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Head and Neck: Epidermoid carcinoma

Written2002-05Hélène Blons
U490INSERM Toxicologie Moléculaire, 45 rue des Saints Pères, 75006 Paris, France

(Note : for Links provided by Atlas : click)

Identity

ICD-Topo C301,C310-C313,C318-C319,C030-C031,C039-C041,C048-C052,C058-C062,C068-C069,C129-C132,C138-C139,C320-C323,C328-C329,C000-C006,C008-C009,C300,C110-C113,C118-C119,C690-C691,C693,C695-C698,C090-C091,C098-C104,C108-C109,C140,C142,C148,C079-C081,C088-C089,C019-C024,C028-C029,C339 ACCESSORY, SINUSES, MIDDLE & INNER EAR / GUM, FLOOR OF MOUTH, & OTHER MOUTH / HYPOPHARYNX / LARYNX / LIP / NASAL CAVITY (INCLUDING NASAL CARTILAGE) / NASOPHARYNX / ORBIT & LACRIMAL GLAND, (EXCL. RETINA, EYE, NOS) / OROPHARNYX / PHARYNX / SALIVARY GLAND / TONGUE / TRACHEA
ICD-Morpho 8070/3 Squamous cell carcinoma, NOS
Atlas_Id 5090
Phylum Head and Neck: Squamous cell carcinoma

Clinics and Pathology

Disease Head and neck cancer as defined here includes the squamous cell carcinomas of the oral cavity, pharynx and larynx. This malignancy is an important public health problem worldwide with more than 500000 new cases diagnosed each year. Patients often present with advanced stage disease and despite combined therapy outcome remains poor. For early stage, patients can be at high risk for second primary when cured of their initial cancer which pose the main threat to survival.
Etiology The major risk factor for head and neck cancer is chronic exposure of epithelia to tobacco smoke and alcohol. Environmental factors such as wood and cement dusts as well as human papilloma virus type 16 and 18 (HPV) infection have been related to an increased risk of developing head and neck squamous cell carcinoma (HNSCC). Recent studies confirm that oropharyngeal tumors are often HPV-positive and compose a distinct clinical and pathological entity with less TP53 mutations and better prognosis as compared to HPV negative tumors. Epstein Barr Virus infection is related to nasopharyngeal SCC in south china and oral cavity tumors are frequent in betel chewers.
Epidemiology Both hereditary and environmental factors are implicated in head and neck carcinogenesis and their roles are difficult to separate. Several cancer prone syndromes are associated with a increased risk of head and neck cancer, including Lynch-II, Bloom syndrome, Fanconi anemia, ataxia telagiectasia and Li-fraumeni syndrome. But genetic susceptibility to head and neck cancer is more likely to be due to various degrees of DNA maintenance after exposure to tobacco carcinogens. Mutagen sensitivity tests, polymorphism in DNA repair enzymes or in carcinogens metabolizing enzymes supports the role of heredity in HNSCC. Among the polymorphism tested, GSTM1 and GSTT1 null phenotypes are associated with an increased risk of HNSCC. Concerning XRCC1, the Arg allele (Arg194Trp) and the Gln allele (Arg399Gln) are also linked to an increased risk of oral and pharyngeal cancers.
Pathology Head and neck cancer are usually diagnosed in men after 50, patients can present with one or more distinct localization (10-15% at diagnosis) and 25% will develop a second cancer within 5 years from diagnosis. Cancer can develop from leucoplakia, erythroplakia or apparently normal epithelium. Premalignant lesions showing abnormal DNA content are at high risk of transformation. Clinical prognosis factors counts, tumor size, node involvement and smoking habits. Tumor markers related to prognosis counts EGFR expression, cyclin D1 or cyclin E expression, serum soluble IL-2 receptor concentrations and loss of chromosome arm 18q.
Treatment First goal is locoregional control achieved by surgery or radiotherapy. For high staged tumors combined surgery+/-radiotherapy+/-chemotherapy can be used. New treatment strategies are in development. Adenovirus have been developed that restore TP53 or P16 activity or that selectively replicates in TP53 deficient cells. Agents that inhibits signal transduction as tyrosine kinase inhibitors are also under evaluation in HNSCC specially those targeting the EGF receptor.

Cytogenetics

Note Chromosomal abnormalities are very frequent in head and neck tumors leading to very complex caryotypes with more than 70% of tumors being aneuploïd. Although most chromosome arms can be targeted by loss or gain of fragments, cytogenetic studies, Comparative Genome Hybridization (CGH) studies and molecular genetics studies demonstrated the existence of recurrent alterations some of which are found early in carcinogenesis. Loss of chromosome arm 3p and/or 9p is found in over 80% of tumors, loss of 17p involves more than 50% of the cases these alterations are associated with early tumor development. Losses of 5q, 8p, 4q 10q or 13q are found in nearly 30% of tumors and loss of 11p in less than 20% these alterations are preferentially associated with tumor progression. Concerning fragments gain, amplification at 11q and 3q clearly participate in head and neck carcinogenesis and concern nearly 70% of the cases. 3q amplification is seen in early tumor development. Studies showed that patterns of chromosomal alterations can be associated with clinical parameters such as deletions at 10q25-q26 and 11p13-p14 that are significant for metastasizing carcinoma and amplification of 11q could be a bad prognosis factor.
Tumor proliferation is known to result from activation of growth promoting pathways and inhibition of growth downregulation pathways. Several chromosomal segments involved in head and neck carcinogenesis harbor genes implicated in growth regulation.
  • Tumor suppressor genes
  • Chromosome arm 3p: At least three regions have been identified at 3p 3p13-3p21, 3p21.3-3p23, 3p25. Four genes have been studied for the presence of inactivating mutations VHL, TGFbRII, FHIT and OGG1. Very few mutations have been found in TGFbRII and only abnormal transcripts were detected for FHIT leading to the conclusion that it is still unclear whether or not these genes are the targets of 3p deletions.
  • Chromosome arm 9p: CDNK2A (P16) is a cell cycle regulatory gene located at 9p that is down regulated in HNSCC through homozygous deletion or promoter hypermethylation.
  • Chromosome arm 17p: TP53 is mutated in over 60% of HNSCC there is a good correlation between mutation and LOH at 17p. In HNSCC 50% of TP53 mutations are nonsense, deletions, insertions or splice site junctions mutations and 50% are missense. It has been clearly demonstrated that smoke carcinogens have a causal role in the formation of TP53 mutations and that the prevalence is greater in heavy smoker patients. TP53 mutations could be an indicator of a bad response to neoadjuvant chemotherapy in HNSCC
  • Chromosome arm 18q: Loss of 18q is linked to bad prognosis in HNSCC. Genes SMAD2, SMAD4 and DCC do not seem to be the right targets. The delineation of a common region of loss at 18q22 did not allow the identification of a new tumor suppressor gene.
  • Chromosome arm 13q: No mutation in RB were identified in HNSCC
  • Chromosome arm 10q: No mutation in Oncogenes
  • Chromosome band 11q13: EMS1, FGF3, FGF4 et CCND1 are amplified in HNSCC
  • Chromosome arm 3q: The PIK3CA gene but not p63 is likely to be the target of 3q26-qter gain.
  • The Wnt, APC, bcatenin pathway: No mutation in the bcatenin gene in HNSCC
  • MAP kinase pathway: The only head and neck tumors with constitutive RAS activation are from Indian and Taiwanese patients that can harbor HRAS or KRAS mutation.
  • Epigenetic alteration in HNSCC: Genes can be inactivated by promoter hypermethylation, in head and neck cancer the phenomenon has been demonstrated for several genes including P16, MGMT and DAP-kinase. DAP-kinase is implicated in INFg mediated apoptosis and DAP-kinase promoter hypermethylation is related to advance stage tumors.
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    Citation

    This paper should be referenced as such :
    Blons, H
    Head, neck squamous cell carcinoma
    Atlas Genet Cytogenet Oncol Haematol. 2002;6(4):304-306.
    Free journal version : [ pdf ]   [ DOI ]
    On line version : http://AtlasGeneticsOncology.org/Tumors/HeadNeckSquamID5090.html


    Other genes implicated (Data extracted from papers in the Atlas) [ 94 ]

    Genes ACVRL1 ADAMTS15 ANLN BIRC2 BMP4 BRCA2 CASP8 CASP9 CBFA2T3 CCNA1
    CCNB1 CDC42 CEBPA CENPF COL16A1 CST6 CTCF CTDSPL CTSH CXCL5
    DCC DKK3 DNAJA3 ECM1 EIF4E ENG EPAS1 EPHA1 EPS8 FABP5
    FBXO31 FOSL1 FOXM1 FURIN FXYD5 GRPR H2AFX HGF HSPB1 HTRA2
    ILK ING1 ING3 ING4 KIAA1524 KLK10 LIMD1 LOX LOXL2 LOXL4
    MAL MAP3K7 MIR100 MIR107 MIR143 MIR200C MTUS1 NAT2 NGFR NME1
    NTSR1 PRDX1 PARVB PLAGL1 PLK1 PTGS2 PTK2 PTK6 RAC2 RHOA
    RHOBTB1 RHOBTB2 RHOC RPS27 S100A2 S100A7 SEMA4D SMAD4 SNAI1 SOCS1
    STAT3 SULF1 EPCAM TALDO1 TBX3 THBS1 THRB TNFAIP3 TP63
    TWIST2 VRK1 XRCC3 ZFP36L1

    External links

    arrayMap Topo ( C30,C31,C03,C4,C04,C5,C05,C6,C06,C12,C13,C32,C00,C11,C69,C09,C10,C14,C07,C8,C08,C01,C2,C02,C33) arrayMap ((UZH-SIB Zurich)   [auto + random 100 samples .. if exist ]   [tabulated segments]
     
     
    Other databaseTumor Portal - Broad Institute
    Other databaseHead and Neck squamous cell carcinoma (HNSC) TCGA Copy Number Portal
    Other databaseHead and neck squamous cell carcinoma ( intOGen )
    Other databaseHead and neck squamous cell carcinoma ( intOGen )
    Other databaseHead and Neck Carcinoma (TCGA)(OASIS Portal)
    Other databaseHead and Neck Squamous Cell Carcinoma [ Genomic Data Commons - NCI TCGA-HNSC]
    Disease databaseHead and Neck: Epidermoid carcinoma
    REVIEW articlesautomatic search in PubMed
    Last year articlesautomatic search in PubMed


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