European Archives of Oto-Rhino-Laryngology

https://doi.org/10.1007/s00405-020-06036-1

REVIEW ARTICLE

Grading systems of oral cavity pre‑malignancy: a systematic review

and meta‑analysis
Flora Yan1   · Priyanka D. Reddy1 · Shaun A. Nguyen1 · Angela C. Chi2 · Brad W. Neville2 · Terry A. Day1

Received: 26 February 2020 / Accepted: 5 May 2020

© Springer-Verlag GmbH Germany, part of Springer Nature 2020

Abstract
Purpose  Oral potentially malignant disorders (OPMDs) may have varying degrees of oral epithelial dysplasia (OED). Tra-
ditional grading schemes separate OED into three-tiers (mild, moderate, and severe). Alternatively, a binary grading system
has been previously proposed that stratifies OED into low-risk and high-risk categories based on a quantitative threshold of
dysplastic pathologic characteristics. This systematic review evaluates the predictive value of a binary OED grading system
and examines agreement between pathologists.
Methods  This meta-analysis queried 4 databases (PubMed, Ovid-MEDLINE, Cochrane, and SCOPUS) and includes 4 stud-
ies evaluating binary OED grading systems. Meta-analysis of proportions and correlations was performed to pool malignant
transformation rates (MTR), risk of malignant transformation between OED categories, and measures of interobserver
agreement.
Results  Pooled analysis of 629 lesions from 4 different studies found a six-time increased odds of malignant transformation
in high-risk lesions over low-risk lesions [odds ratio (OR) 6.14, 95% 1.18–15.38]. Reported ORs ranged from 2.8 to 22.4.
The overall MTR was 26.8%, with the high-risk and low-risk lesions having MTRs of 57.9% (95% CI 0.386–0.723) and
12.7% (95% CI − 0.210 to 0.438), respectively. Pooled unweighted interobserver kappa values for the binary grading system
and three-tiered system were 0.693 (95% CI 0.640–0.740) and 0.388 (95% CI 0.195–0.552), respectively.
Conclusion  Binary grading of OED into low-risk and high-risk categories may effectively determine malignant potential,
with improved interobserver agreement over three-tiered grading. Improved grading schemes of OED may help guide man-
agement (watchful waiting vs. excision) of these OPMDs.

Introduction of OCSCC occurs in a multistep process from initial epi-

Oral cavity squamous cell carcinoma (OCSCC) is one of the
most common head and neck cancers [1]. The 5-year relative
survival rate for cancers of the oral cavity and pharynx is
65%, with survival rates generally lower among those with
oral cavity over oropharyngeal disease [1, 2]. Development
Electronic supplementary material  The online version of this
article (https​://doi.org/10.1007/s0040​5-020-06036​-1) contains
supplementary material, which is available to authorized users.
* Flora Yan
yanf@musc.edu
1
Head and Neck Tumor Center, Department
of Otolaryngology—Head and Neck Surgery, Medical
University of South Carolina, 135 Rutledge Avenue, MSC
550, Charleston, SC 29425, USA
2
Division of Oral Pathology, Medical University of South
Carolina, Charleston, SC, USA
thelial hyperplasia progressing into invasive carcinoma [3].
OCSCCs are often preceded by oral potentially malignant
disorders (OPMDs), which are defined as clinical presenta-
tions that carry a risk of oral cancer development, whether
in a clinically definable precursor lesion or clinically normal
oral mucosa [4]. Such precursor lesions can include oral
leukoplakia, erythroplakia, erythroleukoplakia, and oral sub-
mucous fibrosis. These lesions may demonstrate a varying
prevalence of dysplasia from 5 to 90%, as well as varying
rates of malignant transformation from 6.6 to 36.4% [5–10].
Histological grading of oral epithelial dysplasia (OED) in
these lesions is based on numerous cytological and architec-
tural changes of the epithelium, secondary to loss of normal
maturation and stratification [8, 11].
There have been many proposed approaches to OED
grading, with the most well-known system proposed by the
World Health Organization in 2005. This divided epithelial
precursors lesions into five histologic categories: squamous

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hyperplasia, mild dysplasia, moderate dysplasia, severe dys-
plasia, and carcinoma in situ (CIS) [12]. Although squamous
hyperplasia is considered benign, the spectrum of OED is
separated into mild, moderate, and severe categories. Rec-
ognition of CIS is indicative of non-invasive malignant
transformation. This system was recently updated in 2017,
with CIS now used synonymously with severe dysplasia
and “squamous hyperplasia” no longer being used [13].
The original 3 tiers of mild, moderate, and severe dysplasia
grading still remain.
Malignant transformation rates (MTR) of these grades
have been well reported in the literature. In a meta-analysis
comprised of 24 studies with 1546 oral leukoplakia lesions
treated with ­CO2 laser vaporization, Dong et al. [14] found
a MTR of 5.23% in mild, 12.57% in moderate, and 24.98%
in severe dysplasia, with an overall MTR rate of 4.5%
[14]. Similarly, in a meta-analysis including 9 studies and
992 patients with a mix of treated and untreated lesions,
Mehanna et al. [15] found severe dysplasia/CIS having a
MTR of 24.1% versus that of mild/moderate dysplasia of
10.3%.
OED grade, in addition to numerous patient and lesion-
specific risk factors, can help guide management of these
lesions. There are no clear guidelines regarding treatment or
follow-up of OPMD with OED; however, generally speak-
ing, mild dysplasia may be conservatively managed through
watchful waiting, while severe OED may prompt excision
of the lesion and frequent follow-up for recurrence [16].
Interpretation of the moderate dysplasia category may vary,
with some clinicians taking a “watch and wait approach”
whereas others electing to excise [16–18]. Multiple studies
have shown poor to moderate interobserver agreement when
pathologists have used the three-tiered OED grading sys-
tem [17, 19–22]. As management may be contingent upon
accurate risk stratification and consistent grading of these
lesions, improvements in reliability of and predictive poten-
tial of OED may aid clinicians in best treating these lesions.
In 2006, a working group, coordinated by the WHO Col-
laborating Centre for Oral Cancer and Pre-cancer, proposed
a two-tiered classification method for OED grading to reduce
subjectivity and disagreement [23]. Kujan et al. [17] further
developed this binary system by establishing a numerical
threshold of 4 architectural and 5 cytological dysplastic fea-
tures to differentiate between low-risk and high-risk lesions.
Of note, Kujan et al. used the same architectural and cyto-
logical features evaluated with the WHO 2005 criteria.
Since then, a number of single-institution studies have been
performed to examine the efficacy of this binary grading
system [17, 18, 24–28]. This proposed binary system will
categorize the majority of mild dysplasia into the low-risk
category and the majority of severe dysplasia into the high-
risk category. The majority of previously grade moderate
dysplasia is hypothesized to be categorized into the high-risk
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European Archives of Oto-Rhino-Laryngology
category, but will depend on if histopathological examina-
tion finds greater than 4 architectural and 5 cytological dys-
plastic features.
The aim of this systematic review is to evaluate the pre-
dictive value of binary OED grading for malignant transfor-
mation and to examine the interobserver consensus between
pathologists when using the binary versus the WHO 2005
grading system.
Methods
This systematic review was conducted in accordance with
the Preferred Reporting Items for Systematic Reviews and
Meta-Analyses (PRISMA) guidelines [29]. A query of four
databases was performed, including: PubMed (NLM NIH),
Scopus (Elsevier), Cochrane Library (Wiley) and Ovid
MEDLINE (Wolters Kluwer). The search strategy was
initially queried in PubMed using subject headings (e.g.,
MeSH in PubMed) and keywords for the following concepts:
oral dysplasia, oral premalignant disorders, World Health
Organization, binary, classification, and grading. This Pub-
Med search strategy was modified for the other three data-
bases. The databases were searched from inception through
September 21, 2019. A bibliography search of the included
articles, as well as citing articles, was performed to identify
additional studies to be included. References were uploaded
to EndNote (Clarivate Analytics, Philadelphia, PA, USA)
and screened for relevance. This systematic review does not
involve human subjects and does not require IRB review.
Selection criteria
This systematic review included studies examining diag-
nostic efficacy and reproducibility of the binary classifica-
tion of OED. Studies were considered for inclusion if they
contained: (1) OED confirmed by pathology; (2) histologi-
cal assessment of OED via binary grading with or without
comparison to the WHO 2005 three-tiered grading system;
and (3) rates of malignant transformation or interobserver
consensus kappa values between pathologists. Exclusion
criteria included: (1) insufficient data; (2) non-English lan-
guage; (3) not pertinent classification methods; (4) extra-oral
lesions with epithelial dysplasia.
Data extraction
Two authors (FY and PR) independently extracted data from
each relevant article. Any disagreement between the authors
over the eligibility of particular studies was resolved through
discussion with a third reviewer (SAN).
Extracted data included: study population demograph-
ics, diagnosis of histopathological dysplasia, malignant
European Archives of Oto-Rhino-Laryngology
transformation rate, follow-up time intervals, odds ratio for
malignant transformation, and Cohen’s kappa values for
interobserver agreement. Both unweighted and weighted
kappa values were recorded. The weighted kappa value
assigns more weight towards agreement of closely related
ordinal variables. For example, a disagreement between
mild and moderate dysplasia would be weighted less than a
disagreement between mild and severe dysplasia. Weighted
kappa values are often used when three or more categories
are involved. Because the binary classification system only
has two categories of classification, only unweighted kappa
values were recorded for this. Weighted and unweighted
kappa values were recorded for agreements using the
WHO 2005 grading system. The degree of interobserver
agreement based on the kappa values are as follows: slight
(0.01–0.20), fair (0.21–0.40), moderate (0.41–0.60), sub-
stantial (0.61–0.80), and almost perfect (0.81–0.99) [30].
Quality review and assessment of risk of bias
Level of evidence for each included article was performed
using Oxford Center for Evidence-Based Medicine [31].
The risk of bias was assessed according to the Cochrane
Handbook for Systematic Reviews of Interventions version
5.1.0 [32]. Specifically, the ROBINS-I tool was used as this
systematic review evaluated non-randomized studies. Two
authors (PR and FY) performed a pilot assessment on three
studies to check for consistency of assessment. Both then
performed independent risk assessment on the remaining
studies. All disagreements were resolved by the way of dis-
cussion with a third author (SAN). The risk of bias items
included the following: bias due to confounding, selection
of participants into the study, classification of interventions,
deviations from intended interventions, missing data, meas-
urement of outcomes, and selection of reported results. The
risk of bias for each aspect is graded as “low”, “unclear”,
or “high” [33].
Statistical analysis
Statistical analyses were performed using MedCalc 18.10.2
(MedCalc Software bvba, Belgium). All analyses were
weighted according to the number of patients affected. Meta-
analysis of correlations and proportions were performed to
pool interobserver agreement kappa values, MTR, and odds
ratios. MedCalc uses the Hedges–Olkin method for calculat-
ing the weighted summary correlation coefficient and uses a
Fisher Z transformation of the correlation coefficients [34].
For all meta-analyses, the heterogeneity statistic (I2) is gen-
erated to dictate which analytic model is used. If there was
high heterogeneity (I2 > 50%), the random-effects model was
used; if low heterogeneity, then a fixed-effects model has been
considered allowable. A p < 0.05 was considered to indicate a
statistically significant difference for all statistical tests.
Finally, the Egger tests were performed for further assess-
ment of risk of publication bias [35, 36]. Potential publica-
tion bias was evaluated by visual inspection of the funnel
plot (Supplemental Fig. 1), which statistically examines the
asymmetry of the funnel plot. In a funnel plot, the treatment
effect is plotted on the horizontal axis and the standard error
on the vertical axis [37]. The vertical line represents the
summary estimated derived using fixed-effect meta-analysis.
Two diagonal lines represent (pseudo) 95% confidence lim-
its (effect ± 1.96 SE) around the summary effect for each
standard error on the vertical axis. These show the expected
distribution of studies in the absence of heterogeneity or of
selection bias. In the absence of heterogeneity, 95% of the
studies should lie within the funnel defined by these diago-
nal lines. Publication bias results in asymmetry of the funnel
plot.
Results
Search results
The initial database search provided 334 studies for review
with two additional studies identified from outside sources.
Thirty-two duplicate studies were removed, leaving 304
studies for title and abstract screening. Full text review of
the remaining 36 studies identified 4 studies for quantita-
tive analysis. Figure 1 provides a summary of this literature
search. All studies were classified as Oxford Level of Evi-
dence Type 2b given their retrospective, single-institution
nature [38]. A funnel plot including data points regarding
pooled interobserver agreement demonstrated little publica-
tion bias, as all studies remained within the funnel (Supple-
mental Fig. 1). Assessment for risk of bias for each included
study is summarized in Supplemental Figs. 2 and 3.
Study characteristics
The four included studies [24, 17, 18, 28] comprised a total
of 629 OPMDs in 613 patients, with 284 male and 261
female patients, forming a male: female ratio of 1.09. One
study did not report the sex of their cohort [17]. Average age
was 55.62 years, ranging from 21 to 94 years. The weighted-
average follow-up period was 55.49 months. Table 1 pro-
vides an overview of all studies.
Malignant transformation and survival outcomes
per binary classification and WHO 2005
classification
The overall weighted-mean time to malignant transforma-
tion of high-risk lesions was shorter than that of low-risk
13

Fig. 1  Overview of search
strategy using PRISMA meth-
odology
lesions, at 45.41 months as compared to 74.15 months.
The overall pooled MTR was 26.8%, with high-risk MTR
at 57.9% (95% CI 0.386–0.723) and low-risk MTR at
12.7% (95% CI − 0.210 to 0.438) (Fig. 2). The pooled
odds ratio of high-risk lesions over low-risk lesions for
malignant transformation was 6.14 (95% CI 1.18–15.38).
Multiple studies evaluated survival outcomes at differ-
ent follow-up time points. Diajil et al. [18] examined a
cohort of treated dysplastic lesions and defined disease-
free survival as the absence of recurrent dysplasia or
development of oral cancer. Diajil et al. [18] found DFS
at 2 years to be 68% and 83% for high-risk and low-risk
lesions, respectively. At 5  years, DFS dropped to 29%
and 63% for high-risk and low-risk lesions, respectively
(p = 0.013). Liu et al. [28] and Kujan et al. [17] both eval-
uated survival by the absence of malignancy. Liu et al.
[28] found high-risk lesions demonstrating lower oral
cavity-free survival (OCFS) than low-risk lesions at both
3-year (68% versus 94%) and 5-year (59% versus 91%)
time points (p < 0.001). Kujan et al. [17] evaluated pro-
gression-free survival (PFS), with endpoint being inva-
sive carcinoma. This study found PFS at 22 months to be
20% for high-risk lesions and 83.8% for low-risk lesions
(p = 0.004). Thus, high-risk lesions demonstrated signifi-
cantly decreased survival over low-risk lesions (Table 2).
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European Archives of Oto-Rhino-Laryngology
Interobserver agreement
Three studies examined the interobserver agreement
between pathologists utilizing both the WHO 2005 clas-
sification and the binary classification. The study by Kujan
et al. [17] involved 4 different pathologists, that by Nan-
kivell et al. [24] involved 3 different pathologists, and that
by Diajil et al. [18] involved 2 different pathologists. Most
were oral or head and neck pathologists, except for one
general pathologist in Kujan’s [17] and Nankivell’s [24]
studies each. A ratio was obtained examining the exact
agreement between pathologists, with pooled agreement
occurring in 75.2% of reads using the binary classifica-
tion method, versus 38.6% using the WHO 2005 method.
Table 3 details interobserver agreement based on the clas-
sification system via pooled kappa values. Unweighted
pooled kappa agreement of binary classification was 0.568
versus that of WHO 2005 classification at 0.302. Weighted
kappa of the WHO 2005 method was 0.592. When patho-
logical reads by general pathologists were excluded, the
unweighted kappa agreements for the binary classification
and WHO 2005 method were 0.693 (95% CI 0.640–0.740)
and 0.388 (95% CI 0.195–0.552) respectively, while the
weighted kappa agreement for WHO 2005 was 0.677 (95%
CI 0.514–0.793).
 Table 1  Studies examining malignant transformation
Study (years) Study type Country OLE Subject (n) Male (n) Female (n) Mean Age SD (years) Age range OPMD (n) Treatment Site
age (years)
(years)

Diajil Retrospective United King- 2 100 68 32 52.5 NR 30–94 100 OPMD CO2 Laser 46 FOM; 33
(2013) [18] dom (76OL, tongue; 9 SP; 5
16ELP, 8EP) BM; 4 fauces; 2
alveolus; 1 RM
Kujan Retrospective United King- 2 68 NR NR NR NR NR 68 OED NR NR
(2006) [17] dom
Liu (2012) [28] Retrospective China 2 320 145 175 54.1 11.6 21–83 320 OL Medicationa 121 lateral/ven-
(261), Surgi- tral T, 93 BM,
European Archives of Oto-Rhino-Laryngology

cal Excision 62 dorsal T, 26

(59) gingiva, 12 P, 6
unspecified
Nankivell Retrospective United King- 2 125 71 54 62.0 14.0 24–92 141 OED NR 61 T; 28 BM; 20
(2013) [24] dom P; 16 FOM

BM buccal mucosa, ELP erythroleukoplakia, EP erythroplakia, FOM floor of mouth, OED oral epithelial dysplasia, OL oral leukoplakia, OLE Oxford level of evidence, OPML oral pre-malig-
nant lesion, P palate, RM retromolar, SP soft palate, T tongue
a
 Medication includes vitamin A/unspecified herbal medication

and high‑risk lesions
formation of high-risk lesions over low-risk lesions

Differentiation of “moderate” dysplasia into low‑risk

moderate grade dysplasia category had more variation when

Multiple studies originally graded OED using the WHO

13
sia, and severe grade dysplasia into high-risk dysplasia. The
the binary classification system [24, 17]. In general, most
Fig. 2  Forest plot of studies to determine the risk of malignant trans-

low grade dysplasia was reclassified into low-risk dyspla-

2005 classification and reclassified the same lesions using
 European Archives of Oto-Rhino-Laryngology

reclassified. Specifically, Nankivell et al. [24] reclassified 27

H-R DFS at L-R MT H-R MT time (mo)

cases of moderate dysplasia into 16 (59%) low-risk lesions
and 11 (41%) high-risk lesions. Kujan et al. [17] reclassified

23c (7–84)
30 of their moderate dysplastic lesions into 14 (47%) low
risk and 16 (53%) high risk. Nankivell et al. [24] and Kujan

45.41
39.6
NR
64
et al. [17] both included data regarding malignant transfor-
mation. After reclassification, 14 (88%) high-risk lesions
5 years (%) time (mo)

underwent malignant transformation in Kujan’s cohort [24,

74.15
88.7

69.6
NR

NR
17]. It was unclear how many reclassified low-risk lesions
underwent malignant transformation. Four (36%) reclassi-
fied high-risk lesions and 5 (31%) low-risk lesions under-
went malignant transformation in Nankivell’s cohort [24].
59%b
29%a
NR

NR

Figure 3 shows an example of moderate dysplasia being

reclassified under the binary system.
L-R DFS at
5 years (%)

90.5%b
63%a
NR

NR

Discussion
30/91 (33.0%)
10/26 (38.5%)
H-R MT (%)

28/35 (80%)
3/56 (5.4%)

This is the first systematic review to assess the prognostic

and reproducible capability of binary grading for OEDs. The
57.9%

International Academy of Oral Oncology (IAOO) has listed

3 roles of an effective grading system: (1) to predict whether
27/229 (11.8%)

surgical intervention versus observation is appropriate; (2)

5/33 (15.2%)

9/53 (17.0%)
Overall MT (%) OR high grade (95% CI) L-R MT (%)

2/44 (4.5%)

to prognosticate risk of malignant transformation; and (3) to

be reliably reproducible with high inter- and intra-observer
12.7%

consensus [23]. There been some interest in Kujan’s binary

classification system since its proposal in 2006, as it may add
DFS disease-free survival, H-R high risk, L-R low risk, mo months, MT malignant transformation

objectivity to the art of grading dysplasia, and may effec-

tively fulfill the 3 roles listed above [17].
2.828 (1.82–6.678)

4.59 (1.36–15.38)
6.14 (1.18–15.38)
4.33 (2.55–7.36)

Prognostic value
  DFS defined by free from recurrence of post-excisional OPMD or malignancy

This study revealed a higher MTR in high-risk lesions

22.4

over that of low-risk lesions (57.9% versus 12.7%) with

Table 2  Malignant transformation based on binary classification system

an overall pooled MTR of 26.8%, seen over a follow-up

57/320 (17.8%)
33/68 (48.5%)

19/79 (13.5%)

time of 55.5 months. This pooled MTR was higher than

5/100 (5%)

that reported in the literature based on the WHO 2005 clas-

26.7%

sification, specifically that of Dong et al. [14] (4.5%) and

Mehanna et al. [15] (12.1%). This difference may arise from
the study population themselves, as Dong et al. [14] evalu-
up time (mo)

46c (7–95)

ated only oral leukoplakias treated with C­ O2 laser vaporiza-

22 (24.6)
OPMD (n) Follow-

tion and Mehanna et al. [15] evaluated a mix of treated and

55.49
(SD)

61.2

untreated OEDs. Our study included a mix of treated and

60

 DFS defined by cancer-free survival

untreated lesions. This study’s elevated pooled MTR also

may have been due to inclusion of the study by Kujan et al.
 Median (interquartile range)

[17] which had a particularly high MTR of 48.5%. Neverthe-

100
68
320
141
629

less, this study revealed a six-time increased risk of malig-

Nankivell (2013) [24]

nant transformation of high risk over low risk, independent

Kujan (2006) [17]

of overall MTR of the cohort. High-risk lesions did trans-

Diajil (2013) [18]

Liu (2012) [28]

form at an earlier time interval than that of low-risk lesions,

Study (years)

at 45.4 months versus 74.2 months. This is also reflected

by disease-free survival, which, at all reported time points,
Pooled

was much higher for low-risk lesions over high-risk lesions.

b
a

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European Archives of Oto-Rhino-Laryngology

Table 3  Pooled interobserver Classification system Exact agreement ratio Unweighted kappa Weighted kappa
kappa values based on the
classification system WHO 2005 0.386 (0.299–0.467) 0.302 (0.181–0.414) 0.592 (0.504–0.669)
Binary 0.752 (0.680–0.810) 0.568 (0.463–0.657) NR

Fig. 3  Reclassification of mild,
moderate, severe dysplasia
according to a binary grading
method. a Mild dysplasia. b
Moderate dysplasia. c Severe
dysplasia. d Low-risk dyspla-
sia. e high-risk dysplasia. This
case of moderate dysplasia
(b) reveals 3 architectural
(loss of polarity of basal cells,
increased mitotic figures, and
dyskeratosis) and 4 cytological
(anisonucleosis, anisocytosis,
increased nuclear size, and
nuclear:cytoplasmic ratio)
dysplastic characteristics and
would be reclassified as a low-
risk lesion (d) (black arrow).
Moderate dysplasia can also be
reclassified into the high-risk
category (e) (dotted arrow). The
adjacent patient photographs
show examples of clinical leu-
koplakias on the right ventrolat-
eral tongue that corresponded to
various degrees of microscopic
dysplasia upon biopsy. All
photomicrographs stained with
hematoxylin and eosin, ×200
magnification. Architectural
characteristics (a), cytologic
characteristics (c)

These results indicate the binary classification system to rea-
sonably reflect malignant transformation and prognosticate
survival.
Of the included studies, only Nankivell et al. [24] and
Diajil et al. [18] compared MTR rates between different
grades of the WHO 2005 classification. Nankivell et al.
[24] found an OR of 2.25 of severe dysplasia over moderate,
whereas Diajil et al. [18] found severe dysplasia to have an
OR of 4.6 over mild dysplasia on univariate analysis, respec-
tively. Interestingly, on multivariate analysis, this improved
greatly to OR of 5.99. Kujan et al. [17] also noted significant
association between dysplasia grading, using both binary

13

and WHO 2005 classification, with malignant transforma-
tion. Based on this reported literature, the binary classifica-
tion system has slightly improved potential for malignant
transformation than the WHO 2005 grading system.
In the WHO 2005 classification model, moderate dyspla-
sia has variable predictive value. This review demonstrates
reclassification into low or high-risk categories to have vari-
able results. In Kujan’s study [17], 16 “moderate” dysplastic
lesions were reclassified to high-risk lesions. Fourteen of
these did undergo malignant transformation. In this case,
the binary system was better able to differentiate the cases of
“moderate” dysplasia, often ambiguous in malignant poten-
tial. This is in comparison to Nankivell et al. [24], where
equal proportions of moderate dysplasia re-classified as
high-risk or low-risk lesions, had transformed into malig-
nancies. In addition to considering the number of dysplastic
pathological features, clinical characteristics of the lesion
can be taken into account reclassifying moderate dysplasia
into low-risk and high-risk categories. Also, moderate and
severe dysplasia are often grouped together during assess-
ment of malignant transformation, indicating a slightly pro-
pensity of moderate dysplasia for more aggressive disease.
For example, moderate dysplasia may be reclassified as a
high-risk lesion if presenting with clinical high-risk fea-
tures, such as lateral tongue or floor of mouth involvement,
or speckled, multi-colored appearance.
Comparison to other squamous intraepithelial
lesions of head and neck
Previously, dysplasia of oral and laryngeal squamous
intraepithelial lesions of the head and neck had been graded
similarly based on the degree of epithelial involvement. Of
recent, the WHO 2017 criteria have simplified grading of
laryngeal lesions into a two-tiered system—mainly by uni-
fying the former moderate, severe dysplasia, and carcinoma
in situ into high-grade dysplasia. This change was based
on a series of studies that characterized moderate dysplasia
behaving more similarly to severe rather than mild dysplasia
[39–42]. Crissman and Sakr [43] had proposed a similar
two-tiered classification of laryngeal dysplasia, splitting
into squamous intraepithelial neoplasia (SIN I) (low-grade
dysplasia) and SIN II (high-grade dysplasia). However, two-
tiered classification systems have not been widely accepted
for oral dysplastic lesions. Oral and laryngeal intraepithelial
lesions share many commonalities, both comprised of kerati-
nized mucosal epithelium located within the head and neck.
Small nuances can still distinguish between the two subsites;
one example being that rete ridge elongation is more promi-
nent in OEDs. Although these differences exist, Cho et al.
[44] did not find such characteristics to warrant completely
different methods of evaluation between oral and laryngeal
lesions. For more consistent and reliable evaluation across
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European Archives of Oto-Rhino-Laryngology
all head and neck intraepithelial lesions, it may be worth
considering application of an adapted 2-tiered classification
system over both.
Reproducibility
Several studies have commented on the increased reproduc-
ibility of the binary classification system. This may simply
be because having fewer categories will naturally lower
potential disagreement. However, the structured quantitative
method of explicitly listing out dysplastic features may be a
more objective measure of classification and contribute to
better consensus agreement. The pooled kappa value using
the binary system was 0.568, classifying this as moderate
in agreement [45]. This was compared with the unweighted
kappa of the WHO 2005 system at 0.302. When only path-
ological interpretation by oral pathologists was included,
kappa agreements of reads utilizing both classification
systems improved. In particular, the unweighted kappa of
the binary system was improved over both weighted and
unweighted kappa of WHO 2005. Improved consensus scor-
ing ensures higher reliability of the pathologists’ reads.
Limitations
This systematic review has several limitations. An elec-
tronic search of multiple databases was performed; however,
therein still lies a possibility of missing pertinent studies
not caught by our search strategy. All included studies were
retrospective in nature and carry their own risk of selection
bias, uncontrolled confounding variables, and heterogeneity
in reported outcomes. Studies varied in the types of OPMDs
examined and treatment of which. The studies were also
conducted across two different countries, which may lead to
different interpretations by the pathologists. Also, the pooled
data were limited by a small number of included studies and
small sample size and be more prone to bias. Overall, these
limitations should be considered during the interpretations
of the findings.
Future directions
The simplicity of a binary classification scheme may give
clinicians a better tool in assessing malignant transformation
and thus guiding management. Future prospective studies
are warranted to optimize grading of OED, with possible
tailoring towards type of OPMD. Incorporation of clinical
risk features along with OED severity can be used to create
an effective assessment of malignant potential of OPMDs.
European Archives of Oto-Rhino-Laryngology
Conclusion
Binary classification systems appear to be effective in
determining malignant potential of oral dysplastic lesions
as there are significant differences in malignant transforma-
tion between high-risk and low-risk categories. Pathologists
agree more often when using a binary classification system
over the WHO 2005 three-tiered model. Future prospective
studies may determine optimal grading schemes for OED
and effectively relay malignant potential to clinicians.
Author contributions  FY conceptualization, methodology, formal
analysis, data curation, writing—original draft, writing—review and
editing. PDR data curation, writing—original draft, writing—review
and editing. SAN formal analysis, writing—review and editing. ACC
writing—review and editing, supervision. BWN review and editing,
supervision. TAD conceptualization, methodology, writing—review
and editing, supervision. All authors approved the final version to be
published.
Compliance with ethical standards  thelial dysplasia for prediction of malignant transformation. Oral
Conflict of interest  The authors declare that they have no conflict of
interest.
Ethics approval  Ethical approval was not required as this did not
involve individual patient data.
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