Head and Neck: Laryngeal squamous cell carcinoma

2006-09-01   Charlotte Jin , Yuesheng Jin 

1.Dept clinical Genetics, University Hospital, SE-221 85 Lund, Sweden

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.

Classification

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 (

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

Pubmed IDLast YearTitleAuthors
86251891995Chromosomal abnormalities involving 11q13 are associated with poor prognosis in patients with squamous cell carcinoma of the head and neck.Akervall JA et al
100962531999Epidermal growth factor receptor expression in primary laryngeal cancer: an independent prognostic factor of neck node relapse.Almadori G et al
149698242004Proliferative verrucous leukoplakia: unusual locations of oral squamous cell carcinomas, and field cancerization as shown by the appearance of multiple OSCCs.Bagán JV et al
121247742002Prognostic significance of p16INK4a alterations and 9p21 loss of heterozygosity in locally advanced laryngeal squamous cell carcinoma.Bazan V et al
127025512003A genetic explanation of Slaughter's concept of field cancerization: evidence and clinical implications.Braakhuis BJ et al
155366192004Longitudinal study of smoking patterns in relation to the development of smoking-related secondary primary tumors in patients with upper aerodigestive tract malignancies.Do KA et al
98405191998Retinoblastoma protein expression and prognosis in laryngeal cancer.Dokiya F et al
94628181997Avoidable cancers in the Nordic countries. Tobacco smoking.Dreyer L et al
163742332006Type of alcoholic beverage and the risk of laryngeal cancer.Garavello W et al
114393632001Detailed 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 et al
119795562002Genetic 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 et al
121720092002High-resolution mapping of the 11q13 amplicon and identification of a gene, TAOS1, that is amplified and overexpressed in oral cancer cells.Huang X et al
80622831994PRAD-1/cyclin D1 gene amplification correlates with messenger RNA overexpression and tumor progression in human laryngeal carcinomas.Jares P et al
103282201999Disregulation of p16MTS1/CDK4I protein and mRNA expression is associated with gene alterations in squamous-cell carcinoma of the larynx.Jares P et al
19277111991International variation in the incidence of cancer of the upper digestive and respiratory tract.Jensen OM et al
170657892006Molecular cytogenetic characterization of the 11q13 amplicon in head and neck squamous cell carcinoma.Jin C et al
96696691998FISH characterization of head and neck carcinomas reveals that amplification of band 11q13 is associated with deletion of distal 11q.Jin Y et al
116751312001Cytogenetic and fluorescence in situ hybridization characterization of chromosome 8 rearrangements in head and neck squamous cell carcinomas.Jin Y et al
76067421995Nonrandom chromosome abnormalities in short-term cultured primary squamous cell carcinomas of the head and neck.Jin Y et al
22976811990Multiple clonal chromosome aberrations in squamous cell carcinomas of the larynx.Jin YS et al
94562381998Larynx cancer risk in relation to glutathione S-transferase M1 and T1 genotypes and tobacco smoking.Jourenkova N et al
158213512005Tissue microarray analysis of C-MYC oncogene copy number changes in larynx carcinoma.Koynova DK et al
152671852004Expression of c-myc oncoprotein in laryngeal squamous cell carcinoma.Krecicki T et al
105265321999DNA copy number losses are more frequent in primary larynx tumors with lymph node metastases than in tumors without metastases.Kujawski M et al
92050891997Chromosomal imbalance maps of malignant solid tumors: a cytogenetic survey of 3185 neoplasms.Mertens F et al
91583961997Overexpression of cyclin D1 indicates a poor prognosis in squamous cell carcinoma of the head and neck.Michalides RJ et al
121488572002Cyclin D1 amplification and p16(MTS1/CDK4I) deletion correlate with poor prognosis in head and neck tumors.Namazie A et al
99303651998Loss of heterozygosity at 8p, 9p and 17q in laryngeal cytological specimens.Rizos E et al
156313542004Loss of heterozygosity in laryngeal cancer.Rogowski M et al
150238362004Association between p53 gene mutations and tobacco and alcohol exposure in laryngeal squamous cell carcinoma.Ronchetti D et al
159659042006TP53 mutations and S-phase fraction but not DNA-ploidy are independent prognostic indicators in laryngeal squamous cell carcinoma.Russo A et al
130946441953Field cancerization in oral stratified squamous epithelium; clinical implications of multicentric origin.SLAUGHTER DP et al
103536091999Localization of a putative tumor suppressor gene in the sub-telomeric region of chromosome 8p.Sunwoo JB et al
163095412005Molecular predictors of clinical outcome in patients with head and neck squamous cell carcinoma.Thomas GR et al
161585382005Molecular detection and typing of human papillomavirus in laryngeal carcinoma specimens.Torrente MC et al
75156621994Recurrent cytogenetic abnormalities in squamous cell carcinomas of the head and neck region.Van Dyke DL et al
125144032003p53 and cyclin D1 as prognostic factors in squamous cell carcinoma of the larynx.Vielba R et al
157571922005Loss of FHIT expression in squamous cell carcinoma and premalignant lesions of the larynx.Yuge T et al

Citation

Charlotte Jin ; Yuesheng Jin

Head and Neck: Laryngeal squamous cell carcinoma

Atlas Genet Cytogenet Oncol Haematol. 2006-09-01

Online version: http://atlasgeneticsoncology.org/solid-tumor/5367/head-and-neck-laryngeal-squamous-cell-carcinoma