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

been further extended to include not only a higher-than-
The concept of ‘‘field cancerization’’ was first intro- expected prevalence of multiple local second primary tu-
duced by Slaughter et al. in 1953 when studying the pres- mours and the presence of synchronous distant tumours
ence of histologically abnormal tissue surrounding oral within the UAT, but also the occurrence of multiple oral
squamous cell carcinoma.1,2 It was proposed to explain premalignant lesions.3 Oral leukoplakia, oral submucous
the development of multiple neoplasms of the upper aerodi- fibrosis and erythroplakia, generally considered the three
gestive tract (UAT) observed in head and neck cancer pa- major clinical types of premalignant oral lesions, share
tients as a consequence of continuous exposure of these with oral squamous cell carcinoma (OSCC) the same risk
factors as well as the same events underlying the process
* Corresponding author. Oral Medicine Unit, Division of Maxillofacial, of field cancerization, namely widespread lateral clonal
Diagnostic, Medical and Surgical Sciences, Eastman Dental Institute for
Oral Health Care Sciences, University College of London, University of
expansion of a single progenitor and/or independent molec-
London, 256 Gray’s Inn Road, London, WC1X 8LD, UK. ular events affecting multiple cells separately.4e6 An im-
E-mail address: [email protected] (S. Fedele). 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 intraepithelial neoplasia and/or invasive OSCC. Among
via histological and molecular studies, remain beyond the them, patients presenting multiple synchronous and meta-
limits of resection and may lead to new potentially malig- chronous neoplastic events were considered for further
nant and malignant lesions.3 Even if these second primary data analysis with focus on tumour incidence and locations,
lesions and/or local recurrences are not considered a major clinical management, and prognosis. The study cohort
cause of mortality in head and neck cancer patients,7,8 they belongs to a bigger group of 700 patients who have been
could have a significant impact upon the need for and type diagnosed and regularly reviewed during a period of
of treatment, and overall prognosis of patients. Further- 16 years (1990e2006).
more, recent studies have suggested that a subgroup of The diagnosis of OLP was based upon clinical manifes-
potentially malignant lesions with gross genomic aberra- tations (papular, plaque and/or reticular lesions alone or in
tions (aneuploid erythroplakia and leukoplakia) are charac- association with erosive/ulcerative lesions, mostly but not
terized by a high incidence of multiple and multifocal exclusively bilateral and symmetrical) confirmed by inci-
subsequent tumours and associated mortality.9,10 It is not sional biopsy demonstrating characteristic microscopic
known whether the concept of field cancerization should features including hyperortho-hyperparakeratosis of the
be extended to oral lichen planus (OLP), a chronic inflam- superficial epithelial layers, vacuolar degeneration of the
matory disorder which is increasingly considered to have germinative layer of the epithelium, and subepithelial lym-
malignant potential unrelated to common risk factors phocytic band-like infiltrate.27,28 Patients suspected to have
(e.g. tobacco and alcohol usage) of oral cancer develop- lichenoid lesions related to drugs or oral restorations were
ment.11e16 However, a few preliminary studies have sug- not included. The diagnosis of neoplastic events was based
gested that some patients with OLP-related OSCC have upon clinical examination confirmed by histopathological
a poor prognosis due, at least in part, to a tendency to examination of lesional tissue. Dysplasia/oral carcinoma
develop second primary metachronous oral cancers.17,18 was graded according to the criteria of the World Health
Paralleling this, multifocal and synchronous or meta- Organization.29 The criteria of the American Joint Commit-
chronous areas of malignant transformation (e.g. high- tee on Cancer were used to determine the clinical stage.30
grade dysplasia and invasive carcinomas) characterize other The International Classification of Diseases for Oncology
chronic inflammatory conditions associated with cancer de- (ICD-O) was used to identify the sites of carcinomas: the
velopment, such as Barrett’s oesophagus and ulcerative ICD-O codings were confirmed by a standardized drawing
colitis.19e21 This might thus support the view that the con- provided with each patient file.31
cept of field cancerization may be applied also to these dis- Intraepithelial neoplasia and early invasive oral carci-
orders, probably as a consequence of persistent and noma were treated by surgical excision including, whenever
widespread activation of their stromal inflammatory micro- allowed by anatomical and functional factors, at least
environment, given that activated inflammatory cells and 0.5 cm of healthy tissue at the lateral margin of resection
the cytokine network can act as oncogenic agents, hence and about 0.3e0.5 cm of submucosal tissue as deep margin.
promoting epithelial tumorigenesis.22e25 Subsequent cancers which occurred after treatment were
If OLP is a potentially malignant disease linked to defined as second primary tumours when previous resection
chronic inflammation, it would be expected that some pa- margins were free of intraepithelial neoplasia (severe dys-
tients will have disease that behaves in a manner similar plasia/carcinoma in situ) and/or invasive carcinoma, de-
to that of oral epithelial dysplasia and the other chronic in- fined as negative margins. In instances when carcinoma
flammatory conditions associated with cancer development, and/or intraepithelial was present at the resection margins
giving rise to malignant disease that is recurrent and ag- (defined as positive margins) further wider surgical exten-
gressive. The aim of the present retrospective study was sion to clinically healthy mucosa was undertaken. Patients
to determine the incidence, nature and locations of multiple with mild dysplasia at resection margins were not re-
neoplastic events in patients with a previous history of OLP operated but carefully observed by increased frequency of
to establish if there is a potential of field cancerization of periodic clinical examinations. When considered clinically
the oral mucosa associated with OLP. useful, tolonium chloride staining was used as an adjunc-
tive diagnostic aid.32,33 In all cases, OLP diagnosis, dyspla-
Materials and methods sia grading and status of resection margins were determined
after consensus had been reached independently by two pa-
A cohort of 45 patients diagnosed with OLP at the Oral thologists. Advanced stage oral carcinomas were treated,
Medicine Section of University ‘‘Federico II’’ and who sub- whenever possible, with resective maxillofacial surgery.
sequently developed severe epithelial dysplasia/carcinoma Neck dissection, orofacial reconstruction and postoperative
in situ, defined here as oral intraepithelial neoplasia,26 radiotherapy and/or chemotherapy were provided where
and/or invasive OSCC were retrospectively analysed. All needed. Patients were routinely recalled and clinically
the patients did not have clinical/histological signs of observed every 4 months, except those needing closer
dysplasia or OSCC at the time of OLP diagnosis and all surveillance due to recent development of dysplasia or
developed at least one neoplastic event, namely one intraepithelial neoplasia/invasive carcinoma.34 Clinical
 M.D. Mignogna et al. / EJSO 33 (2007) 383e389 385

criteria used to perform dysplasia/neoplasia surveillance in contiguous and/or distant areas of synchronous multifocal
OLP patients have been previously described34 and were malignant transformation, involving different ICD-O sites.
applied to all patients. The topographic relation between primary and subsequent
neoplastic events is presented in Fig. 3. In brief, in 5 of
Results 25 patients belonging to the subgroup with multiple
OSCC (20 %), the neoplastic events occurred only in the
Malignant transformation: incidence and location same location as the previous ones. However, the remaining
20 patients developed subsequent multifocal intraepithelial
All 45 patients were clinically monitored for at least neoplasias/invasive carcinomas in ICD-O sites distant to
3 years following the diagnosis of OLP (range 3e14 years). that of the preceding tumours. There was a general trend
Twenty (44 %) of the 45 patients were affected by only one of increasing variation in site of neoplastic events with
neoplastic event (occurrence of intraepithelial neoplasia/in- the number of new second primary tumours. Tumours
vasive carcinoma). The remaining 25 developed at least one mostly occurred in the same mucosal areas where OLP le-
second metachronous primary intraepithelial neoplasia/in- sions were already present, even if in some cases they oc-
vasive carcinoma and were therefore subject to further eval- curred in areas of mucosa which clinically appeared to be
uation. In particular, the neoplastic events were distributed non-involved by OLP. With regard to the clinical form of
as follows: 2 in 9 patients (36 % of the subgroup with more OLP, the majority of patients were affected by predomi-
than one neoplastic event), 3 in 7 patients (28 %), 4 in 6 nantly keratotic lichenoid lesions. Those few patients
other patients (24 %), 6 in 1 patient (4 %), and 12 and 16 with erosive painful lesions were managed with short-
in 2 patients (4 % and 4 %, respectively). The course of term courses of topical corticosteroid (clobetasol) therapy
neoplastic events of these 25 patients is detailed in Fig. 1; which, as previously described, does not represent a risk
Fig. 2 shows the clinical course of the whole study group factor for cancer development in patients with OLP.14
of 45 patients with OLP who developed at least one intra-
epithelial neoplasia/invasive carcinoma. The observation Tumour staging and cancer specific mortality
period following the detection of the first oral malignancy
was at least 3 years for the majority of patients with multi- There were 97 neoplastic events subsequent to the diag-
ple neoplastic events (80 %; 20/25), ranging from 3 to nosis of OLP in the 25 patients who developed more than
12 years (mean observation period: 6.75 years). Consider- one malignancy. Among these 91 (93.9 %) were intraepi-
ing also 5 patients with first tumour occurring in 2003 (1 thelial neoplasias (severe dysplasia/carcinoma in situ) or
case) and 2004 (4 cases), the follow-up ranged from 1 to microinvasive carcinomas (1 mm), i.e. stage 0 and I
12 years, with a mean observation period of 5.64 years. oral cancers (TisN0M0 or T1N0M0). The other tumours
While in most cases each neoplastic event was generally were stage IV (T4N1M0) (3 tumours) and stage III
characterized by one single intraepithelial neoplasia/ (T1N1M0) (3 tumours). All stage IV OSCC occurred in
invasive carcinoma involving one oral ICD-O site, in patients with multiple and multifocal metachronous neo-
some patients malignant diseases occurred as two or three plastic events. Two stage III OSCC occurred as a second

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.
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 mainly relies upon the suggested theory that ‘‘true’’ OLP
neoplasia/invasive carcinoma, whereas a third patient had is a benign disorder and that many of the reported OLP
stage III OSCC following multiple neoplastic events. Over- cases developing oral cancer are in fact not OLP, but rather
all, 3 patients died due to their stage IV OSCC, correspond- dysplastic lesions with lichenoid features and non-OLP oral
ing to a cancer-specific-mortality of 12 % (3/25). lichenoid lesions which behave differently from benign
OLP. To support this view, some authors including Eisen-
Characteristics of OLP patients who developed berg,35 Krutchkoff,36, 37 and van der Meij38 have proposed
multiple neoplastic events strict histopathological and/or clinico-pathological diagnos-
tic criteria which should be able to identify, within the large
Seventeen (68 %) of the 25 patients with OLP who sub- group of lichenoid lesions, those with and those without
sequently developed multiple neoplastic events were fe- malignant potential. Nevertheless these criteria have
male. Only two patients were former cigarette smokers not been validated.14,38 In addition, recent studies have
and no one reported misuse of alcoholic beverages or demonstrated that patients with OLP that do fulfil the afore-
smokeless tobacco habit. Three patients required cycles mentioned diagnostic criteria can have malignant transfor-
of topical steroidal therapy to control oral symptoms related mation of lesions.14,38,39 In the present study the patients
to erosive OLP lesions. One patient was treated with with histopathologically detectable oral epithelial dysplasia
systemic 13-cis-retinoic acid, beta-carotene, and alpha- at the time of OLP diagnosis were not included because of
tocopherol as chemopreventive therapy, because of a high the necessity of documenting the progression from non-
incidence of secondary oral tumours. This therapy was dysplastic epithelium to in situ and/or invasive carcinoma,
however discontinued due to side effects (cutaneous toxic- which is the most accepted progression model for most
ity, hypertriglyceridemia and hypercholesterolemia) after solid malignancies, including head and neck cancer.40e43
10 months. The majority of patients who developed multi- There are little data on the characteristics and outcome
ple OSCC had asymptomatic predominantly keratotic (both of OSCC in patients with OLP. Hietanen and co-workers re-
plaque and reticular types) OLP lesions. ported that 5 of their 8 patients with OLP-related OSCC
died within a few months from oral cancer diagnosis, but
Discussion they did not provide further important prognostic informa-
tion such as tumour stage and occurrence of recurrences or
The present study has investigated the characteristics of second primary tumours.17 More recently, we retrospec-
OSCC in patients with previous OLP to determine if the tively examined 21 OLP patients who developed OSCC
oral mucosa of such individuals demonstrates field cancer- and found that 33.3 % and 23.8 % developed second pri-
ization. The malignant transformation of OLP is still mary metachronous tumours of the oral cavity and nodal
a much debated issue. The criticism of available studies 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 on the topographical relationship, the clinical behaviour we
study 20 (44 %) of the 45 patients with OLP developed observed is apparently consistent with the theories of both
only one SCC. In contrast the remaining 25 patients separate and independent cell clones44 and the presence of
(56 %) developed further, often distant, primary OSCC. occult clonal alterations at histologically negative resection
The mean duration to the time of the first OSCC was sim- margins or lateral clonal spread.6,45 During the last few
ilar in both groups. There was no difference in the duration years, it has become evident that the process of field cancer-
of OLP, or types of OLP between the two groups. This high ization is not necessarily associated with field exposure to
incidence of secondary primary tumours strongly parallels environmental carcinogens, and has been described in other
the process of field cancerization observed with OSCC organs such as lung, oesophagus, vulva, cervix, colon,
and oral epithelial dysplasia. breast, bladder, and skin.2 It is interesting to note that with
With regard to topographic relation, the present findings colon cancer the occurrence of carcinoma and dysplasia in
are consistent with the phenomenon of field cancerization patients with chronic inflammatory diseases of the bowel
because of the high frequency (80 %) of different oral loca- is typically multifocal and multicentric, and may present
tions between primary and subsequent intraepithelial neo- several characteristics in common with OLP-related
plasias/invasive carcinomas. In the remaining 20 % of OSCC. Indeed chronic inflammation and immune activation
cases subsequent events occurred in the same location of pri- have been reported to act as oncogenic agents in these disor-
mary neoplasia, notwithstanding the absence of histopatho- ders.15,46,47 It might thus be speculated that the activated in-
logically detectable intraoral neoplasia/invasive carcinoma flammatory cells and cytokine network which act to promote
at lateral and deep resection margins. Although molecular squamous tumorigenesis, may, in the same manner, influ-
studies were not performed, and clonality cannot be assumed 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 in the literature, unlikely to represent a single independent
evident therefore at least in the population of patients pres- prognostic factor.53,54
ently studied that OLP can give rise to field cancerization
of the oral mucosa. This raises the dilemma of how often Conclusions
and by which methods patients with OLP should be re-
viewed. Some authors have indicated that the available Here we have reported for the first time that patients
data do not demonstrate that frequent clinical examinations with OLP may develop multiple and multifocal neoplastic
lead to a decrease in morbidity and mortality from OLP- events, a behaviour which parallels the well known process
related OSCC.48 However, the same criticism has also arisen of field cancerization of oral cancer and some high-risk
with regard to endoscopic dysplasia surveillance in patients potentially malignant diseases. A careful surveillance can
with gastrointestinal disorders associated with cancer devel- detect most tumours in their early intraepithelial and micro-
opment, such as Barrett’s oesophagus and inflammatory invasive phase, leading to a long-term survival even if at the
bowel diseases. In these conditions a reduction of mortality cost of multiple resections. However, a small subgroup of
and morbidity from oesophageal and colorectal cancer has patients seems not to benefit from such surveillance and
not been clearly demonstrated yet, although cancers identi- to be characterized by quick development of advanced-
fied by surveillance are at earlier stages than those diagnosed stage oral carcinomas, with consequent worse prognosis.
without prior endoscopic evaluation and, thus, might have No tools are available up to now to identify these patients
a correspondingly better prognosis.49e51 We previously sug- with such a high-risk profile. Currently there is urgent
gested that periodic recall of OLP patients should be per- need to introduce and validate more precise analyses,
formed at least 3 times a year and based on well-defined such as those looking at molecular changes or DNA aberra-
clinical features, in order to detect intraepithelial neoplasia tions, which have been shown to be affordable in other pre-
and invasive oral carcinomas at an early stage.18,52 The pres- cancerous lesions55e57 and could therefore also be applied
ent data would seem to support this; in particular the results in OLP patients as reliable prognostic factors.
confirm that a careful surveillance programme is able to de-
tect malignant transformation at early intraepithelial and mi-
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