump imprint cytology using these specimens was performed, and the cases were classified into 5 groups based on our classification. The cytological classification was compared with the IASLC classification and the WHO histopathological grading.Results: According to our classification, 32 patients were in Group I, 38 in Group II, 24 in Group III, 27 in Group IV, and 18 in Group V. Compared with the IASLC classification, most of Group I was pTis or pT1mi, and most of Group II was pT1mi or pT1a (p<0.001). There was also a significant relationship between lymph node metastasis and our cytological classification (p<0.001). The histological patterns according to the WHO classification also had a significant relationship with our classification (p<0.001).Conclusion: Our cytological classification correlated not only with the T classification, but also with the adenocarcinoma subclassification of the 8th IASLC classification.

Outcomes and predictive factors for pathological node-positive in radiographically pure-solid, small-sized lung adenocarcinoma.

The indication of limited resection for radiographically pure-solid, small-sized lung adenocarcinoma is controversial. This study aimed to reveal the long-term outcome of standard surgical treatment and determine the predictive factors for pathological lymph node metastasis in optimal candidates undergoing limited surgical resection for pure-solid, small-sized lung adenocarcinoma. The medical records of 107 consecutive patients were retrospectively reviewed at our hospital between December 2002 and December 2013. Inclusion criteria were histopathological diagnosis of lung adenocarcinoma, radiographically pure-solid tumor, ≤ 2cm tumor size measured using thin-section computed tomography, clinical N0M0, patients who underwent lobectomy with systematic or lobe-specific lymph node dissection, and R0 resection. Overall and disease-free survival curves were calculated using the Kaplan-Meier method. Clinicopathological factors predicting pathological node-positive metastasis were identified by univariate and multivariate analysis. The 5-year overall and disease-free survival rates were 91.4% and 87.3%, respectively. Multivariate analysis demonstrated maximum standardized uptake value > 5 as the independent predictor of pathological node-positive metastasis (odds ratio 3.81; 95% confidence interval 1.25-12.3; p = 0.02). In all patients, the pathological node-positive rate was 16.7%; in patients who had a maximum standardized uptake value of ≤ 5, the rate was 7.9%. The long-term outcome of standard surgical treatment was favorable. Maximum standardized uptake value was a significant predictor of pathological node-positive metastasis; however, diagnostic accuracy was not favorable. Therefore, the selection of optimal candidates is difficult, and limited surgical resection may not be applicable in pure-solid, small-sized lung adenocarcinoma.

Distinct Clinicopathologic Characteristics and Prognosis Based on the Presence of Ground Glass Opacity Component in Clinical Stage IA Lung Adenocarcinoma

IntroductionWe evaluated differences in the clinicopathologic characteristics and prognosis based on the presence of ground glass opacity (GGO) components in small-sized lung adenocarcinoma. MethodsWe retrospectively investigated 634 lung adenocarcinomas classed as c-stage IA in the eighth edition TNM classification. Staging was defined according to the solid component size measured by thin-section computed tomography. All tumors were grouped into either a GGO or solid group, based on the presence of a GGO component. ResultsOf the cases, 215 (34%) were classed as c-stage IA1 (T1mi: 88, T1a-GGO: 102, T1a-solid: 25), 255 (40%) as c-stage IA2 (T1b-GGO: 122, T1b-solid: 133), and 164 (26%) as c-stage IA3 (T1c-GGO: 44, T1c-solid: 120). Among the 546 c-stage IA cases excluding the T1mi lesions, Cox regression analysis revealed that presence of GGO was an independently significant prognosticator (p = 0.024). The result was validated in 494 c-stage IA lung adenocarcinomas with a nonpredominant GGO component, showing the presence of GGO as a significant prognosticator (p = 0.048). When we evaluated the prognostic impact of GGO presence in each clinical stage, the 5-year overall survival (OS) was significantly different between the GGO and solid groups (IA1: 97.8% versus 86.6%, p = 0.026; IA2: 89.3% versus 75.2%, p = 0.007; IA3: 88.5% versus 62.3%, p = 0.003). Furthermore, the 5-year overall survival b was distinct in parallel similar pathologic findings when comparing a lepidic versus an invasive component (IA1: 97.9% versus 85.6%, p = 0.031; IA2: 86.1% versus 69.4%, p = 0.007; IA3: 77.5% versus 55.8%, p < 0.001). ConclusionsClinicopathologic and oncologic outcomes were disparate based on the presence of a GGO component in the eighth edition TNM classification of c-stage IA lung adenocarcinoma.

P2.05-020 Prognostic Factors in Patients with Completely Resected Subsolid Node-Negative Lung Adenocarcinoma of 3cm or Smaller

The operative method in ground glass pulmonary nodules is controversial. The prognostic value of histological subtypes in resected node-negative small-sized lung adenocarcinoma has not been widely investigated. This study aim to investigate the prognostic factors in patients with resected small ground glass nodules with consolidation/tumor (C/T) ratio of 0.5 or less determined by chest computed tomography.

1279P - Factors predicting worse outcomes in patients with N0 lung adenocarcinoma of 3cm or smaller

Background: The role of adjuvant chemotherapy for patients with stage I non-small cell lung cancer remains unknown. The prognostic value of histological subtypes in resected node-negative small-sized lung adenocarcinoma has not been widely investigated. This study investigated the prognostic factors in patients with node-negative lung adenocarcinoma of 3cm or smaller to find potential candidates for adjuvant chemotherapy. Methods: A total of 746 patients with completely resected node-negative lung adenocarcinoma of 3cm or smaller were included in the study. Prognostic factors for overall survival or probability of freedom from recurrence (FFR) were investigated. Results: The 5-year overall survival and recurrence-free rates were 86.8% and 84.8%, respectively. During follow-up, 59 (7.9%) patients developed recurrence. Univariate analysis showed that micropapillary/solid predominant group had significantly lower probability of FFR (P = 0.001) in node-negative lung adenocarcinoma of 3cm or smaller. Older age (P = 0.007), greater tumor size (P = 0.006), and micropapillary/solid predominant group (P = 0.031) had significantly lower probability of FFR in multivariate analysis. Conclusions: The new adenocarcinoma classification has significant impact on recurrence in node-negative lung adenocarcinoma of 3cm or smaller. Patients with micropapillary/solid predominant pattern have significant higher risk for recurrence. Legal entity responsible for the study: None Funding: None Disclosure: All authors have declared no conflicts of interest.

Invasive features of small-sized lung adenocarcinoma adjoining emphysematous bullae.

Radiologically small-sized adenocarcinomas are special entities of lung cancer, as their radiological and pathological invasiveness determines the surgical procedures applied; however, the clinicopathological features of small-sized lung adenocarcinoma adjoining cystic airspaces (Ca-ADJ) have yet to be fully clarified. The aim of this study was to elucidate the clinicopathological characteristics, including the programmed death ligand 1 (PD-L1) expression, in patients with Ca-ADJ ≤3.0 cm. A total of 283 patients with resected adenocarcinoma, whose radiological tumour size was ≤3.0 cm without lymph node or distant metastases on preoperative high-resolution computed tomography, were analysed for their clinicopathological and radiological features. Furthermore, the PD-L1 expression was evaluated by immunohistochemistry using an anti-human PD-L1 rabbit monoclonal antibody (clone SP142). Among the 283 patients, 31 (11.0%) patients were reported to have Ca-ADJ. The Fisher's exact test demonstrated that Ca-ADJ was significantly associated with male gender (P < 0.001), a history of smoking (P < 0.001), a high consolidation/tumour ratio (P = 0.026), advanced pathological stage (P < 0.001), the presence of pleural (P < 0.001) and vessel invasion (P < 0.001), histological invasive subtypes (P < 0.001) and wild-type epidermal growth factor receptor (P = 0.001). The patients with Ca-ADJ had a significantly higher maximum standardized uptake value than those without Ca-ADJ (8.4 vs 4.1, P < 0.001). Furthermore, Ca-ADJ was significantly associated with the PD-L1 expression (P < 0.001). Log-rank test showed that patients with Ca-ADJ had a significantly shorter disease-free survival than those without Ca-ADJ (P = 0.001). This study showed that patients with radiologically small-sized Ca-ADJ might exhibit radiologically and pathologically invasive features.

Microsized lung adenocarcinoma vs. small-sized lung adenocarcinoma: clinical characteristics, advantages and surgical implications.

Owing to the advances in imaging techniques such as thin-section computed tomography (CT) and 3D imaging, lung cancer can now be diagnosed at an early stage. The detection of small-sized lung cancer, including the 1 cm in diameter or less, is remarkably increasing. As a consequence, in 2015 the International Association for the Study of Lung Cancer (IASLC) proposed the new TNM staging system of lung and pleural tumours, in which T1 (≤3 cm) non-small-cell lung cancer (NSCLC) tumors were divided based on tumour size into T1a (≤1 cm), T1b (>1 and ≤2 cm) and T1c (>2 and ≤3 cm) (1). In this scenario several studies have investigated the role of limited resections, such as wedge and segmentectomy, in the treatment of small size lung cancer (<2 cm). Particularly, the hypothesis zero is the assumption that, in this type of lung cancer, no significant differences in survival rate are identified when patients who underwent lobectomy and those who were subjected to a limited resection are compared.

Precise Diagnosis of Intraoperative Frozen Section Is an Effective Method to Guide Resection Strategy for Peripheral Small-Sized Lung Adenocarcinoma.

This study investigated the accuracy of intraoperative frozen section (FS) diagnosis for predicting the final pathology (FP) of peripheral small-sized lung adenocarcinoma and evaluated its usefulness in sublobar resection. The records of 803 patients with clinical stage I peripheral lung adenocarcinoma who underwent sublobar resection for FS diagnosis to guide surgical strategy were reviewed. The surgical extension was mainly based on FS. The FS were stratified into atypical adenomatous hyperplasia, adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA), and invasive adenocarcinoma. The diagnostic accuracy of FS, the reasons for the discrepancy between FS and FP, and the clinical influence of the FS errors were evaluated. To assess the survival of patients with different subtypes after surgery, 301 patients were identified for prognosis evaluation. The total concordance rate between FS and FP was 84.4%. When atypical adenomatous hyperplasia, AIS, and MIA were classified together as a low-risk group, the concordance rate was 95.9%. Most discrepant cases were the underestimation of AIS and MIA. The diagnostic accuracy of FS for tumors ≤ 1 cm and larger than 1 cm in diameter was 79.6% and 90.8%, respectively (P < .01). The FS errors had significant clinical impact on 0.9% of the 803 patients due to insufficient resection. The 5-year recurrence-free survival rate (100%) was significantly better for the patients with AIS/MIA than for patients with invasive adenocarcinoma (74.1%, P < .01). Frozen pathology has a high concordance rate with FP. Precise diagnosis by intraoperative FS is an effective method to guide resection strategy for peripheral small-sized lung adenocarcinoma.

Clinical characteristics and advantages of primary peripheral micro-sized lung adenocarcinoma over small-sized lung adenocarcinoma.

Micro-sized lung adenocarcinoma with a tumour of 1.0 cm or less could help identify the patients who would undergo the surgery treatment with limited resection; however, its clinical characteristics and survival rates remain unclear and are to be tested further. Histology, lymphatic metastasis, surgical procedure and survival rates of 366 lung adenocarcinoma patients (from January 2007 to December 2013) with a tumour of 2.0 cm or less were analysed retrospectively. Among these patients, 175 had a primary tumour with a diameter of 1.0 cm or less and 191 had a tumour of 1.1-2.0 cm. The survival of 366 patients was evaluated by the restricted mean survival time (RMST) test, and the risk factors were assessed by multivariable analysis. Larger lesion had a significant relation to old age, male sex, preoperatively carcinoembryonic antigen (CEA) positive, invasive adenocarcinoma (IAC) and advanced-stage disease (P < 0.0001, P = 0.001, P = 0.001, P < 0.0001 and P < 0.0001, respectively). Patients with adenocarcinoma in situ (AIS)/minimally invasive adenocarcinoma obtained a better prognosis than those with IAC (5-year overall survival rate: 98.5 vs 84.3%, P = 0.001; disease-related survival rate: 98.5 versus 85.2%, P = 0.001). The 5-year overall survival rates of patients with a tumour less than 1.0 cm in comparison with 1.1-2.0 cm were 100.0 and 88.4% (P < 0.001), whereas the 5-year lung adenocarcinoma-specific survival rates were 100.0 and 89.0% (P < 0.001), respectively. Multivariable analysis for prognosis of lung adenocarcinoma patients with a tumour 2.0 cm or less in diameter revealed that histology, lymphatic metastasis and advanced pathological stage affected the 5-year overall and disease-related survival rates unfavourably (P < 0.0001, 0.002, 0.001; and P < 0.0001, 0.005, 0.001, respectively), whereas tumour size did not have an obvious influence on survival. Micro-sized lung adenocarcinoma (1.0 cm or less) had specific clinical characteristics and more favourable survival rates. These tumours and a subtype of AIS evaluated by computed tomography images or intraoperative frozen section may be appropriate candidates for a limited resection without mediastinal lymph node dissection.

Cytoplasmic maspin expression is a predictor of poor prognosis in patients with lung adenocarcinoma measuring

Maspin is known to be a tumour suppressor protein, and few studies focused upon its prognostic significance in patients with small-size lung adenocarcinoma have been reported; however, its clinical significance remains controversial. We explored the prognostic value of maspin with particular reference to its subcellular localization in patients with resected lung adenocarcinoma measuring <3cm. Immunohistochemical analyses were performed on resected 110 specimens of lung adenocarcinoma measuring <3cm. Maspin positivity was defined as strong expression in only the cytoplasm and was observed in 27 patients (24.5%). It correlated significantly with the presence of lymph node metastasis (P=0.009) and micropapillary component (P<0.001). The patients were followed-up for 6-88months (median: 71months), and the maspin-positive group had shorter disease-free survival (DFS) and overall survival (OS) by log-rank test (P<0.001, P<0.001, respectively). Using Cox's multivariate analysis, the status of maspin was an independent prognostic factor for DFS and OS (P=0.004, P=0.022, respectively), as well as lymph node metastasis. Cytoplasmic maspin expression could be an independent poor prognostic indicator of patients with lung adenocarcinoma measuring <3cm.

Low papillary structure in lepidic growth component of lung adenocarcinoma: a unique histologic hallmark of aggressive behavior

Small-sized lung adenocarcinomas often contain a lepidic growth component in part. The term lepidic growth has recently been used to represent a growth pattern of neoplastic cells along preexisting alveolar structures. We reviewed 91 small-sized (≤3 cm) invasive lung adenocarcinomas with a lepidic component to study the histopathologic and clinicopathologic characteristics. In the lepidic component of invasive adenocarcinoma, we have identified a morphologically unique structure characterized by proliferation of low papillae, consisting of neoplastic cells piling up toward the alveolar space, and we defined this architecture as "low papillary structure." There were 18 cases with the low papillary structure in the lepidic components, whereas 73 cases did not have the structure. In the lepidic component, the cases with the low papillary structure had higher Ki-67 labeling index (15.7%) and more frequent p53 overexpression (50.0%) than did those without the structure (9.4% and 16.4%, respectively). Based on clinicopathologic findings, the presence of low papillary structure was significantly associated with lymphatic invasion (P = .023) and lymph node metastasis (P = .001). Furthermore, the patients with the low papillary structure in the lepidic components demonstrated significantly shorter disease-free and overall survival than did those without the structure (P = .001 and P = .010, respectively). We conclude that the low papillary structure is a significant histologic feature in a lepidic component and is associated with aggressive cancer behavior in lung adenocarcinoma.

Multiparameter analysis using cell cycle biomarkers for small-size lung adenocarcinoma: prognostic implications

Cell cycle-related molecules play crucial roles in maintaining genomic stability, and can also serve as biomarkers of cell cycle phase distribution at the same time. In this study, we used multiparameter analysis of various biomarkers to investigate their utility for the evaluation of tumor proliferation activities and the prognosis of patients with small-size lung adenocarcinoma. We performed immunohistochemical analysis using five cell cycle-related biomarkers (MCM7, Ki-67, Geminin, Aurora A and H3S10ph) for 102 surgically resected small-size lung adenocarcinomas. We classified them into three phenotypes based on the dominant cell cycle phase distribution of the tumor cell population, and evaluated whether these phenotypes were associated with clinicopathological factors and survival. Phenotype I (MCM7-negative tumors; n=56) was correlated with high or moderate differentiation and reduced local invasiveness (pleural and lymphovascular invasion) compared with phenotype II (MCM7-, Ki-67- and Geminin-positive tumors; n=23) and phenotype III (MCM7-, Aurora A- and H3S10ph-positive tumors; n=17). Five-year survival rates of phenotypes I, II and III were 89.8, 55.4 and 38.6%, respectively, with a significant difference between them (p<0.01). Multivariate analysis revealed that phenotypes II and III were independent prognostic factors in the 79 patients with stage I lung adenocarcinoma. Multiparameter analysis using cell cycle biomarkers for small-size lung adenocarcinoma provided novel insights into the cell cycle phase distribution of dynamic tumor cell populations invivo; it may be possible to evaluate tumor proliferation activities and patient prognosis more precisely if this analytical procedure is used.