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Solid Tumour Section
Review
Lung: Non-small cell carcinoma
Jim Heighway, Daniel C Betticher
Target Identification Group, Roy Castle International Centre for Lung Cancer Research, University of
Liverpool, 200 London Rd, Liverpool L3 9TA, UK (JH); Institute of Medical Oncology, University of Bern,
3010 Bern, Switzerland (DCB)
Published in Atlas Database: February 2004
Online updated version: http://AtlasGeneticsOncology.org/Tumors/LungNonSmallCellID5141.html
DOI: 10.4267/2042/38084
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2004 Atlas of Genetics and Cytogenetics in Oncology and Haematology
some occur more peripherally. The tumour mass
generally extends into the lumen of the airway with
invasion into the underlying wall.
Adenocarcinoma:
A further 30-50% of tumours are defined as
adenocarcinomas (ADC). This tumour type is the most
common in non-smokers and women and it is more
frequently associated with pleural effusions and distant
metastases. ADC may be further sub-classified into:
acinar (gland forming),
papillary,
bronchioalveolar (BAC),
solid with mucin and
mixed.
As most ADC are histologically heterogeneous, they
generally fall into the mixed category. The tumours
usually arise in the smaller peripheral airways (as
distinct from the cartilage bearing bronchi) but they can
be found more centrally. The key diagnostic features of
ADC include gland formation-where the tumour cells
are arranged around a central lumen - and/or mucin
production. ADC is the tumour type most commonly
found associated with fibrotic scars, which are thought
to be caused in some way by the tumour. BAC, which
represents 2-6% of total lung cancer is distinct from
other sub-types both in terms of its growth pattern,
which is lepidic (typically arising beyond the terminal
bronchioloes, where it spreads along the alveolar septa
causing minimal structural damage) and by the fact that
it is non-invasive.
Large cell carcinoma:
Approximately 10% of NSCLC are defined as large
cell carcinomas (LCC). This is a diagnosis of
exclusion. Where a poorly differentiated tumour has
none of the defining features of SCLC, SCC or ADC it
may be classified as LCC: that is, where the cells of the
lesion are not-columnar in shape, do not contain
Identity
Note
See also the overview on lung tumors.
Classification
Non-small cell carcinomas are divided into three main
categories according to the predominant morphology of
the tumour cells as determined by light microscopy.
Although it is possible to distinguish different
histological sub-groups in this way, or by using gene
expression profiling, treatment is currently decided on
the basis of tumour staging, age and performance status
and is independent of tumour histology. In the future,
this may change as new drugs are developed and as
more information is gathered on the predictive power
of such expression profiles.
Clinics and pathology
Pathology
Squamous cell carcinoma:
Approximately 30% of lung tumours are classified as
squamous cell carcinomas (SCC). Whilst this was the
most common sub-type seen in the past, the incidence
of SCC appears to be decreasing relative to
adenocarcinoma, probably as a consequence of
historical changes in the way that cigarettes are smoked
(lower tar and filter tips promoting deeper inhalation).
SCC cells are large, flattened and stratified with a high
cytoplasm to nucleus ratio. Key diagnostic features
include the presence of intracytoplasmic keratin which
may be linked to the presence of intercellular bridges
and squamous
pearl formation. Most SCC arise centrally within the
main, lobar, segmental or subsegmental bronchi but
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mucous, do not show squamous differentiation, and do
not have neuroendocrine properties or small cell
characteristics. Tumours tend to consist of large cells
with abundant cytoplasm, large nuclei and prominent
nucleoli and they may occur peripherally or centrally.
Variants of LCC include clear cell carcinoma, giant cell
carcinoma and large cell neuroendocrine carcinoma
(LCNEC).
Pre-invasive lesions
The bronchial epithelium of the larger airways is a
pseudo-stratified epidermal layer. The most frequent
cell types present are ciliated columnar cells,
interspersed mucous-producing goblet cells and, lying
closely against the basement membrane, multi-potent
basal epithelial cells. The basal (or reserve) cell has a
repair capacity in that it is able to differentiate, as
required, into the other mature cells of the larger
conducting airways. In the smaller terminal and
respiratory bronchioles, basal cells are not present. The
reserve cells of these epithelia are the cuboidal, nonciliated Clara cells. It has been suggested that the multipotent basal cell or a stem cell precursor of such cells
may represent a common lung cancer progenitor.
In chronic smokers, the cells of the tracheo-bronchial
tree are repeatedly exposed to a range of carcinogenic
compounds. Consequently, histolo-gically-recognisable
reactive and pre-neoplastic changes can generally be
seen scattered throughout the airways of long-time
smokers. In situ (pre-invasive) carcinoma (CIS: full
thickness cytological atypia, increased nuclear to
cytoplasmic ratio) is a recognised precursor of
squamous cell carcinoma. This is the end of a spectrum
of pre-neoplastic transformation that ranges from
squamous metaplasia (change in appearance of
cuboidal cells towards squamous morphology) through
mild to severe dysplasia (loss of polarity, increasing
disorder) to CIS. A second pre-neoplastic state is
represented by Atypical Adenomatous Hyperplasia
(AAH). This is a bronchioalveolar proliferation of
slightly atypical cuboidal cells that falls short of the
criteria for BAC: it is a recognised precursor to
adenocarcinoma.
At the molecular level, highly complex patterns of
allelic imbalance (LOH) have been observed in primary
tumours. Again, few if any of these have been strongly
related to diagnosis or prognosis. No balanced
chromosomal translocations have yet been associated
characteristically with NSCLC.
Cytogenetics Morphological
The generally low mitotic index of lung carcinomas
makes karyotypic analysis difficult. However, common
numerical changes observed include the losses of
chromosomes 9 and 13 and trisomy for chromosome 7.
Unbalanced rearrangements have been reported to
occur frequently within chromosomes 1, 3, 5, 6, 7, 8, 9,
11, 13, 14, 15, 17 and 19 and it is thought that the loss
of genetic material due to such events might
encompass, to some lesser extent, all chromosome
arms. Arms which frequently show clear loss include;
9p, 3p,6q, 8p, 9q, 13q, 17p, 18q, 19p, 21q, and 22q
with those often associated with gains being 7p, 7q, 1q,
3q, 5p, 11q and 12q.
Cytogenetics Molecular
Comparative genomic hybridisation (CGH) has been
used to extend conventional karyotypic analysis in
NSCLC. Prominent imbalances seen in several studies
include losses of 3p, 8p, 9p, 13q and 17p and gain of
chromosome arms 1q, 3q, 5p and 8q. Regional
amplification has been reported for 3q26, 8q24, 3q13,
3q28-qter, 7q11.2, 8p11-12, 12p12 and 19q13.1-13.2.
Minimally localised under-represented regions include
3p14-21, 8p21-23 and 17p12-13. CGH analysis has
also suggested that some alterations are more
commonly seen in particular NSCLC sub-types with
gain of 3q24-qter more common in SCC than ADC and
gain of 1q22-32 more common in ADC than SCC.
Genes involved and proteins
Note
Consistent somatic mutation of coding sequence in
primary tumours is strong evidence that a particular
gene has been or is involved in the development of a
neoplastic phenotype. In common with a range of
tumours, particular genes are therefore clearly
associated with NSCLC initiation or progression. These
include TP53 (17p13.1), CDKN2A encoding p16 and
p14 (9p21.3) and KRAS2 (12p12.1). Each of these
genes lies within a region identified cytogenetically as
implicated in NSCLC.
The amplification of chromosomal regions containing
genes implicated in cell growth has also been reported
in primary NSCLC, albeit at a relatively low frequency.
Such data are suggestive of the involvement of these
sequences in neoplasia but they are weaker than direct
mutational evidence given that the amplified regions
generally contain a number of distinct genes, the
relative contributions of each of which to the tumour
phenotype is usually unknown. Genes reported as
Cytogenetics
Note
Lung carcinomas represent the end-stage of the
neoplastic transformation of a stem (or stem-cell like)
cell that has been repeatedly exposed over many years
to high levels of multiple carcinogens. It is therefore
not surprising that the genetic and epigenetic lesions
seen in lung cancer cells are complex.
Correspondingly, frequent numerical and structural
chromosomal alterations are reported in NSCLC.
Whilst many changes are common, some perhaps
occurring more often in one histological class over
another, few if any have been shown to be exclusive to
particular sub-types of disease or prognostic groupings.
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Heighway J, Betticher DC
the possibility that some measure of tumour gene
expression may result from a failure to appropriately
inactivate particular sequences involved in the selfrenewal phenotype of stem-cell (like) progenitors. It is
anticipated that in the future, further detailed molecular
investigations of gene expression in disease and normal
tissues will lead to new prognostic, predictive,
diagnostic, therapeutic and preventative tools.
amplified in primary lesions include CCND1, encoding
cyclin D1 (11q13.3), TP73L, encoding p63 (3q28),
KRAS2 (12p12), MYC (8q24.21) and EGFR (7p11.2).
A number of genes that are encoded from within
chromosomal regions which show LOH or
homozygous deletion in certain lesions have been
identified. Such sequences may show a lack of
expression in primary tumour cells compared to at least
most of the cells in normal lung tissue. This lack of
expression may in turn be correlated with
hypermethylation of the relevant promoter sequence.
Examples of such genes include RASSF1A (3p21) and
CDKN2A (9p21.3). It is tempting to speculate that
genes which show high levels of promoter methylation
in tumour over normal tissue have been somatically
inactivated by such methylation and are therefore likely
to represent causally involved tumour suppressors.
Whilst this may well be true in specific instances,
especially where the gene in question is mutationally
inactivated in a separate fraction of lesions (CDKN2),
it may not be so generally, as the methylation level
seen in the tumour may be completely appropriate for
the cell type of origin of the particular lesion.
Whilst the data suggesting the involvement of an
individual gene in a tumour type might not be
compelling, when pathways or control points are
considered, the evidence often becomes much stronger.
The best example of this is perhaps damage to the
genetic system controlling progression through the G1
restriction point of the cell cycle, beyond which the cell
is committed to divide. Proteins intimately involved in
this key decision point, cyclin D1, p16, and pRB are
frequent targets of NSCLC miss-regulation and may be
involved at the earliest stages of pre-neoplastic
development.
Microarray analyses: Recent microarray analyses have
shown that gene expression profiling can be used to
sub-divide tumours into existing histological classes.
Perhaps more importantly, analyses of adenocarcinoma
series have demonstrated that sub-groups of stage 1
lesions with better or worse survival can be identified
from their expression patterns. Such data suggest that
tumour behaviour may be, at least to some point, fixed
very early in the disease process. From a different
perspective, many genes have been shown to be
commonly differentially expressed (over-represented)
in NSCLC compared to normal lung, to some extent at
least, irrespective of general histology. Such genes are
potential diagnostic targets. More importantly, the
study of their function, normal expression patterns and
mechanisms of expression control may shed
considerable light on the biology of lung cancer and the
characteristics of the cell type(s) of origin. Preliminary
analyses of genomics and/or proteomics highlighted
sequences (S100A2, SERPINB5 encoding maspin and
TP73L, encoding p63) in lung tumours and preneoplastic lesions supports such hypotheses and raise
Atlas Genet Cytogenet Oncol Haematol. 2004; 8(2)
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Atlas Genet Cytogenet Oncol Haematol. 2004; 8(2)
This article should be referenced as such:
Heighway J, Betticher DC. Lung: Non-small cell carcinoma.
Atlas Genet Cytogenet Oncol Haematol. 2004; 8(2):142-145.
145