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Lung tumors: an overview

Written2004-02Jim Heighway, Daniel C Betticher
Institute of Medical Oncology, University of Bern, 3010 Bern, Switzerland (DCB)

(Note : for Links provided by Atlas : click)

Identity

ICD-Topo C340-C343,C348-C349 LUNG & BRONCHUS
Atlas_Id 5030
Phylum Lung, Heart, Skin, Other::Lung tumor
Note The overwhelming majority of lung tumours are carcinomas. Most commonly, they arise from the pseudo-stratified epithelial lining of the bronchial airways but they can also arise from the epithelia of the smaller terminal airways and alveoli. Worldwide, lung cancer is the most common cause of cancer-related death.

Classification

Note Lung cancer diagnosis and classification are currently based primarily on light microscopy, occasionally supplemented by immunohistochemical assays. The use of microarray generated data in the future is likely to radically improve disease sub-classification.
    Lung tumours are divided into two broad categories of
  • small cell carcinoma (SCLC 20-25% of cases) and
  • non-small cell lung cancer (NSCLC 70-80% of cases) based on clinical behaviour and histological appearance.
    Other rarer tumour types include
  • carcinoids (typical or atypical),
  • carcinosarcomas,
  • pulmonary blastomas,
  • giant and spindle cell carcinomas.

    NSCLC is further divided histologically into three main disease subtypes of:

  • squamous cell carcinoma,
  • adenocarcinoma and
  • large cell carcinoma.

    Whilst in certain countries, adenocarcinoma is now the most common disease subtype seen, in other countries, whilst the relative frequency of adenocarcinoma is rising, squamous cell carcinoma still predominates.

  • Clinics and Pathology

    Etiology The smoking of tobacco is the primary cause of lung cancer and patterns of occurrence are largely determined by historical exposure. In general, the contribution of genetic or other environmental factors to lung cancer risk is thought to be small but some may synergise with smoking. Such additional environmental factors include exposure to radon gas (an indoor environmental pollutant), workplace exposures to inorganic fibres (asbestos) or toxic chemical entities, air pollution and ionising radiation. As for many cancers, poor diet appears to be associated with increased disease risk.
    Epidemiology Smoking increases the risk of all histological subtypes but is most strongly associated with squamous cell and small cell disease. Adenocarcinoma is more common in women than in men and more common in non-smokers with disease than smokers. The number of cases attributable to tobacco smoking varies between countries and regions depending on the historical levels of smoking for those regions. A recent estimate for Europe suggested that 90% of male and 60% of female lung cancers were caused by exposure to cigarette smoke.

    The observation that perhaps only 1-2 of every 10 smokers develops clinical lung cancer during their lifetime has been used as an argument to suggest that some level of genetic predisposition modifies disease risk. Whilst this argument is perhaps not compelling, it is not unreasonable and indeed a small number of genetic polymorphisms have been associated with modest increases in lung cancer risk. As lung cancer is usually caused by a chronic exposure of the bronchial epithelium to multiple procarcinogenic (and carcinogenic) agents, it is not surprising that many of these polymorphisms lie in genes associated with the activation (cytochrome P450s) or deactivation (Glutathione S-transferases) of such entities or the repair of subsequently induced damage (TP53). In general, epidemiological analysis has not suggested the existence of highly-penetrant, strongly-predisposing lung cancer associated genetic variants.

    Clinics In the early stages of disease, lung cancer tends to be asymptomatic. Consequently, at the time of diagnosis, most tumours are overtly (stage IIIB, IV) or covertly metastatic. Resectable, localised, disease (stages I-IIIA) is identified in approximately 20% of patients. Generally advanced stage at diagnosis and the relative resistance of the disease to currently available anti-cancer drugs leads to a high mortality rate, with 5-year survival typically between 10 and 15%. The potential benefits and costs of CT screening for the detection of early, asymptomatic lung cancer are currently being evaluated in large randomised trials in several countries.
    Pathology Tumours are classified primarily on their cytological appearance. The relative frequency of subtypes varies in different regions and the figures cited therefore represent broad approximations. Clinically, the most important division is between SCLC and NSCLC. Small cell tumours metastasise very early in the course of the disease but are relatively responsive to chemotherapeutic drugs: they are therefore managed in a different way to non-small cell lesions. Lung cancers are generally heterogeneous, consisting frequently of cells of different histological subtypes. Pathological classifications therefore emphasise the major cell type present in the tissue analysed and may note significant minor components. When components are roughly equal, designations such as adenosquamous carcinoma may be used. This common intra-tumour heterogeneity has led to the suggestion that lung carcinomas arise from a multipotent stem cell-like (or stem cell) component of the bronchial epithelium. Whilst microarray analyses have shown that gene expression can be used effectively to subdivide disease into existing or novel subtypes, it has also highlighted the similarity that lies between these subtypes at the level of gene expression. Such observations are consistent with a common stem cell progenitor.

    NSCLC

  • Squamous cell lung carcinoma comprises approximately 30% of lung cancers. These tumours generally arise centrally within the lungs inside a large bronchus although they may sometimes be peripheral;
  • Adenocarcinomas, representing perhaps 30% of invasive lesions, tend to occur in more peripheral locations arising from the smaller airways but they can be found centrally in a main bronchus;
  • Large cell carcinomas, 10% of lung cancers, are undifferentiated tumours which lack the diagnostic features of the other subtypes. This is therefore to some extent a default classification, made when other specific histology has been excluded.

    SCLC

  • Small cell carcinomas account for 20% of lung cancers. They mostly arise centrally in a large bronchus and are highly invasive and highly metastatic.
  • Treatment Before the appropriate treatment can be defined a careful staging of the disease must be made. The principles of therapy of NSCLC and SCLC are different. SCLC is very seldom surgically resectable, usually widespread at presentation and is generally both more chemosensitive and radiosensitive.

    NSCLC: Treatment is based on the stage of the disease at presentation (which may be assessed by thoracic CT, PET scan, brain MRI). Stage I-II are usually resected (adjuvant chemotherapy can be discussed with the patient) and locally advanced stages (III) are treated by combined modality treatments (neoadjuvant chemotherapy, resection if stage IIIA or radiotherapy). If overt distant metastases are detected, therapy is palliative and chemotherapy has been shown to improve median survival and quality of life.

    SCLC: If the tumour is confined to one hemithorax (limited disease), a combined modality therapy (chemo- and radiotherapy) is indicated: in more advanced disease (overt distant metastases in brain, liver, bones, surrenal glands or other organs) chemotherapy will be palliative though an excellent remission might be obtained in more than half of the patients.

    New therapies based on an improved understanding of the molecular basis of the disease are currently in use or are under development. For example, Gefitinib, a tyrosine kinase inhibitor, is one such example that has been launched on the market in different countries for patients with relapsed or refractory NSCLC after chemotherapy. Further drugs with other defined molecular targets are anticipated.

    Prognosis Once a diagnosis of lung cancer has been made (biopsy, cytology) the disease is staged (I - IV) according to established international criteria. NSCLC patients are divided into different groups based on the TNM classification system. This is a combined grading incorporating tumour size and location (T), lymph node involvement (N) and presence of distant metastasis (M). In general, higher stage (both overall and within each category) correlates with a poorer prognosis with a 5-year survival of 60-70% for T1-2, N0, M0 (stage I) disease and <1% for TX, NX, M1 (stage IV) disease. SCLC is classified as limited (to one hemithorax) or extensive (with distant metastasis) disease with 3-year survival being 5-10% and <1%, respectively.

    Cytogenetics

    Note Lung tumours generally show complex karyotypic changes which involve multiple chromosomes. However, one of the most consistent alterations seen in both SCLC (approaching 100%) and NSCLC (approaching 90%) is a loss of coding potential from the short arm of chromosome 3. Loss of chromosome 3 sequence appears to occur frequently at the very earliest stages of neoplastic transformation, when epithelial cells may show no evidence of morphological alteration.

    Genes involved and Proteins

    Note The loss of p53 function, generally through mutation of the coding sequence is seen in the majority of lung carcinomas. Less dramatically, mutation of KRAS2 occurs in approximately 20% of NSCLC lesions and may indicate a poor prognosis when it is detected in small adenocarcinomas.

    Microarray analyses have shown that many other genes show dramatic differences in expression between lung tumours and normal lung tissue. These differences may be driven by tumour gene amplification, deletion, control region mutation or chromosomal translocation (all apparently relatively rare in primary disease) or perhaps more commonly, may be associated with changes in various types of epigenetic modification of the DNA sequence. The differential expressions may be disease-related in the sense that they are induced directly by DNA damage events in the tumour cell, or they may be only indirectly linked to the disease, in the sense that they are typical of the gene expression patterns of progenitor cells and atypical for the majority of normally differentiated lung cells.


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    Citation

    This paper should be referenced as such :
    Heighway, J ; Betticher, DC
    Lung tumors: an overview
    Atlas Genet Cytogenet Oncol Haematol. 2004;8(2):137-139.
    Free journal version : [ pdf ]   [ DOI ]
    On line version : http://AtlasGeneticsOncology.org/Tumors/LungTumOverviewID5030.html


    Other genes implicated (Data extracted from papers in the Atlas) [ 446 ]

    Genes AAMP ABCC11 ABL1 ACLY ACTN4 ACVRL1 ADAM23 ADAM9 ADAMTS12
    ADAMTS1 ADAMTS9 ADCYAP1 KNL1 AFAP1L2 AFP AGER AKAP12 AKT1 AKT2
    AMFR ANG ANLN APAF1 AREG ARID1A ASCL1 ATF2 ATF2 ATF3
    ATP2B4 ATP5B ATR AURKB AXIN1 AXIN2 AXL BAG1 BARD1 BAX
    BCAR1 CCND1 CCND1 BCL2L14 BCL2L1 BIN1 BIRC2 BMP4 BNIP3L BABAM2
    BUB1 TIGAR CALR CAPG CASP7 CASP9 CAV1 CBFA2T3 CCNA1 CD200
    CD44 CD59 CD82 CD9 CDC25A CDC25A CDC42 CDCP1 CDH13 CDH1
    CDK4 CDT1 CEBPA CENPW AGAP2 CHD5 CHD6 CHEK2 CHFR CHFR
    CHKA CKS1B CKS2 COPS2 CPEB4 CPM CRK CRTC2 CSE1L CST6
    CSTA CSTB CTCF CTDSPL CTHRC1 CTNND1 CTSB CTSH CXCL10 CXCL12
    CXCL17 CXCL5 CYP2A6 CYP2W1 CYP4B1 CYR61 DAPK1 DDC DDIT4 DDR1
    DGKA DIABLO DKK3 DLC1 DLX2 DLX5 DLX6 DMBT1 DMTF1
    DNAJA3 DNMT3A DNMT3B DOCK1 DPP4 DVL1 DYRK1A EBAG9 ECT2 EEF1A1
    EEF1A2 EFEMP1 EGR1 EHMT2 EIF2AK2 EIF3A EIF4E ELAVL1 ENOX2 EPB41L3
    EPHA2 EPHA3 ERBB2 ERBB3 ERCC1 ERGIC3 ERRFI1 ETS1 ETV4 EZH2
    FAM107A FAM57A FBLN5 FBXO11 FBXO31 FEN1 FGF2 FGFR1 FGFR2 FGFR4
    FHIT FOSL1 FOXA1 FOXF1 FOXM1 FOXP1 FSCN1 FST FXYD3 GATA6
    GFI1 GGH GPC5 GPRC5A GPX1 GREB1 GRPR GSTA1 GSTM1 HDAC2
    HDAC3 HGF HLA-G HMGA2 HMGA2 HMGN5 HNRNPD HNRNPK HSPA5 HSPA8
    HSPB1 HSPD1 HSPH1 HTATIP2 KAT5 HTRA1 HTRA3 HUS1 HYAL1 HYAL2
    IDO1 IGF2BP1 IGF2R IGFBP6 IL17A IL1RN IL22 IL23A IL7R ILK
    ING1 ING2 ING3 ING4 INPP4B INTS6 IRS1 IRS2 ITGA11 ITGA1
    ITGA9 KDR CCAR2 KIT KLF6 KLK10 KLK11 KLK5 KLK7 KLK8
    KPNB1 KRAS LATS1 LATS2 LDOC1 LIMD1 LIMK1 LOX LOXL2 LRP1B
    LZTS1 MAGEA3 MAP3K7 MAPK1 MAPK3 MCC MCM3 MEG3 MELK
    RIOX2 MIR100 MIR107 MIR126 MIR133B MIR135A1 MIR141 MIR143 MIR146B MIR150
    MIR183 MIR191 MIR200C MIR296 MIR331 MIR373 MIR449A MIR21 MIR221 MIR222
    MKI67 MMP14 MMP26 ABCC1 MSH6 MST1 MTA1 MTA3 MTHFR MUC4
    MUC6 MYC MYLK NAT1 NAT2 NDUFA13 NFATC2 NKX2-1 NME1
    NMT1 MYCN NNMT NOTCH2 NQO1 NR0B1 NR3C2 NR4A1 NTSR1 NUMB
    OPCML ORAI3 EP300 TP53 PAF1 PARVB PASD1 PAWR PAWR PDCD4
    PDCD5 PDCD6 PDSS2 PERP PFKFB3 PFKFB4 PIAS3 PIK3CA PIK3R1 PIMREG
    PIWIL1 PIWIL2 PKM PLAUR PLK1 PML PPARG PPP1R13L PPP1R9B PRDM2
    PRDX4 PRKCI PTGIS PTK2 PTMA PTN PTPRG PTPRJ PTTG1 PXN
    PYCARD RAD9A RAF1 RARRES1 RASSF1 RASSF5 RB1 RBL2 RBM5 REPS2
    RGS17 RHOA RHOB RHOBTB2 RHOBTB3 RND3 RNF7 ROBO1 MST1R RPRM
    RRM1 RRM2 S100A13 S100A1 S100A4 S100A8 S100A9 SASH1 SDC1 SEMA3B
    SEMA3F SELENOF SELENOP SELENOP SERPINB3 SERPINB5 SET SH3PXD2A SHC1 SIAH2
    STIL SIRT1 SLC16A1 SLC1A5 SLIT2 SLPI SMAD2 SMARCA4 SNCG
    SOX2 SOX4 SPARC SPP1 SRC SRSF1 SRSF3 SRXN1 SSX2
    MMP11 STARD13 STAT5B STEAP1 STK11 STMN1 STOML2 SULF1 SULF2 SYK
    TERF2 TET2 TFF3 TGFB1 TGFBI TGFBR2 TGFBR3 THRB TJP2 TMPRSS4
    TMSB10 TNC TNS4 TOPORS TP53BP2 TP63 TPD52 TPX2 TRIM27 TRIO
    TRO TWIST1 TXN UBE2C USP1 VAV3 VCAN VIP WWOX XRCC3
    YBX1 YPEL3 YPEL5 ZBTB33 ZBTB7A ZMYND10

    External links

    arrayMap Topo ( C34) arrayMap ((UZH-SIB Zurich)   [auto + random 100 samples .. if exist ]   [tabulated segments]
     
     
    Other databaseICGC Data Portal - [LUSC-KR] Lung Cancer - KR
    Other databaseICGC Data Portal - [LUSC-US] Lung Squamous Cell Carcinoma - TCGA, US
    Other databasecBioPortal: Lung Adenocarcinoma (Broad, Cell 2012)
    Other databasecBioPortal: Lung Adenocarcinoma (TCGA, Nature, in press)
    Other databasecBioPortal: Lung Adenocarcinoma (TCGA, Provisional)
    Other databasecBioPortal: Lung Adenocarcinoma (TSP, Nature 2008)
    Other databasecBioPortal: Lung Squamous Cell Carcinoma (TCGA, Nature 2012)
    Other databasecBioPortal: Lung Squamous Cell Carcinoma (TCGA, Provisional)
    Other databaseLung Cancer (My Cancer Genome)
    Other databaseLung adenocarcinoma ( intOGen )
    Other databaseLung adenocarcinoma ( intOGen )
    Other databaseLung squamous cell carcinoma ( intOGen )
    Other databaseLung Adenocarcinoma (TCGA)(OASIS Portal)
    Other databaseLung Squamous Cell Carcinoma (TCGA)(OASIS Portal)
    Other databaseLung Cancer Overview - Disease Synopsis [canSAR]
    Other databaseLung Adenocarcinoma [ Genomic Data Commons - NCI TCGA-LUAD]
    Other databaseLung Squamous Cell Carcinoma [ Genomic Data Commons - NCI TCGA-LUSC]
    Disease databaseLung tumors: an overview
    REVIEW articlesautomatic search in PubMed
    Last year articlesautomatic search in PubMed


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    indexed on : Sat Jun 17 12:10:34 CEST 2017


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