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2018 Management Update of Potentially Premalignant Oral Epithelial Lesions
2018 Management Update of Potentially Premalignant Oral Epithelial Lesions
2018 Management Update of Potentially Premalignant Oral Epithelial Lesions
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 molecular mutations often include inactivation of tumor
(OPMDs) was recommended at the World Health suppressor genes, most notably p53 and p16, loss of het-
Organization (WHO) workshop held in 2005. An oral pre- erozygosity (LOH) at the 3 p and 9 p locations, and
malignant lesion is defined as any lesion or condition of unregulated expression of regulatory molecules, such as
the oral mucosa that has the potential for malignant trans- epidermal growth factor receptor.4-6 Subclinical changes
formation. A new term potentially premalignant oral may accumulate enough to become clinically and/or mi-
epithelial lesions (PPOELs) has recently been used as croscopically apparent as phenotypically distinct from
a broad term to define both histologic and clinical lesions the rest of the oral mucosa. These include PPOELs, car-
that have malignant potential. This encompasses a number cinoma in situ, and frank invasive carcinoma. The concept
of oral lesions, such as leukoplakia, erythroplakia, of “field cancerization,” first popularized by Slaughter
erythroleukoplakia, lichen planus, oral submucous fi- in 1957, states that if a carcinogen has led to a clinical-
brosis (OSF), and oral dysplasia. The recognition and ly detectable premalignant or malignant change in one
management of these premalignant disorders and the un- part of the oral cavity, there is equal risk of that hap-
derstanding of their potential for progression to oral cancer pening in another part of the oral cavity because of a field
will minimize the morbidity and mortality and will have effect.7 This concept can help reconcile not only the pres-
a direct effect on patient survival. ence of multiple primary lesions but also the recurrence
rates of premalignant and malignant lesions after surgi-
BACKGROUND cal or medical intervention.8 It also highlights the presence
Over the last 30 years, there has been a marginal im- of subclinical lesions and makes the entire oral cavity,
provement in the 5-year survival rate of patients with oral especially in high-risk sites, such as the tongue and the
cancer treated with multimodality contemporary therapy. floor of the mouth, susceptible to malignant change. It
Current survival rates for all stages range from 50% to is important to keep this concept in mind when assess-
55%.1 The emphasis on early detection, diagnosis, and ing and managing premalignant and malignant conditions
treatment of premalignant lesions is to prevent their trans- because it mandates long-term follow-up for any patient
formation to oral squamous cell carcinoma (OSCC). Early with a prior history of dysplasia or malignancy because
detection is pivotal to increasing the 5-year survival of the risk of second primary tumor development.
rate because it is directly correlated with stage de-
escalation at initial presentation.2 It is important to DETECTION AND DIAGNOSIS
understand that progression to OSCC is not a singular To date, there have been no reliable and validated in vivo
event, but a gradual process of genetic and histologic chairside adjuncts that have sufficient sensitivity and speci-
changes that lead to malignant transformation. The current ficity to be more superior than clinical examination and
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 Statement of Clinical Relevance
Department of Oral and Maxillofacial Surgery, North Memorial Medical
Center, Minneapolis, MN, USA.
Timely evaluation and therapy of oral premalignant
Received for publication Sep 29, 2017; returned for revision Mar 13, lesions is paramount in preventing their progression
2018; accepted for publication Mar 16, 2018. in to oral cancer. In this article, a clinical protocol that
© 2018 Elsevier Inc. All rights reserved. will guide the practitioner in management of oral pre-
2212-4403/$ - see front matter malignant lesions is proposed.
https://doi.org/10.1016/j.oooo.2018.03.010
628
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Volume 125, Number 6 Awadallah et al. 629
tissue biopsy.9 Adjunctive aids include, but are not limited in vivo study by Baeten et al. tested a specific fluores-
to, photodynamic detection, including autofluorescence, cent conjugated lectin to target this aberrant glycosylation
vital staining (toluidine blue, Lugol’s iodine), and brush on cancerous and dysplastic cells in the oral cavity. The
cytology. These techniques are minimally invasive and study yielded a sensitivity of 89% and a specificity of
have virtually no morbidity, but they do carry consider- 82% in vivo.16
able false-positive and false-negative rates.10-12 Diagnostic Lugol’s iodine solution is made of varying concen-
adjuncts are, therefore, only used as adjuncts to physical trations of iodine and potassium iodide in water. The
examination and the tissue biopsy, which are still con- solution capitalizes on the affinity of iodine to glyco-
sidered the gold standard for detection and diagnosis.9,13,14 gen found in the normal or healthy mucosa. Dysplastic
A brief overview of some established methodology is mucosa and malignant mucosa have negligible glyco-
given below; however, more in-depth information will gen stores, if any, and do not bind the stain. This solution
be provided in another article in this edition. has been shown to be an effective adjunct in guiding the
Toluidine blue is a staining technique that is useful for clinician in obtaining margins clear of intraepithelial neo-
detection of malignant lesions and those with high- plasia or dysplasia during tumor resection.18 A study
grade dysplasia. It is a metachromatic dye that has high performed by McMahon et al. showed a 4% intraepithelial
affinity for anionic groups, such as those found in nucleic neoplasia or dysplasia rate at the surgical margin when
acids. The use of toluidine blue can guide the clinician using Lugol’s iodine solution compared with 32% when
to specific areas for biopsy. Unfortunately, this tech- it was not used in the in the standard group.18
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 TREATMENT
for toluidine blue in the literature range from 57% to 81% PPOELs can be managed conservatively by observa-
and 56% to 67%, respectively.9,10 Both specificity and sen- tion alone. In theory, medical interventions, such as
sitivity increase with the severity of dysplasia.10,11 chemoprevention, are also available, considering the lack
Brush cytology/biopsy is a minimally invasive of medical therapies approved by the U.S. Food and Drug
technique, where a brush is used to obtain a complete Administration. Surgical excision is the invasive man-
transepithelial specimen and not just exfoliated super- agement of choice for this group of lesions. Factors that
ficial cells. The specimen is then fixated on a glass slide influence the type of therapy include patient risk factors
and sent for computer-assisted analysis. Because this is for malignancy (age, gender, and habits) and lesion risk
a transepithelial technique that involves sampling the basal, factors (classification, size, morphology, malignant trans-
intermediate, and superficial layers of a lesion, it cannot formation rate, and location).19 Surgical treatment options
be used to differentiate carcinoma in situ versus inva- include traditional excision, cryosurgery, and carbon
sive carcinoma. This technique’s sensitivity in the literature dioxide (CO2) laser ablation. Nonsurgical treatment falls
varies from 73% to 100% and specificity ranges from 32% into the category of chemoprevention or observation.20
to 94%, respectively.2,15 Chemoprevention is the use of naturally or syntheti-
Autofluorescence and chemiluminescence are based cally fabricated compounds designed to halt malignant
on the assumption that the light-absorbing and reflect- transformation of PPOELs. In addition, they may cause
ing properties of the normal mucosa change in the regression or eradication of PPOELs and increase the
stepwise process of dysplastic and malignant progres- threshold of malignant transformation.8 It uses the same
sion. Currently, there are various commercial products concept of field cancerization but for treatment pur-
that are available on the market and can be used for this. poses. If further researched and mastered, this potential
A systematic review showed that the sensitivity rate and treatment can reduce the risk of postoperative recur-
specificity rate of chemiluminescence in the literature rence rates, stabilize the oral mucosa, and decrease
range from 0% to 100% and from 0% to 75%, respec- morbidity associated with large surgical excisions. Current
tively, and that the sensitivity and specificity rates of chemoprevention compounds in focus include retinoids,
autofluorescence range from 30% to 100% and from epidermal growth factor receptor inhibitors/antagonists,
15.3% to 100%, respectively.9,12 However, both tech- cyclooxygenase-2 inhibitors, p53 modulators, and topicals,
niques were poor in distinguishing between dysplasia/ such as bleomycin.8 The most researched of the above
malignancy, inflammation, and reactive tissue with respect therapies are the retinoids, but these are currently limited
to specificity. With regard to the articles that reported only to the treatment of oral leukoplakia (OL).8,21 However,
100% sensitivity, it was deemed that the lesions were because of the toxicity rate of around 10%, high lesion
clinically apparent by standard visual examination.1,6 A recurrence rate of approximately 54% after stopping
new method based on the change in expression of certain treatment, and the lack of long-term follow-up of pa-
glycan residues on the surface of cancerous and dys- tients, the retinoids has yet to be an approved treatment
plastic cells shows promising initial results.16,17 A chairside for OL.8,9,22
ORAL AND MAXILLOFACIAL PATHOLOGY OOOO
630 Awadallah et al. June 2018
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
Fig. 2. Proliferative verrucous leukoplakia affecting the max-
(MTR) from 3% to 17%.13,23,24 However, there are mul-
illary gingiva and hard palate.
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 than 200 mm2 in area.23,26 The second caveat is that the
it is between 40% and 75%8,13 and is 21% in the mixed MTR is increased with presence of dysplasia compared
erythroleukoplakic form.23 PVL is an ominous form of with its absence.23 The third caveat is that the timing of
OL characterized by a high MTR and post-treatment per- possible malignant transformation is unpredictable. Hence,
sistence. A systematic review performed by Abadie et al. it is prudent to monitor these patients on a regular basis.
showed recurrence and/or progression to carcinoma in The follow-up period, although influenced by the risk
71.2% of patients who had had therapeutic intervention stratification of the patient and the clinical and/or his-
for PVL.25 There is an approximately 7-fold increase risk tologic grade of the lesion, should ideally be for life.
for malignant development with nonhomogeneous leu- Depending on lesion and patient risk factors, the current
koplakia compared with homogeneous leukoplakia and treatment for OL can range from careful observation to
a 5-fold increase in risk when the lesion size is greater 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-
Fig. 1. Leukoplakia on the right buccal mucosa. Vegara et al. showed a recurrence rate of OL ranging from
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Volume 125, Number 6 Awadallah et al. 631
respectively.45 The overall prevalence of HPV in the and provide appropriate counseling and screening for
normal oral mucosa ranges from 0.9% to 12%, but this higher-risk individuals. One systematic review study
infection is usually cleared within 2 years in an immu- estimated that the population attributable risk for
nocompetent host.47 Persistence of the virus beyond this developing SCC was 25% for smoking alone, 18% for
time predisposes patients to mutations leading to ma- alcohol alone, and 40% for combined use of both.49
lignant transformation. There is an ongoing debate about Both these risk factors are dose dependent, with a life-
the association and prevalence of HPV in PPOELs. A sys- time cumulative use that is positively correlated with
tematic review performed by Syrjanen et al. showed an development of OSCC. A meta-analysis study per-
overall odds ratio of 3.87 between all PPOELs and pooled formed by Kansy et al. on 5338 patients with treated
HPV-DNA. The odds ratio was 5.10 when dysplasia was OSCC showed a 30% prevalence rate of all HPV sub-
the specific variable.45 A meta-analysis performed by types and HPV-16/-18 subtypes to be 25% and 18%,
Jayaprakash et al. showed the prevalence of HPV-16 and respectively.50 Secondary prevention is achieved by early
HPV-18 in oral and oropharyngeal dysplasia to be 25%.48 detection of PPOELs and/or the prevention of malig-
A histopathologic analysis performed by Lerman et al. nant transformation.9 Interval screening of individuals can
showed a unique HPV-driven dysplasia to be character- be tailored based on the patient’s risk stratification of de-
ized by karyorrhexis and apoptosis.46,47 On the basis of veloping OSCC and dental/medical compliance. Currently,
the molecular progression model of OSCC/OPSCC, it there are no standardized protocols for follow-up of pa-
is reasonable to envision the concept of chemoprevention tients who have existing PPOELs or previously excised
and the role of HPV vaccination in reducing the inci- lesions. It is emphasized that for diagnosed lesions, the
dence and prevalence of OSCC/OPSCC. time to malignant transformation is unpredictable and
varies from months to years. New lesions can occur ad-
PREVENTION AND MAINTENANCE jacent to previously excised PPOELs or in a different
Primary prevention is ideally the best and the first method location. Patients with a history of a premalignant/
in the management of premalignancy. Ultimately, the dysplastic lesions should be followed up over the long
goal is to prevent premalignancy and its progression term. Surveillance varies by clinician experience and
to malignancy. It is prudent to risk-stratify a patient patient and lesion risk factors. Figure 9 is a proposed
Fig. 9. A proposed treatment and follow-up algorithm for oral premalignant lesions based on dysplasia.
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Volume 125, Number 6 Awadallah et al. 635
algorithm for the management of PPOELs based on their 12. Rashid A, Warnakulasuriya S. The use of light-based (optical) de-
dysplastic characteristics.21,42 tection systems as adjuncts in the detection of oral cancer and oral
potentially malignant disorders: a systematic review. J Oral Pathol
Med. 2015;44:307-328.
CONCLUSIONS 13. Panwar A, Lindau R, Wieland A. Management for premalignant
lesions of the oral cavity. Expert Rev Anticancer Ther. 2014;14:
The management of premalignant lesions is complex, and 349-357.
the current literature regarding the ideal treatment mo- 14. Brennan M, Migliorati CA, Lockhart PB, et al. Management of
dality is conflicting. The transition from normal mucosa oral epithelial dysplasia: a review. Oral Surg Oral Med Oral Pathol
to premalignant or dysplastic mucosa and to finally ma- Oral Radiol Endod. 2007;103(S19):e1-e12.
lignant change is a complex interplay between the 15. Babshet M, Nandimath K, Pervatikar S, Naikmasur V. Efficacy
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cians implement primary prevention to reduce the 40:292-301.
17. Baeten J, Suresh A, Johnson A, et al. Molecular imaging of oral
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Reprint requests:
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51:883-887. Deepak Kademani, DMD, MD
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laser surgery for oral potentially malignant disorders: a longitu- Department of Oral and Maxillofacial Surgery
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337-342. Minneapolis, MN 55422
44. Ho MW, Field EA, Field JK, et al. Outcomes of oral squamous USA
cell carcinoma arising from oral epithelial dysplasia: rationale for Deepak.Kademani@northmemorial.com