Lepidic Predominant Invasive Adenocarcinoma Research Articles

Predictors of Invasiveness in Adenocarcinoma of Lung with Lepidic Growth Pattern.

Lung adenocarcinoma with lepidic growth pattern (LPA) is characterized by tumor cell proliferation along intact alveolar walls, and further classified as adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA) and invasive lepidic predominant adenocarcinoma (iLPA). Accurate diagnosis of lepidic lesions is critical for appropriate prognostication and management as five-year survival in patients with iLPA is lower than in those with AIS and MIA. We aimed to evaluate the accuracy of CT-guided core needle lung biopsy classifying LPA lesions and identify clinical and radiologic predictors of invasive disease in biopsied lesions. Thirty-four cases of adenocarcinoma with non-invasive lepidic growth pattern on core biopsy pathology that subsequently were resected between 2011 and 2018 were identified. Invasive LPA vs. non-invasive LPA (AIS or MIA) was defined based on explant pathology. Histopathology of core biopsy and resected tumor specimens was compared for concordance, and clinical, radiologic and pathologic variables were analyzed to assess for correlation with invasive disease. The majority of explanted tumors (70.6%) revealed invasive disease. Asian race (p = 0.03), history of extrathoracic malignancy (p = 0.02) and absence of smoking history (p = 0.03) were associated with invasive disease. CT-measured tumor size was not associated with invasiveness (p = 0.15). CT appearance of density (p = 0.61), shape (p = 0.78), and margin (p = 0.24) did not demonstrate a significant difference between the two subgroups. Invasiveness of tumors with lepidic growth patterns can be underestimated on transthoracic core needle biopsies. Asian race, absence of smoking, and history of extrathoracic malignancy were associated with invasive disease.

Value of PET/CT Combined with CT Three-dimensional Reconstruction in Distinguishing Different Pathological Subtypes of Early Lung Adenocarcinoma

背景与目的早期肺腺癌中病理亚型以贴壁为主型的浸润性腺癌（lepidic predominant invasive adenocarcinoma, LPA）与原位腺癌（adenocarcinoma in situ, AIS）、微浸润性腺癌（microinvasive adenocarcinoma, MIA）的良好预后相似，临床上也迫切需要能够区分LPA与非LPA型浸润性腺癌（non-lepidic predominant invasive adenocarcinoma, non-LPA）的手段，本研究拟通过正电子发射型计算机断层显像（positron emission computed tomography, PET）/计算机断层扫描（computed tomography, CT）的最大标准化摄取值（maximal standard uptake value, SUVmax）和CT三维重建后参数探讨术前影像学表现为部分实性结节（part-solid nodules, PSNs）的早期肺腺癌不同病理亚型间的关系。方法回顾性分析2016年1月-2019年1月于江苏省苏北人民医院胸外科行解剖性肺切除术且影像学表现为PSNs的早期肺腺癌患者资料，所有患者胸部增强CT和PET/CT资料完整可获取，利用Mimics软件行三维重建，获取肿瘤体积、肿瘤三维平均CT值（3-dimensional mean-CT value, 3Dm-CT）、SUVmax等数据，采用SPSS 25.0进行统计分析，GraphPad Prism 8.3.0绘制受试者工作曲线（receiver operating curve, ROC），P < 0.05为差异有统计学意义。结果最终共计67例患者纳入本研究，按病理亚型不同将所有患者分为两组，AIS、MIA及浸润性腺癌（invasive adenocarcinoma, IAC）中的LPA归为低危组28例（41.8%），其余non-LPA如腺泡型（acinar pattern-predominant adeno-carcinoma, APA）、乳头型（papillary pattern-predominant adenocarcinoma, PPA）、微乳头型（micropapillary pattern-predominant adeno-carcinoma, MPA）归为高危组39例（58.2%），两组间SUVmax（t=3.153, P=0.002）、肿瘤体积（t=3.331, P=0.001)、实性/磨玻璃成分体积（t=2.74, P=0.006) /（t=3.127, P=0.002）、实性/磨玻璃成分3Dm-CT（t=3.655, P < 0.001) /（t=7.082, P < 0.001) 均具有显著统计学意义。ROC曲线提示：SUVmax[曲线下面积（area under curve, AUC）=0.727]、肿瘤体积（AUC=0.740）、磨玻璃成分体积（AUC=0.725）、实性成分3Dm-CT（AUC=0.763）、磨玻璃成分3Dm-CT（AUC=0.756）预测效能最佳。将上述AUC > 0.7的协变量纳入多因素ROC曲线分析，获得联合预测因子（AUC=0.835）具有中等以上预测价值。结论PET/CT中SUVmax和CT三维重建参数与影像学表现为PSNs的早期肺腺癌的不同病理亚型具有显著相关性，联合SUVmax、肿瘤体积、磨玻璃成分体积和实性/磨玻璃成分3Dm-CT对鉴别表现为PSNs的早期肺腺癌的病理亚型具有一定价值。

A proteogenomic profile of early lung adenocarcinomas by protein co-expression network and genomic alteration analysis

The tumourigenesis of early lung adenocarcinomas, including adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA), and lepidic predominant invasive adenocarcinoma (LPA), remains unclear. This study aimed to capture disease-related molecular networks characterising each subtype and tumorigenesis by assessing 14 lung adenocarcinomas (AIS, five; MIA, five; LPA, four). Protein–protein interaction networks significant to the three subtypes were elucidated by weighted gene co-expression network analysis and pairwise G-statistics based analysis. Pathway enrichment analysis for AIS involved extracellular matrix proteoglycans and neutrophil degranulation pathway relating to tumour growth and angiogenesis. Whereas no direct networks were found for MIA, proteins significant to MIA were involved in oncogenic transformation, epithelial-mesenchymal transition, and detoxification in the lung. LPA was associated with pathways of HSF1-mediated heat shock response regulation, DNA damage repair, cell cycle regulation, and mitosis. Genomic alteration analysis suggested that LPA had both somatic mutations with loss of function and copy number gains more frequent than MIA. Oncogenic drivers were detected in both MIA and LPA, and also LPA had a higher degree of copy number loss than MIA. Our findings may help identifying potential therapeutic targets and developing therapeutic strategies to improve patient outcomes.

Expression of PD-L1, PD-L2, and IDO1 on tumor cells and density of CD8-positive tumor-infiltrating lymphocytes in early-stage lung adenocarcinoma according to histological subtype.

This study examined the expression of programmed cell death-ligand 1 (PD-L1), programmed cell death-ligand 2 (PD-L2), and indoleamine 2,3-dioxygenase-1 (IDO1) in tumor cells and cluster of differentiation 8 (CD8)-positive tumor-infiltrating lymphocytes (TILs) in early-stage lung adenocarcinoma according to histological subtypes. We evaluated PD-L1, PD-L2, and IDO1 expression in tumor cells and CD8-positive TILs in surgically resected specimens from 196 stage 0 or I lung adenocarcinoma patients by immunohistochemical staining. We also examined the relationships between the expression of PD-L1, PD-L2, and IDO1 in tumor cells and the density of CD8-positive TILs and clinical factors. Patients were divided into three groups: A, adenocarcinoma in situ and minimally invasive adenocarcinoma (N = 32); B, lepidic predominant invasive adenocarcinoma (IAD; LPA; N = 66); and C, IAD except for LPA (N = 98). PD-L1 was expressed only in Group C, but not in Groups A or B. The positive ratio of PD-L2 was significantly higher in Group C (63.3%), and that of IDO1 was also significantly higher in Group C (65.3%). The density of CD8-positive TILs was significantly higher in Group C (45 ± 2.4). There was no significant difference between the positive ratios of PD-L2 and IDO1 and the density of CD8-positive TILs in Group A (50.0%, 21.9%, and 36 ± 4.1, respectively) or Group B (60.6%, 25.8%, and 44 ± 3.0, respectively). No cases in Groups A and B expressed PD-L1. The expression of immune-related factors, especially PD-L1 and IDO1, was significantly associated with Group C. This is the first report of the detailed examination of PD-L1, PD-L2, IDO1, and CD8 expression in lung adenocarcinoma subtypes with lepidic predominant components. Our results could help identify patients who would benefit from perioperative immunotherapy.

Analysis of Segmental Lymph Node Metastasis and Clinical Features in cT1N0M0 Lung Adenocarcinoma.

The progression of lung adenocarcinoma through lymph node metastasis has been well established; however, the process of segmental lymph node (LSN) metastasis in cT1N0M0 lung adenocarcinoma remains unclear. We aimed to elucidate the markers of lymph node metastasis to different segments in early-stage lung adenocarcinoma and identify new indications for segmentectomy. A total of 200 patients were enrolled in this study. These patients were diagnosed with cT1N0M0 lung adenocarcinoma after positron emission tomography/computed tomography and received lobectomy and lymph node dissection surgeries. Lymph nodes retrieved from each station were sorted. The metastatic status of the isolated (i) LSNs and several characteristics were analyzed. Patients with ground-glass nodules (GGNs) (P=0.025), AIS/MIA/lepidic adenocarcinoma (P=0.038), nodules with a maximum diameter ≤1 cm (P=0.017), maximum standardized uptake value (SUVmax) < 2.5 (P=0.029), serum carcinoembryonic antigen (CEA) levels ≤4.5 ng/ml (P=0.036), and no N1 lymph nodes metastasis (P=0.036) had significantly lower iLSN metastasis rates than those without these characteristics. Pure GGNs, CEA levels ≤4.5 ng/ml, SUVmax < 2.5, tumors with a maximum diameter of ≤1 cm, or those confirmed to be adenocarcinoma in situ, minimally invasive adenocarcinoma, or invasive lepidic-predominant adenocarcinoma by frozen section may indicate segmentectomy. However, segmentectomy is not suitable for patients with metastasis to the N1 lymph nodes.

Prognostic significance of histologic classification and tumor disappearance rate by computed tomography in lung cancer.

We investigated the prognostic value of the International Association for the Study of Lung Cancer (IASLC)/American Thoracic Society (ATS)/European Respiratory Society (ERS) classification and assessed the relationship between pathologic invasiveness and tumor disappearance rate (TDR) in lung adenocarcinoma with ground-glass opacity (GGO). We reviewed data from 202 consecutive patients operated on between 2000 and 2009 for clinical T1-2N0 lung adenocarcinoma with GGO and reclassified their histologic subtypes according to the IASLC/ATS/ERS classification. Thirty-nine patients had adenocarcinoma in situ (AIS), 29 minimally invasive adenocarcinoma (MIA), 75 lepidic predominant invasive adenocarcinoma (LPA), and 59 non-lepidic predominant invasive adenocarcinoma (NLPA). Survival outcomes were compared according to histologic subtype and TDR. The mean age was 58 years and 101 patients (50%) were male. Lobectomy was performed in 161 patients (79.7%), wedge resection in 34 (16.8%), and segmentectomy in 7 (3.5%). Patients with AIS, MIA, and LPA had significantly smaller tumor sizes, earlier pathologic T stages, and lower incidences of lymphatic/pleural invasion than those with NLPA. The 5-year recurrence-free survival (RFS) rates were 95.1%, 94.5%, and 87.6% in the AIS + MIA, LPA, and NLPA groups, respectively (P=0.029). Tumors with a TDR>75% were associated with lepidic predominant histologic subtype and less pathologic invasiveness. The 5-year RFS rates were 97.4% in tumors with a TDR >75% and 87.8% in tumors with a TDR ≤75% (P=0.0009). Histologic subtype according to the IASLC/ATS/ERS classification and TDR both correlated with pathologic invasiveness and predicted survival in patients with lung adenocarcinoma with GGO.

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

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. 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. 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. Clinical T classification considering GGO component may offer more accurate prognosis for patients with lung cancer less than 3 cm in invasive diameter.

P3.13-036 Immunohistochemical and Genetic Characteristics of Lung Cancer Mimicking Organizing Pneumonia

Lung cancer mimicking organizing pneumonia (LCOP) is a novel radiological entity of lung adenocarcinoma that could be misdiagnosed as inflammatory lesions. However, the characteristic biological and genetic features of LCOP are not fully clarified. We used thin-section CT images to select cases of (LCOP) among surgically resected lung adenocarcinoma patients. We compared the clinicopathological characteristics and the immunophenotypes of LCOP (n = 44) and other lepidic-predominant adenocarcinomas (non-LCOP, n = 56). We also analyzed the genomic mutation features of LCOP (n = 4) by whole-exome sequencing (WES). All LCOP lesions were lepidic-predominant invasive adenocarcinoma. Patients with LCOP had significantly superior recurrence-free survival, compared to non-LCOP patients (95.5% and 74.4%; P = 0.006, respectively). Vascular invasion and lymph node metastasis were less frequent in LCOP than in non-LCOP patients (P = 0.001 and P = 0.03, respectively). The cancer cell expression levels of aggressiveness-related molecules, including ezrin, ALDH-1, laminin-5 were similar between LCOP and non-LCOP. On the contrary, the number of tumor promoting stromal cells, i.e., podoplanin-positive cancer-associated fibroblasts and CD204-positive tumor associated macrophages, was significantly lower in LOCP (P = 0.021 and P = 0.037, respectively). WES revealed that ABCB1, DNAH3, MSI2, and SLITRK2 were specifically mutated in LCOP. Our results indicate that LCOP is characterized by fewer tumor-promoting stromal cells, which may contribute to the better prognosis of LCOP patients. Moreover, recognition of specific somatic mutations of LCOP patients may provide information regarding the development and progression of this type of lung cancer.

Immunohistochemical and genetic characteristics of lung cancer mimicking organizing pneumonia

IntroductionLung cancer mimicking organizing pneumonia (LCOP) is a novel radiological entity of lung adenocarcinoma that could be misdiagnosed as inflammatory lesions. However, the characteristic biological and genetic features of LCOP are not fully clarified. Materials and methodsWe used thin-section CT images to select cases of (LCOP) among surgically resected lung adenocarcinoma patients. We compared the clinicopathological characteristics and the immunophenotypes of LCOP (n=44) and other lepidic-predominant adenocarcinomas (non-LCOP, n=56). We also analyzed the genomic mutation features of LCOP (n=4) by whole-exome sequencing (WES). ResultsAll LCOP lesions were lepidic-predominant invasive adenocarcinoma. Patients with LCOP had significantly superior recurrence-free survival, compared to non-LCOP patients (95.5% and 74.4%; P=0.006, respectively). Vascular invasion and lymph node metastasis were less frequent in LCOP than in non-LCOP patients (P=0.001 and P=0.03, respectively). The cancer cell expression levels of aggressiveness-related molecules, including ezrin, ALDH-1, laminin-5 were similar between LCOP and non-LCOP. On the contrary, the number of tumor promoting stromal cells, i.e., podoplanin-positive cancer-associated fibroblasts and CD204-positive tumor associated macrophages, was significantly lower in LOCP (P=0.021 and P=0.037, respectively). WES revealed that ABCB1, DNAH3, MSI2, and SLITRK2 were specifically mutated in LCOP. ConclusionsOur results indicate that LCOP is characterized by fewer tumor-promoting stromal cells, which may contribute to the better prognosis of LCOP patients. Moreover, recognition of specific somatic mutations of LCOP patients may provide information regarding the development and progression of this type of lung cancer.

Abstract 5921: Microenvironmental changes in the progression from adenocarcinoma in situ to early-invasive adenocarcinoma of the lung

Abstract Introduction: Lepidic predominant adenocarcinoma of the lung was classified into adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA) and invasive lepidic predominant adenocarcinoma (LPA) in current WHO classification, 4th edition. Furthermore, LPA is thought to progress in a stepwise fashion from AIS and MIA. However, those classifications were diagnosed by observation of pathologists based on morphology only. The aim of this study was to investigate the microenvironmental changes in the process of development from AIS, MIA to LPA, and subjective marker of stepwise progression. We have published a part of data in this study in Lung Cancer (100:53-62, 2016), and we believe that this study makes a contribution to elucidate the mechanism of development of LPA of the lung. Materials and Methods: Clinicopathological characteristics of AIS (n=51), MIA (n=59), LPA smaller than 3 cm (S-LPA, n=113), and LPA larger than 3 cm (L-LPA, n=47) were analyzed. We then immunohistochemically evaluated the expression levels of epithelial-mesenchymal transition (EMT)-related molecules (E-cadherin, S100A4), invasion-related molecules (laminin-5, ezrin), and growth factor receptors (EGFR) in cancer cells of each group (n=20). The number of tumor-promoting stromal cells, including podoplanin-positive cancer-associated fibroblasts (PDPN+ CAFs), CD204-positive tumor-associated macrophages (CD204+ TAMs), and CD34+ microvessel cells, were also analyzed. Results: LPA-S showed significantly frequent vascular and pleural invasion than MIA (p&amp;lt;0.05); however, no significant difference in those factors was found between S-LPA and L-LPA. Laminin-5 expression in the non-invasive component of MIA was significantly higher than that of AIS (p&amp;lt;0.001). During the progression from MIA to S-LPA, the expression level of laminin-5 in the invasive component was significantly elevated (p&amp;lt;0.01). Moreover, tumor-promoting stromal cells were more frequently recruited in the invasive area of LPA-S (PDPN+ CAFs; p&amp;lt;0.05, CD204+ TAMs; p&amp;lt;0.001, CD34+ microvessel; p&amp;lt;0.05). Ezrin expression in the invasive component of L-LPA was significantly increased (p&amp;lt;0.05) compared to S-LPA; however, the number of tumor- promoting stromal cells were not different between these two groups. Conclusion: Our current study indicated that microenvironmental molecular changes occur during the progression from MIA to S-LPA. Thus, it was suggested that this process may play an important role in disease progression from AIS to LPA of the lung. Citation Format: MASAHITO NAITO, Yukitoshi Satoh, Genichiro Ishii. Microenvironmental changes in the progression from adenocarcinoma in situ to early-invasive adenocarcinoma of the lung [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5921. doi:10.1158/1538-7445.AM2017-5921

Lepidic predominant adenocarcinoma and invasive mucinous adenocarcinoma of the lung exhibit specific mucin expression in relation with oncogenic drivers

ObjectivesTo evaluate MUC1, MUC2, MUC5B, MUC5AC, and MUC6 expression in invasive lepidic predominant adenocarcinoma (LPA) and invasive mucinous adenocarcinoma (IMA) of the lung, and the impact of oncogenic drivers. Materials and methodsMUC1, MUC2, MUC5B, MUC5AC, MUC6, TTF1 and Hnf4α immunohistochemistry was performed on surgical samples from 52 patients with IMA (n=25) or LPA (n=27). We searched for EGFR, KRAS, BRAF, and HER2 mutations and ALK, ROS1, and NRG1 rearrangements. ResultsMUC1, MUC2, MUC5B, MUC5AC, and MUC6 expression was detected in tumor cells in 77%, 2%, 63%, 36%, and 21% of cases, respectively. MUC1 was significantly more overexpressed in LPA. MUC5B, MUC5AC, and MUC6 were typically detected in goblet cells and overexpressed in IMA. Hnf4α-positive IMA (n=11) were TTF1-negative and typically did not expressed MUC1 and expressed MUC5AC and MUC6. Hnf4α-negative IMA (n=14) showed a reverse profile of mucins expression, with MUC1 expression and a lack of MUC5AC and MUC6 expression. EGFR-positive status was significantly associated with LPA, MUC1 expression, and no MUC5B, MUC5AC, or MUC6 expression. KRAS-positive status was significantly associated with IMA and MUC5B and MUC5AC expression. ConclusionsLPA and IMA exhibit specific mucin expression profiles, with MUC1 being associated with LPA, while MUC5B, MUC5AC, and MUC6 were associated with IMA. Hnf4α expression and EGFR and KRAS mutations may play a role in mucin expression profiles of these lung adenocarcinoma subtypes.

Correlation in histological subtypes with high resolution computed tomography signatures of early stage lung adenocarcinoma.

Uncertainty remains on the association between image characteristics of the nodules in computed tomography (CT) scans and lung adenocarcinoma histopathologic subtypes. We aimed to estimate the correlation between preoperative high resolution computed tomography (HRCT) scan and postoperative histopathology of stage IA lung adenocarcinoma in East Asian Chinese population. We retrospectively reviewed the clinical records and HRCT images of 190 patients (106 female and 84 male) with resected, preoperatively untreated stage IA adenocarcinomas. The relationship between image characteristics of nodules at preoperative HRCT and their histological subtypes after resection were analyzed. The one-way ANOVA, chi-square test and logistic regression were used for analysis. In 190 patients with stage IA lung adenocarcinoma, median tumor diameter was significantly lower in lepidic predominant invasive adenocarcinoma (LPA) (15.96±6.95 mm). Univariate analysis revealed that ground-glass opacity (GGO) proportion (P<0.001), margin (P<0.001), border definition (P=0.015), pleural retraction (P<0.001) and enhancement (P<0.001) had statistically significant differences in four histological subtypes. The multivariate analysis referenced for lepidic group which indicated that GGO proportion and pleural retraction were independent associated with acinar group (RR=4.221, 95% CI: 1.770-10.066, P=0.001; RR=0.380, 95% CI: 0.158-0.916, P=0.031, respectively). Male and whose nodule margin with spiculation or lobulation were prone to papillary predominant invasive adenocarcinoma (PPA) (RR=0.288, 95% CI: 0.090-0.920, P=0.036; RR=0.250, 95% CI: 0.070-0.887, P=0.032, respectively). GGO proportion and nodule margin were independent related factors in solid predominant invasive adenocarcinoma (SPA) (RR=13.338, 95% CI: 2.974-59.811, P=0.001; RR=0.097, 95% CI: 0.016-0.606, P=0.013, respectively). Nodules with spiculation or lobulation and less GGO proportion are determinants of histological subtypes with poor prognosis in stage IA lung adenocarcinoma patients according to the 2011 histologic IASLC/ATS/ERS classification.

Microenvironmental changes in the progression from adenocarcinoma in situ to minimally invasive adenocarcinoma and invasive lepidic predominant adenocarcinoma of the lung

ObjectivesInvasive lepidic predominant adenocarcinoma (LPA) of the lung is thought to progress in a stepwise fashion from adenocarcinoma in situ (AIS) and minimally invasive adenocarcinoma (MIA). The aim of this study was to investigate the microenvironmental changes during the development from AIS to LPA. Materials and methodsClinicopathological characteristics of AIS (n=51), MIA (n=59), LPA smaller than 3cm (LPA-S, n=113), and LPA larger than 3cm (LPA-L, n=47) were analyzed. We then evaluated the expression levels of epithelial-mesenchymal transition (EMT)-related molecules (E-cadherin, S100A4), invasion-related molecules (laminin-5, ezrin), stem-cell-related molecules (ALDH-1), and growth factor receptors (c-Met, EGFR) in cancer cells of each group (n=20). The number of tumor-promoting stromal cells, including podoplanin-positive cancer-associated fibroblasts (PDPN+ CAFs), CD204-positive tumor-associated macrophages (CD204+ TAMs), and CD34+ microvessel cells, were also analyzed. ResultsNo significant difference in these characteristics was found between LPA-S and LPA-L. Laminin-5 expression in the non-invasive carcinoma component of MIA was significantly higher than that of AIS (p<0.001). During the progression from MIA to LPA-S, the expression level of laminin-5 in the invasive carcinoma component was significantly elevated (p<0.01). Moreover, tumor-promoting stromal cells were more frequently recruited in the invasive area of LPA-S (PDPN+ CAFs; p<0.05, CD204+ TAMs; p<0.001, CD34+ microvessel; p<0.05). Ezrin expression in the invasive carcinoma component of LPA-L was significantly increased (p<0.05) compared to LPA-S; however, the number of tumor-promoting stromal cells were not different between these two groups. ConclusionOur current results indicated that microenvironmental molecular changes occur during the progression from MIA to LPA-S and suggested that this process may play an important role in disease progression from AIS to LPA.

Impact of smoking on outcome of resected lung adenocarcinoma.

Smoking is a well-known causative factor of lung cancer and the association of smoking with adenocarcinoma is considered to be the weakest. We investigated the influence of smoking on postoperative prognosis in patients with lung adenocarcinoma. One hundred and eighty-one consecutive patients of resected lung adenocarcinoma were studied retrospectively. The histologic subtype was subdivided into 2 groups: lepidic dominant histologic subtype, including adenocarcinoma in situ, minimally invasive adenocarcinoma, and lepidic predominant invasive adenocarcinoma versus other subtypes. The 5-year survival of ever smokers was significantly unfavorable than that of never smokers. Similarly, there was also a relationship between the patients' survival and Brinkman index (BI), with unfavorable survival found in patients with greater smoking histories. Based on a multivariable analysis, pN status and BI were significant factors affecting the postoperative prognosis of patients undergoing surgery. However, gender, serum carcinoembryonic antigen (CEA) level, lepidic dominant histologic subtype and pure/mixed ground-glass opacity (GGO) were not prognostic factors although previous reports showed prognostic significance. These factors that we failed to find the prognostic significance were significantly associated with smoking. The smoking was significantly predictive of an unfavorable prognosis after surgery for lung adenocarcinoma. It is suggested that smoking is associated with serum CEA level, histologic subtype and GGO, resulting in unfavorable outcome.

A proteomic profiling of laser-microdissected lung adenocarcinoma cells of early lepidic-types.

BackgroundIn the new pathologic classification of lung adenocarcinoma proposed by IASLC/ATS/ERS in 2011, lepidic type adenocarcinomas are constituted by three subtypes; adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA) and lepidic predominant invasive adenocarcinoma (LPIA). Although these subtypes are speculated to show sequential progression from preinvasive lesion to invasive lung cancer, changes of protein expressions during these processes have not been fully studied yet. This study aims to glimpse a proteomic view of the early lepidic type lung adenocarcinomas.MethodsA total of nine formalin-fixed and paraffin-embedded (FFPE) lepidic type lung adenocarcinoma tissues were selected from our archives, three tissues each in AIS, MIA and LPIA. The tumor and peripheral non-tumor cells in these FFPE tissues were collected with laser microdissection (LMD). Using liquid chromatography-tandem mass spectrometry (MS/MS), protein compositions were compared with respect to the peptide separation profiles among tumors collected from three types of tissues, AIS, MIA and LPIA. Proteins identified were semi-quantified by spectral counting-based or identification-based approach, and statistical evaluation was performed by pairwise G-tests.ResultsA total of 840 proteins were identified. Spectral counting-based semi-quantitative comparisons of all identified proteins through AIS to LPIA have revealed that the protein expression profile of LPIA was significantly differentiated from other subtypes. 70 proteins including HPX, CTTN, CDH1, EGFR, MUC1 were found as LPIA-type marker candidates, 15 protein candidates for MIA-type marker included CRABP2, LMO7, and RNPEP, and 26 protein candidates for AIS-type marker included LTA4H and SOD2. The STRING gene set enrichment resulted from the protein-protein interaction (PPI) network analysis suggested that AIS was rather associated with pathways of focal adhesion, adherens junction, tight junction, that MIA had a strong association predominantly with pathways of proteoglycans in cancer and with PI3K-Akt. In contrast, LPIA was associated broadly with numerous tumor-progression pathways including ErbB, Ras, Rap1 and HIF-1 signalings.ConclusionsThe proteomic profiles obtained in this study demonstrated the technical feasibility to elucidate protein candidates differentially expressed in FFPE tissues of LPIA. Our results may provide candidates of disease-oriented proteins which may be related to mechanisms of the early-stage progression of lung adenocarcinoma.Electronic supplementary materialThe online version of this article (doi:10.1186/s40169-015-0064-3) contains supplementary material, which is available to authorized users.

Correlation between Serum Carcinoembryonic Antigen Level and Histologic Subtype in Resected Lung Adenocarcinoma.

Recent studies revealed a relationship between ground-glass opacity (GGO) ratio on computed tomography (CT) and serum carcinoembryonic antigen (CEA) level in lung adenocarcinoma. Since an association between lepidic histologic pattern and GGO is well accepted, we investigated the link between histologic subtype and serum CEA level in resected lung adenocarcinoma. One hundred and eighty-one consecutive patients with resected lung adenocarcinoma were studied retrospectively. The histologic subtype was subdivided into 2 groups: lepidic dominant histologic subtype, including adenocarcinoma in situ, minimally invasive adenocarcinoma and lepidic predominant invasive adenocarcinoma versus other subtypes. The 5-year survival of patients with s high serum CEA level was significantly more unfavorable than that with normal levels. Similarly, there was also a relationship between the patient survival and histologic subtype, with favorable survival found in patients with the lepidic dominant histologic subtype. There was a significant relationship between serum CEA level and lepidic dominant histologic subtype overall and in p-stage I patients. Lung adenocarcinomas with non-lepidic dominant histologic subtype are associated with high serum CEA levels.

Comparison of Malignant Grade Between Pure and Partially Invasive Types of Early Lung Adenocarcinoma

The present study investigates the malignant significance of lepidic component presence in predominantly invasive lung adenocarcinoma that comprise less than 50% lepidic growth of the tumor. Among 347 consecutive patients with completely resected clinical stage IA lung adenocarcinoma, we excluded those with adenocarcinoma in situ, minimally invasive, and lepidic predominant invasive adenocarcinoma. We finally assessed 167 patients with predominantly invasive lung adenocarcinoma. We analyzed the clinicopathologic characteristics and prognoses of patients with 49 pure invasive tumors without lepidic growth and 118 partially invasive tumors with lepidic growth. Pure invasive tumors were associated with being male, small tumor size, high maximum standardized uptake, and pleural as well as lymphatic invasion. Nonetheless, the invasive component size of both tumor types was similar. The predominant subtypes of pure andpartially invasive tumors, respectively, were papillary, 17 (34.7%) and 53 (44.9%); acinar, 10 (20.4%) and 51 (43.2%); solid, 19 (38.8%) and 11 (9.3%), and micropapillary 3 (6.1%) and 3 (2.5%; p < 0.001). Recurrence-free survival was significantly worse for patients with pure, compared with partially, invasive tumors (p= 0.045). Among predominantly invasive stage IA lung adenocarcinomas, the malignant potential was higher for pure invasive tumors, and the prognosis was poorer than for partially invasive tumors when the invasive components were of equal sizes. The presence or absence of a lepidic component reflects a difference in subtype predominance and can help to decide the malignant grade of lung adenocarcinoma.

EGFR L858R mutation is associated with lung adenocarcinoma patients with dominant ground-glass opacity.

To retrospectively identify quantitative computed tomographic (CT) features that correlate with the three major driver gene mutations in surgically resected lung adenocarcinomas with dominant ground-glass opacity (GGO) stratified by the International Association for the Study of Lung Cancer (IASLC), American Thoracic Society (ATS), and European Respiratory Society (ERS) classification in a Chinese cohort of patients. Surgically resected lung adenocarcinomas from Shanghai Pulmonary Hospital were enrolled. EGFR, KRAS and EML4-ALK mutations were detected by qPCR. Clinical and pathological characteristics including gender, age, TNM stage, smoking status and CT pattern were analyzed. Histologic subtype was classified according to IASLC/ATS/ERS classification. At preoperative chest CT, the percentage of GGO volume, diameter, solid volume and total tumor volume of each tumor were measured by using a semiautomated algorithm. Distribution of driver gene mutations was evaluated by using the Fisher exact test, the Student's t test, and Pearson correlation analysis. 788 in total and 158 GGO tumors were taken in this cohort. GGO pattern occurred at a significantly higher frequency in younger, female and non-smoking patients. EGFR/KRAS mutations and EML4-ALK fusions were similar between GGO and solid adenocarcinomas. GGO volume and diameter showed correlation with EGFR mutation. With regard to association between lung adenocarcinoma histological subtypes and GGO features, GGO proportion was significantly higher in lepidic predominant adenocarcinomas, including adenocarcinoma in situ, minimally invasive adenocarcinoma, and lepidic predominant invasive adenocarcinoma. No significant differences of driver gene mutations were found between subtypes of lung adenocarcinoma. It is important that we understand GGO lesions of lung adenocarcinoma to identify molecular biomarkers including EGFR, KRAS and EML4-ALK. These markers would offer useful information for determining the appropriate strategy to treat lung adenocarcinoma with GGO lesions detected by helical CT.

Ground-Glass Nodule on Thin-Section CT: Differentiation among AdenocarcinomaIn Situ, Minimally Invasive Adenocarcinoma and Lepidic Predominant Invasive Adenocarcinoma

Poster: ECR 2014 / C-0423 / Nodular ground glass opacities on thin-section CT: differentiation among in situ, minimally invasive and lepidic predominant invasive adenocarcinoma by: M. H. Lee1, D. S. Ryu2, D. Y. Kim3, S.-J. Choi2, J.-H. Ahn2, D. G. Yoo1, J. Jo2, K. Gilhyun4, D. R. Shin2; 1Gangneung/KR, 2Gangneung-si/KR, 3Gangneung-si, Gangwon-do/KR, 4Gangnung/KR

Prognostic Significance of Adenocarcinoma In Situ, Minimally Invasive Adenocarcinoma, and Nonmucinous Lepidic Predominant Invasive Adenocarcinoma of the Lung in Patients With Stage I Disease

According to the IASLC/ATS/ERS classification, the lepidic predominant pattern consists of 3 subtypes: adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA), and nonmucinous lepidic predominant invasive adenocarcinoma. We reviewed tumor slides from 1038 patients with stage I lung adenocarcinoma, recording the percentage of each histologic pattern and measuring the invasive tumor size. Tumors were classified according to the IASLC/ATS/ERS classification: 2 were AIS, 34 MIA, and 103 lepidic predominant invasive. Cumulative incidence of recurrence (CIR) was used to estimate the probability of recurrence. Patients with AIS and MIA experienced no recurrences. Patients with lepidic predominant invasive tumors had a lower risk for recurrence (5-y CIR, 8%) than nonlepidic predominant tumors (n=899; 19%; P=0.003). Patients with >50% lepidic pattern tumors experienced no recurrences (n=84), those with >10% to 50% lepidic pattern tumors had an intermediate risk for recurrence (n=344; 5-y CIR, 12%), and those with ≤10% lepidic pattern tumors had the highest risk (n=610; 22%; P<0.001). CIR was lower for patients with ≤2 cm tumors than for those with >2 to 3 cm tumors (for both total and invasive tumor size), with the difference more pronounced for invasive tumor size (5-y CIR, 13% vs. 21% [total size; P=0.022] and 12% vs. 27% [invasive size; P<0.001]). Most patients with lepidic predominant adenocarcinoma who experienced a recurrence had potential risk factors, including sublobar resection with close margins (≤0.5 cm; n=2), 20% to 30% micropapillary component (n=2), and lymphatic or vascular invasion (n=2). It therefore may be possible to identify lepidic predominant adenocarcinomas that carry a low or high risk for recurrence.