YIJOM-4773; No of Pages 8

Int. J. Oral Maxillofac. Surg. 2019; xxx: xxx–xxx

https://doi.org/10.1016/j.ijom.2021.08.012, available online at https://www.sciencedirect.com

Clinical Paper
Clinical Pathology

Risk factors for oral epithelial S. Gómez-Armayones1,2,

E. Chimenos-Küstner3, C. Arranz4,
S. Tous5,6,7, S. Marquez5,6,
R. M. Penı́n8, B. Quirós5,6,7,
dysplasias to become M. Taberna9,10, L. Alemany5,6,7,
O. Servitje1, M. Mena5,6,7
1
Department of Dermatology, Bellvitge

malignant: clinical implications University Hospital, L’Hospitalet de Llobregat,

Barcelona, Spain; 2Department of
Dermatology, Hospital Clı́nic of Barcelona,
Barcelona, Spain; 3Department of
Odontostomatology, Odontological University
S. Gómez-Armayones, E. Chimenos-Küstner, C. Arranz, S. Tous, S. Marquez, R.M. Hospital of Barcelona, L’Hospitalet de
Penı́n, B. Quirós, M. Taberna, L. Alemany, O. Servitje, M. Mena: Risk factors for oral Llobregat, Barcelona, Spain; 4Department
epithelial dysplasias to become malignant: clinical implications. Int. J. Oral Oral and Maxillofacial Surgery, Bellvitge
Maxillofac. Surg. 2019; xxx: xxx–xxx. ã 2021 International Association of Oral and University Hospital, L’Hospitalet de Llobregat,
Barcelona, Spain; 5Cancer Epidemiology
Maxillofacial Surgeons. Published by Elsevier Inc. All rights reserved. Research Program, Catalan Institute of
Oncology (ICO), L’Hospitalet de Llobregat,
Barcelona, Spain; 6Epidemiology, Public
Health, Cancer Prevention and Palliative Care
Abstract. There is a lack of effective clinical management of oral epithelial Program, IDIBELL, L’Hospitalet de Llobregat,
dysplasias to reduce their risk of malignant transformation and considerable gaps in Barcelona, Spain; 7Centro de Investigación
knowledge regarding the most effective means of treating such lesions. A Biomédica en Red de Epidemiologı́a y Salud
retrospective cohort of biopsy-confirmed oral epithelial dysplasias consecutively Pública (CIBERESP), Instituto de Salud
diagnosed in the period 1995–2014 and followed-up until 2017 was identified from Carlos III, Madrid, Spain; 8Department of
Pathology, Bellvitge University Hospital,
pathology department files. Demographic, clinical and follow-up information was L’Hospitalet de Llobregat, Barcelona, Spain;
collected. Multivariate Cox proportional-hazards models were performed to evaluate 9
Department of Medical Oncology, Catalan
sociodemographic, clinical and pathological factors associated with progression to Institute of Oncology (ICO), L’Hospitalet de
oral squamous cell carcinoma. The study included 144 oral epithelial dysplasias, of Llobregat, Barcelona, Spain; 10Program of
which 42% progressed to oral cancer at the end of follow-up (21 years). Clinical Molecular Mechanisms and Experimental
aspect of the lesion was described for 77 (53.5%) of the patients. Treatment, age, Therapy in Oncology, IDIBELL, L’Hospitalet
de Llobregat, Barcelona, Spain
grade of the lesion and diagnostic period were independent prognostic factors for
progression. When considering only patients with described clinical aspect, only
treatment and grade of the lesion were independently associated with cancer. The
results from this non-selected retrospective cohort of oral epithelial dysplasias
underscore the existing limitations of the current standard-of-care of the patients and Key words: oral squamous cell carcinoma; oral
provide novel insights on the management of these lesions with and without leukoplakia; oral pathology; mouth mucosa.
described clinical aspect. Well-designed, robust prospective studies, a homogenized
staging system and multidisciplinary treatment guidelines are warranted. Accepted for publication 12 August 2021

Introduction
Oral squamous cell carcinoma (OSCC) is
the most common type of head and neck
cancer and may be preceded by oral poten-
tially malignant disorders (OPMDs)1. Most
OMPDs are visible to the naked eye and
present as white or red areas of the mucosa
including lesions such as oral lichen planus
(OLP), leukoplakia, erythroplakia, erythro-
leukoplakia, oral submucous fibrosis, pro-
liferative verrucous leukoplakia or more
widespread conditions2. Some OPMDs
are histopathologically diagnosed as oral
epithelial dysplasia (OED). Moreover,
there are pre-malignant mucosal abnormal-
ities that are clinically not visible and are
only identified under the histopathological
analysis as OED3. OED is one of the most
common diagnoses at the histopathological
evaluation of oral cavity lesions.

0901-5027/000001+08 ã 2021 International Association of Oral and Maxillofacial Surgeons. Published by Elsevier Inc. All rights reserved.

Please cite this article in press as: Gómez-Armayones S, et al. Risk factors for oral epithelial dysplasias to become malignant: clinical
implications, Int J Oral Maxillofac Surg (2021), https://doi.org/10.1016/j.ijom.2021.08.012
YIJOM-4773; No of Pages 8
2 Gómez-Armayones et al.
Incidence and prevalence of OPMDs
can vary between different geographical
areas and populations. Some studies sug-
gest that 2–3% of the population present
leukoplakia at the floor of the mouth,
tongue or buccal mucosa, older patients
being at higher risk4,5. Contrary to other
pathologies, OPMDs are managed by a
broad range of specialists and there is
no consensus about their diagnosis and
management. Nevertheless, most authori-
ties recommend incisional biopsy and his-
tological analyses for diagnosis and on
many occasions, excisional biopsy is per-
formed instead of incisional biopsy and
the former is used as a treatment for these
types of lesions6.
Prognostic factors related to progres-
sion to OSCC in OPMDs with and without
OEDs have been poorly understood until
now. Studies on tumour heterogeneity,
field cancerization, molecular pathogene-
sis and the underlying causative cancer
genes, which could help to understand
the natural history of these lesions and
predict their progression to OSCC, have
been recently reviewed3. Although OSCC
can arise de novo or in the absence of
Fig. 1. Kaplan–Meier curves and log-rank tests for cancer-free survival of oral epithelial dysplasia (OED) by age, gender, tobacco and alcohol
consumption.
Please cite this article in press as: Gómez-Armayones S, et al. Risk factors for oral epithelial dysplasias to become malignant: clinical
implications, Int J Oral Maxillofac Surg (2021), https://doi.org/10.1016/j.ijom.2021.08.012
recognizable previous dysplasia6, dyspla-
sia is considered to be the strongest pre-
dictor of future malignant transformation4.
It is generally assumed that higher grades
of dysplasia have greater risk for progres-
sion. Likewise, patients with oral leuko-
plakia are reported to carry a five-fold
increased risk of developing OSCC and
the transformation rate is estimated at 1.4–
1.5% per year4,7. Leukoplakia is a clinical
diagnosis, and it can include dysplasia at
histopathological analysis in up to 10% of
lesions8.
Location of OPMDs could be another
predicting factor of malignant transforma-
tion, as the floor of the mouth and lateral
tongue have shown a higher risk for cancer
development4,5,6,9,10.
Other factors previously found to be
related to progression to OSCC are the
gender of the patients, older ages, smoking
status, certain clinical types and extent of
the lesion, and the possible effect of a
specific therapeutic approach9,10. A recent
Cochrane Review of interventions for
treating oral leukoplakia to prevent OSCC
concluded that none of the treatments
studied demonstrated prevention for oral
leukoplakia progressing to OSCC, noting
that surgical excision could not be
assessed due to the absence of randomized
controlled trials11. However, recent liter-
ature has shown considerable efficacy of
interventional laser surgery in reducing
malignant transformation rates and in im-
proving early diagnosis and facilitating
minimal intervention for OSCC in fully
documented long-term patient cohort
studies12,13. Whether surgical removal of
the lesions is in fact associated with a
cancer-promoting effect resulting in in-
creased risk of cancer has also been con-
sidered14.
Human papillomavirus (HPV) infection
seems also to play a role in the develop-
ment of OSCC, with estimated attributable
fractions of 2–4.4%15. A recent meta-anal-
ysis estimated that 27% of OEDs harbour
HPV DNA, but whether this has carcino-
genic role remains unclear16. We previ-
ously tested 102 OPMDs for HPV-DNA
and we only obtained four (4.8%) positive
cases. As none of these cases progressed to
OSCC, we concluded that HPV was not a
main prognostic factor for progression to
OSCC in our setting17.
YIJOM-4773; No of Pages 8

Malignant transformation of oral dysplasia 3

Fig. 2. Kaplan–Meier curves and log-rank tests for cancer-free survival of oral epithelial dysplasia (OED) by grade of lesion, OED location,
associated diseases and treatment. HG, high grade;LG, low grade; MG, moderate grade; TRT, treatment.

The limited evidence about progression
to OSCC has hindered the recommenda-
tion of long term follow-up of OPMDs to
detect cancerous changes early18.
This study aimed to identify predictive
factors for the progression of OED to
OSCC during follow-up in a large, unse-
lected sample of Spanish cases, in order to
inform the heterogeneous spectrum of
specialists undertaking the clinical man-
agement of such lesions.
Material and methods
Study design and samples
We conducted a retrospective cohort
study of patients consecutively diagnosed
with OED at Bellvitge University Hospi-
tal and Odontological University Hospital
of Barcelona (Spain) and with available
clinical data. Patients were identified at
the Pathology Department and treated by
Dermatology, Odontology, Maxillofacial
Surgery and Otolaryngology/Plastic Sur-
gery Departments. The OPMDs clinical
criteria in our centre are that all specia-
lists have to select white, and red and
white oral plaques of the oral mucosa
with the aim of ruling out malignant
transformation through the pathological
analysis. The evaluation of factors pre-
dicting progression to malignancy was
based on the histopathological diagnosis
of the cases. Histopathological diagnosis
was selected because clinical lesions
were diagnosed by different medical spe-
cialists while the histopathological diag-
nosis was performed in the same
department for all cases and by the same
pathologist (R.P.). OEDs were diagnosed
according to the guidelines which were
applicable at the time of diagnosis1. All
selected patients had to fulfil pre-estab-
lished inclusion criteria: to be histopath-
ologically diagnosed with OED in the
tongue, gingiva, floor of the mouth, pal-
ate, cheek mucosa or oral cavity not
specified; not having a previous OSCC
or oropharyngeal cancer; having avail-
able data about demographics, clinical
and follow-up information. From all eli-
gible cases, we reviewed medical records
of the patients and collected information
on demographics, smoking and alcohol
consumption, comorbidities, treatment,
and follow-up data up to 2017.
Comorbidities (excluding malignan-
cies) were grouped as follows: cardiovas-
cular diseases; blood, immunological and
endocrine disorders; skin disorders; dis-
eases of the respiratory, digestive and
genitourinary system and others.
Regarding treatment, we collected data
about topical treatment (such as urea,
retinoic acid, triamcinolone), surgery,
CO2 laser and oral retinoids such as aci-
tretin. Patients for who excisional biopsies
of the whole lesion were taken and no
further treatment was performed were
considered as surgically treated.
This study was performed in accordance
with the Declaration of Helsinki. The
study had formal approval by the Ethical
Committee for Clinical and Epidemiolog-
ical research of our research centre, Hos-
pital of Bellvitge, Catalan Institute of
Oncology (ICO), Odontological Universi-
ty Hospital of Barcelona and Hospital of
University of Barcelona (Comitè Ètic
d’Investigació Clı́nica de l’Hospital Uni-

Please cite this article in press as: Gómez-Armayones S, et al. Risk factors for oral epithelial dysplasias to become malignant: clinical
implications, Int J Oral Maxillofac Surg (2021), https://doi.org/10.1016/j.ijom.2021.08.012
YIJOM-4773; No of Pages 8

4 Gómez-Armayones et al.

Table 1. Characteristics of oral epithelial dysplasia (OED) patients and adjusted hazard ratios (HRs) for progression to invasive cancer during
follow-up.
OED patients Adjusted* HR in OED patients
Characteristics
a $
n/N (%) [95% CI] p-Value aHR [95% CI] p-Value#
Age at diagnosis (at mean), years 0.015 0.012
<60 15/65 (0.33) [0.17–0.57] 1.03& [1.01–1.06]
60+ 33/79 (0.49) [0.37–0.64]
Gender 0.093 0.066
Male 28/73 (0.44) [0.32–0.59] 1.78 [0.96–3.31]
Female 20/71 (0.40) [0.23–0.63] Ref.
OED diagnostic date 0.028 0.018
1995–1999 10/17 (0.60) [0.38–0.82] Ref.
2000–2004 11/22 (0.50) [0.32–0.72] 0.72 [0.28–1.87]
2005–2009 12/58 (0.23) [0.14–0.37] 0.26 [0.10–0.67]
2010–2014 15/47 (0.39) [0.25–0.58] 0.56 [0.22–1.42]
Alcohol consumption 0.909
Never 35/100 (0.45) [0.30–0.63]
Ever 13/44 (0.35) [0.20–0.55]
Tobacco consumption 0.773
Never 26/73 (0.48) [0.30–0.71]
Ever 22/71 (0.35) [0.24–0.50]
Previous neoplasia 0.865
No 46/137 (0.43) [0.31–0.57]
Yes 2/7 (0.31) [0.09–0.79]
Grade of OED 0.008 0.040
Low-grade dysplasia 8/48 (0.18) [0.10–0.34] 0.39 [0.16-0.92]
Moderate-grade dysplasia 19/50 (0.54) [0.33–0.78] 1.00 [0.49-2.04]
High-grade dysplasia (in situ SCC) 21/46 (0.49) [0.35–0.65] Ref.
0.385
Associated diseases
No diseases 8/19 (0.45) [0.26–0.70]
Cardiovascular diseases 6/14 (0.44) [0.23–0.74]
Skin diseases 1/9 (0.11) [0.02–0.57]
Respiratory/digestive/genitourinary disorders 10/37 (0.51) [0.20–0.90]
Blood/immunological/endocrine disorders 10/29 (0.38) [0.22–0.59]
Otherb 13/36 (0.42) [0.26–0.62]
OED location 0.128
Tongue 22/56 (0.42) [0.30–0.57]
Buccal mucosa 8/41 (0.23) [0.12–0.41]
Floor of mouth 6/13 (0.46) [0.24–0.75]
Otherc 12/34 (0.51) [0.26–0.82]
Clinical aspect 0.217
Erythroplakia 0/0 (0.0)
Leukoplakia 19/55 (0.53) [0.28–0.82]
Ulcer  leukoplakia 4/10 (0.48) [0.21–0.83]
Verrucous lesion 6/12 (0.71) [0.31–0.98]
Without clinical description 19/67 (0.30) [0.20–0.43]
Treatment 0.013 0.047
No treatment (observation) 6/36 (0.21) [0.09–0.43] Ref.
Topical treatment 1/10 (0.50) [0.09–0.99] 0.64 [0.08–5.42]
Surgery 40/93 (0.47) [0.37–0.59] 2.65 [1.09–6.46]
Otherd 1/5 (0.20) [0.03–0.80] 1.03 [0.12–8.88]
Total 48/144 (0.42) [0.30–0.57]
CI, confidence interval; n, number of patients progressing to invasive cancer during follow-up; N, number of patients; SCC, squamous cell
carcinoma; SD, standard deviation. Statistically significant values (p<0.05) are indicated in bold.
a
Probability to progression to cancer at the end of follow-up.
b
Other: includes mental and nervous system illnesses, ear and eye diseases and musculoskeletal disorders.
c
Other: includes gums, other regions of oral cavity and oral cavity not specified.
d
Other: includes oral retinoid and CO2 laser.
$
Log-rank test p-value.
&
Age at diagnosis included in the model as a continuous variable.
#
Log-likelihood ratio test p-value.
*
Adjusted by age at diagnosis, gender, period of diagnosis, grade of OED and treatment.

versitari de Bellvitge, L’Hospitalet de Llo- privacy and anonymization were taken Statistical analyses
bregat, Spain) on 23 January 2014 (ref. into account in compliance with the cur-
PR351/13). Adequate measures to ensure rent European and Spanish laws and reg- Descriptive analyses were performed for
data protection, confidentiality, patient ulations. each variable to explore differences be-

Please cite this article in press as: Gómez-Armayones S, et al. Risk factors for oral epithelial dysplasias to become malignant: clinical
implications, Int J Oral Maxillofac Surg (2021), https://doi.org/10.1016/j.ijom.2021.08.012
YIJOM-4773; No of Pages 8

Malignant transformation of oral dysplasia 5

Table 2. Characteristics of oral epithelial dyplasia (OED) patients with described clinical aspect and adjusted hazard ratios (HRs) for progression
to invasive cancer during follow-up.
OED patients Adjusted* HR in OED patients
Characteristics
a $
n/N (%) [95% CI] p-Value aHR [95%CI] p-Value#
Age at diagnosis (at mean) 0.108
<60 9/34 (0.62) [0.21–0.98]
60+ 20/43 (0.57) [0.39–0.75]
Gender 0.122
Male 17/40 (0.52) [0.33–0.74]
Female 12/37 (0.56) [0.26–0.90]
OED diagnostic date 0.027
1995–1999 6/7 (0.86) [0.54–0.99]
2000–2004 6/10 (0.60) [0.33–0.88]
2005–2009 7/31 (0.25) [0.13–0.46]
2010–2014 10/29 (0.45) [0.26–0.70]
Alcohol consumption 0.942
Never 21/53 (0.61) [0.33–0.90]
Ever 8/24 (0.44) [0.21–0.75]
Tobacco consumption 0.938
Never 17/43 (0.62) [0.32–0.90]
Ever 12/34 (0.43) [0.25–0.66]
Previous Neoplasia 0.256
No 27/74 (0.56) [0.33–0.82]
Yes 2/3 (0.67) [0.23–0.99]
Grade of OED 0.036 0.044
Low grade dysplasia 4/25 (0.18) [0.07–0.41] 0.41 [0.13–1.31]
Moderate grade dysplasia 12/25 (1.00) [-] 1.58 [0.69–3.59]
High grade dysplasia (in situ SCC) 13/27 (0.53) [0.34–0.73] Ref.
Associated diseases 0.882
No diseases 4/10 (0.40) [0.17–0.75]
Cardiovascular diseases 3/8 (0.40) [0.15–0.80]
Skin diseases 1/3 (0.33) [0.05–0.95]
Respiratory/digestive/genitourinary disorders 7/22 (1.00) [-]
Blood/immunological/endocrine disorders 4/14 (0.30) [0.13–0.62]
Otherb 10/20 (0.59) [0.36–0.83]
OED location 0.723
Tongue 11/32 (0.38) [0.23–0.59]
Buccal mucosa 7/20 (0.41) [0.22–0.69]
Floor of the mouth 4/9 (0.44) [0.20–0.80]
Otherc 7/16 (1.00) [-]
Clinical aspect 0.238
Erythroplakia 0/0 (0.0)
Leukoplakia 19/55 (0.53) [0.28–0.82]
Ulcer  leukoplakia 4/10 (0.48) [0.21–0.83]
Verrucous lesion 6/12 (0.71) [0.31–0.98]
Treatment 0.020 0.017
No treatment (observation) 2/12 (0.27) [0.07–0.76] Ref.
Topical treatment 1/9 (0.50) [0.09–0.99] 0.40 [0.04–4.46]
Surgery 26/56 (0.54) [0.39–0.70] 3.01 [0.68–13.30]
Total 29/77 (0.57) [0.33–0.82]
CI, confidence interval; n, number of patients progressing to invasive cancer during follow-up; N, number of patients; SCC, squamous cell
carcinoma; SD, standard deviation. Statistically significant values (p<0.05) are indicated in bold.
a
Probability to progression to cancer at the end of follow-up.
b
Other: includes mental and nervous system illnesses, ear and eye diseases and musculoskeletal disorders.
c
Other: includes gums, other regions of oral cavity and oral cavity not specified.
$
Log-rank test p-value.
#
Log-likelihood ratio test p-value.
*
Adjusted by grade of OED and treatment; cases treated with CO2 laser (n = 1) and oral retinoids (n = 1) were reclassified as treated with surgery
or not treated (observation), respectively, due to the low number of cases.

tween males and females and between
OEDs with and without described clinical
aspect using Chi2 test and analysis of
variance (ANOVA) test when appropriate.
Cancer-free survival (CFS) was calculated
from the date of OED diagnosis to the date
of OSCC diagnosis. The cumulative
probability of survival was estimated by
Kaplan–Meier analysis. The log-rank test
was used to compare different survival
curves, and adjusted hazard ratios (aHRs)
and their 95% confidence intervals (Cis)
were estimated using proportional hazard
regression (Cox model) for CFS. All sig-
nificant covariates in the univariable anal-
ysis were considered in the multivariable
analyses. Forward selection of the covari-
ates was used, adding at each step the
covariate that best improved the model
(significant log-likelihood ratio test and
AIC criteria). Statistical significance for

Please cite this article in press as: Gómez-Armayones S, et al. Risk factors for oral epithelial dysplasias to become malignant: clinical
implications, Int J Oral Maxillofac Surg (2021), https://doi.org/10.1016/j.ijom.2021.08.012
YIJOM-4773; No of Pages 8
6 Gómez-Armayones et al.
all analyses was set at the two-sided 0.05
level. Data analyses were performed with
STATA software v.15.1 (Stata Corp., Col-
lege Station, TX, USA) and R software.
Results
A total of 154 OED consecutive patients
who first presented in the clinic from 1
January 1995 to 21 June 2014 were
recruited. Cases located at the oropharynx
(n = 10) were excluded. Supplementary
Table S1 shows the baseline demographic
and clinical characteristics of the 144
OED cases finally included, overall and
by gender. Half of patients (73, 50.7%)
were men and smokers (73, 50.7%), and
the mean age at diagnosis was 60.6 (stan-
dard deviation (SD) = 13.8) years. More
than half of the patients were non-drinkers
(100 patients, 69.4%) and the different
grades of OED (low, moderate or high)
were equally distributed in the sample.
Clinical aspect of the lesion was available
for 77 of 144 OEDs (53.5%). Of these, 55
were leukoplakias. Only seven patients
(4.9%) were diagnosed with a previous
neoplasia different from head and neck
cancer or non-melanoma skin cancer.
The most prevalent co-morbidities were
respiratory/digestive/genitourinary disor-
ders (37 patients, 25.7%). Tongue was
the most common site of the lesion
(38.9%). Surgery and/or excisional biopsy
was the most performed treatment (93
patients, 64.6%) followed by observation
(36 patients, 25.0%) and topical treatment
(10 patients, 6.9%). The only difference
between male and female patients was the
consumption of tobacco and alcohol,
which was more frequent in men (Supple-
mentary Table S1). When comparing
cases with and without described clinical
aspect, differences were observed in the
treatment that patients received, with
patients without described clinical aspect
receiving less treatment, or treatments
different than surgery or topical treatment,
than patients with described clinical as-
pect (Supplementary Table S2). Treat-
ment choice did not differ by the grade
of the OED among patients without de-
scribed clinical aspect, but OEDs with
described clinical aspect were treated dif-
ferently according to the grade of OED
(Supplementary Table S3).
After 1.5 years of follow-up, 25% of
patients had progressed to OSCC, whereas
after 5 years of follow-up the estimate
increased up to 33%. Those estimates
differed by grade of OED, with lower
CFS rates at different follow-up times
for high-grade dysplasias as compared
with low or moderate grade dysplasias.
Please cite this article in press as: Gómez-Armayones S, et al. Risk factors for oral epithelial dysplasias to become malignant: clinical
implications, Int J Oral Maxillofac Surg (2021), https://doi.org/10.1016/j.ijom.2021.08.012
After 2 months of follow-up, 25% of
patients with high-grade lesions had al-
ready progressed to OSCC whereas 25%
of patients with moderate-grade lesions
progressed to OSCC after more than 1
year of follow-up.
Figures 1 and 2 show Kaplan–Meier
curves and log-rank tests for CFS of all
OEDs by gender, age, alcohol and tobacco
consumption, grade of OED (low, moder-
ate and high grade dysplasia), OED loca-
tion (tongue, buccal mucosa, floor of the
mouth and others), associated diseases
(cardiovascular disease; skin disorders;
diseases of the respiratory, digestive and
genitourinary system; blood, immunolog-
ical and endocrine disorders; others), and
treatment (observation, topical treatment,
surgery or biopsy excision).
Adjusted Cox proportional hazard mod-
els for CFS showed that surgery as type of
treatment (aHR = 2.22, 95% CI 0.96–
5.11), older ages (aHR = 1.03, 95% CI
1.01–1.06), grade of OED (aHR for low
grade with respect to high grade = 0.35,
95% CI 0.15–0.84) and older diagnostic
periods (aHR for 2005–2009 period with
respect to 1995–1999 = 0.27, 95% CI
0.10–0.70) were independent prognostic
factors for progression to OSCC during
follow-up. Male gender was marginally
non-significantly associated with a higher
risk of progression to OSCC (Table 1).
Other variables such as alcohol and tobac-
co consumption, comorbidities and previ-
ous neoplasia did not show an independent
prognostic value in either of the groups.
When only considering OEDs with de-
scribed clinical aspect (Table 2), only
grade of dysplasia and treatment were
independently associated with a higher
risk of progression to OSCC.
Discussion
Effective clinical management of OPMDs
to prevent OSCC is a research priority for
the World Health Organization (WHO)
Collaborating Centre of Oral Cancer and
Precancer. However, there are still consid-
erable gaps in knowledge regarding the
most effective means of treating such
lesions and about factors related to pro-
gression. Moreover, despite OPMDs being
managed by a broad range of specialists in
clinical practice, agreed guidelines for
classification and treatment of such lesions
are still lacking.
To date, pathology is still used as the
diagnostic tool for OPMD management
and also for its predictive value. The pres-
ence of dysplasia has been found to be a
strong predictor for malignant transforma-
tion of OPMDs, but the prognostic value
of the grade of the dysplasia is controver-
sial10,19. The 2005 WHO classification
including low, moderate and severe dys-
plasia1 has been widely used but lately, in
an attempt to simplify this classification
and minimize interobserver variability, a
binary system categorizing into low- and
high-risk lesions was developed and pro-
posed by the WHO to be adopted20.
We found that the probability of OEDs
progressing to OSCC at the end of follow-
up was 42%. The reported malignant
transformation rates range between 5
and 36%21. Differences between studies
may be due to geographical region, num-
ber of patients and duration of follow-
up10. Low- and moderate-grade dysplasia
showed higher CFS rates than high-grade
dysplasias at different follow-up times.
In our cohort of OEDs, older ages, older
diagnostic periods, lesion grade and sur-
gical treatment were found to be indepen-
dent prognostic factors for progression of
OEDs to OSCC. A higher risk of malig-
nant transformation in older patients has
already been reported22. The prognostic
advantage of patients diagnosed between
2005 and 2009 might be explained by the
improvement in the accuracy of the histo-
logic diagnosis of OED rather than by
improved therapeutic approaches, which
have not dramatically changed during the
last decades. Tobacco and alcohol use, co-
morbidities or anatomical location of the
lesion were not found to be independent
factors for progression of OEDs to OSCC,
although those have been previously ob-
served as prognostic factors for malignant
transformation4,9,23. The limitation of the
retrospective nature of our study could
explain these results.
Although both active treatment and sur-
veillance are the current standards-of-
care, those approaches may not prevent
malignant transformation of OEDs. The
reason remains uncertain but possible
explanations such as the field of cancer-
ization or genetic changes have been pro-
posed during the last decades3. Although
some molecular studies assessing the risk
of progression of OEDs to detect cancer-
associated genetic changes have been per-
formed24, those biomarkers are not used in
clinical practice. There is no evidence on
whether surgical excision can prevent ma-
lignant transformation of OEDs due to the
absence of randomized controlled trials
designed to assess this issue, because
those would be somehow unethical and
thus unfeasible.
Other authors have also found higher
rates of malignant transformation among
patients treated with surgery25, but these
results must be interpreted with caution
YIJOM-4773; No of Pages 8
and could be explained by the fact that
apparently most severe cases or wide-
spread lesions will more likely undergo
surgery. Lack of general recommenda-
tions, a standardized staging system or
treatment guidelines constrain some
clinics to decide the most appropriate
treatment according to their own experi-
ence. Most likely, low-grade dysplastic
lesions are monitored while moderate
and severe cases are surgically removed
if progression to OSCC is suspected26.
Interestingly, we did observe treatment
differences according to the grade of the
lesion, but only among those OEDs with
described clinical aspect (Supplementary
Table S3).
We also found differences in treatment
choice depending on whether the OEDs
had or did not have a described clinical
aspect: OEDs without described clinical
aspect were less treated or treated with
treatments other than surgery or topical
treatment, than OEDs with described clin-
ical aspect. This may be due to a specific
diagnosis such as verrucous lesion which
is higher risk, leading to more aggressive
treatment. We also obtained different
results from adjusted Cox proportional
hazard models for CFS when only consid-
ering OEDs with described clinical aspect,
but those should be interpreted with cau-
tion because the power of the analysis was
limited due to the sample size.
There is limited information on malig-
nant transformation rates and associated
factors of OEDs without described clinical
aspect, and how those correlate with the
ones for OPMDs3,7. Conversely, a previ-
ous metanalysis has estimated different
malignant transformation rates of OPMDs
and OEDs by subtype7. A recent study
analysing the molecular differences be-
tween oral leukoplakias with and without
OEDs found that dysplastic oral leukopla-
kias are molecularly distinct from oral
leukoplakias without dysplasia27. Another
large, population-based study on risk of
progression of oral leukoplakias estimated
a modest accuracy of biopsy decision to
identify OSCC, underscoring the need for
routine biopsy of such lesions regardless
of clinical impression28. Finally, the VII
World Workshop on Oral Medicine con-
ducted a systematic review of longitudinal
studies to identify prognostic biomarkers
for oral leukoplakia and did not find suffi-
cient evidence to support any validated
biomarker29.
Our results on non-selected consecu-
tively diagnosed OEDs add to the current
state of the science towards improved
management of OPMDs and OEDs. Our
study also provides novel insights into
Please cite this article in press as: Gómez-Armayones S, et al. Risk factors for oral epithelial dysplasias to become malignant: clinical
implications, Int J Oral Maxillofac Surg (2021), https://doi.org/10.1016/j.ijom.2021.08.012
Malignant transformation of oral dysplasia
malignant transformation of OEDs with-
out described clinical aspect as compared
to OPMDs with OEDs. However, the
results need to be interpreted with caution
due to some study limitations. The retro-
spective nature of our cohort may have
hampered the thorough characterization
of the patients according to risk factors
such as lesion size, because this informa-
tion was not reported at most clinical
records. Lesion size can also impact
treatment choice and outcome, because
large widespread lesions are more diffi-
cult to remove surgically. We did not
perform a histopathological re-evalua-
tion of the cases specifically for the study
but considered only the initial histopath-
ological diagnosis performed during the
clinical practice. However, our results
thus represent a real-world clinical set-
ting. Clinical aspect of the OEDs was
only described for 53.5% of the OEDs
and we cannot rule out the possibility that
some lesions had indeed clinical features
which were not properly recorded. As
this study involves different medical spe-
cialists, decision making about treatment
and interventions are not homogeneous
and depend on clinical management or
experience and knowledge of each phy-
sician. There may also be considerable
heterogeneity in the study sample as
cases came from different sources with-
out a predetermined protocol for case
selection. This heterogeneity limits the
ultimate clinical significance of our
results and stresses the need for a homog-
enized staging system and treatment
guidelines. Moreover, medical records
frequently did not distinguish between
complete excision and biopsy partial ex-
cision. We did not consider including a
minimum follow-up in order to not lose
cases and also because the minimum time
to malignant transformation was 0.01
years. However, this is a very short fol-
low-up, and we cannot rule out the pos-
sibility that this is more likely to be an
incorrect original diagnosis rather than
an evolution into an OSCC.
Our results have clinical implications
and underscore the need to homogenize
the diagnosis and treatment of OEDs and
OPMDs. Establishing a staging of these
lesions based on different clinical, histo-
logical and molecular features, as well as
treatment guidelines according to such
staging, are warranted. Those homoge-
nized staging systems and treatment
guidelines should be developed from a
multidisciplinary approach and agreed
by different medical specialties. Further
research with well-designed, robust pro-
spective studies is also needed.
7
Funding
No funds were obtained for the current
study.
Competing interests
M.T. has received scientific advisory
board fees, speaker’s fees, travel grants
or non-financial support from Merck,
Astra Zeneca, Nanobiotics, MSD and
Bristol Meyers. The Cancer Epidemiology
Research Program (S.T., B.Q., S.M., M.T.,
L.A., M.M.) has received sponsorship for
grants from Merck and Co., Seegene and
GSK. The remaining authors have de-
clared no conflicts of interest.
Ethical approval
Ethical approval was granted by the Ethi-
cal Committee in Clinical Investigation of
investigation projects of the Hospital of
Bellvitge (PR351/13).
Patient consent
Patient consent was not required for this
study.
Appendix A. Supplementary data
Supplementary material related to this
article can be found, in the online version,
at doi:https://doi.org/10.1016/j.ijom.2021.
08.012.
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Address:
Sara Gómez-Armayones
Department of Dermatology of Universitary
Hospital of Bellvitge and Hospital Clı́nic of
Barcelona University of Barcelona
Barcelona
Spain
Tel.: +34 932275400. +34 932275438
E-mail: sgomeza@clinic.cat