Moderator of

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  MS 25 - Lung Carcinogenesis (ID 43)

  • Event: WCLC 2015
  • Type: Mini Symposium
  • Track: Screening and Early Detection
  • Presentations: 5
  • Moderators:W.A. Franklin, H. Kato
  • Coordinates: 9/09/2015, 14:15 - 15:45, Mile High Ballroom 2a-3b

  • 15718

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    MS25.01 - Early Airway Disease (ID 1958)

    14:20 - 14:35  |  Author(s): S.M. Janes
    • Abstract
    • Presentation

    Abstract:
    In my talk I will report a prospective surveillance program, longitudinally following patients with pre-invasive disease over a 10 year period. It is the largest study of its kind and demonstrates unexpectedly high rates of both local progression to invasive cancer of high grade lesions and the development of synchronous tumours elsewhere in the lung. Further I will show data identifying both gene expression and epigenetic signatures predicting progression of these lesions. These signatures may provide the biomarker strategy we require to identify those patients with lesions at high risk of progression and therefore requiring treatment. Lung cancer accounts for more deaths than breast, prostate and colon cancers combined. Over three quarters of lung cancer patients are diagnosed at a late stage when curative treatment is not possible. Initiatives are underway to detect lung cancer earlier. CT screening of high risk smokers or ex smokers is proven to save lives through increased detection of largely early stage adenocarcinomas (1, 2). Meanwhile sputum cytometry and autofluorescence bronchoscopy of high risk individuals are under investigation as screening tools for the early detection of major airway squamous cell carcinomas in several studies. Squamous carcinogenesis is initiated by pre-invasive dysplastic lesions in the central airways and therefore lends itself to bronchoscopic evaluation. Bronchial dysplasia represents the earliest stages of what is traditionally thought to be a stepwise progression towards invasive disease commencing with squamous hyperplasia and metaplasia followed by mild, moderate, severe dysplasia (SD) and carcinoma-in-situ (CIS) with lesions possessing a greater mutational burden at each stage (WHO classification) (Figure 1). With progression of the lesion there are characteristic morphological changes and increasing cytological disarray. Initial changes affect only the basal epithelium, whilst ‘full thickness’ change is seen in the more advanced CIS. Once the basement membrane has been breached, invasive squamous cell carcinoma has developed. Figure 1 Our early findings, and those of others, have challenged this traditional stepwise model. With longitudinal follow up, few low grade dysplasia lesions (LGD: hyperplasia, metaplasia mild and moderate dysplasia) are seen to progress and largely remain indolent or often regress. High grade dysplasia lesions (HGD: SD and CIS) however, more frequently persist or progress to invasive disease. Bronchial dysplastic lesional destiny is unpredictable and despite research examining the genetic and epigenetic changes that occur, as yet no robust biomarker is able to determine which lesions will continue to progress to invasive disease. Low grade lesions rapidly progressing to cancer have been reported, and these rare lesions have been found to possess a high degree of chromosomal instability including DNA copy number alterations even at a metaplastic stage, seeming to confer a committed course to cancer development. It is likely that close analysis of these rare lesions and other high grade lesions that progress will lead to greater biological insight regarding key lung cancer driver mechanisms. Autofluorescence bronchoscopy (AFB) using blue-violet excitation light has made progress in facilitating not only the detection and delineation of extent of early stage invasive cancers in the airway but also the identification of precancerous central airway lesions that are generally missed on CT. AFB detection of precancerous lesions has been shown to have sensitivity exceeding that of white light bronchoscopy (WLB) alone. The sensitivity of combining AFB with WLB improves detection of bronchial premalignant and malignant lesions up to 96.8% versus 76.3% for WLB alone, whilst corresponding negative predictive values are 97.2% versus 83.1% (3). Treatment of precancerous lesions might be expected to lead to improved survival in those patients harboring them. However our lack of knowledge of the natural history of these lesions, the appearance of new lesions, the regular occurrence of separate lung primaries and the lack of interventional studies in this area leaves the role of early intervention (both surgical and local tissue sparing procedures) under dispute. Due to this poverty of knowledge, our strategy, in keeping with previously published studies, has been the surveillance of all grades of dysplasia. These include our own, initial observations that suggest a low rate of lesion progression but high synchronous invasive cancer occurrence (4, 5). This early experience indicates patients with preinvasive disease are at a globally high risk of developing lung cancer, although not necessarily from the lesion under observation and multiple lesions both centrally and peripherally commonly develop over time. Due to the shared risk factor of tobacco smoke exposure, patients often have significant respiratory and cardiovascular co-morbidity and radical treatment of preinvasive disease may lead to insufficient lung capacity to offer curative intervention to future invasive lung cancer. 1. NCCN Clinical Practise Guidelines in Oncology. Lung Cancer Screening. Version http://www.nccn.org/professionals/physician_gls/pdf/lung_screening.pdf 2. National Lung Screening Trial Research Team, Aberle DR, Berg CD, Black WC, Church TR, Fagerstrom RM, Galen B, Gareen IF, Gatsonis C, Goldin J, Gohagan JK, Hillman B, Jaffe C, Kramer BS, Lynch D, Marcus PM, Schnall M, Sullivan DC, Sullivan D, Zylak CJ. The National Lung Screening Trial: overview and study design.Radiology. 2011 Jan;258(1):243-53. 3. Hanibuchi M, Yano S, Nishioka Y, Miyoshi T, Kondo K, Uehara H, Sone S. Autofluorescence bronchoscopy, a novel modality for the early detection of bronchial premalignant and malignant lesions. J Med Invest. 2007 Aug;54(3-4):261-6. 4. George JP, Banerjee AK, Read CA, O'Sullivan C, Falzon M, Pezzella F, Nicholson AG, Shaw P, Laurent G, Rabbitts PH. Surveillance for the detection of early lung cancer in patients with bronchial dysplasia. Thorax. 2007 Jan;62(1):43-50. 5 Auerbach O, Stout AP, Hammond EC, et al. Changes in bronchial epithelium in relation to cigarette smoking and in relation to lung cancer. N Engl J Med 1961;265:255–67.
    
    
    
    

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  • 15719

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    MS25.02 - Transcriptional Profiling of Malignant Lesions (ID 1959)

    14:35 - 14:50  |  Author(s): B. Gomperts
    • Abstract
    • Presentation

    Abstract:
    Epithelial cancers are thought to arise in a stepwise fashion from premalignant lesions and removal of premalignant lesions in epithelia such as colon and cervix has made a major improvement in survival in these cancers. However, premalignant lesions of the airway epithelium are poorly understood and it is not even known whether they represent a true premalignant state. This is in large part because of the heterogeneity of premalignant lesions of the airway and the fact that most of them will spontaneously resolve, even in high-risk patients. Premalignant lesions are thought to arise because of aberrant repair after injury but our understanding of the biology of normal repair after injury of the airways is limited and thus we do not know what the mechanisms are that drive aberrant repair and even less what the mechanisms are that drive the development of invasive non-small cell lung cancer. In order to increase our understanding of premalignant lesions of the airway, we laser-microdissected representative cell populations along the purported squamous cell lung cancer pathological continuum of patient-matched normal basal cells, premalignant lesions, and tumor cells. We obtained sufficient mRNA to perform high throughput RNA-sequencing. We discovered transcriptomic changes and identified genomic pathways altered with initiation and progression of SCC within individual patients. We used immunofluorescent staining to confirm gene expression changes in premalignant lesions and tumor cells, including increased expression of SLC2A1, CEACAM5, and PTBP3 at the protein level and increased activation of MYC via nuclear translocation. Cytoband enrichment analysis revealed coordinated loss and gain of expression in chromosome 3p and 3q regions, respectively, during carcinogenesis. We also identified several pathways that were upregulated in a stepwise fashion with progression of lesions. One of the pathways found to be upregulated with stepwise progression was redox regulation. Low levels of Reactive Oxygen Species (ROS) are known to be critical for cell regulation, while high levels of ROS are toxic to cells. We found that airway basal stem cells have low levels of ROS at baseline, but injury results in an increase in ROS and this flux from low to higher levels of ROS mediates proliferation of the basal cells via signaling through ROS/Nrf2/Notch1. Perturbation of this pathway at the level of Nrf2 or Notch both in vitro and in vivo results in excessive proliferation of basal cells and the formation of premalignant lesions with hyperplasia and dysplasia of the repairing airway epithelium. Our results provide much needed information about the biology of airway epithelial repair, premalignant lesions and the molecular changes that occur during stepwise carcinogenesis of squamous cell lung cancer, and it highlights a novel approach for identifying some of the earliest molecular changes associated with initiation and progression of lung carcinogenesis within individual patients.
    
    

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  • 15720

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    MS25.03 - Peripheral Premalignancy (ID 1960)

    14:50 - 15:05  |  Author(s): M.S. Tsao
    • Abstract
    • Presentation
    • Slides

    Abstract:
    The recently published Fourth Edition of the WHO Classification of Tumours of the Lung[1] recognizes atypical adenomatous hyperplasia (AAH) and adenocarcinoma in situ (AIS) as pre-invasive or premalignant precursor lesions of invasive adenocarcinoma, which arises mostly in the periphery of the lung. In the previous (Third) Edition of WHO classification, AIS was classified as bronchiolo-alveolar carcinoma (BAC), one of the subtypes of malignant adenocarcinoma.[2,3] Reclassification of AIS into the preinvasive category represents a conceptual confirmation of its role in multi-stage pathogenesis of peripheral lung adenocarcinoma.[4-7] This is consistent with the histological hallmark of lack of invasion in AIS, and its association with 100% survival after surgical resection. The neoplastic nature of these lesions are supported at the molecular level with the identification of known genomic aberrations found in invasive lung adenocarcinoma.[8,9] AIS is characterized histologically by the lepidic proliferation of neoplastic epithelium along pre-existing alveolar structures and lacking stromal, vascular or pleural invasion (Figure 1). A majority of AIS is composed of non-mucinous neoplastic cells with Clara cell and/or type-2 pneumocyte phenotype. Mucinous AIS is rare. By definition, AIS is limited to tumors that is ≤ 3 cm in greatest diameter and by TNM classification, is classified a Tis. AIS commonly shows varying degree of stromal thickening by fibrosis and chronic inflammatory cell infiltrate, with some cases showing focal or central area of fibrosis or scar. Around these areas, entrapment of the tumor cells within architecturally distorted and thickened alveolar septa give rise to morphological appearances of invasion. This remains one of the areas of diagnostic difficulty in distinguishing AIS from minimally invasive adenocarcinoma (MIA). However, limited data suggests that MIA is also associated with 100% curability by surgical resection. A majority of AAH are identified incidentally during microscopic examination of non-cancerous lung of surgically resected adenocarcinoma (Figure 2). The reported incidence in lung adenocarcinoma cases may reach up to 30%, and the reported number of lesion can reach up to 40/case, depending on the extent of sampling. They are typically ≤ 5 mm, but size is not a diagnostic criteria for its diagnosis. Histologically it is characterized by slightly thickened alveolar septa that are lined by atypical appearing cuboidal to low columnar epithelial cells with gaps in between them. These cells have similar ultrastructural features as AIS cells, mainly those of type-2 pneumocyte and/or Clara cell. A spectrum of nuclear atypia may be observed but grading has not been recommended, as they have not been demonstrated as reproducible or correlated with neoplastic progression. AAH is considered a precursor of AIS, as they may harbor KRAS or EGFR mutations. In some cases, the histological distinction between AAH and AIS can be very challenging, even though both lesions are considered cured by surgical resection. Further deep genomic analyses of AAH and AIS can provide greater insights into the multistep molecular carcinogenesis of lung adenocarcinoma and potentially novel prevention strategies for this disease. References: 1. WHO Classification of Tumours of the Lung, Pleura, Thymus and Heart. Travis WD, Brambilla E, Burke AP, Marx A, Nicholson AG. IARC Press, Lyon, 2015, page 46-50. 2. World Health Organization International Histological Classification of Tumours. Histological Typing of Lung and Pleural Tumours. Travis WD, Colby TV, Corrin B, Shimosato Y, Brambilla E. Springer Verlag, Berlin, Heidelberg, New York, 1999, page 21-29. 3. WHO Classification of Tumours, Pathology and Genetics. Tumours of the Lung, Pleura, Thymus and Heart. Travis WD, Brambilla E, Muller-Hermelink HK,, Harris CC. IARC Press: Lyon 2004, page 35-44, 73-75. 4. Miller RR, Nelems B, Evans KG, Muller NL, Ostrow DN. Glandular neoplasia of the lung. Cancer 1988;61:1009-1015. 5. Kitamura H, Kameda Y, Ito T, Hayashi H. Atypical adenomatous hyperplasia of the lung. Implications for the pathogenesis of peripheral lung adenocarcinoma. Am J Clin Pathol 1999;111:610-22. 6. Mori M, Rao SK, Popper HH, Cagle PT, Fraire AE. Atypical adenomatous hyperplasia of the lung: A probably forerunner in the development of adenocarcinoma of the lung. Mod Pathol 2001;14:72-84. 7. Chapman AD, Kerr KM. The association between atypical adenomatous hyperplasia and primary lung cancer. Br J Cancer 2000;83:632-36. 8. Westra WH, Baas IO, Hruban RH, Askin FB, Wilson K, Offerhaus GJ, Slebos RJ. K-ras oncogene activation in atypical alveolar hyperplasias of the human lung. Cancer Res 1996;56:2224. 9. Sakamoto H, Shimizu J, Horio Y, Ueda R, Takahashi T, Mitsudomi T, Yatabe Y. Disproportionate representation of KRAS gene mutation in atypical adenomatous hyperplasia, but even distribution of EGFR gene mutation from preinvasive to invasive adenocarcinomas. J Pathol 2007;212:287-94. Figure 1. Adenocarcinoma in situ Figure 1 Figure 2. Atypical Adenomatous Hyperplasia. Figure 2
    
    
    
    
    
    

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  • 15721

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    MS25.04 - Molecular Pathology of Alveolar Premalignancy (ID 1961)

    15:05 - 15:20  |  Author(s): M. Noguchi
    • Abstract
    • Presentation
    • Slides

    Abstract:
    Adenocarcinoma in situ (AIS) of the lung has an extremely favorable prognosis. However, early but invasive adenocarcinoma (eIA) sometimes has a fatal outcome. We examined epigenetical and genetic abnormalities of very early adenocarcinoma and compared them to early but advanced adenocarcinoma. We had previously compared the expression profiles of AIS with those of eIA showing lymph node metastasis or a fatal outcome, and found that stratifin (SFN, 14-3-3 sigma) was a differentially expressed gene related to cell proliferation. Here, we performed an in vivo study to clarify the role of SFN in progression of lung adenocarcinoma. Suppression of SFN expression in A549 (a human lung adenocarcinoma cell line) by siSFN significantly reduced cell proliferation activity and the S-phase subpopulation. In vivo, tumor development or metastasis to the lung was reduced in shSFN-transfected A549 cells. Moreover, we generated SFN-transgenic mice (Tg-SPC-SFN[+/-]) showing lung-specific expression of human SFN under the control of a tissue-specific enhancer, the SPC promoter. We found that Tg-SPC-SFN[+/-] mice developed lung tumors at a significantly higher rate than control mice after administration of chemical carcinogen, NNK (Fig 1). Interestingly, several Tg-SPC-SFN+/- mice developed tumors without NNK. These tumor cells showed high hSFN expression. These results suggest that SFN facilitates lung tumor development and progression. SFN appears to be a novel oncogene with potential as a therapeutic target. Next, gnetic abnormality in early-stage lung adenocarcinoma was examined. Six in situ lung adenocarcinomas and nine small but invasive adenocarcinomas were examined by array-comparative genomic hybridization (array-CGH), and candidate genes of interest were screened. To examine gene abnormalities, 83 cases of various types of lung carcinoma were examined by quantitative real-time genomic PCR (qPCR) and immunohistochemistry (IHC). The results were then finally verified using another set of early-stage adenocarcinomas. Array-CGH demonstrated frequent amplification at chromosome 3q26, and among the 7 genes located in this region, we focused on the epithelial cell transforming sequence 2 (ECT2) oncogene, as ECT2 amplification was detected only in invasive adenocarcinoma, and not in in situ carcinoma. FISH and IHC analyses also detected amplification and overexpression of ECT2 in invasive adenocarcinoma (Fig 2), and this was correlated with both the Ki-67 labeling index and mitotic index. In addition, it was associated with disease-free survival and overall survival of patients with lung adenocarcinoma. These results were verified using another set of early-stage adenocarcinomas resected at another hospital. Abnormality of the ECT2 gene occurs at a relatively early stage of lung adenocarcinogenesis and would be applicable as a new biomarker for prognostication of patients with lung adenocarcinoma. Figure 1Figure 2
    
    
    
    
    
    

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  • 15722

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    MS25.05 - Premalignant Lesions: Cytokines and Microenvironment (ID 1962)

    15:20 - 15:35  |  Author(s): S.M. Dubinett
    • Abstract
    • Presentation

    Abstract not provided

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