|

Received: 11 September 2017    Accepted: 14 September 2017

DOI: 10.1111/odi.12781

P R O F S C U L LY M E M O R I A L I S S U E

Oral leukoplakia remains a challenging condition

A Villa1,2  | S Sonis1,2,3

1
Division of Oral Medicine and Dentistry,
Brigham and Women’s Hospital, Dana Farber Crispian Scully had many interests in the realm of oral diseases. But oral leukoplakia
Cancer Institute, Boston, MA, USA was one that piqued his curiosity when he was still an academic neophyte and re-
2
Department of Oral Medicine Infection and mained a topic which he studied throughout his enormously productive career. It is
Immunity, Harvard School of Dental Medicine,
Boston, MA, USA easy to understand why. While the clinical manifestations of oral leukoplakia are com-
3
Biomodels LLC, Watertown, MA, USA mon, we still do not fully understand why one version of the condition is benign, while
another, similar in appearance, progresses to a malignancy. The diagnosis of oral leu-
Correspondence
Alessandro Villa, Division of Oral Medicine koplakia is based on expert clinical and histopathological examamination. Management
and Dentistry, Brigham and Women’s Hospital,
and treatment of leukoplakia remain challenging especially for large lesions and the
Boston, MA, USA.
Email: [email protected] proliferative subtype. This review aims to provide a general overview on leukoplakia,
explore current challenges in its diagnosis and management and discuss the opportu-
nities to better understand the condition.

KEYWORDS
genomics, leukoplakia, management

1 |  INTRODUCTION and neoplastic forms of the condition and potential clinical methods
to define the two spanned his career. His passion and persistence for
In preparing this paper to honor and remember Crispian, we started by the subject are reflected by the title of the lead Anniversary Review
doing a PubMed search using two keywords: “Scully C and leukopla- he wrote for this journal in 2014: Challenges in predicting which oral
kia.” No surprise, Crispian’s writing on the topic was prolific—51 hits. mucosal potentially disease will progress to neoplasia (Scully, 2014).
But what was surprising was that his passion and interest in the topic The conclusions he notes in the manuscript remain relevant and criti-
were evident from his student days, especially with respect to the cal today: “Probably the greatest challenge to those managing patients
question of differentiating premalignant from malignant disease. True with oral diseases is the dilemma of attempting to predict which oral
to form, Crispian’s thinking was innovative. He recognized that leuko- erythroplakias, leukoplakias, lichenoid and other potentially malignant
plakias varied widely in its premalignant/malignant potential, that such mucosal disease…will progress to neoplasia.” As we review below,
differences were biologically driven and that, consequently, molecular Crispian’s vision, innovation, teaching, and writings have influenced
evidence (what we call biomarkers today) might have clinical utility in the progress within this space.
determining the risk of progression. His solo-­authored manuscript en-
titled “Serum β2 microglobulin in oral malignancy and premalignancy,”
published in 1981 described the results of a clinical study in which 2 | LEUKOPLAKIA: A CLINICAL ENTITY
Crispian found that serum levels of β2 microglobulin were elevated
in patients displaying evidence of both oral carcinoma or keratosis/ Leukoplakia as defined by the World Health Organization (WHO)
dysplasia (Scully, 1982). And like many of Crispian’s concepts, the per- is a “white plaque of questionable risk having excluded (other)
sistence of interest in the topic becomes a component of his legacy known diseases or disorders that carry no increased risk for
(Saddiwal et al., 2017). cancer”(Warnakulasuriya, Johnson, & van der Waal, 2007). Leukoplakia
Crispian’s subsequent contributions on the topic of leukoplakia and, is a clinical term which is typically modified based on histopathologi-
particularly the identification of biological differences between benign cal examination. The pooled prevalence estimated for leukoplakia of

© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd. All rights reserved

Oral Diseases. 2018;24:179–183. wileyonlinelibrary.com/journal/odi |  179

  
 |
180       VILLA and SONIS

the oral cavity is between 1.5% (1.4%–1.6% 95% confidence interval 4 | FROM LEUKOPLAKIA TO ORAL
[CI]) and 2.6% (1.7%–2.7% 95%CI) with no gender predilection (Petti, SQUAMOUS CELL CARCINOMA
2003). The risk factors associated with oral leukoplakia are similar
to those for oral cancer and include tobacco smoking, heavy alcohol Leukoplakia is thought to progress from hyperkeratosis or hyperplasia
consumption, betel nut chewing, old age and UV light exposure (for (or the so called KUS) (Woo, Grammer, & Lerman, 2014), to various
lesions of the lip) (Arduino, Bagan, El-­Naggar, & Carrozzo, 2013; Petti degrees of dysplasia (mild, moderate, and severe), and ultimately car-
& Scully, 2006). cinoma in situ and/or OSCC (Lumerman et al., 1995; Warnakulasuriya
Clinically, different forms of leukoplakias exist; homogeneous et al., 2007). The presence of dysplastic areas in the epithelium of the
leukoplakia is characterized by a flat and uniform white plaque with oral cavity has been associated with an increased risk of malignant
well-­defined margins (at least one). Non-­homogeneous leukoplakia transformation. While many leukoplakias are outright dysplasias or
presents with areas of erythema accompanied by areas of nodular- invasive SCCs at the time of biopsy, several non-­dysplastic keratotic
ity and verrucousity (van der Waal, 2010). Oral proliferative verrucous lesions (KUS) also transform to invasive carcinoma over time. In 1984,
leukoplakia (PVL) is a distinct subset of non-­homogenous leukopla- Silverman et al. showed that 16% of patients with oral “benign hy-
kia. PVL may involve a single large site, but is frequently multifocal perkeratosis” underwent malignant transformation (Silverman et al.,
and often occurs on the gingiva, buccal mucosa, and tongue in both 1984). Similarly, in a study by Schepman, van der Meij, Smeele, & van
contiguous and non-­contiguous sites of the oral cavity (Bagan, Scully, der Waal (1998) patients with leukoplakia with a histopathological di-
Jimenez, & Martorell, 2010; Bagan et al., 2003; Pentenero, Meleti, agnosis of “benign hyperkeratosis” developed OSCC in 30% of the
Vescovi, & Gandolfo, 2014; Warnakulasuriya et al., 2007). Of note, cases.
PVL is more common in females and is usually not associated with The evolution from dysplasia to invasive cancer is not yet well un-
tobacco smoking. derstood. A key step to improving oral cancer outcomes is to identify
The diagnosis of oral leukoplakia is based on expert oral clinico- the molecular factors driving disease initiation and progression, as
pathologic examination. PVLs or large leukoplakias require multiple these factors may represent good candidates for targeted therapies.
periodic biopsies at different site to detect different grades of dys- To date, there have been a few molecular studies to outline these fac-
plasia or oral squamous cell carcinoma (OSCC) (Villa & Woo, 2017). tors in oral leukoplakia and oral cancer (Banerjee, Bhattacharyya, &
Approximately 10%–17% of cases may be missed if only a single bi- Vishwanatha, 2005; Garnis et al., 2009; Sumino et al., 2013). In the
opsy is obtained (Lee et al., 2007; Pentenero et al., 2003). past few years, there has been an increasing interest in genes that
predispose to oral carcinogenesis from oral leukoplakia. In particular,
recent studies have shown that genetic analysis may be promising in
3 |  THE MALIGNANT TRANSFORMATION predicting the malignant progression of oral leukoplakias (Bremmer
OF ORAL LEUKOPLAKIA et al., 2011; Saintigny et al., 2011). The identification of risk-­predicting
genes related to the malignant transformation may play a signifi-
The malignant transformation rate of leukoplakia varies depending cant role in determining an individual’s risk of developing cancer and
on the type of leukoplakia considered. Homogenous leukoplakias ­therefore guide treatment decisions.
have a lower risk of transformation (0.6%–5%) compared to the non-­ Oral dysplasias are associated with a significant rate of malignant
homogeneous cases (20%–25%) (Napier & Speight, 2008; Reibel, transformation (5%–36%) (Cowan et al., 2001; Hsue et al., 2007; Lian
2003; van der Waal & Axell, 2002). PVL is the most aggressive en- Ie et al., 2013; Liu et al., 2012; Lumerman et al., 1995; Silverman
tity with a malignant transformation rate of 61.0% over an average et al., 1984), yet the underlying molecular mechanisms and pathways
follow-­up period of 7.4 years with an overall 40.0% mortality rate involved in oral cancer development have not been fully elucidated
(Abadie, Partington, Fowler, & Schmalbach, 2015; Pentenero et al., (Warnakulasuriya & Ariyawardana, 2016). Recent research suggests
2014). The oral sites associated with a higher risk of dysplasia and/ that the progression from dysplasia into invasive cancer, based on
or cancer are the ventral tongue, floor of the mouth, and soft palate models established at other sites (e.g., melanoma and cervical can-
(Scully, 2014; Warnakulasuriya & Ariyawardana, 2016). Large lesions cer), involves a stepwise accumulation of genetic and epigenetic al-
(≥200 mm2) are five times more likely to undergo malignant transfor- terations (including somatic gene mutations, DNA double-­strand
mation (Holmstrup, Vedtofte, Reibel, & Stoltze, 2006). breaks, and copy-­number alterations) (Cervigne et al., 2014; Jessri,
Previous studies have shown that the malignant transforma- Dalley, & Farah, 2017; Vogelstein & Kinzler, 2015). The main steps
tion rate of dysplasia or carcinoma in situ (CIS) is 5%–36%, with that lead to the development of cancer include a breakthrough phase,
higher rates in individuals who consume betel leaf (Cowan, Gregg, an expansion phase, and an invasive phase (Kuffer & Lombardi, 2002;
Napier, McKenna, & Kee, 2001; Hsue et al., 2007; Lian Ie, Tseng, Su, Vogelstein & Kinzler, 2015; Woo, Cashman, & Lerman, 2013). During
& Tsai, 2013; Liu et al., 2012; Lumerman, Freedman, & Kerpel, 1995; the breakthrough phase, a very specific mutation occurs and the cell
Silverman, Gorsky, & Lozada, 1984). When “hyperkeratosis without begins to divide abnormally. The lesion (e.g., leukoplakia) becomes vis-
dysplasia” (or keratosis of unknown significance (KUS)) was consid- ible only after a few years. In the second phase, an additional driver-­
ered, 11%–30% of cases developed invasive carcinoma (Holmstrup gene mutation develops to give rise to the tumor. Finally, during the
et al., 2006; Lee et al., 2006; Roed-­Petersen, 1971; Scully, 2014). third phase the tumor invades the surrounding tissues. Leukoplakia
VILLA and SONIS |
      181

may share some of the same driver-­gene mutations observed in OSCC Jolst, Renstrup, & Roed-­Petersen, 1968; Silverman et al., 1984;
and carry similar chromosomal instability, such as loss of heterozygos- Vedtofte, Holmstrup, Hjorting-­Hansen, & Pindborg, 1987); 0%–
ity, DNA aneuploidy, and telomerase dysfunction, which have all been 15% when carbon dioxide laser was used; and 10%–25% in patients
associated with malignant transformation (Oulton & Harrington, 2000; who underwent photodynamic therapy (Vohra et al., 2015). As a re-
Sen, 2000; Siebers et al., 2013). Approximately 20%–45% of oral ep- sult of multiple recurrences post-­treatment, several topical agents
ithelia dysplasia showed DNA aneuploidy with a higher prevalence in for oral cancer chemoprevention have been tested in the past dec-
more severe dysplasias and in those lesions that underwent malignant ades (Chau et al., 2017). In particular, topical retinoids, bleomycin,
transformation (Donadini et al., 2010; Gouvea et al., 2013; Torres-­ adenovirus, cyclooxygenase inhibitors, and phytochemical-­enriched
Rendon, Stewart, Craig, Wells, & Speight, 2009). Studies have shown agents have been used for oral leukoplakias. A recent systematic
that telomerase activity was upregulated with increasing grade of oral review has shown that the mean complete response rate for topi-
dysplasia, indicating an important role of telomerase hyperactivation cal retinoid therapy was 32% (Chau et al., 2017), for 1% bleomycin
in carcinogenesis (Liao, Mitsuyasu, Yamane, & Ohishi, 2000; Miyoshi was 40.2%, and for 0.5% bleomycin was 25%. However, all of these
et al., 1999). agents were once again associated with recurrence of the disease.
Aberrant expression of p16INK4a, p53 (Angiero et al., 2008;
Nasser, Flechtenmacher, Holzinger, Hofele, & Bosch, 2011; Pitiyage,
Tilakaratne, Tavassoli, & Warnakulasuriya, 2009) and mutations of 6 | CONCLUSION
genes on 3p, 9p, 11q, and 17p (particularly TP53) may be associated
with an increased cancer risk (Califano et al., 2000; Graveland et al., Crispian was a translational scientist who recognized and advocated
2013). In addition, DNA hypermethylation at specific loci (such as for the integration and application of advances in cell biology into the
CDKN2A, CDH1, and MGMT) has been detected in both oral dyspla- field of oral medicine. He specifically recognized the opportunity and
sias and OSCC with altered expression of miRNAs (such as miR-­345, potential of genetic signatures for leukoplakia, and genotyping or bio-
miR-­21, and miR-­18b), which have been associated with the progres- marker analysis in predicting which leukoplakias were most likely to
sion of oral potentially malignant disorders (including leukoplakia) transform (or not) to invasive cancer. But perhaps most importantly,
(Brito, Gomes, Guimaraes, Campos, & Gomez, 2014; Kato et al., 2006; Crispian never forgot the importance of the role of the front-­line
Kulkarni & Saranath, 2004). clinician in decision-­making and the responsibilities associated with
More recently, preclinical data suggested that immune modula- providing patients with the most valid information on which to make
tion plays a critical role in oral carcinogenesis (Ferris, 2015). With treatment choices.
recent advances in immuno-­oncology demonstrating the efficacy of
immune checkpoint inhibitors targeting the programmed cell death
AU T HO R CO NT R I B U T I O NS
protein-­1 (PD-­1) axis in advanced squamous cell carcinoma of the
head and neck (Chow et al., 2016; Ferris et al., 2016), there is sig- Dr. Alessandro Villa was involved with the conceptualization, meth-
nificant interest in understanding the impact of anti-­PD-­1 therapy in odology and papers review. He wrote the original draft/manuscript
early OSCC and in cancer prevention. A recent study from Yagyuu and is accountable for all aspects of the work. Dr. Stephen T. Sonis
et al. (2017) suggested that nearly 50% of high-­grade oral leukoplakia was involved with the conceptualization of the paper. He critically
samples were ligand of PD-­1 (PD-­L1) positive. Moreover, PD-­L1 pos- reviewed and edited the manuscript. He approved the final version
itivity and CD8 + T-­cell count were significantly associated with the to be published.
degree of dysplasia among these samples (p < .001). These findings
suggest that antitumor immunity may be suppressed through upregu-
O RC I D
lation of PD-­L1 among leukoplakia lesions, which could promote oral
carcinogenesis. A Villa  http://orcid.org/0000-0002-1966-6000

REFERENCES
5 | MANAGEMENT OF ORAL LEUKOPLAKIA
Abadie, W. M., Partington, E. J., Fowler, C. B., & Schmalbach, C. E. (2015).
Optimal management of proliferative verrucous leukoplakia: A system-
Management and treatment of leukoplakia remain challenging es-
atic review of the literature. Otolaryngology–Head and Neck Surgery,
pecially for large lesions and PVLs. Often times, patients present 153, 504–511.
with multifocal non-­contiguous lesions (PVL) with a histopathologi- Angiero, F., Berenzi, A., Benetti, A., Rossi, E., Del Sordo, R., Sidoni, A., …
cal diagnosis of “hyperkeratosis no dysplasia,” yet 70%–100% will Dessy, E. (2008). Expression of p16, p53 and Ki-­67 proteins in the pro-
gression of epithelial dysplasia of the oral cavity. Anticancer Research,
develop cancer over time. Current strategies for oral leukoplakia
28, 2535–2539.
include surgery, a “watch-­and-­see” approach, and medical treat-
Arduino, P. G., Bagan, J., El-Naggar, A. K., & Carrozzo, M. (2013). Urban
ment (Farah et al., 2014; Lodi et al., 2016; Ribeiro, Salles, da Silva, & legends series: Oral leukoplakia. Oral Diseases, 19, 642–659.
Mesquita, 2010). Recurrence after surgical excision ranged from 0% Bagan, J. V., Jimenez, Y., Sanchis, J. M., Poveda, R., Milian, M. A., Murillo, J.,
to 35% (Holmstrup et al., 2006; Lumerman et al., 1995; Pindborg, & Scully, C. (2003). Proliferative verrucous leukoplakia: High incidence
 |
182       VILLA and SONIS

of gingival squamous cell carcinoma. Journal of Oral Pathology and Jessri, M., Dalley, A. J., & Farah, C. S. (2017). Deficient double-­strand
Medicine, 32, 379–382. break repair in oral squamous cell carcinoma cell lines. Journal of Oral
Bagan, J., Scully, C., Jimenez, Y., & Martorell, M. (2010). Proliferative verru- Pathology & Medicine, https://doi.org/10.1111/jop.12576.
cous leukoplakia: A concise update. Oral Diseases, 16, 328–332. Kato, K., Hara, A., Kuno, T., Mori, H., Yamashita, T., Toida, M., & Shibata, T.
Banerjee, A. G., Bhattacharyya, I., & Vishwanatha, J. K. (2005). Identification (2006). Aberrant promoter hypermethylation of p16 and MGMT genes
of genes and molecular pathways involved in the progression of prema- in oral squamous cell carcinomas and the surrounding normal mucosa.
lignant oral epithelia. Molecular Cancer Therapeutics, 4, 865–875. Journal of Cancer Research and Clinical Oncology, 132, 735–743.
Bremmer, J. F., Brakenhoff, R. H., Broeckaert, M. A., Belien, J. A., Leemans, Kuffer, R., & Lombardi, T. (2002). Premalignant lesions of the oral mucosa.
C. R., Bloemena, E., … Braakhuis, B. J. (2011). Prognostic value of A discussion about the place of oral intraepithelial neoplasia (OIN). Oral
DNA ploidy status in patients with oral leukoplakia. Oral Oncology, 47, Oncology, 38, 125–130.
956–960. Kulkarni, V., & Saranath, D. (2004). Concurrent hypermethylation of multi-
Brito, J. A., Gomes, C. C., Guimaraes, A. L., Campos, K., & Gomez, R. S. ple regulatory genes in chewing tobacco associated oral squamous cell
(2014). Relationship between microRNA expression levels and histo- carcinomas and adjacent normal tissues. Oral Oncology, 40, 145–153.
pathological features of dysplasia in oral leukoplakia. Journal of Oral Lee, J. J., Hung, H. C., Cheng, S. J., Chen, Y. J., Chiang, C. P., Liu, B. Y., … Kok,
Pathology & Medicine, 43, 211–216. S. H. (2006). Carcinoma and dysplasia in oral leukoplakias in Taiwan:
Califano, J., Westra, W. H., Meininger, G., Corio, R., Koch, W. M., & Prevalence and risk factors. Oral Surgery, Oral Medicine, Oral Pathology,
Sidransky, D. (2000). Genetic progression and clonal relationship of re- Oral Radiology, and Endodontics, 101, 472–480.
current premalignant head and neck lesions. Clinical Cancer Research, Lee, J. J., Hung, H. C., Cheng, S. J., Chiang, C. P., Liu, B. Y., Yu, C. H., … Kok,
6, 347–352. S. H. (2007). Factors associated with underdiagnosis from incisional
Cervigne, N. K., Machado, J., Goswami, R. S., Sadikovic, B., Bradley, G., biopsy of oral leukoplakic lesions. Oral Surgery, Oral Medicine, Oral
Perez-Ordonez, B., … Kamel-Reid, S. (2014). Recurrent genomic alter- Pathology, Oral Radiology, and Endodontics, 104, 217–225.
ations in sequential progressive leukoplakia and oral cancer: Drivers of Lian Ie, B., Tseng, Y. T., Su, C. C., & Tsai, K. Y. (2013). Progression of precan-
oral tumorigenesis? Human Molecular Genetics, 23, 2618–2628. cerous lesions to oral cancer: Results based on the Taiwan National
Chau, L., Jabara, J. T., Lai, W., Svider, P. F., Warner, B. M., Lin, H. S., … Fribley, Health Insurance Database. Oral Oncology, 49, 427–430.
A. M. (2017). Topical agents for oral cancer chemoprevention: A sys- Liao, J., Mitsuyasu, T., Yamane, K., & Ohishi, M. (2000). Telomerase activity
tematic review of the literature. Oral Oncology, 67, 153–159. in oral and maxillofacial tumors. Oral Oncology, 36, 347–352.
Chow, L. Q., Haddad, R., Gupta, S., Mahipal, A., Mehra, R., Tahara, M., … Liu, W., Shi, L. J., Wu, L., Feng, J. Q., Yang, X., Li, J., … Zhang, C. P. (2012). Oral
Seiwert, T. Y. (2016). Antitumor activity of pembrolizumab in biomarker-­ cancer development in patients with leukoplakia—Clinicopathological
unselected patients with recurrent and/or metastatic head and neck factors affecting outcome. PLoS One, 7, e34773.
squamous cell carcinoma: Results from the phase Ib KEYNOTE-­012 Lodi, G., Franchini, R., Warnakulasuriya, S., Varoni, E. M., Sardella, A., Kerr,
expansion cohort. Journal of Clinical Oncology, 34, 3838–3845. A. R., … Worthington, H. V. (2016). Interventions for treating oral leuko-
Cowan, C. G., Gregg, T. A., Napier, S. S., McKenna, S. M., & Kee, F. (2001). plakia to prevent oral cancer. The Cochrane Database of Systematic Reviews,
Potentially malignant oral lesions in northern Ireland: A 20-­year population-­ CD001829. https://doi.org/10.1002/14651858.CD001829.pub4.
based perspective of malignant transformation. Oral Diseases, 7, 18–24. Lumerman, H., Freedman, P., & Kerpel, S. (1995). Oral epithelial dyspla-
Donadini, A., Maffei, M., Cavallero, A., Pentenero, M., Malacarne, D., Di sia and the development of invasive squamous cell carcinoma. Oral
Nallo, E., … Giaretti, W. (2010). Oral cancer genesis and progression: Surgery, Oral Medicine, Oral Pathology, Oral Radiology, and Endodontics,
DNA near-­diploid aneuploidization and endoreduplication by high res- 79, 321–329.
olution flow cytometry. Cellular Oncology, 32, 373–383. Miyoshi, Y., Tsukinoki, K., Imaizumi, T., Yamada, Y., Ishizaki, T., Watanabe, Y.,
Farah, C. S., Woo, S. B., Zain, R. B., Sklavounou, A., McCullough, M. J., & … Kubota, Y. (1999). Telomerase activity in oral cancer. Oral Oncology,
Lingen, M. (2014). Oral cancer and oral potentially malignant disorders. 35, 283–289.
International Journal of Dentistry, 2014, 853479. Napier, S. S., & Speight, P. M. (2008). Natural history of potentially malig-
Ferris, R. L. (2015). Immunology and immunotherapy of head and neck can- nant oral lesions and conditions: An overview of the literature. Journal
cer. Journal of Clinical Oncology, 33, 3293–3304. of Oral Pathology & Medicine, 37, 1–10.
Ferris, R. L., Blumenschein, Jr G., Fayette, J., Guigay, J., Colevas, A. D., Licitra, Nasser, W., Flechtenmacher, C., Holzinger, D., Hofele, C., & Bosch, F. X.
L., … Gillison, M. L. (2016). Nivolumab for recurrent squamous-­cell car- (2011). Aberrant expression of p53, p16INK4a and Ki-­67 as basic bio-
cinoma of the head and neck. The New England Journal of Medicine, 375, marker for malignant progression of oral leukoplakias. Journal of Oral
1856–1867. Pathology & Medicine, 40, 629–635.
Garnis, C., Chari, R., Buys, T. P., Zhang, L., Ng, R. T., Rosin, M. P., & Lam, W. L. Oulton, R., & Harrington, L. (2000). Telomeres, telomerase, and cancer:
(2009). Genomic imbalances in precancerous tissues signal oral cancer Life on the edge of genomic stability. Current Opinion in Oncology, 12,
risk. Molecular Cancer, 8, 50. 74–81.
Gouvea, A. F., Santos Silva, A. R., Speight, P. M., Hunter, K., Carlos, R., Pentenero, M., Carrozzo, M., Pagano, M., Galliano, D., Broccoletti, R., Scully,
Vargas, P. A., … Lopes, M. A. (2013). High incidence of DNA ploidy C., & Gandolfo, S. (2003). Oral mucosal dysplastic lesions and early
abnormalities and increased Mcm2 expression may predict malignant squamous cell carcinomas: Underdiagnosis from incisional biopsy. Oral
change in oral proliferative verrucous leukoplakia. Histopathology, 62, Diseases, 9, 68–72.
551–562. Pentenero, M., Meleti, M., Vescovi, P., & Gandolfo, S. (2014). Oral prolifera-
Graveland, A. P., Bremmer, J. F., de Maaker, M., Brink, A., Cobussen, P., tive verrucous leucoplakia: Are there particular features for such an am-
Zwart, M., … Brakenhoff, R. H. (2013). Molecular screening of oral pre- biguous entity? A systematic review. The British Journal of Dermatology,
cancer. Oral Oncology, 49, 1129–1135. 170, 1039–1047.
Holmstrup, P., Vedtofte, P., Reibel, J., & Stoltze, K. (2006). Long-­term Petti, S. (2003). Pooled estimate of world leukoplakia prevalence: A system-
treatment outcome of oral premalignant lesions. Oral Oncology, 42, atic review. Oral Oncology, 39, 770–780.
461–474. Petti, S., & Scully, C. (2006). Association between different alcoholic bev-
Hsue, S. S., Wang, W. C., Chen, C. H., Lin, C. C., Chen, Y. K., & Lin, L. M. erages and leukoplakia among non-­ to moderate-­drinking adults: A
(2007). Malignant transformation in 1458 patients with potentially ma- matched case-­control study. European Journal of Cancer, 42, 521–527.
lignant oral mucosal disorders: A follow-­up study based in a Taiwanese Pindborg, J. J., Jolst, O., Renstrup, G., & Roed-Petersen, B. (1968). Studies
hospital. Journal of Oral Pathology & Medicine, 36, 25–29. in oral leukoplakia: A preliminary report on the period pervalence
VILLA and SONIS |
      183

of malignant transformation in leukoplakia based on a follow-­up Torres-Rendon, A., Stewart, R., Craig, G. T., Wells, M., & Speight, P. M.
study of 248 patients. Journal of the American Dental Association, 76, (2009). DNA ploidy analysis by image cytometry helps to identify oral
767–771. epithelial dysplasias with a high risk of malignant progression. Oral
Pitiyage, G., Tilakaratne, W. M., Tavassoli, M., & Warnakulasuriya, S. (2009). Oncology, 45, 468–473.
Molecular markers in oral epithelial dysplasia: Review. Journal of Oral Vedtofte, P., Holmstrup, P., Hjorting-Hansen, E., & Pindborg, J. J. (1987).
Pathology & Medicine, 38, 737–752. Surgical treatment of premalignant lesions of the oral mucosa.
Reibel, J. (2003). Prognosis of oral pre-­malignant lesions: Significance of International Journal of Oral and Maxillofacial Surgery, 16, 656–664.
clinical, histopathological, and molecular biological characteristics. Villa, A., & Woo, S. B. (2017). Leukoplakia-­A diagnostic and management
Critical Reviews in Oral Biology and Medicine, 14, 47–62. algorithm. Journal of Oral and Maxillofacial Surgery, 75, 723–734.
Ribeiro, A. S., Salles, P. R., da Silva, T. A., & Mesquita, R. A. (2010). A review Vogelstein, B., & Kinzler, K. W. (2015). The Path to cancer—Three strikes
of the nonsurgical treatment of oral leukoplakia. International Journal of and you’re out. The New England Journal of Medicine, 373, 1895–1898.
Dentistry, 2010, 186018. Vohra, F., Al-Kheraif, A. A., Qadri, T., Hassan, M. I., Ahmed, A.,
Roed-Petersen, B. (1971). Cancer development in oral leukoplakia: Warnakulasuriya, S., & Javed, F. (2015). Efficacy of photodynamic ther-
Follow-­up of 331 patients. Journal of Dental Research, 80, 711. apy in the management of oral premalignant lesions. A systematic re-
Saddiwal, R., Hebbale, M., Sane, V. D., Hiremutt, D., Gupta, R., & Merchant, view. Photodiagnosis and Photodynamic Therapy, 12, 150–159.
Y. (2017). Estimation of serum beta 2-­microglobulin levels in individuals van der Waal, I. (2010). Potentially malignant disorders of the oral and oro-
exposed to carcinogens: Clinical study in Indian population. Journal of pharyngeal mucosa; present concepts of management. Oral Oncology,
Maxillofacial and Oral Surgery, 16, 53–57. 46, 423–425.
Saintigny, P., Zhang, L., Fan, Y. H., El-Naggar, A. K., Papadimitrakopoulou, van der Waal, I., & Axell, T. (2002). Oral leukoplakia: A proposal for uniform
V. A., Feng, L., … Mao, L. (2011). Gene expression profiling predicts the reporting. Oral Oncology, 38, 521–526.
development of oral cancer. Cancer Prevention Research, 4, 218–229. Warnakulasuriya, S., & Ariyawardana, A. (2016). Malignant transforma-
Schepman, K. P., van der Meij, E. H., Smeele, L. E., & van der Waal, I. (1998). tion of oral leukoplakia: A systematic review of observational studies.
Malignant transformation of oral leukoplakia: A follow-­up study of a Journal of Oral Pathology & Medicine, 45, 155–166.
hospital-­based population of 166 patients with oral leukoplakia from Warnakulasuriya, S., Johnson, N. W., & van der Waal, I. (2007). Nomenclature
The Netherlands. Oral Oncology, 34, 270–275. and classification of potentially malignant disorders of the oral mucosa.
Scully, C. (1982). Serum beta 2 microglobulin in recurrent aphthous stomatitis Journal of Oral Pathology & Medicine, 36, 575–580.
and Behcet’s syndrome. Clinical and Experimental Dermatology, 7, 61–64. Woo, S. B., Cashman, E. C., & Lerman, M. A. (2013). Human papillomavirus-­
Scully, C. (2014). Challenges in predicting which oral mucosal potentially associated oral intraepithelial neoplasia. Modern Pathology, 26,
malignant disease will progress to neoplasia. Oral Diseases, 20, 1–5. 1288–1297.
Sen, S. (2000). Aneuploidy and cancer. Current Opinion in Oncology, 12, Woo, S. B., Grammer, R. L., & Lerman, M. A. (2014). Keratosis of unknown
82–88. significance and leukoplakia: A preliminary study. Oral Surgery, Oral
Siebers, T. J., Bergshoeff, V. E., Otte-Holler, I., Kremer, B., Speel, E. J., van Medicine, Oral Pathology and Oral Radiology, 118, 713–724.
der Laak, J. A., … Slootweg, P. J. (2013). Chromosome instability pre- Yagyuu, T., Hatakeyama, K., Imada, M., Kurihara, M., Matsusue, Y.,
dicts the progression of premalignant oral lesions. Oral Oncology, 49, Yamamoto, K., … Kirita, T. (2017). Programmed death ligand 1 (PD-­L1)
1121–1128. expression and tumor microenvironment: Implications for patients with
Silverman, Jr S., Gorsky, M., & Lozada, F. (1984). Oral leukoplakia and ma- oral precancerous lesions. Oral Oncology, 68, 36–43.
lignant transformation. A follow-­up study of 257 patients. Cancer, 53,
563–568.
Sumino, J., Uzawa, N., Okada, N., Miyaguchi, K., Mogushi, K., Takahashi,
How to cite this article: Villa A, Sonis S. Oral leukoplakia remains
K., … Amagasa, T. (2013). Gene expression changes in initiation and
a challenging condition. Oral Dis. 2018;24:179–183. https://doi.
progression of oral squamous cell carcinomas revealed by laser micro-
dissection and oligonucleotide microarray analysis. International Journal org/10.1111/odi.12781
of Cancer, 132, 540–548.