Received: 1 July 2019 Revised: 14 October 2019 Accepted: 18 October 2019

DOI: 10.1002/hed.26006

CLINICAL REVIEW

Potentially malignant disorders of the oral cavity and oral

dysplasia: A systematic review and meta-analysis of
malignant transformation rate by subtype

Oreste Iocca MD, DDS1,2 | Thomas P. Sollecito DMD, FDSRCSEd3 |

Faizan Alawi DDS | Gregory S. Weinstein MD | Jason G. Newman MD5
4 5
|
Armando De Virgilio MD, PhD1,2 | Pasquale Di Maio MD6 |
Giuseppe Spriano MD1,2 | Simón Pardiñas López DDS, MS7 |
Rabie M. Shanti DMD, MD5,8
1
Department of Otorhinolaryngology—Head and Neck Surgery, Humanitas Clinical and Research Center, Rozzano, Milano, Italy
2
Department of Biomedical Sciences, Humanitas University, Pieve Emanuele (MI), Italy
3
Department of Oral Medicine, University of Pennsylvania School of Dental Medicine, Philadelphia, Pennsylvania
4
Department of Pathology, University of Pennsylvania School of Dental Medicine, Philadelphia, Pennsylvania
5
Department of Otorhinolaryngology—Head and Neck Surgery, University of Pennsylvania Health System, Philadelphia, Pennsylvania
6
Giovanni Borea Civil Hospital, Department of Otolaryngology-Head and Neck Surgery, Sanremo, Italy
7
Periodontology and Oral Surgery, Clínica Médico Dental Pardiñas, Cell Therapy and Regenerative Medicine Group, Centre for Advanced Scientific
Research (CICA) and Biomedical Research Institute of A Coruña (INIBIC) Strategic Group, Universidade da Coruña (UDC), University Hospital
Complex of A Coruña (CHUAC), Galician Health Service (SERGAS), A Coruña, Spain
8
Department of Oral and Maxillofacial Surgery, University of Pennsylvania School of Dental Medicine, Philadelphia, PA

Correspondence
Oreste Iocca, Department of Abstract
Otorhinolaryngology—Head and Neck Importance: Potentially malignant disorders of the oral cavity (OPMD) are a
Surgery, Humanitas Clinical and Research
heterogeneous group of lesions associated with a variable risk of malignant trans-
Center, Viale Manzoni 56, 20138,
Rozzano, Milano, Italy. formation (MT) to invasive cancer. Leukoplakia (LE), lichen planus (LP), oral
Email: oi243@nyu.edu lichenoid lesions (OLL), oral erythroplakia (OE), oral submucous fibrosis (OSF),
and proliferative verrucous leukoplakia (PVL) are among the most common of
these lesions. Oral dysplasia is a mucosal area characterized by cellular and archi-
tectural derangement, which may be associated with OPMDs or not.
Objective: To define the MT rate of OPMDs and the risk of development into
cancer of mild vs moderate/severe oral dysplasia. This in order to implement
adequate follow-up strategies and treatment decisions.
Study design: We performed a systematic review and meta-analysis on studies
reporting the MT rates of OPMDs and oral dysplasia. Ninety-two studies were
included for the analysis. Cumulative rates were reported for OPMDs overall
and as a subgroup, a comparison was made of mild vs moderate/severe dyspla-
sia. Meta-regression on OPMD and year of publication was also performed.
Main outcome and measures: Overall MT rates of OPMDs and odds ratio of
MT of mild vs moderate/severe dysplasia.

Head & Neck. 2019;1–17. wileyonlinelibrary.com/journal/hed © 2019 Wiley Periodicals, Inc. 1

2 IOCCA ET AL.

Results: Overall MT rate across all OPMD groups was 7.9% (99% confidence
interval [CI] 4.9%-11.5%). MT rates of the specific OPMD subgroups were as
follows: LP 1.4% (99% CI 0.9%-1.9%), LE 9.5 (5.9%-14.00%), OLL 3.8% (99% CI
1.6%-7.00%), OSF 5.2% (99% CI 2.9%-8.00%), OE 33.1% (99% CI 13.6%-56.1%),
and PVL 49.5% (99% CI 26.7%-72.4%). Regarding the dysplasia grades compari-
son, the meta-analysis showed that moderate/severe dysplasia is meaningfully
associated to a much greater risk of MT compared to mild dysplasia with an
odds ratio of 2.4 (99% CI 1.5-3.8). Heterogeneity was not significant. Annual
MT rates were approximated based on the average follow-up as reported in the
various subgroups. Lichen planus had an annual MT of 0.28%, OLL of 0.57%,
leukoplakia of 1.56%, PVL of 9.3%, and OSF of 0.98%. Mild dysplasia had an
annual MT of 1.7%, while severe dysplasia of 3.57%. Meta-regression showed a
significant negative correlation of PVL MT rate and year of the study
(P value <.001).
Conclusions and relevance: OPMDs and oral dysplasia are relatively com-
mon conditions that general practitioners, head and neck, and oral medicine
specialists, face in their everyday practice. Our analysis confirms the significant
risk of MT of these lesions, although variable among the subgroups. Moderate/
severe dysplasia bears a much higher risk of cancer evolution than mild dyspla-
sia. It is important to raise public health awareness on the MT rates of these
conditions, at the same time efficacious communication with the patient is of
utmost importance. This, coupled with strict follow-up measures and optimal
treatment strategies, would help in reducing the transformation of these oral
conditions into invasive cancer.

1 | INTRODUCTION chewing is associated with OSF,6 which is highly prevalent

Potentially malignant disorders of the oral cavity (OPMD)
are a quite heterogenous group of mucosal lesions associ-
ated with an increased risk of malignant transformation
(MT) to invasive cancer. It has been estimated that the over-
all worldwide prevalence of OPMD is around 4.5%, with
wide differences according to the geographic regions exam-
ined.1 Leukoplakia (LE), lichen planus (LP), oral lichenoid
lesions (OLL), oral submucous fibrosis (OSF), and prolifera-
tive verrucous leukoplakia (PVL), and erythroplakia
(EP) are among the most common OPMDs encountered in
clinical practice.2 Erythroplakia is most often associated
with severe dysplasia, carcinoma in situ, or frank carci-
noma.3 Rarer pathological entities include oral discoid
lupus erythematous, oral graft vs host disease, and oral
epidermolysis bullosa.4
OPMD are related to numerous etiologic factors, which
may be genetic and/or environmental. Tobacco, alcohol, and
betel chewing have been most often associated with the
development of specific lesions. In detail, LE has been consis-
tently linked to tobacco use and alcohol consumption.5 Betel
among Asian populations. On the other hand, LP and PVL
do not consistently show a strong association with known
environmental agents; for this reason, genetic or other
unknown factors may play a role in their etiopathogenesis.7,8
OLL were recently defined9 as a pathologic lesion very simi-
lar to LP but frequently associated with an identifiable etio-
logic factor (eg, dental amalgam restoration).
Regardless of the heterogeneity in etiology and mode of
presentation, diagnosis of a OPMD is based on clinical man-
ifestations and histopathologic examination. Once a diagno-
sis is made, OPMDs pose a clinical challenge because of
their intrinsic potential to develop into invasive squamous
cell carcinoma, and for this reason proper follow-up and
therapies should be considered. Areas of dysplasia may or
may not be found associated to OPMD lesions, when this
happens it is often found on erythroplakia areas.10 If muco-
sal dysplasia is detected by histopathology, the possibility of
cancer development increases in a variable amount of
time.11 Oral dysplasia is a histological diagnosis character-
ized by abnormal derangement from normal epithelial
architecture and cells atypia. The World Health
TABLE 1 Studies included for definitive quantitative analysis
Follow-up range
(mean follow-up) Malignant
IOCCA ET AL.

or mean Dysplasia transformation

follow-up in cases events on
years (according (when no dysplasia
Smoker Malignant to how it was No. No. No. No. details on cases
Study/year Type of Type of Mean M/F or transformation reported in the low-grade mild- moderate severe grade were (when
(reference) study lesion n Males Females age total events study) dysplasia dysplasia dysplasia dysplasia reported) reported)
Silverman13 Prospective PVL 54 11 43 62 3/14 (17) 28 1–27 (7.7) 16
14
Bagan Retrospective PVL 55 19 36 67 20 27 7.53
Fettig15 Retrospective PVL 10 6 4 65 NA (3) 6 3 (3)
Zakrezewska16 Restrospective PVL 10 5 5 63.5 4/2 (6) 10 6-14 (6.6)
17
Hansen Retrospective PVL 30 6 24 60 5/13(18) 26 1-20(6)
Gouvea18 Retrospective PVL 12 0 12 70 3 4 315(6,5)
Gandolfo19 Retrospective PVL 47 10 37 65.9 17 19 6,9
20
Borgna Retrospective PVL 48 24 24 70 33 23 3,4
Thomson21 Retrospective PVL 80 41 39 62.3 NA 2 4
Campisi22 Retrospective PVL 58 22 36 66.5 17 25 NA
Upadhyaya23 Retrospective PVL 20 6 14 64 12 9 1-18 (7,7)
24
Thorn Prospective LP 611 409 202 53 336 9 7.5
Andreasen25 Retrospective LP 115 NA NA NA NA 9 NA
Silverman26 Prospective LP 214 62 152 54 27 5 7.5
Voûte27 Register based LP 113 34 79 48.3 NA 3 8
Barnard28 Retrospective LP 241 NA NA NA NA 9 NA
Rode29 Retrospective LP 55 11 44 58.3 NA 0 2
Eisen30 Prospective LP 723 179 544 NA NA 6 4.4
Xue31 Retrospective LP 674 230 444 NA 174 4 NA
van der Prospective LP 67 NA NA 52.5 NA 0 4.7
Meij9
Kesi
c32 Retrospective LP 163 49 114 54 NA 2 NA
Carbone33 Retrospective LP 808 315 493 NA 629 15 8.8
34
Bermejo-Fenoll Retrospective LP 550 128 422 56 NA 5 2.00
Torrente- Retrospective LP 65 25 40 59 18 2 1.60
Castells35
Bombeccari36 Prospective LP 327 98 229 NA NA 8 5.10
Fulling37 Prospective LP 225 108 219 NA NA 1 3.60
Shen38 Retrospective LP 518 165 353 46.3 43 5 3.40
Kaplan39 Retrospective LP 171 51 120 59.1 NA 6 4.30

(Continues)
3
 4

TABLE 1 (Continued)
Follow-up range
(mean follow-up) Malignant
or mean Dysplasia transformation
follow-up in cases events on
years (according (when no dysplasia
Smoker Malignant to how it was No. No. No. No. details on cases
Study/year Type of Type of Mean M/F or transformation reported in the low-grade mild- moderate severe grade were (when
(reference) study lesion n Males Females age total events study) dysplasia dysplasia dysplasia dysplasia reported) reported)
Bardellini40 Retrospective LP 204 41 163 54.5 NA 2 NA
Gümrü41 Retrospective LP 370 110 260 49.84 303 1 NA
Radochová42 Retrospective LP 171 55 116 55.2 29 0 NA
Shklar43 Retrospective LP 600 NA NA NA NA 3 NA
44
Lauritano Retrospective LP 87 31 56 59.2 NA 1 5.40
Gonzalez-Moles45 Prospective LP 21 NA NA 58 NA 2 5.00
Kovesi46 Register based LP 326 122 204 55 48 1 NA
47
Bandyopadhyay Retrospective LP 102 74 58 NA NA 0 NA
Laniosz48 Retrospective LP 102 106 197 55.4 146 7 10.40
Brzak49 Retrospective LP 537 158 379 52 96 0 1.00
50
Warnakulasuriya Retrospective LP 607 NA NA NA NA 6 1
Casparis51 Retrospective LP 423 NA NA 58 NA 5 NA
Rodstrom52 Register based LP 1028 351 677 55 NA 5 6.8
Ingafou53 Retrospective LP 690 251 439 52 NA 13 NA
Gorsky54 Register based LP 157 62 95 NA NA 2 1-15 (1.5)
Markopoulos55 Retrospective LP 326 240 86 54.8 NA 4 0,5–10 (4.8)
Rajentheran56 Retrospective LP 832 520 223 57 NA 7 NA
Chainani-Wu57 Retrospective LP 229 75 154 55 NA 4 11.00
Pakfretat58 Retrospective LP 420 147 273 41.6 NA 3 NA
Monoarz59 Register based LP 280 NA NA 51 NA 8 NA
Vincent60 Register based LP 100 24 76 64.2 NA 0 1
Brown61 Retrospective LP 193 138 54.9 NA 0 NA
Salem62 Retrospective LP 72 40 32 18–72 NA 4 3,2
Kaplan39 Retrospective LP 171 51 120 59.1 NA 6 1–16 (4.3)
63
Laeijendecker Retrospective LP 200 68 132 53 NA 3 7–13 (10)
Oliveira64 Retrospective LP 110 26 84 53.8 NA 0 NA
Budimir65 Retrospective LP 563 NA NA NA NA 4 7.5
66
Irani Retrospective LP 112 39 73 44.5 NA 6 NA 5 7 6
Bornstein67 Retrospetive LP 18 NA NA 56.3 NA 1 2.1-8.8 (3.7)
Hsue68 Retrospective LP 143 NA NA NA NA 3 3.60
IOCCA ET AL.

(Continues)
TABLE 1 (Continued)
Follow-up range
(mean follow-up) Malignant
IOCCA ET AL.

or mean Dysplasia transformation

follow-up in cases events on
years (according (when no dysplasia
Smoker Malignant to how it was No. No. No. No. details on cases
Study/year Type of Type of Mean M/F or transformation reported in the low-grade mild- moderate severe grade were (when
(reference) study lesion n Males Females age total events study) dysplasia dysplasia dysplasia dysplasia reported) reported)
Casparis51 Retrospective OLL 115 NA NA 58 NA 5 NA
Warnakulasuriya50 Restrospective OLL 115 NA NA 2 9
Van der Meij9 Prospective OLL 125 NA NA 52.5 NA 4 4.5
Gonzalez-Moles45 Prospective OLL 21 NA NA 58 NA 1 NA
69
Rock Prospective OLL 73 30 43 NA 45 6 1.3–14 (5.3) 73 6
Einhorn70 Prospective Leukoplakia 782 522 260 53 133 31 1-44 (11.7)
Pindborg71 Prospective Leukoplakia 1411 1411 264 48 NA 63 1–20
72
Silverman Prospective Leukoplakia 4762 4524 238 NA NA 6 2
Chuang73 Register based Leukoplakia/ 5142 47 NA 161 1–5
erythroplakia
Banoczy74 Prospective Leukoplakia 670 461 209 NA NA 40 1–30 (10)
Gandara-Vila75 Restrospective Leukoplakia 85 45 40 59 38 7 4 19 4 3 5
Banoczy74 Prospective Leukoplakia 68 NA NA 60 NA 9 6.3 13 43 12 9
Kramer76 Retrospective Leukoplakia 29 NA NA NA NA 7 1-19 (4.2)
Pogrel77 Prospective Leukoplakia 19 7 12 8 NA 3 4–15
Gupta78 Prospective Leukoplakia 410 NA NA NA NA 3 1-10 (8.5) 90 6
Roch-berry79 Retrospective Leukoplakia 117 NA NA NA NA 20 NA
Silverman80 Prospective Leukoplakia/ 257 NA NA 20-89 (45) NA 45 7.2 22 8
Erythroplakia
Lind81 Retrospective Leukoplakia 157 74 31 NA NA 14 9.3 16 24 7 8
82
Hogenwind Retrospective Leukoplakia 46 50 34 NA 41 3 1–8 (2.5) 5 3 5 1
Schepman83 Retrospective Leukoplakia 166 76 90 23-91 (57) 93 20 2,5 55 12
Saito84 Prospective Leukoplakia 142 80 62 37-65(52) NA 2 0,8-16 (4) 48 36 7 7
85
Napier Retrospective Leukoplakia 50 18 32 13-88 (58) NA 17 2–14 (8.2)
Holmstrup86 Retrospective Leukoplakia 169 NA NA NA 197 18 1–20 (6) 13 43 12 12
Hsue68 Retrospective Leukoplakia 423 NA NA 47.5 NA 23 3.6 138 15 13 8
87
Arduino Retrospective Leukoplakia 207 107 100 60 NA 15 1–16 (4.5) 7 7 1 15
Warnakulasuriya50 Prospective Leukoplakia 335 NA NA NA 23 9 5 11 8 23
Brzak49 Retrospective Leukoplakia 157 60 79 19-91 (52) 65 1 10
Liu88 Retrospective Leukoplakia 320 145 175 21-83 (54) 11 57 1–20 (5.1) 27 30 57
89
Ho Prospective Leukoplakia 91 49 42 NA NA 23 5 40 31 20 23
5

(Continues)
 6

TABLE 1 (Continued)
Follow-up range
(mean follow-up) Malignant
or mean Dysplasia transformation
follow-up in cases events on
years (according (when no dysplasia
Smoker Malignant to how it was No. No. No. No. details on cases
Study/year Type of Type of Mean M/F or transformation reported in the low-grade mild- moderate severe grade were (when
(reference) study lesion n Males Females age total events study) dysplasia dysplasia dysplasia dysplasia reported) reported)
Brouns90 Prospective Leukoplakia 144 44 100 26-98 (59) NA 16 1–12 (5) 40 16 8
Lee91 Prospective Leukoplakia 70 33 37 60 39 22 NA 61 9 22
Wang92 Retrospective Leukoplakia 1688 NA NA NA NA 79 NA
Lumerman93 Retrospective Leukoplakia/ 44 20 24 28-89 (61.3) NA 7 NA 19 18 6 7
Erythroplakia
Hazarey94 Retrospective OSF 1000 830 170 30 NA 33 1–5
Murti95 Prospective OSF 66 NA NA 48-81 (64.6) NA 5 10
Chuang73 Register based OSF 2333 NA NA 45 NA 114 1–5
Yang96 Retrospective OSF 587 NA NA NA NA 42 6.3
Mincer97 Retrospective Erythroplakia 16 NA NA NA NA 3 1–8
98
Vedofte Retrospective Erythroplakia 14 NA NA NA NA 5 4
Amagasa99 Retrospective Erythroplakia 12 NA NA NA NA 6 3
Shafer100 Retrospective Erythroplakia 58 NA NA NA NA 33 NA
101
Lapthanasupkul Retrospective Erythroplakia 9 NA NA NA NA 6 NA

Abbreviations: F, female; LP, lichen planus; M, male; NA, not applicable; OLL, oral lichenoid lesion; OSF, oral submucous fibrosis; PVL, progressive verrucous leukoplakia.
IOCCA ET AL.
IOCCA ET AL.
Organization classifies dysplasia as mild, moderate, and
severe (including carcinoma in situ).12 The presence of a
dysplastic area always bears the risk of transformation to
invasive carcinoma, although its MT rate is variably
reported in the literature.11
It is important to properly implement adequate man-
agement strategies and to provide effective surveillance
programs for the most commonly encountered OPMD.
For this reason, it is vital to have a reliable estimate of
the MT rates of OPMD as a whole group and by subtype.
Studies on MT rates of the various OPMD are highly vari-
able, and a comprehensive quantitative review is lacking.
Furthermore, the carcinoma development potential of
mild, moderate, or severe dysplasia should be evaluated
quantitatively given that this pathological entity may be
associated with various OPMD lesions.
For this reason, a systematic review and meta-analysis
was performed on the MT rates of LE, LP, OLL, OSF, and
PVL. Secondary analysis was made comparing the risk of
malignant progression of various grades of oral dysplasia.
2 | MATERIALS AND METHODS
2.1 | Search strategy and selection
criteria
We performed a systematic review and meta-analysis
according to the Meta-analysis of Observational Studies in
Epidemiology (MOOSE) checklist. We searched PubMed,
Embase, and Scopus, up to February 1, 2019. No language
restriction was applied. Literature search and subsequent
analysis were focused on papers reporting MT rates of oral
leukoplakia, oral lichen planus, oral submucous fibrosis,
proliferative verrucous leukoplakia, and oral lichenoid
lesions. The identification of studies to be included or con-
sidered for the systematic review and the subsequent statis-
tical analysis was made combining these search terms:
“oral precancerous lesion,” “oral precancer,” “oral
premalignant,” “oral premalignant disorders,” “oral
leukoplakia,” “oral erythroplakia,” “lichen planus,” “oral
lichenoid,” “oral submucous fibrosis,” “proliferative ver-
rucous leukoplakia,” “oral dysplasia,” “MT rate.” We
excluded case reports, studies including less than five
patients, studies in which MT rate was not reported. Data
extraction was performed by two investigators (O.I. and
P.D.M.), who searched for studies independently. Identifi-
cation of studies was performed through screening of the
titles and selecting the abstracts for full-text inclusion. The
reviewers screened all the abstracts and their suitability
for the subsequent analysis according to the prespecified
inclusion and exclusion criteria. Interexaminer (kappa)
Cohen's test was conducted to evaluate the selection of
7
titles, abstracts and complete reading with interpretation
of the article, resulting in concordance test values of
k = 0.77. Risk of bias was performed by two authors
(O.I. and P.D.M.) according to the Newcastle-Ottawa scale
for the assessment of nonrandomized studies for meta-
analysis. Any disagreement among the reviewers was
resolved by a third author (R.S.). If duplicate studies were
identified, they were eliminated from the analysis.
2.2 | Data synthesis and statistical
analysis
From the included studies, a database (Table 1) was created
for the extraction of data regarding the study name, year of
publication, type of OPMD examined, number of partici-
pants, patients' demographics, smoking habits, presence of
dysplasia, and grade of dysplasia when reported, MT rate on
dysplasia when reported, MT rate in total, recurrence rate if
reported, follow-up range in years. Single-arm meta-analysis
of overall malignant transformation rates was conducted,
and comparison meta-analysis of mild vs moderate/severe
dysplasia was performed; analyses were done using the R
software for statistical computing (R 2.10.1; “meta” package).
Subgroup meta-analysis was conducted according to the type
of OPMD examined. Arcsine transformation of the data was
performed for the analysis on overall MT rates; this has been
11845 potentially relevant articles identified
on PubMed, Embase, and Scopus
7521 articles excluded on the basis of title
176 articles for full text assessment
84 articles excluded after full text evaluation
92 articles included for systematic review, meta-
analysis, and meta-regression
FIGURE 1 Flow chart for inclusion of studies
8 IOCCA ET AL.

shown to provide more reliable results than other transfor- included studies, we decided to adopt a statistical conserva-
mations when rare events are examined.102 As reported in a tive approach; for this reason, a 99% confidence interval
previous paper,103 given the observational nature of the (CI) was chosen for calculations. Restricted maximum

F I G U R E 2 Forest plot of subgroup meta-analysis

on MT rate. I2 is the statistics for heterogeneity. CI,
confidence interval; Ev, event transformation into
cancer; LP, lichen planus; OLL, oral lichenoid lesion;
OSF, oral submucous fibrosis; PVL, progressive
verrucous leukoplakia; Trt, total number of patients
[Color figure can be viewed at wileyonlinelibrary.com]
IOCCA ET AL. 9

likelihood was the method used for the random effects meta-
analysis on overall transformation rate. Results on MT were
reported as overall rate. DerSimonian-Laird method with a
95% CI was instead used for the random effects meta-analysis
on mild vs moderate/severe dysplasia, in this case results
were reported as odds ratio (OR) of MT. Also, a minimal cor-
rection factor of 0.01 was used for “0” events in order to
reduce the distortion of data for excessive correction. Annual
transformation rates were approximated for every OPMD
and for oral dysplasia, and this was performed by taking into
account the average follow-up in years for every single sub-
group, corrected arbitrarily assigning a value close to the
mean when a study did not report details regarding follow-
up. Sensitivity analysis was conducted eliminating all the
studies in which follow-up information was not available
(Figure S1). This analysis was performed to understand if the
inclusion of studies with unclear follow-up may have an
influence on the final results. A meta-regression analysis was
conducted for every OPMD in order to assess the possible
relationship of a specific study-level covariate (year of publi-
cation) with the MT rate. This was made because it has been
hypothesized that the change in definitions and histopatho-
logical reporting of OPMD have changed during the decades
and could have influenced the reported transformation rates.
3 | RESULTS
Literature search retrieved results of 11 845 articles
(Figure 1). After title/abstract screening, 4324 papers were
selected for abstract evaluation. Of these, 92 studies were
included in the final analysis.[13–15, 17–19, 22, 25–28, 30, 31, 36, 37,
40, 41, 43–51, 54, 56, 57, 59–62, 65–69, 71–74, 76–81, 83–85, 87, 88, 90–92, 94–97,
99–101, 104–137]
Fourty-six reports were on LP, 5 on OLL, 28 on
LE, 8 on OE, 4 on OSF, and 11 on PVL (all the studies taken
for every subgroup sum up to a figure higher than 92 because
some studies focused on more than one OPMD). The num-
bers of patients analyzed cumulatively from the single
included studies were as follows: 14 362 LP, 449 OLL, 17 830
LE, 3 986 OSF, 424 PVL, and 342 OE. Most of the studies
were retrospective in design; prospective and registry-based
data were also included. Mean follow-up in the included

TABLE 2 Results of cumulative meta-analysis by subgroup and overall

Cumulative MT rate (99% confidence interval)

Arcsine square root transformed data, random MT rate
Subgroup effects method restricted maximum likelihood per year
Lichen planus 1.4% (0.9%-1.9%) 0.28%
Oral lichenoid lesions 3.8% (1.6%-7.0%) 0.57%
Leukoplakia 8.6% (5.1%-13.0%) 1.56%
Erythroplakia 33.1% (13.6%-56.2%) 2.7%
Proliferative verrucous leukoplakia 49.5% (26.7%-72.4%) 9.3%
Oral submucous fibrosis 5.2% (2.9%-8.0%) 0.98%
Overall 7.9% (4.9%-11.5%) NA

Abbreviation: NA, not applicable.

Studies

Saito
Lumerman
Holmstrup
Hsue
Banoczy
Hogenwind
Arduino
Liu
Lind
Warnakulasuriya

Overall (I^2=19.05 % , P=0.268)

0.02 0.04 0.1 0.19 0.38 0.96 1.92 3.85 9.61 19.23 38.45 64.9
Odds Ratio (log scale)

FIGURE 3 Meta-analysis of mild vs moderate/severe dysplasia. I2 is the statistics for heterogeneity. CI, confidence interval; Ev, event
transformation into cancer; Trt, total patients with moderate/severe dysplasia; Ctrl, total patients with mild dysplasia [Color figure can be
viewed at wileyonlinelibrary.com]
10
studies ranged from 12 months to 20 years, although the
majority (72 out of 92) had a mean or median follow-up
greater than 2 years, in 27 reports the follow-up information
was not available. The reported mean age in all the studies
was greater than 40 years across all OPMD subgroups.
Regarding gender composition, it was different according to
the OPMD examined. The M:F ratio was 0.6:1 for LP, 3.87:1
for LE, 0.56:1 for PVL, and 4.88:1 for OSF. Data on dysplasia
were extracted from 20 studies. Ten studies clearly differenti-
ated between mild, moderate, and severe dysplasia or carci-
noma in situ.
Results of the proportion meta-analysis (Figure 2 and
Table 2) showed that the overall MT rate across all OPMD
IOCCA ET AL.
F I G U R E 4 Bubble plot of
meta-regression on PVL MT rate
plotted against year of study.
Intercept 42.280, lower bound 8.873,
upper bound 75.687. SE, 12.96.
P value, .001 [Color figure can be
viewed at wileyonlinelibrary.com]
F I G U R E 5 Bubble plot of
meta-regression on LP MT rate
plotted against year of study.
Intercept −0.086, lower bound
−0.503, upper bound 0.332. SE,
0.162. P value, .598 [Color figure can
be viewed at wileyonlinelibrary.com]
F I G U R E 6 Bubble plot of
meta-regression on LE MT rate
plotted against year of study.
Intercept 0.009, lower bound −8.599,
upper bound 8.617. SE, 3.342.
P value, .998 [Color figure can be
viewed at wileyonlinelibrary.com]
groups was 7.9% (99% CI 4.9%-11.5%). Heterogeneity was
high (I2 98.6% P < 0.05). MT rates of the specific OPMD
subgroups were as follows: LP 1.4% (99% CI 0.9%-1.9%), LE
9.5% (99% CI 5.9%-14.00%), OLL 3.8% (99% CI 1.6%-7.00%),
OSF 5.2% (99% CI 2.9%-8.00%), PVL 49.5% (99% CI 26.7%-
72.4%), and erythroplakia 33.1% (99% CI 13.6%-56.2%).
Regarding the dysplasia grades comparison (Figure 3),
the meta-analysis showed that moderate/severe dysplasia is
meaningfully associated with a much greater risk of MT
compared to mild dysplasia with an OR of 2.4 (99% CI
1.5-3.8). Heterogeneity was not significant.
Annual MT rates were approximated based on the
average follow-up as reported in the various subgroups
IOCCA ET AL.
F I G U R E 7 Bubble plot of
meta-regression on erythroplakia
MT rate plotted against year of
study. Lower bound −7.539, upper
bound 7.617. SE, 5.342. P value, .898
[Color figure can be viewed at
wileyonlinelibrary.com]
(Table 2). Lichen planus had an annual MT of 0.28%,
OLL of 0.57%, leukoplakia of 1.56%, PVL of 9.3%, OSF of
0.98%. Mild dysplasia had an annual MT of 1.7%, while
severe dysplasia of 3.57%.
Sensitivity analysis, in which studies with unclear
follow-up were eliminated, showed a higher MT rate
(9.5% 99% CI 5.6%-14.3%; Figure S1]. This is to be
expected because studies in which observation time is not
reported maybe have a shorter follow-up and, intuitively,
less time to observe development of cancer.
Meta-regression showed a significant negative corre-
lation (Figure 4) for PVL studies regarding transforma-
tion rates and year of publication (P value <.001). No
significant relationship emerged between MT rate and
year of publication for LP, erythroplakia, and LE studies
(Figures 5–7).
4 | DISCUSSION
The results of the present systematic review and meta-
analysis further corroborate the results of previous
research regarding the fact that the most common OPMD
have a significant risk of MT rate.11,28,136,138 In fact, each
type of OMPD has a highly variable rate of transforma-
tion to invasive carcinoma. It is well known that some
forms of OPMD have higher rates of transformation
while others have a lower risk. The results of our analysis
clarified these rates in quantitative terms. Interestingly,
the MT rates of each OPMD came out to be significantly
different than zero. This further confirms what in the
oral pathology literature had been discussed and corrobo-
rated for decades, in other words that the risk of carcinoma
progression is always a possibility and should be considered
in the clinical follow-up of patients affected by OPMDs.
Overall, if the most common OPMDs are examined,
there will be a MT rate of 7.9% (99% CI 4.9-11.5). In detail,
lichen planus has a low risk of overall MT (1.4%, 99% CI
0.9%-1.9%) and an approximated annual MT of 0.28%.
These results suggest that the transformation into cancer is
11
a low probability event. Nevertheless, it does happen in a
small fraction of patients. Until long-term studies with ade-
quate stratification will allow to understand which patients
are at risk of cancer development, these results show the
importance of proper follow-up strategies in all the patients
affected by lichen planus in order to detect every lesions
change that may suggest the transformation into cancer. A
checkup two times a year has been deemed feasible and
appropriate by some authors.139
OLL has a MT rate of 3.8% (99% CI 1.6%-7.00%) and a
more than double risk of MT rate compared to lichen
planus, with an annual MT of 0.57%. OLL is associated with
dental restorative materials such as amalgam, drugs such as
antihypertensive medications, and various antimicrobials,
among the others. Clinicians should be aware of the histo-
pathological distinction from LP.140 Our results confirm that
the distinction between these two pathological entities has
sound basis and should be applied to every clinical study in
the future. Also, in this specific scenario a strict follow-up is
recommended.
OSF showed a significant MT rate of 5.2% (99% CI
3.8-9.6) with a yearly evolution to cancer of 0.98%. Man-
agement of this peculiar lesion, mostly prevalent in Asian
populations, is difficult,1 mainly for its associated func-
tional impairment and burning symptoms141; its treat-
ment may be subdivided into conservative or surgical
depending on the severity of symptoms,142 but it should
take into account the nonnegligible risk of progression to
cancer.
LE is the most common OPMD136 with wide varia-
tions according to different geographical locations exam-
ined. Anyway, MT rate of LE is clinically relevant. From
our analysis 9.5% (99% CI 5.9%-14.00%) of lesions evolved
into cancer, with an annual transformation rate of 1.56%.
The significant MT imposes aggressive follow up mea-
sures and appropriate management strategies. It is not
clear if complete elimination of the lesion significantly
reduces the risk of MT. Many studies evaluated different
therapeutic approaches, both surgical and nonsurgical.5
Unfortunately, due to the high heterogeneity of the
12
treatment strategies, it is difficult to give clear indications
on which is the best treatment approach. It is possible to
give tentative indications that small lesions and lesions
showing moderate and severe dysplasia should be excised
with clear margins. All patients should be then followed
up indefinitely for recurrence or the development of new
leukoplakias. The management of wide lesions without
dysplasia is more problematic; in this case, the clinician
should weigh the morbidity of an extensive removal ver-
sus the risk of cancer development. Recurrence has been
reported in approximately 7%-38% of cases independently
of the treatment approach.143
Erythroplakia has a high risk of evolution to frank
carcinoma. In fact, most red lesions of the oral mucosa
already present carcinoma in situ or invasive disease at
the moment of diagnosis.113 In our analysis, when dys-
plastic lesions were excluded, erythroplasic lesions
showed a MT rate of 33.1% (99% CI 13.6%-56.2%). Given
this high risk, it is advisable that any red lesion would be
biopsied. Treatment depends upon histological diagnosis.
Anyway, it is advisable that lesions would be totally
removed, when technically feasible. Strict follow-up
remains of utmost importance.
PVL management is difficult because of high MT rate
(49.5%, 99% CI 26.7-72.4). These lesions usually arise in
old women and are usually extensive at presentation,
thus obtaining a removal with good clinical margins may
be difficult given the spread on extensive areas of the oral
cavity. On the other hand, MT rate is extremely high,
with an estimated yearly MT of 9.3%. For this reason,
partial or total surgical removal (when feasible), repeated
biopsies, and strict follow-up measures seem the most
reasonable management of this subset of patient.144
We conducted a meta-regression to further investigate
heterogeneity within subgroups, in detail it was assumed
that MT rates could have changed substantially during
the decades given the change in OPMD definition, diag-
nostic criteria, or management approaches. In fact, studies
on PVL MT rate seem to be inversely correlated with year
of publication. It can be speculated that since 1985 greater
attention of head and neck and oral medicine specialists
led to proper follow-up and management approaches. For
this reason, a better control over MT rate has likely been
achieved compared to three decades ago. On the opposite,
the nonsignificant results of meta-regression on lichen,
leukoplakia, and eryhtroplakia studies may suggest that
the likely MT rate for these three entities it is consistent
and unchanged in the last decades.
Results of meta-analysis on dysplasia confirm that a
much higher risk is present for moderate/severe than
mild, this is in line with the previous literature145 and
consistent with the recent management algorithms.11
The results showed that the odds of MT rate in
IOCCA ET AL.
moderate/severe dysplasia are much higher than mild
dysplasia (OR 2.37 99% CI 1.47-3.79). This confirms the
need of surgical removal of severe dysplasia lesions and
long-term follow-up for the affected patients.
Limits of the present investigation are various; first,
many of the included studies are retrospective observa-
tional reports, which somewhat impairs the possibility of
adjustment for specific biases. Stratification of patients
according to smoking/chewing tobacco status, associated
pathologies, and analysis of specific anatomical subsites
would allow to better understand the risk of MT and to
implement appropriate management strategies. This infor-
mation is present in some but not all the studies, for this
reason a quantitative stratified evaluation was deemed not
to be methodologically appropriate. Second, reports on
therapy are highly variable, some studies evaluate purely
medical approaches, some others purely surgical, or do
not specify if any treatment was made. Moreover, the scar-
city of data on recurrence and repeated biopsies made it
impossible to perform an analysis on recurrent cases
(if this occurred). For this reason, the results of the present
analysis are derived without considering the treatment
approach adopted in every single study. Third, some stud-
ies do not report details on follow-up. Finally, it could be
argued that it is not completely appropriate to extrapolate
an overall MT rate on such heterogeneous group of
OPMDs. On the other hand, the scope of this article is to
highlight that all the OPMDs have a significant risk of MT
and for this reason proper preventive, therapeutic, and
communicative strategies should be implemented when
OPMD are encountered in clinical practice. Moreover, the
clear subgroup stratification helps in recognizing the vari-
able MT rate for every OPMD examined.
The strengths of the present study are as follows: to
the best of our knowledge, this is the most extensive
quantitative analysis on OPMDs and dysplasia with a
focus on MT rates. The results of the present study
should help the clinician in understanding the natural
history of these relatively common mucosal pathologies,
which should help in implementing appropriate manage-
ment strategies and preventive measures. At the same
time, a quantification of MT may help in better commu-
nicating to the patients the risks and the best approach to
their disease. Moreover, we adopted a robust statistical
methodology, providing wide CIs (99%), in such a way
that the results are more conservative and allow space for
cautious conclusions.
In conclusion, OPMD and oral dysplasia are relatively
common conditions that general practitioners, head and
neck, and oral medicine specialists face in their everyday
practice. It is important to raise public health awareness
on the MT rates of these conditions, at the same time effi-
cacious communication with the patient is of utmost
IOCCA ET AL.
importance. This, coupled with strict follow-up measures
and optimal treatment strategies, would help in reducing
the transformation of these oral conditions into invasive
cancer. In the future, the development of more refined
pathology tools, based on genetic profile/molecular
markers, would help in improving the management of
every single OPMD. Also, more long term, properly strat-
ified clinical studies, would allow to obtain a more per-
sonalized approach for the patients affected by OPMDs
and dysplasia of the oral cavity.
A U T H O R C O N T R I B U T I O NS
O.I.: design, writing, editing, data collection, and statisti-
cal analysis; T.P.S.: revision, writing, and supervision;
F.A.: revision, writing, and supervision; G.W.: revision
and supervision; J.G.N.: revision and supervision; P.D.M.:
data collection and writing; A.D.V.: writing and revision;
G.S.: revision and supervision; S.P.L.: writing and revi-
sion; R.M.S.: design, writing, and revision.
ORCID
Oreste Iocca https://orcid.org/0000-0002-4444-248X
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SU PP O R TI N G I N F O RMA TI O N
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article.
How to cite this article: Iocca O, Sollecito TP,
Alawi F, et al. Potentially malignant disorders of
the oral cavity and oral dysplasia: A systematic
review and meta-analysis of malignant
transformation rate by subtype. Head & Neck. 2019;
1–17. https://doi.org/10.1002/hed.26006