EJSO 33 (2007) 383e389 www.ejso.

com

Field cancerization in oral lichen planus

M.D. Mignogna a, S. Fedele a,b,*, L. Lo Russo a, C. Mignogna c, G. de Rosa c, S.R. Porter b
a
Section of Oral Medicine, Department of Odontostomatological and Maxillofacial Sciences,
University ‘‘Federico II’’, Via Pansini 5, 80130, Naples, Italy
b
Oral Medicine Unit, Division of Maxillofacial, Diagnostic, Medical and Surgical Sciences, UCL Eastman Dental Institute,
University College of London, University of London, 256 Gray’s Inn Road, London, WC1X 8LD, UK
c
Section of Pathology, Department of Biomorphologic and Functional Sciences,
University ‘‘Federico II’’, Via Pansini 5, 80130, Naples, Italy
Accepted 21 September 2006
Available online 3 November 2006

Abstract

Background: The concept of field cancerization describes the tendency of patients with premalignant and malignant lesions of head and
neck mucosal sites to develop multiple carcinomas of the upper aerodigestive tract. Here we address whether this concept should be ex-
tended also to patients affected by oral lichen planus (OLP), an inflammatory disorder associated with an increased risk of cancer
development.
Methods: Data from a cohort of 45 patients with OLP who subsequently developed severe dysplastic changes and/or oral squamous cell
carcinoma were retrospectively reviewed. Patients who presented more than one oral neoplastic event were considered for further data anal-
ysis as regards incidence, localization, management and prognosis.
Results: Twenty (44.4 %) patients were affected by one single neoplastic event while 25 (55.6 %) developed multiple and often multifocal
oral dysplastic and/or malignant events. In most cases, a careful surveillance programme led to diagnosis and effective treatment of oral
neoplasias at an early intraepithelial and microinvasive stage, leading to long-term survival. In some patients, however, additional primary
tumours occurred suddenly with rapid invasion, leading to advanced stage diagnosis and poor prognosis. Overall, three patients (12 %) died
due to malignant oral disease.
Conclusions: Patients with OLP and subsequent development of dysplasia/ oral squamous cell carcinoma are at risk of having multiple and
multifocal neoplastic events of the oral cavity, a phenomenon which parallels the concept of field cancerization of traditional head and neck
cancers. If detected at an early stage, these neoplasias can be managed with superficial and complete resection. However a small number of
patients have loco-regional tumour spread despite a standard surveillance protocol.
Ó 2006 Elsevier Ltd. All rights reserved.

Keywords: Field cancerization; Oral cancer; Oral lichen planus; Inflammation; Prognosis; Precancerous lesions

Introduction areas to carcinogenic agents. Since then, the concept has

The concept of ‘‘field cancerization’’ was first intro-
duced by Slaughter et al. in 1953 when studying the pres-
ence of histologically abnormal tissue surrounding oral
squamous cell carcinoma.1,2 It was proposed to explain
the development of multiple neoplasms of the upper aerodi-
gestive tract (UAT) observed in head and neck cancer pa-
tients as a consequence of continuous exposure of these
* Corresponding author. Oral Medicine Unit, Division of Maxillofacial,
Diagnostic, Medical and Surgical Sciences, Eastman Dental Institute for
Oral Health Care Sciences, University College of London, University of
London, 256 Gray’s Inn Road, London, WC1X 8LD, UK.
E-mail address: s.fedele@eastman.ucl.ac.uk (S. Fedele).
been further extended to include not only a higher-than-
expected prevalence of multiple local second primary tu-
mours and the presence of synchronous distant tumours
within the UAT, but also the occurrence of multiple oral
premalignant lesions.3 Oral leukoplakia, oral submucous
fibrosis and erythroplakia, generally considered the three
major clinical types of premalignant oral lesions, share
with oral squamous cell carcinoma (OSCC) the same risk
factors as well as the same events underlying the process
of field cancerization, namely widespread lateral clonal
expansion of a single progenitor and/or independent molec-
ular events affecting multiple cells separately.4e6 An im-
portant clinical implication of such a process is that fields

0748-7983/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.ejso.2006.09.028
384 M.D. Mignogna et al. / EJSO 33 (2007) 383e389
of oral mucosa, apparently healthy but proven to be altered
via histological and molecular studies, remain beyond the
limits of resection and may lead to new potentially malig-
nant and malignant lesions.3 Even if these second primary
lesions and/or local recurrences are not considered a major
cause of mortality in head and neck cancer patients,7,8 they
could have a significant impact upon the need for and type
of treatment, and overall prognosis of patients. Further-
more, recent studies have suggested that a subgroup of
potentially malignant lesions with gross genomic aberra-
tions (aneuploid erythroplakia and leukoplakia) are charac-
terized by a high incidence of multiple and multifocal
subsequent tumours and associated mortality.9,10 It is not
known whether the concept of field cancerization should
be extended to oral lichen planus (OLP), a chronic inflam-
matory disorder which is increasingly considered to have
malignant potential unrelated to common risk factors
(e.g. tobacco and alcohol usage) of oral cancer develop-
ment.11e16 However, a few preliminary studies have sug-
gested that some patients with OLP-related OSCC have
a poor prognosis due, at least in part, to a tendency to
develop second primary metachronous oral cancers.17,18
Paralleling this, multifocal and synchronous or meta-
chronous areas of malignant transformation (e.g. high-
grade dysplasia and invasive carcinomas) characterize other
chronic inflammatory conditions associated with cancer de-
velopment, such as Barrett’s oesophagus and ulcerative
colitis.19e21 This might thus support the view that the con-
cept of field cancerization may be applied also to these dis-
orders, probably as a consequence of persistent and
widespread activation of their stromal inflammatory micro-
environment, given that activated inflammatory cells and
the cytokine network can act as oncogenic agents, hence
promoting epithelial tumorigenesis.22e25
If OLP is a potentially malignant disease linked to
chronic inflammation, it would be expected that some pa-
tients will have disease that behaves in a manner similar
to that of oral epithelial dysplasia and the other chronic in-
flammatory conditions associated with cancer development,
giving rise to malignant disease that is recurrent and ag-
gressive. The aim of the present retrospective study was
to determine the incidence, nature and locations of multiple
neoplastic events in patients with a previous history of OLP
to establish if there is a potential of field cancerization of
the oral mucosa associated with OLP.
Materials and methods
A cohort of 45 patients diagnosed with OLP at the Oral
Medicine Section of University ‘‘Federico II’’ and who sub-
sequently developed severe epithelial dysplasia/carcinoma
in situ, defined here as oral intraepithelial neoplasia,26
and/or invasive OSCC were retrospectively analysed. All
the patients did not have clinical/histological signs of
dysplasia or OSCC at the time of OLP diagnosis and all
developed at least one neoplastic event, namely one
intraepithelial neoplasia and/or invasive OSCC. Among
them, patients presenting multiple synchronous and meta-
chronous neoplastic events were considered for further
data analysis with focus on tumour incidence and locations,
clinical management, and prognosis. The study cohort
belongs to a bigger group of 700 patients who have been
diagnosed and regularly reviewed during a period of
16 years (1990e2006).
The diagnosis of OLP was based upon clinical manifes-
tations (papular, plaque and/or reticular lesions alone or in
association with erosive/ulcerative lesions, mostly but not
exclusively bilateral and symmetrical) confirmed by inci-
sional biopsy demonstrating characteristic microscopic
features including hyperortho-hyperparakeratosis of the
superficial epithelial layers, vacuolar degeneration of the
germinative layer of the epithelium, and subepithelial lym-
phocytic band-like infiltrate.27,28 Patients suspected to have
lichenoid lesions related to drugs or oral restorations were
not included. The diagnosis of neoplastic events was based
upon clinical examination confirmed by histopathological
examination of lesional tissue. Dysplasia/oral carcinoma
was graded according to the criteria of the World Health
Organization.29 The criteria of the American Joint Commit-
tee on Cancer were used to determine the clinical stage.30
The International Classification of Diseases for Oncology
(ICD-O) was used to identify the sites of carcinomas: the
ICD-O codings were confirmed by a standardized drawing
provided with each patient file.31
Intraepithelial neoplasia and early invasive oral carci-
noma were treated by surgical excision including, whenever
allowed by anatomical and functional factors, at least
0.5 cm of healthy tissue at the lateral margin of resection
and about 0.3e0.5 cm of submucosal tissue as deep margin.
Subsequent cancers which occurred after treatment were
defined as second primary tumours when previous resection
margins were free of intraepithelial neoplasia (severe dys-
plasia/carcinoma in situ) and/or invasive carcinoma, de-
fined as negative margins. In instances when carcinoma
and/or intraepithelial was present at the resection margins
(defined as positive margins) further wider surgical exten-
sion to clinically healthy mucosa was undertaken. Patients
with mild dysplasia at resection margins were not re-
operated but carefully observed by increased frequency of
periodic clinical examinations. When considered clinically
useful, tolonium chloride staining was used as an adjunc-
tive diagnostic aid.32,33 In all cases, OLP diagnosis, dyspla-
sia grading and status of resection margins were determined
after consensus had been reached independently by two pa-
thologists. Advanced stage oral carcinomas were treated,
whenever possible, with resective maxillofacial surgery.
Neck dissection, orofacial reconstruction and postoperative
radiotherapy and/or chemotherapy were provided where
needed. Patients were routinely recalled and clinically
observed every 4 months, except those needing closer
surveillance due to recent development of dysplasia or
intraepithelial neoplasia/invasive carcinoma.34 Clinical
 M.D. Mignogna et al. / EJSO 33 (2007) 383e389
criteria used to perform dysplasia/neoplasia surveillance in
OLP patients have been previously described34 and were
applied to all patients.
Results
Malignant transformation: incidence and location
All 45 patients were clinically monitored for at least
3 years following the diagnosis of OLP (range 3e14 years).
Twenty (44 %) of the 45 patients were affected by only one
neoplastic event (occurrence of intraepithelial neoplasia/in-
vasive carcinoma). The remaining 25 developed at least one
second metachronous primary intraepithelial neoplasia/in-
vasive carcinoma and were therefore subject to further eval-
uation. In particular, the neoplastic events were distributed
as follows: 2 in 9 patients (36 % of the subgroup with more
than one neoplastic event), 3 in 7 patients (28 %), 4 in 6
other patients (24 %), 6 in 1 patient (4 %), and 12 and 16
in 2 patients (4 % and 4 %, respectively). The course of
neoplastic events of these 25 patients is detailed in Fig. 1;
Fig. 2 shows the clinical course of the whole study group
of 45 patients with OLP who developed at least one intra-
epithelial neoplasia/invasive carcinoma. The observation
period following the detection of the first oral malignancy
was at least 3 years for the majority of patients with multi-
ple neoplastic events (80 %; 20/25), ranging from 3 to
12 years (mean observation period: 6.75 years). Consider-
ing also 5 patients with first tumour occurring in 2003 (1
case) and 2004 (4 cases), the follow-up ranged from 1 to
12 years, with a mean observation period of 5.64 years.
While in most cases each neoplastic event was generally
characterized by one single intraepithelial neoplasia/
invasive carcinoma involving one oral ICD-O site, in
some patients malignant diseases occurred as two or three
Figure 1. Course of neoplastic events in 25 OLP patients presenting at least two intraepithelial neoplasias/invasive carcinomas. Month 0 corresponds to first
tumour occurrence. Each black diamond represents a single further neoplastic event. Red squares indicate patient’s death.
385
contiguous and/or distant areas of synchronous multifocal
malignant transformation, involving different ICD-O sites.
The topographic relation between primary and subsequent
neoplastic events is presented in Fig. 3. In brief, in 5 of
25 patients belonging to the subgroup with multiple
OSCC (20 %), the neoplastic events occurred only in the
same location as the previous ones. However, the remaining
20 patients developed subsequent multifocal intraepithelial
neoplasias/invasive carcinomas in ICD-O sites distant to
that of the preceding tumours. There was a general trend
of increasing variation in site of neoplastic events with
the number of new second primary tumours. Tumours
mostly occurred in the same mucosal areas where OLP le-
sions were already present, even if in some cases they oc-
curred in areas of mucosa which clinically appeared to be
non-involved by OLP. With regard to the clinical form of
OLP, the majority of patients were affected by predomi-
nantly keratotic lichenoid lesions. Those few patients
with erosive painful lesions were managed with short-
term courses of topical corticosteroid (clobetasol) therapy
which, as previously described, does not represent a risk
factor for cancer development in patients with OLP.14
Tumour staging and cancer specific mortality
There were 97 neoplastic events subsequent to the diag-
nosis of OLP in the 25 patients who developed more than
one malignancy. Among these 91 (93.9 %) were intraepi-
thelial neoplasias (severe dysplasia/carcinoma in situ) or
microinvasive carcinomas (1 mm), i.e. stage 0 and I
oral cancers (TisN0M0 or T1N0M0). The other tumours
were stage IV (T4N1M0) (3 tumours) and stage III
(T1N1M0) (3 tumours). All stage IV OSCC occurred in
patients with multiple and multifocal metachronous neo-
plastic events. Two stage III OSCC occurred as a second
386 M.D. Mignogna et al. / EJSO 33 (2007) 383e389
Figure 2. Clinical course of 45 OLP patients who developed at least one intraepithelial neoplasia and/or invasive carcinoma.
neoplastic event subsequent to the first intraepithelial
neoplasia/invasive carcinoma, whereas a third patient had
stage III OSCC following multiple neoplastic events. Over-
all, 3 patients died due to their stage IV OSCC, correspond-
ing to a cancer-specific-mortality of 12 % (3/25).
Characteristics of OLP patients who developed
multiple neoplastic events
Seventeen (68 %) of the 25 patients with OLP who sub-
sequently developed multiple neoplastic events were fe-
male. Only two patients were former cigarette smokers
and no one reported misuse of alcoholic beverages or
smokeless tobacco habit. Three patients required cycles
of topical steroidal therapy to control oral symptoms related
to erosive OLP lesions. One patient was treated with
systemic 13-cis-retinoic acid, beta-carotene, and alpha-
tocopherol as chemopreventive therapy, because of a high
incidence of secondary oral tumours. This therapy was
however discontinued due to side effects (cutaneous toxic-
ity, hypertriglyceridemia and hypercholesterolemia) after
10 months. The majority of patients who developed multi-
ple OSCC had asymptomatic predominantly keratotic (both
plaque and reticular types) OLP lesions.
Discussion
The present study has investigated the characteristics of
OSCC in patients with previous OLP to determine if the
oral mucosa of such individuals demonstrates field cancer-
ization. The malignant transformation of OLP is still
a much debated issue. The criticism of available studies
mainly relies upon the suggested theory that ‘‘true’’ OLP
is a benign disorder and that many of the reported OLP
cases developing oral cancer are in fact not OLP, but rather
dysplastic lesions with lichenoid features and non-OLP oral
lichenoid lesions which behave differently from benign
OLP. To support this view, some authors including Eisen-
berg,35 Krutchkoff,36, 37 and van der Meij38 have proposed
strict histopathological and/or clinico-pathological diagnos-
tic criteria which should be able to identify, within the large
group of lichenoid lesions, those with and those without
malignant potential. Nevertheless these criteria have
not been validated.14,38 In addition, recent studies have
demonstrated that patients with OLP that do fulfil the afore-
mentioned diagnostic criteria can have malignant transfor-
mation of lesions.14,38,39 In the present study the patients
with histopathologically detectable oral epithelial dysplasia
at the time of OLP diagnosis were not included because of
the necessity of documenting the progression from non-
dysplastic epithelium to in situ and/or invasive carcinoma,
which is the most accepted progression model for most
solid malignancies, including head and neck cancer.40e43
There are little data on the characteristics and outcome
of OSCC in patients with OLP. Hietanen and co-workers re-
ported that 5 of their 8 patients with OLP-related OSCC
died within a few months from oral cancer diagnosis, but
they did not provide further important prognostic informa-
tion such as tumour stage and occurrence of recurrences or
second primary tumours.17 More recently, we retrospec-
tively examined 21 OLP patients who developed OSCC
and found that 33.3 % and 23.8 % developed second pri-
mary metachronous tumours of the oral cavity and nodal
metastases respectively, an unusual behaviour considering
 M.D. Mignogna et al. / EJSO 33 (2007) 383e389 387

Figure 3. Topographical relationship between primary and subsequent neoplastic events in: (A) 9 OLP patients with only one further neoplastic event after the
primary one (patient 4, 10, 12, 13, 14, 15, 17, 21, 23). Individual locations are represented by ellipses numbered with patients’ number. Blue ellipses represent
tumours involving the same area as the preceding one. Red ellipses indicate tumours occurring in distant oral sites; (B) 14 OLP patients who developed from
2 to 5 further neoplastic events after the primary one (patient 1, 2, 3, 6, 8, 9, 11, 16, 18, 19, 20, 22, 24, 25). Individual locations are represented by ellipses
numbered with patients’ number. Small blue ellipses represent metachronous neoplastic events occurring in single oral sites. Large blue ellipses represent
synchronous neoplasias involving more than one contiguous site. Red ellipses represent synchronous neoplasias involving more than one distant site; (C) one
OLP patient (patient 7) who developed 11 further metachronous neoplastic events after the primary one (12 in total). Individual locations are represented by
blue ellipses numbered with patient’s number; (D) one OLP patient (patient 5) who developed 15 further neoplastic events after the primary one (16 in total).
Individual locations are represented by ellipses numbered with patient’s number. Small blue ellipses represent metachronous neoplastic events occurring in
single oral sites. Large blue ellipses represent synchronous neoplasias involving more different contiguous sites. Red ellipses and squares represent synchro-
nous neoplasias involving different distant sites.

the early stage of their first oral cancers.18 In the present
study 20 (44 %) of the 45 patients with OLP developed
only one SCC. In contrast the remaining 25 patients
(56 %) developed further, often distant, primary OSCC.
The mean duration to the time of the first OSCC was sim-
ilar in both groups. There was no difference in the duration
of OLP, or types of OLP between the two groups. This high
incidence of secondary primary tumours strongly parallels
the process of field cancerization observed with OSCC
and oral epithelial dysplasia.
With regard to topographic relation, the present findings
are consistent with the phenomenon of field cancerization
because of the high frequency (80 %) of different oral loca-
tions between primary and subsequent intraepithelial neo-
plasias/invasive carcinomas. In the remaining 20 % of
cases subsequent events occurred in the same location of pri-
mary neoplasia, notwithstanding the absence of histopatho-
logically detectable intraoral neoplasia/invasive carcinoma
at lateral and deep resection margins. Although molecular
studies were not performed, and clonality cannot be assumed
on the topographical relationship, the clinical behaviour we
observed is apparently consistent with the theories of both
separate and independent cell clones44 and the presence of
occult clonal alterations at histologically negative resection
margins or lateral clonal spread.6,45 During the last few
years, it has become evident that the process of field cancer-
ization is not necessarily associated with field exposure to
environmental carcinogens, and has been described in other
organs such as lung, oesophagus, vulva, cervix, colon,
breast, bladder, and skin.2 It is interesting to note that with
colon cancer the occurrence of carcinoma and dysplasia in
patients with chronic inflammatory diseases of the bowel
is typically multifocal and multicentric, and may present
several characteristics in common with OLP-related
OSCC. Indeed chronic inflammation and immune activation
have been reported to act as oncogenic agents in these disor-
ders.15,46,47 It might thus be speculated that the activated in-
flammatory cells and cytokine network which act to promote
squamous tumorigenesis, may, in the same manner, influ-
ence clonal spreading and thus support the process of field
388 M.D. Mignogna et al. / EJSO 33 (2007) 383e389
cancerization in these chronic inflammatory disorders. It is
evident therefore at least in the population of patients pres-
ently studied that OLP can give rise to field cancerization
of the oral mucosa. This raises the dilemma of how often
and by which methods patients with OLP should be re-
viewed. Some authors have indicated that the available
data do not demonstrate that frequent clinical examinations
lead to a decrease in morbidity and mortality from OLP-
related OSCC.48 However, the same criticism has also arisen
with regard to endoscopic dysplasia surveillance in patients
with gastrointestinal disorders associated with cancer devel-
opment, such as Barrett’s oesophagus and inflammatory
bowel diseases. In these conditions a reduction of mortality
and morbidity from oesophageal and colorectal cancer has
not been clearly demonstrated yet, although cancers identi-
fied by surveillance are at earlier stages than those diagnosed
without prior endoscopic evaluation and, thus, might have
a correspondingly better prognosis.49e51 We previously sug-
gested that periodic recall of OLP patients should be per-
formed at least 3 times a year and based on well-defined
clinical features, in order to detect intraepithelial neoplasia
and invasive oral carcinomas at an early stage.18,52 The pres-
ent data would seem to support this; in particular the results
confirm that a careful surveillance programme is able to de-
tect malignant transformation at early intraepithelial and mi-
cro-invasive stages, which are in general characterized by
a very good prognosis. Most of the present group of patients
with OLP and subsequent multiple and multifocal OSSC had
a favourable outcome. On the basis of observation time after
first tumour, analysis of survival was available for a period of
at least 5 years in 16 patients and 3 years in 20 patients. Ac-
cordingly, the 5-year survival was 93.8 % (15 patients out of
16 being still alive 5 years after first tumour) and the 3-year
survival was 100 % (20 patients out of 20 being still alive
3 years after first tumour). Nevertheless in a small subgroup
of the present patients who developed multiple and multifo-
cal OSSC (6 out of 25), regular clinical surveillance was not
able to detect early malignant transformation, with oral
carcinomas being detected at an advanced stage. Three of
these 6 patients died as a consequence of their oral
malignancies. It is evident therefore that in a minority of pa-
tients, malignant transformation may not be visibly
detectable possibly reflecting a rapid transition to intraepi-
thelial neoplasia and then to invasive carcinoma within
a few months.
Furthermore, it is unlikely that the high incidence of sec-
ondary tumours observed in the present study could have
been caused by inadequate surgical resection (macroscopic
margin of 0.5 cm of clinically uninvolved mucosa obtained
in most cases; further resection if lateral/deep margins were
proven to be involved by moderate/severe dysplastic
changes and/or invasive carcinoma). Although a macro-
scopic margin of 1 cm or wider has often been suggested
to remove fields of normal-appearing mucosa surrounding
advanced oral OSCC, more recent studies have underlined
that the condition of surgical margins is an ill-defined issue
in the literature, unlikely to represent a single independent
prognostic factor.53,54
Conclusions
Here we have reported for the first time that patients
with OLP may develop multiple and multifocal neoplastic
events, a behaviour which parallels the well known process
of field cancerization of oral cancer and some high-risk
potentially malignant diseases. A careful surveillance can
detect most tumours in their early intraepithelial and micro-
invasive phase, leading to a long-term survival even if at the
cost of multiple resections. However, a small subgroup of
patients seems not to benefit from such surveillance and
to be characterized by quick development of advanced-
stage oral carcinomas, with consequent worse prognosis.
No tools are available up to now to identify these patients
with such a high-risk profile. Currently there is urgent
need to introduce and validate more precise analyses,
such as those looking at molecular changes or DNA aberra-
tions, which have been shown to be affordable in other pre-
cancerous lesions55e57 and could therefore also be applied
in OLP patients as reliable prognostic factors.
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