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Solid Tumour Section
Review
Head and neck: Laryngeal squamous cell
carcinoma
Charlotte Jin, Yuesheng Jin
Department of Clinical Genetics, Lund University Hospital, 221 85 Lund, Sweden
Published in Atlas Database: September 2006
Online updated version: http://AtlasGeneticsOncology.org/Tumors/LarynSquamCellID5367.html
DOI: 10.4267/2042/38388
This work is licensed under a Creative Commons Attribution-Non-commercial-No Derivative Works 2.0 France Licence.
© 2007 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Classification
developing these tumors. Avoiding cigarettes and
alcohol could prevent about 90% of laryngeal SCC.
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.
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
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
Atlas Genet Cytogenet Oncol Haematol. 2007;11(1)
42
Head and neck: Laryngeal squamous cell carcinoma
Jin C, Jin Y
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 3050% of the cases. Overrepresentation of genetic
material occurs often in chromosomal arms 3q, 7p, 8q,
9q, and in chromosomal band 11q13.
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, 7q31pter, 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 cancerization'
but 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
Atlas Genet Cytogenet Oncol Haematol. 2007;11(1)
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,
was 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
43
Head and neck: Laryngeal squamous cell carcinoma
Jin C, Jin Y
Jin Y, Heim S, Mandahl N, Biörklund A, Wennerberg J,
Mitelman F. Multiple clonal chromosome aberrations in
squamous cell carcinomas of the larynx. Cancer Genet
Cytogenet 1990;44:209-216.
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.
Jensen OM. International variation in the incidence of cancer of
the upper digestive and respiratory tract. Adv Otorhinolaryngol
1991;46:124-133.
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 8q2324. 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.
Jin Y, Mertens F, Mandahl N, Heim S, Olegǻrd C, Wennerberg
J, Biörklund A, Mitelman F. Chromosome abnormalities in
eighty-three head and neck squamous cell carcinomas:
Influence of culture conditions on karyotypic pattern. Cancer
Res 1993;53:2140-2146.
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Atlas Genet Cytogenet Oncol Haematol. 2007;11(1)
This article should be referenced as such:
Jin C, Jin Y. Head and neck: Laryngeal squamous cell
carcinoma.
Atlas
Genet
Cytogenet
Oncol
Haematol.2007;11(1):42-45.
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