Head and Neck: Laryngeal squamous cell carcinoma

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

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) FISH analysis has recently been undertaken to verify and in detail characterize the most common recurrent chromosomal changes in head and neck SCC (HNSCC), including laryngeal SCC. FISH has demonstrated that cytogenetically detectable hsr in these tumors almost always corresponds to amplification of DNA sequences originating from 11q13, and the amplicons mapped vary in size from 3.5 to 4.5 Mb with a core of 1.5 - 1.7 Mb, and often many oncogenes in this region are coamplified, including CCND1, FGF3, FGF4, EMS1, and SHANK2. Another finding is that the amplification of 11q13 is often concomitant with deletion of distal 11q. The latter finding indicates that not only the amplification of one or more dominantly acting oncogenes in 11q13, but also loss of a tumor suppressor gene in the distal part of 11q, are critical for the development of laryngeal SCC. Detailed FISH characterization of pericentromeric rearrangements, in particular for chromosomes 1 and 8, with the use of YAC clones spanning the pericentromeric region of chromosomes, suggest that the essential outcome of these rearrangements at DNA level is the resulting genomic imbalances, i.e., loss or gain of neoplasia-associated genes. Furthermore, more precise mapping of breakpoints on chromosomal arms 1p and 8p has delineated critical regions for deletions within 1p11-p13 and the subtelomeric region of 8p. Genetic imbalances revealed by CGH, allelotyping, and LOH studies A large scale effort has been devoted to the identification of tumor suppressor gene loci and amplified oncogenes in laryngeal carcinomas. Earlier loss of heterozygosity (LOH) studies focused on specific chromosomal arms pointed out the frequent loss of alleles from 3p, 8p, 9p, 13q and 17p in head and neck SCC (HNSCC) in general as well as in laryngeal SCC. A number of recent studies based on allelotyping or comparative genomic hybridization (CGH) indicate that HNSCC, including laryngeal SCC, display massive and widespread genomic imbalances and that certain chromosome segments are lost more often than others. Combined data in these studies indicate that the most frequent imbalances is loss of genetic material from 3p, 8 p, 9p, 13q, and 17p, found in more than 50% of the cases and less frequently, deletions in 3q, 4p, 4q, 6p, 6q, 8p, 8q, 11q, 14q, 17q, 19q, and 20p observed in 30-50% of the cases. Overrepresentation of genetic material occurs often in chromosomal arms 3q, 7p, 8q, 9q, and in chromosomal band 11q13.
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) [ 21 ]

Genes	ACVR1	ANXA1	ASH2L	CCNA1	CDC25A	CHD5	CTCF	GRN	HYAL1	LOXL2
	MCM5	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 : Sat Jun 17 12:10:32 CEST 2017

For comments and suggestions or contributions, please contact us