Special Topic: Potentially premalignant oral epithelial lesions (PPOEL)

Vol. 125 No. 6 June 2018

Management update of potentially premalignant oral

epithelial lesions
Michael Awadallah, DDS, MD, Matthew Idle, FRCS, Ketan Patel, DDS, PHD, and Deepak Kademani, DMD, MD

The term oral potentially malignant disorders, proposed at the World Health Organization workshop in 2005, has now been renamed
potentially premalignant oral epithelial lesions (PPOELs). It is important to differentiate among PPOELs, which is a broad term to
define a wide variety of clinical lesions, and oral epithelial dysplasia, which should be reserved specifically for lesions with biopsy-
proven foci of dysplasia. PPOELs encompass lesions that include leukoplakia, erythroplakia, erythroleukoplakia, lichen planus,
and oral submucous fibrosis. The primary goal of management of dysplasia includes prevention, early detection, and treatment
before malignant transformation. The aim of this article is to inform the clinician about management of PPOELs. (Oral Surg Oral
Med Oral Pathol Oral Radiol 2018;125:628–636)

The term oral potentially malignant disorders
(OPMDs) was recommended at the World Health
Organization (WHO) workshop held in 2005. An oral pre-
malignant lesion is defined as any lesion or condition of
the oral mucosa that has the potential for malignant trans-
formation. A new term potentially premalignant oral
epithelial lesions (PPOELs) has recently been used as
a broad term to define both histologic and clinical lesions
that have malignant potential. This encompasses a number
of oral lesions, such as leukoplakia, erythroplakia,
erythroleukoplakia, lichen planus, oral submucous fi-
brosis (OSF), and oral dysplasia. The recognition and
management of these premalignant disorders and the un-
derstanding of their potential for progression to oral cancer
will minimize the morbidity and mortality and will have
a direct effect on patient survival.
BACKGROUND
Over the last 30 years, there has been a marginal im-
provement in the 5-year survival rate of patients with oral
cancer treated with multimodality contemporary therapy.
Current survival rates for all stages range from 50% to
55%.1 The emphasis on early detection, diagnosis, and
treatment of premalignant lesions is to prevent their trans-
formation to oral squamous cell carcinoma (OSCC). Early
detection is pivotal to increasing the 5-year survival
rate because it is directly correlated with stage de-
escalation at initial presentation.2 It is important to
understand that progression to OSCC is not a singular
event, but a gradual process of genetic and histologic
changes that lead to malignant transformation. The current
oral cancer progression model results from genetic
changes leading to the accumulation and progression of
molecular mutations that translate to a functional and/
or phenotypic change of the normal oral mucosa.3-5 These
Department of Oral and Maxillofacial Surgery, North Memorial Medical
Center, Minneapolis, MN, USA.
Received for publication Sep 29, 2017; returned for revision Mar 13,
2018; accepted for publication Mar 16, 2018.
© 2018 Elsevier Inc. All rights reserved.
2212-4403/$ - see front matter
https://doi.org/10.1016/j.oooo.2018.03.010
molecular mutations often include inactivation of tumor
suppressor genes, most notably p53 and p16, loss of het-
erozygosity (LOH) at the 3 p and 9 p locations, and
unregulated expression of regulatory molecules, such as
epidermal growth factor receptor.4-6 Subclinical changes
may accumulate enough to become clinically and/or mi-
croscopically apparent as phenotypically distinct from
the rest of the oral mucosa. These include PPOELs, car-
cinoma in situ, and frank invasive carcinoma. The concept
of “field cancerization,” first popularized by Slaughter
in 1957, states that if a carcinogen has led to a clinical-
ly detectable premalignant or malignant change in one
part of the oral cavity, there is equal risk of that hap-
pening in another part of the oral cavity because of a field
effect.7 This concept can help reconcile not only the pres-
ence of multiple primary lesions but also the recurrence
rates of premalignant and malignant lesions after surgi-
cal or medical intervention.8 It also highlights the presence
of subclinical lesions and makes the entire oral cavity,
especially in high-risk sites, such as the tongue and the
floor of the mouth, susceptible to malignant change. It
is important to keep this concept in mind when assess-
ing and managing premalignant and malignant conditions
because it mandates long-term follow-up for any patient
with a prior history of dysplasia or malignancy because
of the risk of second primary tumor development.
DETECTION AND DIAGNOSIS
To date, there have been no reliable and validated in vivo
chairside adjuncts that have sufficient sensitivity and speci-
ficity to be more superior than clinical examination and
Statement of Clinical Relevance
Timely evaluation and therapy of oral premalignant
lesions is paramount in preventing their progression
in to oral cancer. In this article, a clinical protocol that
will guide the practitioner in management of oral pre-
malignant lesions is proposed.

628
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Volume 125, Number 6
tissue biopsy.9 Adjunctive aids include, but are not limited
to, photodynamic detection, including autofluorescence,
vital staining (toluidine blue, Lugol’s iodine), and brush
cytology. These techniques are minimally invasive and
have virtually no morbidity, but they do carry consider-
able false-positive and false-negative rates.10-12 Diagnostic
adjuncts are, therefore, only used as adjuncts to physical
examination and the tissue biopsy, which are still con-
sidered the gold standard for detection and diagnosis.9,13,14
A brief overview of some established methodology is
given below; however, more in-depth information will
be provided in another article in this edition.
Toluidine blue is a staining technique that is useful for
detection of malignant lesions and those with high-
grade dysplasia. It is a metachromatic dye that has high
affinity for anionic groups, such as those found in nucleic
acids. The use of toluidine blue can guide the clinician
to specific areas for biopsy. Unfortunately, this tech-
nique is not very sensitive or specific in the case of lesions
that are either benign or have a low- to intermediate-
grade dysplasia. Overall, the sensitivity and the specificity
for toluidine blue in the literature range from 57% to 81%
and 56% to 67%, respectively.9,10 Both specificity and sen-
sitivity increase with the severity of dysplasia.10,11
Brush cytology/biopsy is a minimally invasive
technique, where a brush is used to obtain a complete
transepithelial specimen and not just exfoliated super-
ficial cells. The specimen is then fixated on a glass slide
and sent for computer-assisted analysis. Because this is
a transepithelial technique that involves sampling the basal,
intermediate, and superficial layers of a lesion, it cannot
be used to differentiate carcinoma in situ versus inva-
sive carcinoma. This technique’s sensitivity in the literature
varies from 73% to 100% and specificity ranges from 32%
to 94%, respectively.2,15
Autofluorescence and chemiluminescence are based
on the assumption that the light-absorbing and reflect-
ing properties of the normal mucosa change in the
stepwise process of dysplastic and malignant progres-
sion. Currently, there are various commercial products
that are available on the market and can be used for this.
A systematic review showed that the sensitivity rate and
specificity rate of chemiluminescence in the literature
range from 0% to 100% and from 0% to 75%, respec-
tively, and that the sensitivity and specificity rates of
autofluorescence range from 30% to 100% and from
15.3% to 100%, respectively.9,12 However, both tech-
niques were poor in distinguishing between dysplasia/
malignancy, inflammation, and reactive tissue with respect
to specificity. With regard to the articles that reported
100% sensitivity, it was deemed that the lesions were
clinically apparent by standard visual examination.1,6 A
new method based on the change in expression of certain
glycan residues on the surface of cancerous and dys-
plastic cells shows promising initial results.16,17 A chairside
REVIEW ARTICLE
Awadallah et al. 629
in vivo study by Baeten et al. tested a specific fluores-
cent conjugated lectin to target this aberrant glycosylation
on cancerous and dysplastic cells in the oral cavity. The
study yielded a sensitivity of 89% and a specificity of
82% in vivo.16
Lugol’s iodine solution is made of varying concen-
trations of iodine and potassium iodide in water. The
solution capitalizes on the affinity of iodine to glyco-
gen found in the normal or healthy mucosa. Dysplastic
mucosa and malignant mucosa have negligible glyco-
gen stores, if any, and do not bind the stain. This solution
has been shown to be an effective adjunct in guiding the
clinician in obtaining margins clear of intraepithelial neo-
plasia or dysplasia during tumor resection.18 A study
performed by McMahon et al. showed a 4% intraepithelial
neoplasia or dysplasia rate at the surgical margin when
using Lugol’s iodine solution compared with 32% when
it was not used in the in the standard group.18
TREATMENT
PPOELs can be managed conservatively by observa-
tion alone. In theory, medical interventions, such as
chemoprevention, are also available, considering the lack
of medical therapies approved by the U.S. Food and Drug
Administration. Surgical excision is the invasive man-
agement of choice for this group of lesions. Factors that
influence the type of therapy include patient risk factors
for malignancy (age, gender, and habits) and lesion risk
factors (classification, size, morphology, malignant trans-
formation rate, and location).19 Surgical treatment options
include traditional excision, cryosurgery, and carbon
dioxide (CO2) laser ablation. Nonsurgical treatment falls
into the category of chemoprevention or observation.20
Chemoprevention is the use of naturally or syntheti-
cally fabricated compounds designed to halt malignant
transformation of PPOELs. In addition, they may cause
regression or eradication of PPOELs and increase the
threshold of malignant transformation.8 It uses the same
concept of field cancerization but for treatment pur-
poses. If further researched and mastered, this potential
treatment can reduce the risk of postoperative recur-
rence rates, stabilize the oral mucosa, and decrease
morbidity associated with large surgical excisions. Current
chemoprevention compounds in focus include retinoids,
epidermal growth factor receptor inhibitors/antagonists,
cyclooxygenase-2 inhibitors, p53 modulators, and topicals,
such as bleomycin.8 The most researched of the above
therapies are the retinoids, but these are currently limited
only to the treatment of oral leukoplakia (OL).8,21 However,
because of the toxicity rate of around 10%, high lesion
recurrence rate of approximately 54% after stopping
treatment, and the lack of long-term follow-up of pa-
tients, the retinoids has yet to be an approved treatment
for OL.8,9,22
ORAL AND MAXILLOFACIAL PATHOLOGY
630 Awadallah et al.
ORAL LEUKOPLAKIA
OL is defined by the WHO as a white patch that cannot
be scraped or wiped off and is not attributable to any
pathophysiology or disease process. It is essential to rule
out other processes that OL can clinically mimic, such
as candidiasis, lichen planus, nicotinic stomatitis,
leukoedema, healing aphthous ulcers, white sponge nevus,
and frictional keratosis. It is important to keep in mind
that OL is a clinical diagnosis and not a histologic one.
Various forms of OL have been distinguished in the
current literature, each with distinct clinical morpholo-
gy and biology. These forms can be categorized into 2
broad types and further subtyped, depending on texture,
thickness, color, and regularity, and as homogeneous (thin
and thick) or nonhomogeneous (erythroleukoplakia, ver-
rucous, ulcerated).23 Figures 1 and 2 depict homogeneous
and nonhomogeneous OL.
The overall prevalence rate for OL ranged from 1%
to 5%, with a range of malignant transformation rate
(MTR) from 3% to 17%.13,23,24 However, there are mul-
tiple caveats to the above statement. The first is that the
MTR is higher in non-homogeneous leukoplakia, espe-
cially in the verrucous proliferative (PVL) type, where
it is between 40% and 75%8,13 and is 21% in the mixed
erythroleukoplakic form.23 PVL is an ominous form of
OL characterized by a high MTR and post-treatment per-
sistence. A systematic review performed by Abadie et al.
showed recurrence and/or progression to carcinoma in
71.2% of patients who had had therapeutic intervention
for PVL.25 There is an approximately 7-fold increase risk
for malignant development with nonhomogeneous leu-
koplakia compared with homogeneous leukoplakia and
a 5-fold increase in risk when the lesion size is greater
Fig. 1. Leukoplakia on the right buccal mucosa.
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June 2018
Fig. 2. Proliferative verrucous leukoplakia affecting the max-
illary gingiva and hard palate.
than 200 mm2 in area.23,26 The second caveat is that the
MTR is increased with presence of dysplasia compared
with its absence.23 The third caveat is that the timing of
possible malignant transformation is unpredictable. Hence,
it is prudent to monitor these patients on a regular basis.
The follow-up period, although influenced by the risk
stratification of the patient and the clinical and/or his-
tologic grade of the lesion, should ideally be for life.
Depending on lesion and patient risk factors, the current
treatment for OL can range from careful observation to
surgical intervention.27 Incisional biopsy followed by his-
topathologic examination is the gold standard for the initial
management of OL.27 The use of previously mentioned
chemopreventive methods in clinically controlled trials
have yet to show any promise in the prevention of ma-
lignant transformation and recurrence.28 A study performed
by Kuribayashi et al.20 looked at the long-term outcome
of watchful observation in the management of OL. Those
authors observed 218 patients with 237 OL lesions
between 2001 and 2010; incisional biopsies were ini-
tially performed and the degree of dysplasia ranged from
none (124) to severe (1), with a mean follow-up time of
41.1 months. They observed that 135 lesions remained
unchanged, 30 reduced in size or clinical severity, 44 had
vanished, 17 clinically deteriorated, and 11 trans-
formed to OSCC.20 Careful and regular observation is
reserved for the thin homogeneous type of OL that is not
associated with moderate or severe dysplasia because of
the relatively low MTR. The current surgical treatment
modalities include cold knife excision, CO2/Nd:YAG/KTP
lasers, or a combination of excision and laser treatment.29
A recent systematic review of 33 studies by Mogedas-
Vegara et al. showed a recurrence rate of OL ranging from
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Volume 125, Number 6
Fig. 3. Erythroleukoplakia affecting the right lateral tongue.
1% to 40.7% and an MTR ranging from 0% to 15.4%
when using a CO2 laser.29 A retrospective study on 94
surgically excised lesions with cold knife performed by
Holmstrup et al. showed a recurrence rate of 13% and
an MTR of 12% after a mean follow-up period of 7.5
years.22 Surgical intervention with cold knife excision and/
or CO2 laser is usually reserved for nonhomogeneous OL,
especially the erythroleukoplakic type; those associ-
ated with moderate to severe dysplasia; and the verrucous
proliferative type.20-22,29,30
ORAL ERYTHROPLAKIA
Oral erythroplakia (OE) is morphologically defined as
a red, velvety plaque or patch that cannot be attributed
to any other pathophysiologic process and is also a di-
agnosis of exclusion. OE can stand alone or be associated
with OL. In the latter case, it is classified as an
erythroleukoplakia (Figure 3). The incidence and prev-
alence of OE is much less than that of OL. However, OE
has one of the higher MTRs (up to 50%) of all the
PPOELs.26 The histologic study of biopsied homoge-
neous OE showed 51% invasive carcinoma, 40%
carcinoma in situ, and 9% mild or moderate dysplasia.26
OE represents a highly suspicious lesion that many prac-
titioners will consider as the first clinical sign of squamous
cell carcinoma.31 It is highly recommended that these
lesions be excised to the submucosal level when the
tongue is not involved or to the superficial muscular level
if the tongue is involved. As a result of the high MTR
and incidence of dysplasia, carcinoma in situ, and frank
carcinoma in OE, watchful observation or conservative
treatment should be avoided and surgical intervention be
implemented early, along with risk factor aversion and
long-term surveillance.9,13,14
ORAL SUBMUCOUS FIBROSIS
OSF is a progressive fibrotic disease of the aerodigestive
tract, but mainly affecting the oral cavity. Deranged
collagen metabolism is the underlying pathophysi-
REVIEW ARTICLE
Awadallah et al. 631
ologic process.32,33 This disease predominantly affects
individuals living in the South East Asian countries, has
equal gender predilection, and is seen in the second to
third decades of life.32 Multiple etiologic factors have been
linked to this disease and include nutritional deficiencies,
such as those of vitamins, iron, and zinc; autoantibod-
ies; and the molecule capsaicin in chilies. However, the
most predominant etiologic factor reported in the liter-
ature, with the strongest link, is the use of areca nut and
its derived products, including betel quid and gutkha.
Gutkha is a grainy light brown substance that contains
high concentrations of areca nut; it is combined with
tobacco and provides a central stimulation leading to
higher addiction than that to chewing tobacco.33
One of the specific, but not sensitive, presenting clin-
ical symptom is a new intolerance to spicy foods. Initial
clinical signs include formation of vesicles and ulcers,
especially on the hard palate and buccal mucosa. At the
latter stages of the disease, the patient will start having
xerostomia, restriction of tongue range of motion, and
progressively decreased elasticity of the buccal mucosa,
lips, and floor of the mouth. Dense fibrotic bands can be
palpated within the oral tissues, and the color of the
mucosa will become more opaque and blanched.33 Ul-
timately, the disease culminates with generalized fibrosis
of the oral cavity and progressing trismus.
OSF has an average MTR range of 7% to 30%.13 Man-
agement of OSF is primarily to monitor for any malignant
transformation, halt disease progression, and, most
importantly, alleviate trismus to allow for speech, mas-
tication, oncologic surveillance, and dental hygiene. This
can be accomplished medically or surgically and is tai-
lored to the severity of the disease and trismus. This
disease is currently considered irreversible once trismus
has developed.32,33 Initial therapy consists of cessation of
betel nut use.13 Conservative therapy is aimed at halting
disease progression and alleviating trismus.13 It is a
multimodality approach that includes micronutrient
supplementation, enzymatic degradation, physical reha-
bilitation, pharmacologic intervention, and antioxidant
therapy.32,33 Enzymatic degradation mainly utilizes 3
enzymes to undermine the fibrosed soft tissue matrix: hy-
aluronidase, collagenase, and chymotrypsin. Ultimately,
the goal of enzymatic therapy is to improve trismus.32,33
Pharmacologic therapy includes anti-inflammatory/
immunomodulators, which include corticosteroids mainly,
interferon-γ, immunized milk, and placental extracts.13,32,33
These are meant to alleviate symptoms of inflamma-
tion. However, they are not particularly helpful in the later
stages of the disease. Other pharmacologic agents utilize
vasogenic therapy to maintain and promote vascular in-
tegrity in and around the lesion for delivery of nutrients
and further pharmacologic therapy; they include, most
notably, polyphenols, which are byproducts of tea
pigments; pentoxyphylline; buflomedil hydrochloride; and
ORAL AND MAXILLOFACIAL PATHOLOGY
632 Awadallah et al.
nylonrin.32,33 Antioxidant-based therapy with beta caro-
tene, vitamin E, and lycopene aims at reducing and/or
eliminating the oxygen free radicals produced by the me-
tabolism of the areca nut.32,33 Surgical therapy is aimed
at alleviating trismus via excision and release of fi-
brotic bands or tissue with conventional reconstructive
techniques, which include local/regional advancement
flaps and microvascular flaps.32
ORAL LICHEN PLANUS
Lichen planus is a systemic mucocutaneous disease that
commonly affects the oral mucosa but can also affect skin,
nails, the scalp, and the vaginal mucosa. It usually mani-
fests at the third to seventh decades of life.34 The disease
has a strong female predilection. Intraorally, the buccal
mucosa, tongue, and gingiva are the most common sites;
lesions are usually bilateral and symmetric.35 The patho-
physiology is currently understood as a T cell–mediated
autoimmune destruction of the basal cells of the
epithelium.13,35
In the oral cavity, there are various morphologic forms
of the disease, most commonly the reticular, papular,
plaque-like, bullous, atrophic, and erosive forms. The
classic form of OLP is the reticular type.34 It presents as
an interconnecting lace of slightly raised, thin, white lines
called Wickham striae, which are pathognomonic for
OLP.34,35 Diagnosis of OLP can be made with clinical
examination, especially the lesion presents as the
classic reticular type; tissue biopsy; and/or direct
immunofluorescence.36 The range of MTR in the liter-
ature of OLP is 0% to 5%, with the more accepted MTR
average being 1%.34,35 However, a higher incidence of
MTR was found in smokers, alcohol users, patients in-
fected by hepatitis C virus, those with the erosive and
atrophic types, and those with histopathologic dyspla-
sia found on biopsy.35,36
The mainstay of treatment of localized OLP is local
medical therapy. Primary treatment for OLP is with topical
corticosteroids, such as triamcinolone acetonide and
beclomethasone.37 Second-line therapies include other
topical agents, such as retinoids, cyclosporine, calcineurin
inhibitors, and possibly photodynamic therapy. However,
a systematic review of 28 randomized controlled trials
performed by Thongprasom et al. showed no differ-
ence between steroids and calcineurin inhibitors with
regard to reducing pain.38 In addition, no difference was
noted in the type of steroid used in reduction of pain.38
ORAL EPITHELIAL DYSPLASIA
It is known that oral epithelial dysplasia (OED) is often
the precursor to OSCC. Oral dysplasia is diagnosed his-
tologically and defined by the WHO as a precancerous
lesion of stratified squamous epithelium characterized
by cellular atypia and loss of normal maturation and
stratification short of carcinoma in situ.3,23,39 The pres-
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June 2018
Fig. 4. Severe dysplasia on the right hard palate–soft palate
junction.
ence and the grade of dysplasia contribute to the malignant
transformation potential for all the above PPOELs.3,9,14,19
OLP, OSF, OL, and OED are the gross clinical mani-
festations of the accumulating microscopic dysplastic
changes of normal cellular architecture9,13,14,39 (Figures 4
and 5). However, PPOELs and clinically normal mucosa
can progress to OSCC without the presence of dyspla-
sia. Not all dysplastic lesions will progress to OSCC.9,14,39
The overall MTR of OED in the literature can range from
6% to 36%.39 Current literature reports that variables that
affect the MTR are the site of the lesion—the tongue and
the floor of the mouth being at the higher end of the MTR
spectrum—along with the grade of dysplasia.3 There are
conflicting reports with regard to grading severity being
correlated with MTR.23,40,41 A study performed by Dost
et al. on 368 patients with biopsy-proven OED con-
cluded that the severity of dysplasia based on 2 separate
systems, the 3-tier 2005 WHO classification and the binary
system proposed by Kujan et al., was not associated with
the risk of malignant transformation.40 Even though there
are similar studies that discredit the correlation of degree
of dysplasia and MTR, the majority of the literature cur-
rently supports that OED presence and severity correlates
with MTR.3
Contemporary treatment modalities include excision
with cold knife, CO2 laser ablation, antioxidant therapy,
immunomodulating therapy, or any combination of the
above. Antioxidant and immunomodulating therapies, such
as those used in OSF, utilize systemic lycopene and topical
bleomycin. In addition, systemic cis-retinoid acid is
also used as an antioxidant.14 Currently, the most ac-
ceptable treatment modality is surgical intervention with
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Volume 125, Number 6
Fig. 5. Histologic moderate-to-severe dysplasia.
Fig. 6. Severely dysplastic proliferative verrucous leukopla-
kia of the bilateral maxillary alveolar gingiva, hard and soft
palates, and associated homogeneous oral leukoplakia.
excision, laser ablation, or a combination of both29,41-43
(Figures 6–8). Despite use of surgical modalities, there
is still a considerable amount of recurrence and trans-
formation to malignancy. 22,40 A retrospective study
performed by Holmstrup et al. on 94 surgically excised
homogeneous and nonhomogeneous OLs, of which 71%
were associated with a degree of dysplasia, showed re-
currence and a malignant transformation rates of 13%
and 12%, respectively, after a follow-up period of 1.5 to
18.6 years.22 The average time to malignant transformation
was 7.5 years.22 A longitudinal cohort study performed by
Thomson et al. on 590 patients with CO2 laser–excised
PPOELs, of which 88% were associated with dysplasia
or carcinoma in situ, showed persistence and malignant
REVIEW ARTICLE
Awadallah et al. 633
Fig. 7. After wide local excision and reconstruction with a split
thickness skin graft.
Fig. 8. Eleven months after treatment of proliferative verru-
cous leukoplakia.
transformation rates of 9% and 16%, respectively, after
an average follow-up period of 7.3 years.43 The average
time to malignant transformation was 87.3 months.43 There
are currently no widely accepted and concrete guide-
lines or recommendations on the frequency of follow-
up for patients who have a diagnosis of OED.14 However,
follow-up should be regular and frequent, especially for
lesions with moderate to severe dysplasia.41,42,44 This can
be inferred from the concept of field cancerization, un-
predictable time to malignant transformation, and
recurrence rate. Follow-up is also tailored to patient- and
lesion-specific factors, which include age, gender, sub-
stance use, anatomic location, and degree of dysplasia.3,23,40
HUMAN PAPILLOMAVIRUS AND DYSPLASIA
Human papillomavirus (HPV) has been identified as a
risk factor for the development of oropharyngeal squa-
mous cell carcinoma (OPSCC). Of the several subtypes,
HPV-16 and HPV-18 are deemed to pose a high risk for
the development of OPSCC.45,46 Two viral oncoproteins,
E6 and E7, derived from the HPV gene, have been iso-
lated, and their presence is necessary for malignant
transformation to SCC. These oncoproteins exert their
repressive effects on p53 and Rb tumor suppressor activity,
ORAL AND MAXILLOFACIAL PATHOLOGY
634 Awadallah et al.
respectively.45 The overall prevalence of HPV in the
normal oral mucosa ranges from 0.9% to 12%, but this
infection is usually cleared within 2 years in an immu-
nocompetent host.47 Persistence of the virus beyond this
time predisposes patients to mutations leading to ma-
lignant transformation. There is an ongoing debate about
the association and prevalence of HPV in PPOELs. A sys-
tematic review performed by Syrjanen et al. showed an
overall odds ratio of 3.87 between all PPOELs and pooled
HPV-DNA. The odds ratio was 5.10 when dysplasia was
the specific variable.45 A meta-analysis performed by
Jayaprakash et al. showed the prevalence of HPV-16 and
HPV-18 in oral and oropharyngeal dysplasia to be 25%.48
A histopathologic analysis performed by Lerman et al.
showed a unique HPV-driven dysplasia to be character-
ized by karyorrhexis and apoptosis.46,47 On the basis of
the molecular progression model of OSCC/OPSCC, it
is reasonable to envision the concept of chemoprevention
and the role of HPV vaccination in reducing the inci-
dence and prevalence of OSCC/OPSCC.
PREVENTION AND MAINTENANCE
Primary prevention is ideally the best and the first method
in the management of premalignancy. Ultimately, the
goal is to prevent premalignancy and its progression
to malignancy. It is prudent to risk-stratify a patient
Fig. 9. A proposed treatment and follow-up algorithm for oral premalignant lesions based on dysplasia.
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June 2018
and provide appropriate counseling and screening for
higher-risk individuals. One systematic review study
estimated that the population attributable risk for
developing SCC was 25% for smoking alone, 18% for
alcohol alone, and 40% for combined use of both.49
Both these risk factors are dose dependent, with a life-
time cumulative use that is positively correlated with
development of OSCC. A meta-analysis study per-
formed by Kansy et al. on 5338 patients with treated
OSCC showed a 30% prevalence rate of all HPV sub-
types and HPV-16/-18 subtypes to be 25% and 18%,
respectively.50 Secondary prevention is achieved by early
detection of PPOELs and/or the prevention of malig-
nant transformation.9 Interval screening of individuals can
be tailored based on the patient’s risk stratification of de-
veloping OSCC and dental/medical compliance. Currently,
there are no standardized protocols for follow-up of pa-
tients who have existing PPOELs or previously excised
lesions. It is emphasized that for diagnosed lesions, the
time to malignant transformation is unpredictable and
varies from months to years. New lesions can occur ad-
jacent to previously excised PPOELs or in a different
location. Patients with a history of a premalignant/
dysplastic lesions should be followed up over the long
term. Surveillance varies by clinician experience and
patient and lesion risk factors. Figure 9 is a proposed
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Volume 125, Number 6
algorithm for the management of PPOELs based on their
dysplastic characteristics.21,42
CONCLUSIONS
The management of premalignant lesions is complex, and
the current literature regarding the ideal treatment mo-
dality is conflicting. The transition from normal mucosa
to premalignant or dysplastic mucosa and to finally ma-
lignant change is a complex interplay between the
environment and the host. Host factors include genet-
ics and immune system function. Environmental factors
include exposure to carcinogens, including betel liquid,
tobacco, alcohol, and HPV. It is imperative that clini-
cians implement primary prevention to reduce the
prevalence and incidence of premalignant disease re-
sulting from known and preventable causes. This is
achieved through education and empowering of pa-
tients against exposure to those environmental carcinogens.
If primary prevention fails, then early detection and in-
tervention are key when managing a PPOEL. Diagnosis
and treatment of a PPOEL is based on histopathology,
with surgical excision or ablation being reserved for dys-
plastic lesions.39,51
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Reprint requests:
Deepak Kademani, DMD, MD
North Memorial Medical Center
Department of Oral and Maxillofacial Surgery
3366 Oakdale Ave. N Suite 200
Minneapolis, MN 55422
USA
Deepak.Kademani@northmemorial.com