OtolaryngologyHead and Neck Surgery (2007) 136, 401-404

ORIGINAL RESEARCH

Behavior of oral squamous cell carcinoma

in subjects with prior lichen planus
Amanda A. Muoz, MD, Robert I. Haddad, MD, Sook-Bin Woo, MD,
and Neil Bhattacharyya, MD, Stanford, CA; and Boston, MA
OBJECTIVE: To characterize the clinical behavior of oral squamous cell carcinomas (OSCCA) arising in patients with pre-existing oral lichen planus (OLP).
STUDY DESIGN AND SETTING: Retrospective case-control
study. Disease-free interval, time to first recurrence, subsequent
therapy, and overall survival were calculated and compared between cases and controls matched for age, gender, primary site,
and tumor stage.
RESULTS: In 10 identified subjects with OLP/OSCCA, mean
time from OLP diagnosis to OSCCA was 5.5 years. Three subjects
suffered a local recurrence and two developed a second primary
OSCCA. Mean actuarial survival for OLP patients was 119 months
vs 42 months for the control patients, though this difference was
not significant (P 0.201, log-rank).
CONCLUSIONS: OLP/SCCA subjects may exhibit better actuarial survival than SCCA patients despite a somewhat higher rate
of local recurrence and second primary SCCA. Further study is
required to characterize the behavior of OSCCA arising in preexisting OLP.
2007 American Academy of OtolaryngologyHead and Neck
Surgery Foundation. All rights reserved.

ral lichen planus (OLP) is a chronic inflammatory

disease that affects approximately 1% to 2% of the
general population.1 Though controversial, OLP is thought
to be a premalignant lesion in a subgroup of cases, potentially leading to the development of oral squamous cell
carcinoma (OSCCA). Although numerically small, the reFrom the Department of OtolaryngologyHead and Neck Surgery,
Stanford University School of Medicine (Dr Muoz); Dana-Farber Cancer
Institute and Harvard Medical School, Boston (Dr Haddad); Department of
Oral Medicine, Brigham and Womens Hospital, Boston (Dr Woo); and
Division of Otolaryngology, Brigham and Womens Hospital, and Department of Otology and Laryngology, Harvard Medical School (Dr Bhattacharyya).
This research was conducted with support from the Clinical Research
Fellowship Program at Harvard Medical School offered by the Doris Duke

ported rate of transformation of OLP to OSCCA varies

greatly in the literature, from 0.5% to upwards of 5%.2 The
genetic changes that may lead to malignant transformation
have also been widely studied; proposed mechanisms include hepatitis C virus infection status,3 loss of heterozygosity,1 changes in the p53 system,4 and others. It is generally accepted that increased clinical surveillance is
integral to the long-term care of the patient with OLP, in
order to more carefully screen for changes that may
indicate malignant transformation. Though it is known
that OLP poses some elevated risk related to the development of OSCCA, relatively little is known about the
clinical behavior of OSCCAs that develop in OLP subjects as compared to those OSCCAs in subjects without
prior OLP.
In 2002, Mignogna et al reviewed the records of 21
patients with OLP and subsequent OSCCA. They confirmed
the increased risk of malignant transformation that has been
reported as compared to the general population, and found
that OLP/OSCCA subjects were more likely to develop a
second or third oral malignancy and more likely to have
nodal metastases than control subjects with OSCCA alone.5
We sought to determine if the cancers that develop in OLP
sites behave differently from the cancers in patients without
previous OLP. To do this, we compared long-term clinical
data between OLP/SCCA subjects and subjects with
OSCCA alone.
Charitable Foundation, the Harvard PASTEUR Program, and the Harvard
Office of Enrichment Programs.
Presented at the Annual Meeting of the American Academy of
OtolaryngologyHead and Neck Surgery, Toronto, ON, Canada, September 17-20, 2006.
Reprint requests: Neil Bhattacharyya, MD, FACS, Division of Otolaryngology, 45 Francis St., Boston, MA 02115.
E-mail address: neiloy@massmed.org.

0194-5998/$32.00 2007 American Academy of OtolaryngologyHead and Neck Surgery Foundation. All rights reserved.
doi:10.1016/j.otohns.2006.09.023
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402

OtolaryngologyHead and Neck Surgery, Vol 136, No 3, March 2007

METHODS
A retrospective review was conducted of all cases of newly
diagnosed SCCA involving the oral cavity and oropharynx
from January 1, 1992 through December 31, 2004 at our
tertiary care head neck cancer center. This study was approved by our hospitals human studies research committee
and conducted in compliance with the Healthcare Information Portability and Accountability Act. Cases with an associated diagnosis of oral cavity lichen planus were identified by review of pathological diagnoses, cross-referencing
a prospectively maintained International Classification of
Diseases (ICD-9) diagnosis database, and/or review of
surgical procedure logs. Medical records, electronic medical records, and radiographic studies were reviewed for
each case of OLP. Data were collected for date of first
diagnosis of lichen planus, age, gender, tobacco and
alcohol use, and pathological subtype of OLP. Additional
data were collected for the diagnosis of SCCA including
age at diagnosis, primary site, AJCC stage, radiographic
findings, and treatments administered including surgery,
radiation, and chemotherapy. Follow-up data were obtained including disease-free interval, time to first recurrence, subsequent therapy, and overall survival.
Control patients were obtained from the Surveillance, Epidemiology and End Results database for the time period 19732001. Control patients were matched 2:1 according to primary
site, age at SCCA diagnosis (within five years), gender, and
TNM stage.6,7 Survival comparisons were conducted between
the control patients and the OLP patients with respect to overall
survival with the Kaplan-Meier method and the log-rank test
with statistical significance set at P 0.05.

RESULTS
Upon initial review, 13 cases of SCCA associated with oral
lichen planus were identified. Three cases were excluded

from analysis because there existed a diagnosis of SCCA of

the oral cavity before a subsequent clinical or pathological
diagnosis of OLP. Therefore a total of 10 patients with a
previous diagnosis of OLP and a subsequent diagnosis of
SCCA of the head and neck were available for analysis. In
all cases, the SCCA arose at the site of pre-existing OLP.
The mean age was 73 years (range, 54-92 years) and all
patients were female. Seven of 10 cases possessed tissue
confirmation of their OLP available for review at our institution, and were reviewed by a dedicated head and neck
and/or oral pathologist. For the three other cases, the diagnosis of OLP was established clinically prior to the diagnosis of SCCA by a specialist in oral medicine/oral pathology,
and these patients were followed for a number of years
antedating the diagnosis of SCCA.
The mean duration from diagnosis of OLP to development of subsequent SCCA was 5.5 years (range, 0 months
to 30 years [in the 0-month interval patient, tissue pathology
diagnosed SCCA arising with a surrounding mucosa involved with OLP]). The primary site for the development of
subsequent SCCA was: oral tongue (four), buccal mucosa
(two), maxillary alveolar ridge (two), and mandibular alveolar ridge (two). Only two of 10 patients reported any
previous tobacco use (42- and 65-pack-year history, respectively). None of the OLP patients abused alcohol. The
distribution of tumors in our study group according to primary site and TNM staging is depicted in Table 1.
All patients were initially treated with surgical resection
of their primary site lesion. In addition, four patients also
underwent neck dissection (three supraomohyoid neck dissections and one modified radical neck dissection). Five
patients were found to have positive surgical margins after
the first resection. Two patients additionally received chemotherapy. Three patients also received radiation therapy
(one patient preoperatively and two patients postoperatively).

Table 1
Description of study population with oral SCCA arising in the setting of OLP

Subject

Gender

Age (y) at
OSCCA
diagnosis

1
2
3
4
5

F
F
F
F
F

43
87
80
57
59

6
7
8
9
10

F
F
F
F
F

79
75
70
63
71

Primary SCCA site

Lateral tongue
Buccal mucosa
Retromolar trigone
Mandibular ridge
Hard palate/maxillary
alveolar ridge
Buccal mucosa
Lateral tongue
Posterolateral tongue
Ventral tongue
Alveolar ridge

TNM stage at
diagnosis
T1
T1
T2
T4
T4

Duration of
follow-up (m)

Status at study
conclusion*

143.4
44.9
15.2
14.5
13.9

ADF
AWD
AWD
DOD
ADF

9.7
24.9
9.8
77.6
0.6

ADF
ADF
ADF
AWD
AWD

N0 M0
N0 M0
N0 M0
N1 M0
N2b M0

T1 N0 M0
T2 N0 M0
T2 N0 M0
T2 N0 M0
T4a N2b M0

*ADF, alive, disease-free; AWD, alive with disease; DOD, died of disease.

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Muoz et al

Behavior of oral squamous cell carcinoma . . .

Of the 10 patients, three patients were found to have

local recurrence at the first primary site. These recurrences
were identified at six months, 3.5 years, and four years after
initial diagnosis. Two of these patients were found to have
yet another additional primary site recurrence at one year
and 4.5 years after initial diagnosis of SCCA. Both of these
patients received additional surgical therapy. None of the
patients was found to have regional recurrence or distant
metastases at the conclusion of the study period.
Two of 10 patients developed a second primary at a
different primary site occurring at 3.5 years and 10 months
after the first primary diagnosis. Duration of follow-up
ranged from one month to 145 months with a mean follow-up of 35.9 months. At the conclusion of the study, five
patients were alive without disease, four patients were alive
with disease, and one patient died of disease.
Nine of the 10 patients were successfully matched to
control patients with oral SCCA for age at diagnosis, sex,
and TNM stage. The sole patient that could not be successfully matched lacked complete information for tumor stage.
Mean age at SCCA diagnosis was not different between the
OLP patients in the control patients (P 0.465, Student
t test). Mean actuarial survival for patients with OLP was
119 months vs 42 months for the control patients; however,
this difference was not statistically significant (P 0.201,
log-rank test). The Kaplan-Meier survival curves for the
oral lichen planus patients vs the control patients are presented in Figure 1.

DISCUSSION
The malignant transformation from OLP to OSCCA remains controversial for several reasons. First, the discrepancy that exists in pathologic diagnosis between OLP, li-

Figure 1 Kaplan-Meier survival curves for oral SCCA in patients with oral lichen planus and control patients.

403

chenoid dysplasia, and true oral malignancy can blur the

difference between OLP-related OSCCA and OSCCA that
develops on its own.1 Additionally, the rates of malignant
transformation have varied across the multiple populations
that have been studied, and many different transformation
mechanisms have been described. Though it is very important to refine the diagnostic criteria for OLP and to identify
the specific genetic mechanisms by which malignant transformation might take place, it is also important for clinical
practice to know whether or not OSCCAs that come from
OLP lesions behave clinically differently from OSCCAs in
non-OLP subjects.
The characteristics of the current OLP-OSCCA cohort
mirror many of the characteristics that have been identified
in the OLP-OSCCA relationship. Only two out of our 10
subjects were tobacco smokers, and none of our subjects
abused alcohol; both of these risk factors occur at a much
higher incidence in the population with OSCCA absent
OLP. The time from OLP diagnosis to development of
OSCCA in our population was 5.5 years; Hietanen et al
observed a time from OLP to OSCCA diagnosis of 3.4
years,8 and the population studied by Mignogna et al had a
mean time to OSCCA development of 2.6 years. Three of
10 (30%) of our subjects had positive lymph nodes at the
time of diagnosis (Table 1); Mignogna et al found that 5/21
(24%) of their OLP/SCCCA subjects had positive neck
nodes. Of note, three patients were diagnosed with T4
lesions based on bone involvement. This underscores the
importance of following patients with OLP involving the
attached gingivae or retromolar trigone since SCCA arising
in the setting of oral lichen planus at these sites may ultimately be diagnosed as T4 lesions.
The three subjects with recurrence at the primary site
may represent an additional trend in the behavior of OLPrelated OSCCAs. In addition, two of these three OLP subjects had a further second recurrence at the primary site. It
may be that OLP/OSCCAs are more likely to recur in the
primary site after treatment than OSCCAs without prior
OLP. The proportion of subjects with second primary formation (as opposed to primary site recurrence) in our group
(2/10, one at 10 months and one at 2.5 years after first
diagnosis of OSCCA) is similar to that found in the Mignogna et al study population (2/21).5
Finally, the actuarial survival of 119 months in OLP/
OSCCA subjects vs 42 months in the OSCCA-alone group
indicates that there may be a trend toward longer survival in
OLP-related OSCCAs. This could represent differences at
the genetic level between OSCCAs that develop via OLPrelated changes and OSCCAs that do not, or they may also
be due to the influences of other factors such as tobacco and
alcohol abuse. Interestingly, the population in the study by
Hietanen et al reported 5/8 OLP/SCCA subjects who died
within 13 months of OSCCA diagnosis.8
Shortcomings of our study (and the data available in the
literature) include the small sample size and its retrospective
nature. We continue to collect prospective data on our

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404

OtolaryngologyHead and Neck Surgery, Vol 136, No 3, March 2007

surviving OLP subjects in order to integrate their long-term

clinical data for future analyses. Additionally, all of the
OLP subjects were female. Though females have a higher
incidence of autoimmune and chronic inflammatory conditions, it would be interesting to see whether OLP-related
OSCCAs are more common in females vs males. This trend,
however, has not been identified in past retrospective reviews of OLP and malignant transformation, and hence a
more comprehensive study of male and female OLP subjects is necessary to examine more thoroughly long-term
clinical outcomes. In addition, tobacco and/or alcohol use
may have negatively influenced survival within the control
group. Because we had only two patients with a significant
tobacco exposure and no patients with alcohol exposure,
both of these habitual comorbidities may have contributed
to survival differences between the two groups. Further
study will be required to determine the influence of tobacco
and/or alcohol use on malignant transformation, recurrence,
and survival for SCCA ex OLP patients. Despite these
shortcomings, we believe that these data provide an initial
basis for further study of the clinical behavior of OLPrelated OSCCAs.
Many of our subjects on retrospective review had to be
excluded due to lack of tissue diagnosis of OLP. We elected to
only include patients with a tissue diagnosis or who were
clinically diagnosed and followed by an expert oral medicine
physician at our institution. For future studies, it will be important to document OLP status on patients that may carry a
clinical OLP diagnosis, and to adhere to the strict pathologic
diagnostic criteria, including OLP subtype, outlined in many
other studies.9 Furthermore, tissue obtained at the diagnosis of
OLP may also hold clues as to those patients more likely to
develop oral SCCA subsequently. Additionally, the clinical
surveillance of OLP subjects is not standardized at our institution. Several authors have recommended increased clinical
surveillance to check for malignant transformation in OLP
subjects, but the recommendations for examination frequency
have varied from every two months to bi-annually.2,5 Strict and
more uniform follow-up would enable us to include more OLP
subjects in our study and would give us more consistent data
on time to malignant transformation.

CONCLUSIONS
In summary, OLP-related OSCCAs may have a different
profile of clinical behavior than OSCCAs that arise in patients without pre-existing OLP. OLP subjects may have a
higher risk of recurrence in the primary site and a higher
incidence of formation of a second primary tumor, but
despite this they may also have longer actuarial survival.
Further research and closer surveillance of this population is
needed to better inform our understanding of OLP and its
relationship to OSCCA.9

REFERENCES
1. Epstein JB, Wan LS, Gorsky M, et al. Oral lichen planus: Progress in
understanding its malignant potential and the implications for clinical management. Oral Surg Oral Med Oral Pathol 2003;96(1):327.
(Grade D).
2. van der Meij EH, Schepman K, vander Waal I. The possible premalignant character of oral lichen planus and oral lichenoid lesions: A
prospective study. Oral Surg Oral Med Oral Pathol 2003;96(2):164 71.
(Grade B).
3. Gandolfo S, Richiardi L, Carrozzo M, et al. Risk of oral squamous cell
carcinoma in 402 patients with oral lichen planus: a follow-up study in
an Italian population. Oral Oncol 2004;40:77 83. (Grade B).
4. Ogmundsdottir HM, Hilmarsdottir H, Astvaldsdottir A, et al. Oral
lichen planus has a high rate of TP53 mutations. A study of oral mucosa
in Iceland. Oral Surg Oral Med Oral Pathol 2002;93(5):586 92.
5. Mignogna MD, Lo Russo L, Fedele S, et al. Clinical behaviour of
malignant transforming oral lichen planus. Eur J Surg Oncol 2002;28:
838 43. (Grade C).
6. Bhattacharyya N, Nayak VK. Survival outcomes for second primary
head and neck cancer: a matched analysis. Otolaryngol Head Neck Surg
2005;132:63 8.
7. Bhattacharyya N. A matched survival analysis for squamous cell carcinoma
of the head and neck in the elderly. Laryngoscope 2003;368 72.
8. Hietanen J, Paasonen MR, Kuhlefelt M, et al. A retrospective study of
oral lichen planus patients with concurrent or subsequent development
of malignancy. Oral Oncol 1999;35:278 82. (Grade B).
9. van der Meij EH, van der Waal I. Lack of clinicopathologic correlation
in the diagnosis of oral lichen planus based on the presently available
diagnostic criteria and suggestions for modifications. J Oral Pathol Med
2003;32(9):50712. (Grade D).

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