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I. Linnoila

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    MTE 20 - Biology and Pathology of Neuroendocrine Cancers (Ticketed Session) (ID 72)

    • Event: WCLC 2015
    • Type: Meet the Expert (Ticketed Session)
    • Track: Small Cell Lung Cancer
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/08/2015, 07:00 - 08:00, 708+710+712
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      MTE20.02 - Biology and Pathology of Neuroendocrine Cancers: Small Cell Lung Cancer - Call for Action (ID 2006)

      07:00 - 08:00  |  Author(s): I. Linnoila

      • Abstract
      • Presentation
      • Slides

      Introduction: Small cell lung cancer (SCLC) is the most common and most virulent neuroendocrine (NE) carcinoma. For pathological and therapeutic reasons human lung cancers are traditionally divided into non-SCLCs (NSCLCs) and SCLCs which currently account for 10 – 15% of all lung cancers. While prognosis for all lung cancers is poor, it is dismal for SCLC with less than 5% for patients surviving for five years. As molecular characterization of NSCLCs is quickly taking hold in guiding personalized care of cancer patients, the approach to SCLC is still based on principles developed decades ago. There has been practically no improvement in survival for past thirty years. Following the 2013 congressional mandate demanding concentrated research focus on such recalcitrant cancers as SCLC and pancreatic cancer it will hopefully be changing. Epidemiology and Histology: SCLC is strongly associated with smoking history and commonly found both in women and men at their sixties. It is mostly a centrally located submucosal mass in major airways although peripheral tumors have been reported. At the time of diagnosis, most SCLCs have already metastasized. There are no known premalignant lesions. Histologically the tumors are characterized by sheets of poorly differentiated cells with finely granular chromatin pattern and inconspicuous nuclei, and scanty cytoplasm among other features. Mitoses (>10 per high power field), areas of necrosis and ‘Azzopardi effect’ are consistent with aggressive nature and high DNA content of the tumor. When SCLC is associated with any of the histologic types of NSCLC, it is called combined SCLC (1). Neuroendocrine (NE) Features and the Cell of Origin: Ultrastructurally SCLC is characterized by the presence of scattered dense core vesicles, a hall mark of endocrine differentiation. Functionally the cells reveal a variety of NE properties such as uptake and synthesis of bioactive amines, hormones and neuropeptides, the presence of neural receptors such as nicotinic acetylcholine receptors, antigens and ion channels with the neuron-like ability to conduct electric currents. Consequently, SCLCs may be associated with ectopic hormone secretion or paraneoplastic syndromes. In addition, airway epithelium harbors a rare cell type with similar properties that is only visible using special techniques such as electron microscopy or immunohistochemistry and called pulmonary NE cells (2). In normal lung they occur as solitary cells or innervated clusters called neuroepithelial bodies or NEBs. It has been commonly believed that the pulmonary NE cell is the precursor of SCLC although there has been no direct evidence. Recent studies applying sophisticated tracing techniques in transgenic mice support the hypothesis while still leaving open the question what happens in human lung (3). Spectrum of Neuroendocrine (NE) Differentiation in Lung Cancers: SCLC is the prototype of pulmonary NE cancers but up a third of all lung cancers may reveal a degree of NE differentiation. They range from well differentiated carcinoids and atypical carcinoids to less well differentiated SCLCs and large cell NE carcinomas (LCNECs) and finally to 10% of NSCLCs that show focal NE differentiation (NSCLC-NEs). Notably the cancers are molecularly, histogenetically, morphologically distinct entities and should be distinguished from SCLCs. Clinically SCLCs and LCNECs are high-grade NE tumors while NSCLC-NEs appear to be a more controversial entity. Molecular Pathology: SCLC presents a complex genomic landscape with a high number of mutations due to the toxic impact of tobacco smoke. The field is rapidly evolving. However, both Rb and p53 are almost invariably inactivated in SCLCs. Rb is altered in many human NE cancers regardless of the tissue of origin, while p53 mutations are common in NSCLCs. In contrast, SCLCs lack Ras mutations which are typical of many NSCLCs. Moreover, SCLCs may show overexpression or amplification of MYC genes. In addition, achaete-scute homolog 1 (ASCL1), a transcription factor required for proper development of pulmonary NE cells (2), is pivotal for the survival of a majority of SCLCs and as well as NSCLC with NE features (4). Accordingly, ASCL1 is a lineage-specific oncogene for SCLCs. Efforts to identify relevant pathways regulated by this gene as well as others that might provide molecular targets for treatments are ongoing on several fronts. Tools for Investigation: Because SCLC is routinely diagnosed mainly using small bronchial biopsies or needle aspiration cytology specimens prior to cytotoxic chemo- and radiotherapies there has been a chronic shortage of suitable material for molecular and biological research. Fortunately, there are many well characterized human SCLC cell lines available that quite accurately recapitulate both molecular and histopathological features of the primary tumors. More recently, a range of genetically engineered mouse models have been generated based on the conditional ablation of both Rb and p53 tumor suppressor genes with select other genetic alterations (5). In vivo models provide important material to investigate sequential evolution of SCLC including metastases, molecular profiling and preclinical studies (6). Summary and Conclusions: SCLC is a neuroendocrine (NE) carcinoma with dismal prognosis and no substantial improvements in therapies for several decades. While the identification of effective therapies remains a major challenge, advances in understanding the biology, improved molecular techniques and sophisticated animal models have opened up novel avenues for the development of targeted therapies. References: 1. Travis WD et al. (2004). Pathology and genetics of tumors of the lung, pleura, thymus and heart. Lyon: IARC Press. 2. Linnoila, R.I. (2006). Lab Invest 86, 425-44 3. Sutherland, K.D., Proost, N., Brouns, I., Adriaensen, D., Song, J.-Y., and Berns, A. (2011).Cancer Cell 19, 754–764. 4. Augustyn, A., Borromeo, M., Wang, T., Fujimoto, J., Shao, C., Dospoy, P.D., Lee, V., Tan, C., Sullivan, J.P., Larsen, J.E., Girard, L., Behrens, C., Wistuba, I.I., Xie, Y., Cobb, M.H., Gazdar, A.F., Johnson, J.E., Minna, J.D. (2014). Proc Natl Acad Sci U S A. 111 ,14788-93. 5. Gazdar, A.F., Savage, T.K., Johnson, J.E., Berns, A., Sage, J., Linnoila, R.I., MacPherson, D., McFadden, D.G., Farago, A., Jacks, T., Travis, W.D., Brambilla, E. (2015). J Thorac Oncol. 10, 553-64. 6. McFadden, D.G., Papagiannakopoulos, T., Taylor-Weiner, A., Stewart, C., Carter, S.L., Cibulskis, K., Bhutkar, A., McKenna, A., Dooley, A., Vernon, A.,et al. (2014). Cell 156, 1298–1311.

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