Written | 2006-09 | Charlotte Jin, Yuesheng Jin |
Dept clinical Genetics, University Hospital, SE-221 85 Lund, Sweden |
Identity |
ICD-Topo | C320-C323,C328-C329 LARYNX |
ICD-Morpho | 8070/3 Squamous cell carcinoma, NOS |
Atlas_Id | 5367 |
Phylum | Head and Neck: Larynx::Squamous cell carcinoma |
WHO/OMS Classification | Head and Neck |
Classification |
Note | The larynx extends from the tip of the epiglottis to the inferior border of the cricoid cartilage. The vast majorities of malignant neoplasms of the larynx arise from the surface epithelium and are therefore classified as keratinizing or nonkeratinizing squamous cell carcinomas (SCC). Other rare malignant forms include verrucous carcinoma, adenocarcinoma, fibrosarcoma, and chondrosarcoma. |
Laryngeal carcinoma infiltrates locally in the mucosa and beneath the mucosa and can metastasize via the lymphatic system and the bloodstream. According to their anatomical localization, laryngeal carcinomas could be subdivided into: 1) supraglottic carcinomas, confined to the supraglottic space and spreading interiorly into the preepiglottic space. 2) glottic carcinomas, rarely spreading into the supraglottic area but rather into the subglottic space. 3) subglottic carcinomas, often showing an infiltrative growth pattern unrestricted by tissue barriers. |
Clinics and Pathology |
Epidemiology | Laryngeal carcinoma accounts for a small fraction of all human malignancies (less than 2%), but the incidence varies among geographically. Laryngeal SCC occurs most often in the sixth and seventh decades. Men are more frequently affected than women. The etiology is not well known, but exposure of the mucosa to a wide variety of ingested and inhaled exogenous carcinogenic agents, such as tobacco smoke, alcohol, and HPV infections greatly increases the risk of developing these tumors. Avoiding cigarettes and alcohol could prevent about 90% of laryngeal SCC. |
Pathology | Histopathologically, laryngeal SCC can further be classified into: well differentiated (more than 75% keratinization), moderately differentiated (25-75% keratinization), and poorly differentiated (<25% keratinization). Carcinoma of the supra- and subglottic larynx are more likely to be non-keratinizing and poorly differentiated, and, in general, they are often large at the time of diagnosis, and have a more aggressive behavior and tend to metastasize early (20-40% of the cases). In contrast, lesions of the true vocal cords are typically small when detected, and more often moderately to well differentiated, rarely metastasize, and tend to be associated with a better prognosis. |
Cytogenetics |
Note | Chromosome abnormalities 115 laryngeal carcinomas with clonal chromosome abnormalities have been reported. In general, the karyotypes are relatively complex with a nonrandom pattern of deleted and amplified chromosome segments. This is in line with the notion that laryngeal carcinoma, like most other malignancies, develops through the accumulation of multiple genetic changes. The chromosomes most frequently involved in structural rearrangements are chromosomes 1, 2, 3, 4, 5, 7, 8, 11, 12, and 15, with breakpoints clustering to the pericentromeric regions, i.e., the centromeric bands p10 and q10 and the juxtacentromeric bands p11 and q11, accounting for 43% of the total breakpoints. The most common imbalances brought about by numerical and unbalanced structural rearrangements are loss of chromosomal region 3p21-pter, part of or the entire chromosome arms 4p, 6q, 8p, 10p, 13p, 14p, 15p, and 17p, and gain of chromosomal regions 3q21-ter, 7q31-pter, and 8q. A total of 17 recurrent structural aberrations, mostly in the form of whole-arm translocations, isochromosomes (i), and deletions (del), have been identified. The most common among them were i(8q), i(3q), i(5p), del(3)(p11), and homogeneously staining regions (hsr), a cytogenetically detectable sign of gene amplification, in band 11q13. A subgroup of laryngeal SCC have had multiple, unrelated abnormal clones, with simple, often balanced structural rearrangements or numerical changes. These clones have always had near-diploid chromosome numbers. The finding of such cytogenetic polyclonality could be interpreted as evidence of field cancerizationbut it cannot be ruled out that the cytogenetically unrelated clones are united by a submicroscopic, pathogenetic mutation; the cytogenetic differences would then only reflect differences in clonal evolution. The third alternative is that some of the near-diploid clones actually represent preneoplastic lesions or genetically damaged, nonneoplastic epithelial or stromal cells in the tumor surrounding. Fluorescence in situ hybridization (FISH) Genetic imbalances revealed by CGH, allelotyping, and LOH studies |
Cytogenetics Morphological | Functional studies of genes involved by chromosomal imbalances |
Cytogenetics Molecular | Tumor suppressor genes (TSG) Chromosomal arms 3p: Partial and entire loss of 3p is one of the most common changes in laryngeal SCC detected by various techniques. A number of TSG are localized in this chromosomal arm. Among them, only FHIT was investigated in laryngeal SCC and its precursor lesions. In a recent study, decreased expression of this gene, through deletion or promoter methylation was detected in about 42% of SCC and 23% of dysplasia lesions. Chromosome arm 8p: Loss of 8p has been mapped in detail with the use of microsatellite markers. However, no candidate TSG in this arm has so far been investigated in these neoplasms. Chromosome arm 9p: CDKN2A (also known as p16), localized at 9p21, has been extensively investigated in laryngeal SCC. Using various detection techniques, such as immunohistochemistry and RT-PCR, it was shown that loss of CDKN2A expression, through either homozygous deletion or promoter hypermethylation, were present in 52-82 % of HNSCC, including laryngeal SCC. Furthermore, a number of studies have shown that the decreased expression of this gene was associated with poor survival in patients with laryngeal SCC. Chromosomal arm 13q: Allelic loss of the RB1 gene, mapped to 13q14, is frequent in laryngeal SCC. Expression analysis of RB1 has yielded inconsistent results, and the role of RB1 inactivation in laryngeal SCC has not been clearly established. Chromosome arm 17p: TP53 mutation and the alteration of its protein have been extensively studied in laryngeal SCC. These studies suggest that TP53 mutations occur early in the neoplastic transformation of these tumors. Furthermore, a significant correlation between expression of mutated TP53 and clinical outcome has been shown in patients with laryngeal SCC; overexpression of mutated TP53 predicts poor disease-free and overall survival rates. Oncogenes Chromosomal band 11q13: The pathogenetic importance of 11q13 rearrangements is supported by extensive molecular studies showing that genomic amplification of several loci within this band, including oncogenes CCND1, FGF3, FGF4, and EMS1, is found in up to 30% of primary HNSCC including laryngeal SCC. Among the genes in the amplicon, CCND1 appears to be the prime target as its overexpression has been demonstrated by various molecular techniques in about 15-60% percent of primary HNSCC. Interestingly, a recent study has shown that Cyclin D1 overexpression alone can induce extension of the replicate life span of normal keratinocytes, and the combination of cyclin D1 overexpression and TP53 inactivation led to their immortalization. Several attempts have been made to correlate cytogenetic or molecular genetic data with clinical outcome in laryngeal carcinoma patients, and it has been shown that 11q13 rearrangements and amplification/overexpression of CCND1 are associated with a poor prognosis. Chromosome arm 7p: Overrepresentation of partial or entire chromosome 7 has been a common finding in HNSCC and laryngeal SCC. Epidermal growth factor receptor EGFR and the insulin like growth factors IGFB1 and IGFB2 are three potentially interesting genes located in the 7p13-22 region. The EGFR gene has been extensively investigated in HNSCC and laryngeal SCC and their precursor lesions. The results of these studies suggest that amplification and/or overexpression of EGFR gene occurs in the relatively early stage of the development of HNSCC and a high level of EGFR gene accumulation probably plays an important role in the progression to invasive cancer. Furthermore, overexpression of this gene has been significantly associated with short disease-free and overall survival in HNSCC and laryngeal SCC patients. Chromosome 8q: Partial or entire gain of 8q through the formation of isochromosome i(8q) and unbalanced structural rearrangements is one of the most common structural changes in laryngeal SCC. Several genes of interest, such as MYC and PTK2, are localized at 8q23-24. In a number of recent studies using FISH, tissue microarray and immunohistochemistry, a high frequency (30-68%) of MYC gain/amplification and overexpression has been observed in laryngeal SCC. |
Bibliography |
Chromosomal abnormalities involving 11q13 are associated with poor prognosis in patients with squamous cell carcinoma of the head and neck. |
Akervall JA, Jin Y, Wennerberg JP, Zätterström UK, Kjellén E, Mertens F, Willén R, Mandahl N, Heim S, Mitelman F |
Cancer. 1995 ; 76 (5) : 853-859. |
PMID 8625189 |
Epidermal growth factor receptor expression in primary laryngeal cancer: an independent prognostic factor of neck node relapse. |
Almadori G, Cadoni G, Galli J, Ferrandina G, Scambia G, Exarchakos G, Paludetti G, Ottaviani F |
International journal of cancer. Journal international du cancer. 1999 ; 84 (2) : 188-191. |
PMID 10096253 |
Proliferative verrucous leukoplakia: unusual locations of oral squamous cell carcinomas, and field cancerization as shown by the appearance of multiple OSCCs. |
Bagán JV, Murillo J, Poveda R, Gavaldá C, Jiménez Y, Scully C |
Oral oncology. 2004 ; 40 (4) : 440-443. |
PMID 14969824 |
Prognostic significance of p16INK4a alterations and 9p21 loss of heterozygosity in locally advanced laryngeal squamous cell carcinoma. |
Bazan V, Zanna I, Migliavacca M, Sanz-Casla MT, Maestro ML, Corsale S, Macaluso M, Dardanoni G, Restivo S, Quintela PL, Bernaldez R, Salerno S, Morello V, Tomasino RM, Gebbia N, Russo A |
Journal of cellular physiology. 2002 ; 192 (3) : 286-293. |
PMID 12124774 |
A genetic explanation of Slaughter's concept of field cancerization: evidence and clinical implications. |
Braakhuis BJ, Tabor MP, Kummer JA, Leemans CR, Brakenhoff RH |
Cancer research. 2003 ; 63 (8) : 1727-1730. |
PMID 12702551 |
Longitudinal study of smoking patterns in relation to the development of smoking-related secondary primary tumors in patients with upper aerodigestive tract malignancies. |
Do KA, Johnson MM, Lee JJ, Wu XF, Dong Q, Hong WK, Khuri FR, Spitz MR |
Cancer. 2004 ; 101 (12) : 2837-2842. |
PMID 15536619 |
Retinoblastoma protein expression and prognosis in laryngeal cancer. |
Dokiya F, Ueno K, Ma S, Eizuru Y, Furuta S, Ohyama M |
Acta oto-laryngologica. 1998 ; 118 (5) : 759-762. |
PMID 9840519 |
Avoidable cancers in the Nordic countries. Tobacco smoking. |
Dreyer L, Winther JF, Pukkala E, Andersen A |
APMIS. Supplementum. 1997 ; 76 : 9-47. |
PMID 9462818 |
Type of alcoholic beverage and the risk of laryngeal cancer. |
Garavello W, Bosetti C, Gallus S, Maso LD, Negri E, Franceschi S, La Vecchia C |
European journal of cancer prevention : the official journal of the European Cancer Prevention Organisation (ECP). 2006 ; 15 (1) : 69-73. |
PMID 16374233 |
Detailed gene expression analysis but not microsatellite marker analysis of 9p21 reveals differential defects in the INK4a gene locus in the majority of head and neck cancers. |
Grüttgen A, Reichenzeller M, Jünger M, Schlien S, Affolter A, Bosch FX |
The Journal of pathology. 2001 ; 194 (3) : 311-317. |
PMID 11439363 |
Genetic differences detected by comparative genomic hybridization in head and neck squamous cell carcinomas from different tumor sites: construction of oncogenetic trees for tumor progression. |
Huang Q, Yu GP, McCormick SA, Mo J, Datta B, Mahimkar M, Lazarus P, Schäffer AA, Desper R, Schantz SP |
Genes, chromosomes & cancer. 2002 ; 34 (2) : 224-233. |
PMID 11979556 |
High-resolution mapping of the 11q13 amplicon and identification of a gene, TAOS1, that is amplified and overexpressed in oral cancer cells. |
Huang X, Gollin SM, Raja S, Godfrey TE |
Proceedings of the National Academy of Sciences of the United States of America. 2002 ; 99 (17) : 11369-11374. |
PMID 12172009 |
PRAD-1/cyclin D1 gene amplification correlates with messenger RNA overexpression and tumor progression in human laryngeal carcinomas. |
Jares P, Fernández PL, Campo E, Nadal A, Bosch F, Aiza G, Nayach I, Traserra J, Cardesa A |
Cancer research. 1994 ; 54 (17) : 4813-4817. |
PMID 8062283 |
Disregulation of p16MTS1/CDK4I protein and mRNA expression is associated with gene alterations in squamous-cell carcinoma of the larynx. |
Jares P, Nadal A, Fernández PL, Pinyol M, Hernández L, Cazorla M, Hernández S, Beá S, Cardesa A, Campo E |
International journal of cancer. Journal international du cancer. 1999 ; 81 (5) : 705-711. |
PMID 10328220 |
International variation in the incidence of cancer of the upper digestive and respiratory tract. |
Jensen OM |
Advances in oto-rhino-laryngology. 1991 ; 46 : 124-133. |
PMID 1927711 |
Molecular cytogenetic characterization of the 11q13 amplicon in head and neck squamous cell carcinoma. |
Jin C, Jin Y, Gisselsson D, Wennerberg J, Wah TS, Strömbäck B, Kwong YL, Mertens F |
Cytogenetic and genome research. 2006 ; 115 (2) : 99-106. |
PMID 17065789 |
FISH characterization of head and neck carcinomas reveals that amplification of band 11q13 is associated with deletion of distal 11q. |
Jin Y, Höglund M, Jin C, Martins C, Wennerberg J, Akervall J, Mandahl N, Mitelman F, Mertens F |
Genes, chromosomes & cancer. 1998 ; 22 (4) : 312-320. |
PMID 9669669 |
Cytogenetic and fluorescence in situ hybridization characterization of chromosome 8 rearrangements in head and neck squamous cell carcinomas. |
Jin Y, Jin C, Wennerberg J, Höglund M, Mertens F |
Cancer genetics and cytogenetics. 2001 ; 130 (2) : 111-117. |
PMID 11675131 |
Nonrandom chromosome abnormalities in short-term cultured primary squamous cell carcinomas of the head and neck. |
Jin Y, Mertens F, Jin C, Akervall J, Wennerberg J, Gorunova L, Mandahl N, Heim S, Mitelman F |
Cancer research. 1995 ; 55 (14) : 3204-3210. |
PMID 7606742 |
Multiple clonal chromosome aberrations in squamous cell carcinomas of the larynx. |
Jin YS, Heim S, Mandahl N, Biörklund A, Wennerberg J, Mitelman F |
Cancer genetics and cytogenetics. 1990 ; 44 (2) : 209-216. |
PMID 2297681 |
Larynx cancer risk in relation to glutathione S-transferase M1 and T1 genotypes and tobacco smoking. |
Jourenkova N, Reinikainen M, Bouchardy C, Dayer P, Benhamou S, Hirvonen A |
Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. 1998 ; 7 (1) : 19-23. |
PMID 9456238 |
Tissue microarray analysis of C-MYC oncogene copy number changes in larynx carcinoma. |
Koynova DK, Tsenova VS, Toncheva DI |
ORL; journal for oto-rhino-laryngology and its related specialties. 2005 ; 67 (2) : 92-95. |
PMID 15821351 |
Expression of c-myc oncoprotein in laryngeal squamous cell carcinoma. |
Krecicki T, Fraczek M, Jelen M, Zatonski T, Szkudlarek T, Dus D |
Acta oto-laryngologica. 2004 ; 124 (5) : 634-637. |
PMID 15267185 |
DNA copy number losses are more frequent in primary larynx tumors with lymph node metastases than in tumors without metastases. |
Kujawski M, Aalto Y, Jaskula-Sztul R, Szyfter W, Szmeja Z, Szyfter K, Knuutila S |
Cancer genetics and cytogenetics. 1999 ; 114 (1) : 31-34. |
PMID 10526532 |
Chromosomal imbalance maps of malignant solid tumors: a cytogenetic survey of 3185 neoplasms. |
Mertens F, Johansson B, Höglund M, Mitelman F |
Cancer research. 1997 ; 57 (13) : 2765-2780. |
PMID 9205089 |
Overexpression of cyclin D1 indicates a poor prognosis in squamous cell carcinoma of the head and neck. |
Michalides RJ, van Veelen NM, Kristel PM, Hart AA, Loftus BM, Hilgers FJ, Balm AJ |
Archives of otolaryngology--head & neck surgery. 1997 ; 123 (5) : 497-502. |
PMID 9158396 |
Mitelman Database of Chromosome Aberrations in Cancer. |
Mitelman F, Johansson B, Mertens F eds, 2005 |
http.. |
Cyclin D1 amplification and p16(MTS1/CDK4I) deletion correlate with poor prognosis in head and neck tumors. |
Namazie A, Alavi S, Olopade OI, Pauletti G, Aghamohammadi N, Aghamohammadi M, Gornbein JA, Calcaterra TC, Slamon DJ, Wang MB, Srivatsan ES |
The Laryngoscope. 2002 ; 112 (3) : 472-481. |
PMID 12148857 |
Loss of heterozygosity at 8p, 9p and 17q in laryngeal cytological specimens. |
Rizos E, Sourvinos G, Spandidos DA |
Oral oncology. 1998 ; 34 (6) : 519-523. |
PMID 9930365 |
Loss of heterozygosity in laryngeal cancer. |
Rogowski M, Walenczak I, Pepiń'ski W, Skawroń'ska M, Sieśkiewicz A, Klatka J |
Roczniki Akademii Medycznej w Bialymstoku (1995). 2004 ; 49 : 262-264. |
PMID 15631354 |
Association between p53 gene mutations and tobacco and alcohol exposure in laryngeal squamous cell carcinoma. |
Ronchetti D, Neglia CB, Cesana BM, Carboni N, Neri A, Pruneri G, Pignataro L |
Archives of otolaryngology--head & neck surgery. 2004 ; 130 (3) : 303-306. |
PMID 15023836 |
TP53 mutations and S-phase fraction but not DNA-ploidy are independent prognostic indicators in laryngeal squamous cell carcinoma. |
Russo A, Corsale S, Agnese V, Macaluso M, Cascio S, Bruno L, Surmacz E, Dardanoni G, Valerio MR, Vieni S, Restivo S, Fulfaro F, Tomasino RM, Gebbia N, Bazan V |
Journal of cellular physiology. 2006 ; 206 (1) : 181-188. |
PMID 15965904 |
Field cancerization in oral stratified squamous epithelium; clinical implications of multicentric origin. |
SLAUGHTER DP, SOUTHWICK HW, SMEJKAL W |
Cancer. 1953 ; 6 (5) : 963-968. |
PMID 13094644 |
Localization of a putative tumor suppressor gene in the sub-telomeric region of chromosome 8p. |
Sunwoo JB, Sun PC, Gupta VK, Schmidt AP, El-Mofty S, Scholnick SB |
Oncogene. 1999 ; 18 (16) : 2651-2655. |
PMID 10353609 |
Molecular predictors of clinical outcome in patients with head and neck squamous cell carcinoma. |
Thomas GR, Nadiminti H, Regalado J |
International journal of experimental pathology. 2005 ; 86 (6) : 347-363. |
PMID 16309541 |
Molecular detection and typing of human papillomavirus in laryngeal carcinoma specimens. |
Torrente MC, Ampuero S, Abud M, Ojeda JM |
Acta oto-laryngologica. 2005 ; 125 (8) : 888-893. |
PMID 16158538 |
Recurrent cytogenetic abnormalities in squamous cell carcinomas of the head and neck region. |
Van Dyke DL, Worsham MJ, Benninger MS, Krause CJ, Baker SR, Wolf GT, Drumheller T, Tilley BC, Carey TE |
Genes, chromosomes & cancer. 1994 ; 9 (3) : 192-206. |
PMID 7515662 |
p53 and cyclin D1 as prognostic factors in squamous cell carcinoma of the larynx. |
Vielba R, Bilbao J, Ispizua A, Zabalza I, Alfaro J, Rezola R, Moreno E, Elorriaga J, Alonso I, Baroja A, de la Hoz C |
The Laryngoscope. 2003 ; 113 (1) : 167-172. |
PMID 12514403 |
Loss of FHIT expression in squamous cell carcinoma and premalignant lesions of the larynx. |
Yuge T, Nibu K, Kondo K, Shibahara J, Tayama N, Sugasawa M |
The Annals of otology, rhinology, and laryngology. 2005 ; 114 (2) : 127-131. |
PMID 15757192 |
Citation |
This paper should be referenced as such : |
Jin, Y ; Jin, C |
Head, neck: Laryngeal squamous cell carcinoma |
Atlas Genet Cytogenet Oncol Haematol. 2007;11(1):42-45. |
Free journal version : [ pdf ] [ DOI ] |
On line version : http://AtlasGeneticsOncology.org/Tumors/LarynSquamCellID5367.html |
Other genes implicated (Data extracted from papers in the Atlas) [ 22 ] |
Genes | ACVR1 | ANXA1 | ASH2L | CCNA1 | CDC25A | CHD5 | CTCF | GRN | HYAL1 | LOXL2 |
MCM5 | MCM7 | MKI67 | PARK7 | PTBP1 | PTK6 | S100A2 | SNAI1 | SPAM1 | STMN1 | |
STOML2 | ZFX |
External links |
arrayMap | Topo ( C32) arrayMap ((UZH-SIB Zurich) [auto + random 100 samples .. if exist ] [tabulated segments] |
Disease database | Head and Neck: Laryngeal squamous cell carcinoma |
REVIEW articles | automatic search in PubMed |
Last year articles | automatic search in PubMed |
© Atlas of Genetics and Cytogenetics in Oncology and Haematology | indexed on : Mon Dec 14 18:30:30 CET 2020 |
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