Vol. 9, 249 –256, March 2000
Cancer Epidemiology, Biomarkers & Prevention
Review
Oral Field Cancerization: Carcinogen-induced Independent Events or
Micrometastatic Deposits?
Monique G. C. T. van Oijen and Pieter J. Slootweg1
Department of Pathology [M. G. C. T. v. O., P. J. S.], and Jordan Laboratory,
Department of Haematology [M. G. C. T. v. O.], University Medical Center
Utrecht, 3508 GA Utrecht, the Netherlands
Abstract
Patients with a head and neck squamous cell carcinoma
(HNSCC) often develop multiple (pre)malignant lesions.
This finding led to the field cancerization theory, which
hypothesizes that the entire epithelial surface of the
upper aerodigestive tract has an increased risk for the
development of (pre)malignant lesions because of multiple
genetic abnormalities in the whole tissue region.
Demonstration of alterations in histologically normal
tumor-adjacent mucosa from HNSCC patients supported
this hypothesis. Currently, the question has been raised
whether multiple lesions develop independently from each
other or from migrated malignant or progenitor cells.
The majority of the mucosal alterations appear to be
related to the exposure to alcohol and/or tobacco.
Moreover, almost all primary remote tumors from
HNSCC patients appear to be clonally unrelated.
Therefore, there is more evidence that field cancerization
is due to multiple independent events than to migration
of genetically altered cells.
Introduction
Epidemiology of HNSCC. Worldwide, HNSCC2 is the sixth
most common malignancy in men and accounts for approximately 5% of malignant tumors in the population of developed
countries (1–3). However, in parts of Southeast Asia, head and
neck cancer is the most common malignancy, accounting for up
to 50% of malignant tumors (1, 4). These percentages reflect
the prevalence of the specific risk factors in these geographic
regions: tobacco and alcohol in the developed countries and
chewing of betel quid in South East Asia (3). Studies of the
epidemiology of HNSCC have identified tobacco and alcohol
use as independent risk factors, but when both factors are
combined there is a synergistic effect (3, 5, 6).
Survival of HNSCC patients depends on tumor size, nodal
Received 8/18/99; revised 12/15/99; accepted 12/23/99.
The costs of publication of this article were defrayed in part by the payment of
page charges. This article must therefore be hereby marked advertisement in
accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1
To whom requests for reprints should be addressed, at Department of Pathology
(H04-312), University Medical Center Utrecht, P. O. Box 85500, 3508 G.A. Utrecht, the Netherlands. Phone: 31-30-2506561; Fax: 31-30-2544990; E-mail:
[email protected].
2
The abbreviations used are: HNSCC, head and neck squamous cell carcinoma;
MPT, multiple primary tumor; UADT, upper aerodigestive tract; TAM, tumoradjacent mucosa; EGFR, epidermal growth factor receptor; TGF-␣, transforming
growth factor ␣; LOH, loss of heterozygosity; CDK, cyclin-dependent kinase.
stage, and success of initial treatment and has not improved
very much during the last decades (7). In general, a 5-year
survival rate of 50% can be obtained, although some anatomical
sites are associated with a less favorable prognosis than others.
The prognosis of HNSCC patients is adversely influenced by
the development of second primary tumors (8). The incidence
rate of second primary tumors is 10 –35%, depending on both
the location of the first primary tumor and the age of the patient
(8 –10).
Different Oral Field Cancerization Theories. The finding
that HNSCC patients often present widespread premalignant
lesions and MPTs in their UADT led Slaughter et al. (11) in
1953 to postulate the concept of field cancerization. They
hypothesized that the entire epithelial surface of the UADT has
an increased risk for the development of (pre)malignant lesions
because of multiple genetic abnormalities in the whole tissue
region.
The mucosal changes in the entire UADT were generally
considered to be the result of exposure to carcinogens that
caused multiple genetic abnormalities in the whole tissue region
(11). The multiple squamous cell lesions described in the oral
field cancerization process were thought to have developed
independently of each other.
An alternative theory for the occurrence of multiple (pre)malignant lesions has been proposed in the last decade and is based
on the premise that any transforming event is rare and that the
multiple lesions arise due to widespread migration of transformed
cells through the whole aerodigestive tract (12–14). Two types of
migration might be involved in the concept of this last theory: (a)
migration of tumor cells by, for example, saliva (micrometastases);
or (b) intraepithelial migration of the progeny of the initially
transformed cells (Fig. 1). If metastatic cells from a HNSCC
migrate through the blood or lymph system, they usually settle in
the lung or in the first lymph node encountered. Therefore, this
route would not lead to tumor deposits in the mucosal surface that
lines the UADT.
Information about all of the different theories can be
gathered by two different ways of investigation. One way is to
search for differences in alterations between histologically normal TAM from smokers/alcohol drinkers and normal TAM
from nonsmokers/nondrinkers. If there are migrating tumor
cells, one expects them to be present in TAM from smoking as
well as nonsmoking HNSCC patients. Thus, TAM from smoking as well as nonsmoking HNSCC patients should exhibit the
same alterations. These alterations should be absent in smoking
healthy individuals, as in those cases, there is no source for
migrating tumor cells. Furthermore, any observed TAM alterations should be identical with the alterations in the primary
tumor in case of migration of advanced tumor cells, whereas in
case of migrating progenitor cells, at least some early tumorigenic alterations would be identical between TAM and the
invasive tumor. In contrast, when there are no migrating cells,
TAM changes in smoking HNSCC patients have to be regarded
as smoking-induced independent events and therefore should
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Fig. 1. Different field cancerization theories. HNSCC patients frequently develop more than one tumor and often have widespread premalignant lesions. The
different theories for the occurrence of these multiple lesions are depicted.
be absent in TAM from nonsmoking HNSCC patients. Moreover, some of the alterations in TAM in smoking HNSCC
patients should also be present in normal mucosa from healthy
smokers.
The second way to investigate the different theories is to
investigate the clonality of the multiple (pre)malignant lesions
by analysis of early genetic alterations in the development of
HNSCC. The separate lesions would share common genetic
alterations if they would have developed from a single clone.
Clonal relationship between multiple lesions points to migration of tumor cells or progenitor cells. If no clonal relationship
between multiple lesions can be found, independent development of the lesions is more likely. Both pathways above outlined will be followed in this review article. We will start by
reviewing the field changes and their relationship with the most
important epidemiological risk factors as far as available data
justify. After evaluating whether these data are in support of
either the migration or the independent origin theory, we will
pay attention to the studies in which clonal relationship between
MPTs was studied and discuss whether data on clonality of
MPTs support any of both theories: migration of precursor cells
or independent tumor development. Finally, some clinical implications of these studies will be mentioned.
Oral Field Changes and Their Relationship with Risk
Factors
Morphological Changes. In 1962, Nieburgs et al. (15) reported malignancy-associated changes within smear cells of
normal buccal mucosa in patients with malignant disease. The
changes consisted of an increase in nuclear size, discontinuous
nuclear membrane, numerous Feulgen-negative areas, increased associated chromatin surrounding the clear areas, and
absence of a single large nucleolus. Incze et al. (16) confirmed
the increase in nuclear area in normal oral mucosa remote from
HNSCCs using ultrastructural analysis. They also described an
altered nuclear to cytoplasmic area ratio.
A reduction in cytoplasmic area was later shown by Ogden
et al. (17, 18). They suggested that tobacco might play a role in
this alteration. However, they could only show a nonsignificant
tendency for the influence of tobacco and alcohol on this
morphological change in the HNSCC patients (18). Alternative
causative factors, such as chronic inflammation, irradiation, and
chemotherapy, were all excluded, and they speculated about
an additional influence of the malnutrition that was present in
most patients (17, 18). Cancer-free smokers, though, showed a
slight increase in nuclear area compared to cancer-free nonsmokers (19).
Aneuploidy and Chromosomal Aberrations. In the last decade, other field changes have been reported. Although
polyploid cells were not detected in normal tumor-distant mucosa (18), aneuploidy was observed in hyperplastic/inflammatory mucosa that subsequently developed in an invasive carcinoma (20). This aneuploidy was not detected in hyperplastic/
inflammatory mucosa from healthy individuals. Hittelman et al.
(21) determined by using chromosome in situ hybridization that
genomic instability in the upper aerodigestive epithelial field
increases the risk to develop a HNSCC.
A whole series of chromosomal aberrations was shown by
fluorescence in situ hybridization in cells from brushes from
macroscopically normal cheek opposite the site of the HNSCC
(22). Unfortunately, only one patient out of the 10 investigated
patients did not smoke. This patient did not show chromosomal
changes in the normal cells; however, one patient is obviously
not enough to draw any conclusion about the role of tobacco in
these chromosomal aberrations. The mucosa from cancer-free
control smokers was compared with mucosa from cancer-free
nonsmokers. No significant chromosome aneusomies were detected, although a trend toward aneusomies of chromosomes 2,
6, and Y was observed in the mucosa from smokers (22).
In another study, polysomies of chromosomes 7 and 17
were observed in TAM from HNSCC patients (23, 24). Almost
all patients smoked, which might suggest that the polysomies
were smoking induced. However, the polysomies were significantly higher in TAM than in tumor-distant mucosa, which
refutes this idea. A significant loss of chromosome Y was
detected in TAM from smoking HNSCC patients, but this loss
appeared not to be present in the nonsmoking patients (25).
In another publication on chromosomal aberrations in
HNSCC patients, the investigators used microsatellite analysis
(26). Allelic loss of chromosome 13 was detected in 10 of 16
informative TAM samples when they were compared to blood
samples. No data on a relationship of this finding with smoking
could be detected.
Alterations in Cytokeratin Expression. Cytokeratins are the
intermediate filament proteins found in the cytoplasm of all
epithelial cells. There are at least 20 different keratin polypeptides that are expressed in different combinations, depending on
the type of epithelium and the degree of differentiation (27).
Aberrant expression of cytokeratins has been shown during the
process of HNSCC carcinogenesis (28, 29). Presence of cytokeratins 7, 8, 13, 16, and 19 was observed at abnormal anatomical sites or at abnormal intraepithelial levels in normal mucosa
from HNSCC patients (30 –33).
Only one study is available in which cytokeratin expression was studied in relation to smoking habits. Expression of
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cytokeratins 7 and 8 in TAM occurred more frequently in the
smoking group of patients than in the nonsmoking group (31).
Changes in Blood Group Antigens of the ABH System.
Histo-blood group antigens are cell surface carbohydrates that
show changes in expression related to tissue type, differentiation state and cell motility capacity. Type 2 chain ABH-carbohydrate structures are distributed broadly in epithelial and endothelial cells, independent of the patient’s ABO blood group.
In normal oral and laryngeal epithelium, type 2 chain ABHantigens are expressed on parabasal cells (34). A 4-fold lower
expression of type 2 chain ABH-antigen was shown in exfoliated cells from macroscopically normal mucosa from six different places distant from the HNSCC, compared with healthy
individuals (32). Because the ABH type 2 chain expression was
always lower in the mucosa from the patients than in the
mucosa from healthy controls, this antigen may be promising as
a negative marker for field change and risk indication.
Foci of Cyclin D1 Expression. Cyclins are cell cycle regulators that are functional only when associated with CDKs. Cyclin D1 regulates the G1-S transition in the cell cycle and is
functional when it is associated with either cdk4 or cdk6 (35).
Amplification of the chromosome 11q13 region, which results
in overexpression of the proto-oncogene cyclin D1 has been
described in about half of the HNSCC (36, 37). Cyclin D1
amplification has been shown in premalignant lesions and the
amplification frequency progresses from premalignant lesions
to invasive carcinoma (36). Bartkova et al. (37) observed
clearly defined foci of cyclin D1 expression in sections of
normal mucosa adjacent to HNSCC that were not seen in
sections of normal mucosa from healthy individuals. Whether
this finding relates to smoking habits has not been addressed.
Increased Expression of the Epidermal Growth Factor Receptor. One of the cellular oncogenes that play a role in the
development of HNSCC is the EGFR. This gene encodes the
receptor of the growth factors epidermal growth factor and
TGF-␣. Ligand binding to the extracellular domain of the
EGFR causes receptor dimerization, which activates tyrosine
kinase function. This leads to autophosphorylation and subsequent phosphorylation of intracellular target proteins, which
results in proliferation (38).
EGFR mRNA overexpression, as well as protein overexpression, has been demonstrated in nearly all HNSCCs (39 –
41). EGFR expression increases during the development of
normal epithelium to dysplastic epithelium and further increases when dysplasia becomes an invasive carcinoma (42).
Several studies have shown increased expression of the
EGFR in TAM (39 – 46). In five of these studies, an overexpression of the protein was observed (42– 46), one study described an elevated mRNA level (40), and one study showed
amplification of the EGFR gene (45). The EGFR overexpression was almost as high in TAM from nonsmoking/nondrinking
HNSCC patients as in TAM from smoking/drinking HNSCC
patients (43). No increase in EGFR expression was observed in
mucosa from cancer-free smokers compared to cancer-free
nonsmokers (43). Furthermore, both Grandis et al. (46) and
Van Oijen et al. (43) showed that EGFR expression in the
mucosa from the HNSCC patients was less elevated when the
epithelium was located more distant to the tumor (43, 46).
These results suggest a paracrine effect on the EGFR expression due to factors released by the tumor and not due to
influence of smoking.
Elevated TGF-␣ mRNA. Besides investigation of the EGFR
also one of its ligands, TGF-␣, was investigated. It was shown
that the mRNA level of TGF-␣ was 5-fold increased in normal
TAM compared with mRNA levels in control normal mucosa
(40), but whether this relates to smoking is unknown.
Increased Proliferation. One of the characteristics of a tumor
is an increased proliferation. Shin et al. (47) showed a sequential increase in proliferating cell nuclear antigen expression in
head and neck tumorigenesis.
An increased number of proliferating epithelial cells was
also shown in TAM from HNSCC patients (47, 48). This
increase in proliferation was related rather to smoking than to
the presence of a HNSCC, as it was only detected in the TAM
from smoking HNSCC patients. No increase was observed in
TAM from nonsmoking HNSCC patients (49). This increase in
proliferating cells was observed not only in TAM from smoking
HNSCC patients but also in mucosa of the UADT from healthy
smokers (49). A trend toward an increased proliferation was
also shown in the mucosa from ex-smoking cancer-free and
HNSCC patients. Thus, the elevated proliferation persists for
some time after quitting smoking. The higher proliferative
activity in the epithelium of the UADT from smokers and
ex-smokers may well constitute a fertile soil for genetic events
culminating in the development of HNSCC.
p53 Overexpression. Loss of function of the tumor suppressor
p53 can result in uncontrolled cell division and progressive
genomic instability (50). Abnormalities of the p53 tumor suppressor gene are among the most frequent molecular events
in cancer. More than 90% of the HNSCCs contain mutated
p53 (51), and in 50% of the tumors, LOH of p53 has been
shown (52).
Mutant p53 has a higher stability than wild-type p53,
which allows accumulation to levels detectable by immunohistochemistry (53, 54). The frequency of p53-positive cells gradually increases as oral epithelium progresses from normal to
hyperplasia to dysplasia to carcinoma (55, 56). Focal p53
positivity was detected more often in normal TAM than in
healthy control epithelium (56 – 60). Mutations in the p53 gene
were identified in both normal TAM and tumor-distant mucosa
from HNSCC patients, in contrast to healthy nonsmokers (58,
61, 62). These mutations were polyclonal and differed from
those detected in the adjacent tumor (58, 61).
Focal overexpression of p53 might reflect an increased
risk of second primary tumors in these patients. Previously, it
was shown that more p53 positive cell clusters were present in
epithelium surrounding multicentric HNSCC as compared to
unicentric HNSCC (63). Furthermore, p53 expression above
the basal cell layers in oral mucosa has been found to be an
early event of malignant transformation and has predictive
value for the development of HNSCC (60). This notion is in
contrast with another study in which the investigators found
that p53 overexpression in TAM could not predict the likelihood of a second primary squamous cell carcinoma (64). However, no distinction was made between basal and suprabasal
p53 expression in that study.
The possible role of smoking in inducing p53 overexpression in TAM was examined by immunohistochemistry (57). No
differences in uniformly spread overexpression of p53 were
observed between the mucosa from smoking and nonsmoking
HNSCC patients compared to healthy controls.
In contrast to the uniformly spread p53 overexpression,
focal overexpression of p53 occurred more frequently in normal
epithelium from smoking HNSCC patients than from nonsmoking HNSCC patients and from healthy control individuals (57).
However, the elevated number of p53 positive cell clusters
could not be detected in mucosa from healthy smokers. This
indicates that besides the exposure to tobacco, other environ-
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mental factors and/or genetic factors must contribute to the
abundance of p53 positive cell clusters in TAM. Exposure to
alcohol was an additional factor in the HNSCC patients (57)
and might have played a role in the development of the p53
positive cell clusters together with the influence of tobacco. In
addition to the findings in tissue sections (57), p53 overexpression and mutations were detected in some clusters of cultured
cells from normal mucosa of healthy smokers (62). These data
on p53 gene alterations and p53 protein overexpression in
apparently healthy TAM suggest a pivotal role for p53 in the
early phase of oral carcinogenesis.
Lack of bcl-2 Expression. In normal tissue, there is a balance
between cell proliferation and programmed cell death (apoptosis). Alterations of both pathways contribute to a clonal expansion of cancer cells. bcl-2, an apoptosis inhibitor, and its family
members (among others, bax, an apoptosis inducer) play an
important role in the regulation of the apoptotic pathway (65).
Apoptosis itself did not vary significantly in the different stages
of HNSCC tumorigenesis (66). However, there was lack of
bcl-2 expression in HNSCC and in normal TAM compared to
control mucosa. No data on relationship with smoking were
mentioned (66). Because bcl-2 is supposed to inhibit apoptosis,
one would expect an increase in bcl-2 expression during tumorigenesis and therefore the lack of bcl-2 expression is rather
surprising. However, to estimate the bcl-2 activity, the expression of bcl-2 has to be interpreted in the context of levels of
other bcl-2/bax family members.
Increased Glutathione S-Transferase. Glutathione S-transferases are detoxification enzymes that comprise different isoclasses (␣-, ␮-, ␲-, and ␶-class), of which the expression levels
are tissue specific and dependent on polymorphisms (67). Glutathione S-transferases are multifunctional, intracellular, soluble, or membrane-bound enzymes, which catalyze the conjugation of many electrophilic hydrophobic compounds with the
tripeptide GSH. Glutathione S-transferase ␮ is an isozyme with
a marked specificity for catalyzing the conjugation of epoxides,
such as benzo(a)-4,5-oxide and sterene-7– 8-oxide, carcinogenic components in cigarette smoke (68). A 2-fold higher risk
of laryngeal cancer has been shown among smokers who lack
the glutathione S-transferase ␮ isoenzyme (69). In contrast,
glutathione S-transferases were increased in dysplastic oral
lesions and HNSCC (70).
The expression of all glutathione S-transferase isoenzymes
was significantly higher in the suprabasal and superficial layers
of normal oral mucosa from HNSCC patients who subsequently
developed a second primary tumor than in normal oral mucosa
from HNSCC patients who were free of disease for at least 7
years (71). Also, in cell scrapes of macroscopically normal
TAM, elevated levels of glutathione S-transferase ␮- and
␲-class were observed (71). Whether these findings have any
relationship with smoking habits has not been assessed. The
reason for these increased levels is an intriguing fact, because
elevated levels of detoxification enzymes protect against carcinogenic attacks. It may reflect a futile response to the presence of carcinogenic metabolites from tobacco, because all
investigated individuals smoked. It becomes even more complex when one realizes that malignant tissue might benefit from
the higher levels of glutathione S-transferase in case of chemotherapy (70). The reason for the high levels of glutathione
S-transferase may not yet be clear; nevertheless, it seems to
have a predictive value for the development of a (second)
primary tumor.
Expression of the Proto-oncogene Product eIF4E. Control
of gene expression at the translational level is important in cell
growth and proliferation. A key participant in regulation of
translation is the proto-oncogene product eIF4E or mRNA 5⬘
cap-binding protein (72). This protein has been found to be
expressed at an elevated level in HNSCC (73). Also, histologically normal margins of resected HNSCCs showed overexpression of eIF4E (73). Relationships with smoking habits were
not investigated.
Protein Tyrosine Kinase and Protein Tyrosine Phosphatase
Activity. Phosphorylation of proteins on tyrosyl residues is a
key mechanism in signal transduction pathways that control
growth, differentiation, and cellular architecture of normal and
malignant cells (74). This phosphorylation is strictly regulated
by protein tyrosine kinases and protein tyrosine phosphatases.
Normal TAM showed a 2.2-fold increase in protein tyrosine
kinase activity compared to the control mucosa from healthy
individuals. In addition, in the TAM, a 1.7-fold elevated ratio of
protein tyrosine kinase activity to protein tyrosine phosphatase
activity was observed (75). Whether these findings are related
with smoking habits is unknown.
A Relationship with Tobacco Exposure Has Been Established for Some TAM Changes. When these data are summarized, it appears that TAM contains a lot of alterations,
which means that genetic abnormalities are indeed distributed
throughout the epithelium of the entire UADT. Additional
research is required to assess which field changes have carcinogenetic significance and which are merely epiphenomenal.
It seems that TAM from smoking HNSCC patients shows
alterations not found in nonsmoking patients (Fig. 2), which
implies that TAM in smoking patients harbors altered cells that
are absent in nonsmoking patients. If these cells have migrated
from adjacent tumors, one would expect some changes in TAM
from nonsmoking patients, which is not supported by these
data. In addition, some of the field changes observed (increased
nuclear area, increased proliferation, and mutations in p53)
were already present in healthy smokers without a tumor being
present as source of migrating cells (19, 49, 62). Therefore,
unless we assume that TAM in both smoking and nonsmoking
patients contains migrating cells that do not betray themselves
by showing as yet unknown alterations, these results support
the idea that TAM changes in HNSCC patients are carcinogen
induced, independent events rather than being the result of
migrated transformed cells.
This notion is also supported by the epidemiological finding that the risk of developing second primary HNSCCs is
higher in smokers/drinkers than in nonsmokers/nondrinkers (8,
9). Moreover, this risk decreases when the patient quits smoking and stops abusing alcohol (8).
Clonality Studies
As outlined in the Introduction, comparing the genetic alterations occurring in MPTs of the head and neck area will also be
helpful in assessing the strength of either the migration or the
independency theory in explaining oral field cancerization. If
multiple tumors develop due to migration of malignant cells
from a primary source, then the tumors and dysplasias from the
same patient should show identical genetic alterations, whereas
in case of independent origin, these alterations will be different.
For these studies, various clonal markers have been used.
Clonal Markers. To investigate the relationship between
MPTs, good clonal markers are needed. To qualify as a marker,
such a genetic alteration should (a) occur very early in the
development of the primary lesion, (b) be maintained during
progression of the lesion, (c) exhibit sufficient variability, and
(d) be applicable in the majority of the lesions. We will mention
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Fig. 2. Smoking-induced field changes.
The abuse of tobacco is related to field
changes in TAM from HNSCC patients
(p53 mutations, chromosome Y loss,
increased proliferation, cytokeratin 7
and 8 expression, and morphological
changes). These smoking-induced field
changes might be the beginnings of
new, independently developing lesions.
the genetic markers that have been used to assess the clonal
relationship between separate squamous lesions in the aerodigestive tract and discuss whether they meet the above outlined
4 requirements.
One of the genetic alterations used is the pattern of Xchromosome inactivation (13). However, when using X-chromosome inactivation as marker for investigation of the clonal
relation between tumors lying close to each other, one has to
realize that X-chromosome inactivation occurs relatively early
in embryonic development, resulting in large patches of cells
derived from a common ancestor cell and thus having the same
X-chromosome inactivated (76). In addition, X-chromosome
inactivation can be nonrandom or cell type specific (77).
Karyotypes of tumors have also been used as a clonal
marker (78). However, tissue culture is required for this type of
analysis, which might cause additional genetic alterations.
Another kind of clonal markers that has been used involves LOH patterns for microsatellite markers at different
chromosomal loci (12, 14, 79, 80). LOH at loci on chromosome
arms 3p, 9p, and 17p have been shown to occur early in
carcinogenesis (12, 80 – 84). Only a single change might occur
in a LOH pattern of about 10 microsatellite markers during
tumor progression and metastasizing (80, 85). However, LOH
at loci on chromosomes 3p, 9p, and 17p occurs so frequently
(80) that complete loss of all markers may be present in many
of the lesions, which means that the variability of these markers
is not high enough to draw conclusions about clonal relationships between all lesions.
Finally, p53 mutations have been used as a clonal marker
(51, 55, 61, 80, 86). p53 mutations are an early event in the
development of HNSCC because they are already present in
normal tissue distant from tumors (56, 58, 61), in normal tissue
from healthy smokers (62), and in premalignant lesions (56).
These mutations are diverse enough (80) and stable during
metastasizing (87). Thus p53 mutations in HNSCC patients
appear to be very useful as clonal marker, whereas the other
markers are less suitable due to lack of variability and stability
or due to technical requirements.
Polyclonality of MPTs in the Head and Neck. Most studies
that used clonal markers to investigate the relationship between
MPTs or to investigate dysplastic lesions occurring in the
UADT and that were remote from each other showed polyclonality between these lesions (14, 79, 80, 86, 88, 89). Only a
limited amount of MPTs showed the same genetic alterations as
evidenced by showing identical microsatellite alterations, LOH
patterns, or cytogenetic features (14, 78, 79, 90). However, the
overwhelming majority of remote MPTs show no clonal relationships and can therefore be assumed to have developed
independently.
HNSCC or adjacent premalignant lesions that are located
very close to each other more often show identical genetic
changes. Califano et al. (12) observed a clonal relationship
between five HNSCCs and the tumor-adjacent premaligant
lesions by using LOH pattern analysis. Two patients with
synchronous HNSCC tumors lying close to each other were
investigated for clonality by Van Oijen et al. (80). The first
patient showed an identical p53 mutation and an identical LOH
pattern in both tumors, whereas the other patient did not show
identical aberrations. This strongly suggests that in the first
patient, migration of malignant cells has occurred. In the nine
other patients investigated with HNSCC lying remote from
each other, no clonality was observed. Thus, in patients in
whom two HNSCCs are not separated by a large distance, some
tumors might have developed from the same primary lesion,
whereas other tumors have developed independently.
More evidence for the existence of lesions arising independently in the UADT came from the diversity of p53 mutations identified in histologically normal TAM from HNSCC
patients (58, 61). All identified mutations differed from the p53
mutation in the matched HNSCC. This excludes the possibility
that new lesions in these patients develop by migrated tumor
cells, as well as the explanation that early lesions in TAM occur
due to migration of progenitor cells with a p53 mutation.
One precaution needs to be considered. The conclusion
that MPTs develop independently is only tenable when one can
exclude the possibility that there is migration of cells with a yet
unknown genetic alteration that had arisen prior to all “early
alterations” investigated. However, it is difficult to imagine that
progenitor cells, with only a minimal genetic alteration, would
have the capacity to migrate intraepithelially over large distances. Neither is it very plausible that such progenitor cells
would be displaced by salivary flow, after which they settle
elsewhere for outgrowth, because progenitor cells do not have
any invasive or metastatic potential. Furthermore, it has been
shown that a few “early” transformed cells that are surrounded
by normal cells do not succeed in the development of a new
lesion (91).
In the bronchial tree, the situation may be different, as
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Franklin et al. (92) reported a case harboring the same p53
mutation in dysplastic bronchial mucosal samples taken from
different locations. Migration of p53 mutated progenitor cells is
highly likely to have occurred in that patient, unless this particular p53 mutation was induced independently in these different lesions as a consequence of a specific carcinogen.
Clinical Relevance and Conclusions
The finding that field changes frequently occur in TAM of
HNSCC patients creates a different view on tumor excision
margins that contain molecularly altered cells (93, 94). The
conclusion that the margin is tumor positive if it shows the
presence of genetically altered cells does not necessarily hold
true for every molecular marker used. The molecular marker
used has to be specific for that particular tumor. For example,
the observation that the same p53 mutation is present in the
margin (95) as well as as in the tumor might be useful; however,
the detection of overexpression of eIF4E in the margins (73) is
not specific for that tumor and more likely reflects a field
change caused by smoking.
Most field changes appear to be induced by smoking,
which implies carcinogen-induced field cancerization rather
than field cancerization due to migrated transformed cells. We
also conclude that almost no remote multiple tumors develop
due to migration of tumor cells. They seem to develop independently as a result of the continuous carcinogenetic influence
of alcohol and/or tobacco. Therefore, patients with a HNSCC
should be advised to quit smoking to reduce the risk of the
development of MPTs, especially because HNSCC patients
seem to be more susceptible (9, 96) to tumor development than
cancer-free smokers.
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Oral Field Cancerization: Carcinogen-induced Independent
Events or Micrometastatic Deposits?
Monique G. C. T. van Oijen and Pieter J. Slootweg
Cancer Epidemiol Biomarkers Prev 2000;9:249-256.
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