Head and Neck Pathology and Radiology 2011downloads.hindawi.com/journals/specialissues/816763.pdf · 2019-08-07 · Head and Neck Pathology and Radiology 2011 Guest Editors: Neil

Head and Neck Pathology and Radiology 2011Guest Editors: Neil S. Norton, Preetha P. Kanjirath, Pilar Hita-Iglesias, and Paul C. Edwards

International Journal of Dentistry

Head and Neck Pathology and Radiology 2011

International Journal of Dentistry


Guest Editors: Neil S. Norton, Preetha P. Kanjirath,Pilar Hita-Iglesias, and Paul C. Edwards

Copyright © 2012 Hindawi Publishing Corporation. All rights reserved.

This is a special issue published in “International Journal of Dentistry.” All articles are open access articles distributed under the CreativeCommons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the originalwork is properly cited.

Editorial Board

Ali Abdalla, EgyptYahya Acil, GermanyJasim M. Albandar, USAEiichiro Ariji, JapanManal Awad, UAEAshraf F. Ayoub, UKSilvana Barros, USASema Belli, TurkeyMarilia Buzalaf, BrazilGiuseppina Campisi, ItalyFrancesco Carinci, ItalyLim K. Cheung, Hong KongBrian W. Darvell, KuwaitHugo De Bruyn, BelgiumDong M. Deng, The NetherlandsShinn-Jyh Ding, TaiwanJ. D. Eick, USAAnnika Ekestubbe, SwedenCarla Evans, USAVincent Everts, The NetherlandsStefano Fedele, UKG. Nogueira Filho, CanadaRoland Frankenberger, GermanyGerald Glickman, USAValeria V. Gordan, USARosa H. Grande, BrazilYoshitaka Hara, Japan

James K. Hartsfield, USAYumiko Hosoya, JapanSaso Ivanovski, AustraliaChia-Tze Kao, TaiwanElizabeth Kay, UKHeidrun Kjellberg, SwedenKristin Klock, NorwayKee-Yeon Kum, Republic of KoreaManuel Lagravere, CanadaDaniel M. Laskin, USAClaudio R. Leles, BrazilLouis M. Lin, USAA. D. Loguercio, BrazilTommaso Lombardi, SwitzerlandMartin Lorenzoni, AustriaAdriano Loyola, BrazilMaria Machado, BrazilJukka H. Meurman, FinlandHendrik Meyer-Luckel, GermanyKonstantinos Michalakis, GreeceMasashi Miyazaki, JapanYasuhiro Morimoto, JapanCarlos A. Munoz-Viveros, USAHiroshi Murata, JapanRavindra Nanda, USAToru Nikaido, JapanJoseph Nissan, Israel

Chikahiro Ohkubo, JapanAthena Papas, USAPatricia Pereira, USARoberta Pileggi, USAA. B. M. Rabie, Hong KongMichael E. Razzoog, USAAndre Reis, BrazilStephen Richmond, UKGeorge E. Romanos, USAKamran Safavi, USATuula Salo, FinlandGilberto Sammartino, ItalyRobin Seymour, UKTimo Sorsa, FinlandGianrico Spagnuolo, ItalyAndreas Stavropoulos, DenmarkDimitris N. Tatakis, USAShigeru Uno, JapanJacques Vanobbergen, BelgiumMarcos Vargas, USAAhmad Waseem, UKIzzet Yavuz, TurkeyCynthia Yiu, Hong KongLi-wu Zheng, Hong KongQiang Zhu, USASpiros Zinelis, Greece

Contents

Head and Neck Pathology and Radiology 2011, Neil S. Norton, Preetha P. Kanjirath, Pilar Hita-Iglesias,and Paul C. EdwardsVolume 2012, Article ID 320319, 1 page

Cone-Beam Computed Tomography and Radiographs in Dentistry: Aspects Related to Radiation Dose,Diego Coelho Lorenzoni, Ana Maria Bolognese, Daniela Gamba Garib, Fabio Ribeiro Guedes,and Eduardo Franzotti Sant’AnnaVolume 2012, Article ID 813768, 10 pages

Supernumerary Teeth in Indian Children: A Survey of 300 Cases, Amita Sharma and Varun Pratap SinghVolume 2012, Article ID 745265, 5 pages

Oral Leukoplakia as It Relates to HPV Infection: A Review, L. Feller and J. LemmerVolume 2012, Article ID 540561, 7 pages

Technical Considerations in Rehabilitation of an Edentulous Total Glossectomy Patient, Pravin Bhirangi,Priyanka Somani, K. P. Dholam, and Gurmeet BachherVolume 2012, Article ID 125036, 4 pages

Cell Transformation and the Evolution of a Field of Precancerization As It Relates to Oral Leukoplakia,L. Feller and J. LemmerVolume 2011, Article ID 321750, 5 pages

Hindawi Publishing CorporationInternational Journal of DentistryVolume 2012, Article ID 320319, 1 pagedoi:10.1155/2012/320319

Editorial


Neil S. Norton,1 Preetha P. Kanjirath,2 Pilar Hita-Iglesias,3 and Paul C. Edwards4

1 Department of Oral Biology, School of Dentistry, Creighton University, Omaha, NE 68178, USA2 Preclinical Program, College of Dental Medicine-Illinois, Midwestern University, 555-31st Street, 102 Redwood Hall,Downers Grove, IL 60515, USA

3 Department of Periodontics and Oral Medicine, School of Dentistry, University of Michigan, Ann Arbor, MI 48109, USA4 Oral and Maxillofacial Surgery, School of Dentistry, University of Michigan, Ann Arbor, MI 48109, USA

Correspondence should be addressed to Neil S. Norton, [email protected]

Received 11 December 2012; Accepted 11 December 2012

Copyright © 2012 Neil S. Norton et al. This is an open access article distributed under the Creative Commons Attribution License,which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Beyond an examination of the dentition and surroundingperiodontal tissues, one of the most important tasks of thedental clinician is the accurate diagnosis and management ofpatients with nontooth-related conditions of the head andneck. For patients with these conditions, it is imperative thatthe dental clinician performs a comprehensive evaluationand assessment on patients to increase the potential for a suc-cessful outcome. The skills of a myriad of specialists will beinvolved, including those in oral and maxillofacial pathology,radiology, oral medicine, head and neck anatomy, and theprimary care provider.

In this special issue dedicated to head and neck pathologyand radiology, the manuscripts selected for publication fur-ther demonstrate the significance of the relationship des-cribed between the specialists and primary care provider. Thearticle by D. C. Lorenzoni et al. highlights radiology anddiscusses the radiation doses that are associated with plainradiographs, cone beam computed tomography (CBCT),and conventional computed tomography (CT), placing aspecial emphasis on orthodontics. A. Sharma and V. P. Singhthoroughly summarize a study detecting supernumeraryteeth in Indian children in 300 cases using clinical and radio-graphic examination. In one of their two articles in thisspecial issue, L. Feller and J. Lemmer provide an exten-sive review on oral leukoplakia and its relationship to humanpapillomavirus (HPV). P. Bhirangi et al. elaborate on thetechnical steps for the prosthetic rehabilitation of an eden-tulous glossectomy patient. In the other article, L. Feller andJ. Lemmer critically review cell transformation and the evo-lution of a field of precancerization as it relates to oral leuko-plakia.

Acknowledgments

This special issue on head and neck pathology and radiologywould not be possible without the invaluable work of my fel-low guest editors. Thus, I would like to offer my sincerethanks and appreciation to Dr. P. P. Kanjirath, from Midwest-ern University, USA, Dr. P. H.-Igelsias, and Dr. P. C. Edwardsfrom the University of Michigan at Ann Arbor, USA. Eachof them worked tirelessly on this project. Additionally, Iwould like to offer my thanks to the authors that contributedtheir research to this special issue. Finally, this special issuewould not be possible without the numerous reviewers thatselflessly offered their expertise—to them I offer my sinceregratitude. On behalf of Drs. P. P. Kanjirath, P. H.-Igelsias, P.C. Edwards and myself, it is our sincere hope that you enjoythis special issue and find each of the articles as fascinatingand instructive as we do.

Neil S. NortonPreetha P. Kanjirath

Pilar Hita-IglesiasPaul C. Edwards

Hindawi Publishing CorporationInternational Journal of DentistryVolume 2012, Article ID 813768, 10 pagesdoi:10.1155/2012/813768

Review Article

Cone-Beam Computed Tomography and Radiographs inDentistry: Aspects Related to Radiation Dose

Diego Coelho Lorenzoni,1 Ana Maria Bolognese,1 Daniela Gamba Garib,2

Fabio Ribeiro Guedes,3 and Eduardo Franzotti Sant’Anna1

1 Department of Orthodontics, Federal University of Rio de Janeiro Dental School, Avenida Professor Rodolpho de Paulo Rocco,Ilha do Fundao 21941-590, Rio de Janeiro, RJ, Brazil

2 Department of Orthodontics, Bauru Dental School and Hospital of Rehabilitation of Craniofacial Anomalies, Universtity of Sao Paulo,17012-101 Bauru, SP, Brazil

3 Department of Dental Radiology, Federal University of Rio de Janeiro Dental School, 21941-590 Rio de Janeiro, RJ, Brazil

Correspondence should be addressed to Eduardo Franzotti Sant’Anna, [email protected]

Received 14 July 2011; Revised 19 September 2011; Accepted 31 January 2012

Academic Editor: Neil S. Norton

Copyright © 2012 Diego Coelho Lorenzoni et al. This is an open access article distributed under the Creative CommonsAttribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work isproperly cited.

Introduction. The aim of this study was to discuss the radiation doses associated with plain radiographs, cone-beam computedtomography (CBCT), and conventional computed tomography (CT) in dentistry, with a special focus on orthodontics. Methods. Asystematic search for articles was realized by MEDLINE from 1997–March 2011. Results. Twenty-seven articles met the establishedcriteria. The data of these papers were grouped in a table and discussed. Conclusions. Increases in kV, mA, exposure time, and fieldof view (FOV) increase the radiation dose. The dose for CT is greater than other modalities. When the full-mouth series (FMX)is performed with round collimation, the orthodontic radiographs transmit higher dose than most of the large FOV CBCT, but itcan be reduced if used rectangular collimation, showing lower effective dose than large FOV CBCT. Despite the image quality, theCBCT does not replace the FMX. In addition to the radiation dose, image quality and diagnostic needs should be strongly takeninto account.

1. Introduction

The high prevalence and increase in the number of childrenreceiving orthodontic care [1] bring up an important issue:the use of ionizing radiation for diagnosis also increases thepotential impact on public health [2]. These concerns existbecause of the ability of X-rays to induce mutations in DNA,thereby increasing the risk of cancer [3]. Moreover, childrenmay express increased susceptibility to environmental haz-ards, chronic infection and inflammation, dietary factors,and long-term medication due to differences in the uptake,metabolism, and excretion of potential mutagens [4] and arecent study has suggested a relationship between exposureto dental radiographs and a greater risk of thyroid cancer [5].

During the last century, dental diagnostic imaging wasdominated by radiographs, which are two-dimensional rep-resentations of three-dimensional structures, with associated

overlap and distortion. With the introduction of cone-beamcomputed tomography (CBCT), there was much interestin the technology due to its advantages: improved imagequality, three-dimensional reconstruction, a 1 : 1 ratio thatallowed reliable measurements, the possibility for craniofa-cial visualization, and lower radiation doses compared totraditional CT.

However, it is necessary to monitor the radiation dosesinvolved in these exams. Some concepts are relevant forthis understanding, such as the methodology employed inresearch studies within the field. The majority of thesestudies use human head and neck phantoms built withtissues that mimic human tissues in regard to layers andradiation absorption. In some models, human skeletons areused [6]. The phantom is made in the form of detachablecross-sections with apertures created for the placement ofdosimeters in the regions of interest. Many of these locations

2 International Journal of Dentistry

would be unfeasible in vivo. The dosimeters measure the ab-sorbed dose in each region/tissue.

The description of the radiation dose transmitted tothe patient must be based on the effective dose (E), meas-ured in Sieverts (Sv). This description is recommended bythe International Commission on Radiological Protection(ICRP) [7] because it considers not only the dose, but alsothe type, quantity, sensitivity, and carcinogenic potential ofthe irradiated tissue [8]. Current estimates of per capitaannual U.S. dose are 6200 µSv with almost 3000 µSv comingfrom diagnostic procedures. Ubiquitous background sourcesaccount for 3100 µSv annual dose or 8.5 µSv per day [9].

The effective dose in a given tissue (ET) is calculated bythe following equation [10]: ET = wT · HT , where wT is thetissue weighting factor, which represents the radiosensitivityof the tissue/organ and thereby the contribution of this tissueto the total risk, and HT is the equivalent dose for eachtissue/organ. The sum (

∑) of the ET for each tissue/organ

provides the total effective dose (E).The equivalent dose (HT) for a tissue/organ, in Sv, is re-

presented by the following formula: HT = wR ·DT · fT , wherewR is the radiation weighting factor (for X-rays, this value is1), DT is the mean dose absorbed in the dosimeters in gray(Gy), and fT is the irradiated fraction of tissue in relation toits total volume in the body (normal values described in theliterature) [11].

The tissue/organ weighting factors, wT , are provided andupdated by the ICRP (Table 1). The most widely used versionis from 1990 [7] and is based on mortality rates used to esti-mate the risk of cancers in various tissues. Updates in 2005[12] and 2007 [10] included the salivary glands and changesin some tissue-weighting factors according to recent ratesof cancer incidence, which are better descriptors of cancerburden, especially for those cancer types with high survivalrates [13]. The recommendations from 2005 were the draftfor the ICRP 2007 recommendations, and the two are, there-fore, relatively comparable. Thus, depending on the versionof the ICRP recommendations, different effective doses arefound for the same level of irradiation. Some articles use theabsorbed dose (Gy), which is less relevant because it doesnot consider the relative contribution of different organs/tis-sues to the total risk [14].

When using ionizing radiation, the ALARA [15] (aslow as reasonably achievable) principle must be respected.Nevertheless, discussions about radiation doses and theircontributing factors do exist, and this requires vigilance inobtaining the best possible cost-benefit relationship betweendosage and information. Consequently, the sources of radia-tion used in dentistry (radiography, CBCT, and CT) and theinfluence of the image acquisition protocol on these doses isdiscussed, especially in orthodontics.

2. Materials and Methods

2.1. Literature Search Strategy. The literature on radiationdoses used in dentistry was systematically reviewed. Thearticles were located by an online search using MEDLINEfrom 1997 to March 2011. The keyword used in this search

was “radiation dose,” combined with 31 descriptors to res-trict it to dentistry (Figure 1). The bibliographies of theselected articles were analyzed in search of research that wasnot found on MEDLINE.

2.2. Inclusion Criteria for Articles. Initially, articles in Englishwere selected according to their title and abstract, followedby a complete reading of the text. The studies included in theanalysis fulfilled the following criteria:

(1) evaluation of radiation dose in radiographs and/orCBCT and/or CTs used in dentistry;

(2) the use of phantom or thermoluminescent dosime-ters;

(3) results that showed effective dose and ICRP used;

(4) tomography of the maxilla and/or mandible and/orthe entire head with the assessments of smaller areasdiscarded;

(5) radiographs included, including a complete peri-apical examination, and/or a complete interproxi-mal examination, and/or a panoramic and/or lat-eral cephalometric/PA and/or maxillary/mandibularocclusal examination.

The CBCT studies were divided according to their FOV[11]: small FOV (spherical diameter or cylinder height≤10 cm; captures most of one or both arches, but not allof the anatomy of the maxilla); medium FOV (sphericaldiameter or cylinder height between 10 and 15 cm; capturesthe entire dentition and temporomandibular joints, butgenerally does not include the complete soft profile of thechin and nose, which is necessary for orthodontic care);large or extended FOV (spherical diameter or cylinder height>15 cm; captures the maxillofacial complex, chin and nose).

3. Results

There were 94.742 articles identified with the keywordradiation dose, which were reduced to 27 after applicationof the criteria. Table 2 lists these data. It is important toknow that some of the devices presented in Table 2 are notthe most current versions available. For example, the CBCTdevices such as Classic i-CAT, NewTom 9000, NewTom 3G,and Iluma already have new versions (Next Generation i-CAT, NewYom 5G and Iluma Elite). The CB MercuRay is notcurrently available for purchase. They were all kept in Table 2because they can still be used in some centers.

4. Discussion

Methodological variations explain the different doses for thesame exam, where these include phantoms made by differentcompanies or positioned asymmetrically, as well as variationsin dosimeters, their sensors [16], their locations on thephantoms, and their number [17]. Many researchers do notinclude the calvaria [6, 8, 15, 18–24] and cervical vertebrae[18, 21, 23, 24] when counting the red bone marrow,esophagus [8, 18–21, 23–26], skin [25], and remaining

International Journal of Dentistry 3

Pumped searchDecember 1997 to March 2011

keyword “radiation dose”

94742 articles

Keyword “radiation dose”combined with 31 descriptors

“Facial”“Face”“Dental”“Dentofacial”“Tooth”“Teeth”“Maxillofacial”“Maxilla”“Maxillary”“Mandible”“Mandibular”“Craniofacial”“Skull”“Cranial”“Oral”

“Buccal”“Jaw”“Mouth”“Dentistry”

“CBCT”“CB-CT”

“Volumetric CT”

“Multidetector CT”“MDCT”“Multiple row detector CT”

94693 studies excluded bycombination with descriptors,

by title or abstract

22 studies excluded byinclusion criteria

27 studies includedin revision

“Volumetric computed tomography”

“CT computed tomography”“CT”

“Cone-beam”

“Cone beam”“Conebeam”

Figure 1: Flow chart of the search process.

Table 1: Tissue-weighting factors for calculation of effective radiation dose.

Tissue ICRP 1990 ICRP 2005 ICRP 2007

Bone Marrow 0.12 0.12 0.12

Breast 0.05 0.12 0.12

Colon 0.12 0.12 0.12

Lung 0.12 0.12 0.12

Stomach 0.12 0.12 0.12

Gonads 0.20 0.05 0.08

Esophagus 0.05 0.05 0.04

Bladder 0.05 0.05 0.04

Liver 0.05 0.05 0.04

Thyroid 0.05 0.05 0.04

Bone surface 0.01 0.01 0.01

Brain RT 0.01 0.01

Skin 0.01 0.01 0.01

Salivary glands Not included 0.01 0.01

Kidney RT 0.01 RT

Remainder Tissues 0.05a 0.10b 0.12c

RT: Remainder tissues; aadrenals/brain /upper large intestine/small intestine/kidney/muscle/pancreas/spleen/thymus/uterus.bAdipose tissue/adrenals/connective tissue/extrathoracic airways/gallbladder/heart wall/lymphatic nodes/muscle/pancreas/prostate/spleen/thymus/uterus/cer-vix.cAdrenals/extrathoracic region/gallbladder/heart/prostate/kidneys/small intestine/lymphatic nodes/oral mucosa/muscle/pancreas/spleen/thymus/uterus/cervix(text in boldface represents tissues used for calculation of maxillofacial dose).

tissues in the calculation of the effective dose [6, 18, 19,21, 23, 24]. The ICRP version used is important due tothe inherent variations in the different weighting factors.The 1990 ICRP [7] did not include the salivary glands,which are highly irradiated in dentistry, and some authorsincluded them among the remainder tissues of the ICRP,which considerably increased the effective dose (Table 2).

This tissue was incorporated in the ICRP from 2005 [12] and2007 [10], and this explains the larger doses measured.

4.1. Image Acquisition Protocol. Increases in kV, mA, andexposure time result in higher effective doses for any exam[6, 11, 12, 16, 27–29]. The adjustments in CBCT images vary;


Table 2: Effective doses. (ExcGland or IncGland: salivary glands excluded or included; Mx: Maxilla; Md: Mandible).

Exams/equipment/adjustment provided

Effective Dose (µSv)

ICRP 60-1990ICRP 2005 ICRP 103-2007

ExcGland IncGland

PANORAMIC RADIOGRAPHS

PM2002CCProlinePlanmeca/70 kVp/7 mA/18 s [25] 3.8

VeraviewepocsMorita 77 kV/5 mA/8.1 s [8] 5.2

OrthophosSiemens/62 kV/16 mA/14.1 s [38] 9 16.4

PM2002CCProLinePlanmeca/64 kV/6 mA/15 s [39] 4 9

PromaxPlanmeca/66 kV/6 mA/16 s [16] 17 26

PM2002CCProlinePlanmeca/73 kV/5 mA/15 s [18] 10

Digital/PM2002CCProline2000Planmeca/66 kV/4 mA/18 s [16] 8 12

Digital/PM2002CCProline2000Planmeca/66 kV/8 mA/18 s [16] 23 38

Digital/CranexExcelSoredex/65 kV/6 mA/19 s [40] 4.5 12.3

Digital/Verawiewepocs5DMorita/70 kV/4 mA/8.2 s [40] 2.5 5.5

Digital/ECProlinePlanmeca/64 kV/7 mA/18.3 s [40] 5.7 14.9

Digital/Orthoralix9200DDEGendex/74 kV/4 mA/12 s [40] 2.4 4.7

Digital/ProMaxPlanmeca/Adult [6] 20 23

Digital/ProMaxPlanmeca/68 kV/13 mA/16 s [13] 7.1 24.3

Digital/OrthophosXGSirona/64 kV/8 mA/14.1 s [13] 4.3 14.2

Digital/OrthophosPlusDSSirona/66 kVp/16 mA/14.1 s [30] 6.2 22

Digital/VeraviewepocsMorita/67 kV/5 mA/8.1 s [8] 2.7

Digital/Veraviewepocs3DMorita/70 kV/5 mA/7.4 s [8] 2.9

Digital/CranexTomeSoredex/70 kV/4 mA/15 s [40] 3.3 8.1

LATERAL CEPHALOMETRIC RADIOGRAPHS

OrthophosCSiemens/77 kV/14 mA/0.5 s [19] 2.3

PM2002CCProLinePlanmeca/70 kV/12 mA/0.9 s [39] 2 3

CranexTomeSoredex/70 kVp/10 mA/0.4 s [20] 3 3.7

CranexTomeSoredex/Collimation/70 kVp/10 mA/0.4 s [20] 1.6 2.2

PM2002CCProlinePlanmeca/80 kV/12 mA/0.5 s [18] 5

Digital/OrthophosDSCephSiemens/73 kV/15 mA/15.8 s [19] 1.1

Digital/ProLineCephCMPlanmeca/Collimation/70 kVp/10 mA/23 s [21] 1.7 3.4

Digital/CranexTomeSoredex/Collimation/70 kVp/4 mAs [21] 1.6 2.2

Digital/InterayVarian/77 kVp/6.5 mAs [13] 3.7 5.6

PA CEPHALOMETRIC RADIOGRAPHS

Digital/InterayVarian/75 kVp/11 mAs [13] 3.9 5.1

INTRAORAL RADIOGRAPHS

IntraPlanmeca/FullMouthRadiographs/70 kV/8 mA/Digital or F-speedfilm/RectangularCollimation [13]

12.2 34.9

IntraPlanmeca/FullMouthRadiographs/70 kV/8 mA/Digital or F-speedfilm/RoundCollimation [13]

58.4 170.7

IntraPlanmeca/FullMouthRadiographs/RoundCollimation/Adult [6] 115 129

IntraPlanmeca/Bitewing(04)/70 kV/8 mA/Digital or F-speedfilm/RectangularCollimation [6]

1 5

SiemensHeliodent70Dentotime/OcclusalMx [18] 7

LARGE FOV CONE BEAM CT

Classic i-CAT/FOV22 cm/120 kV/3–8 mA [27] 92.8 182.1

Classic i-CAT/FOV22 cm/120 kV/5.7 mA [12] 134.8 193.4

Classic i-CAT/FOV22 cm/120 kV/3–8 mA/2× 20 s [28] 82

Next Generation i-CAT/FOV23 cm/120 kV/5 mA/19 mAs/8.9 s [11] 37 74

NewTom3G/FOV19 cm/110 kV/1.5 mA/8.09 mAs/36 s [11, 12] 44.7 58.9 68


Table 2: Continued.



ICRP 60-1990ICRP 2005 ICRP 103-2007

ExcGland IncGland

NewTom3G/FOV19 cm/110 kV/<15 mA [28] 30

NewTom9000/FOV23 cm/110 kV/5.4 mA [15] 56.2

CBMercuRay/FOV19 cm/100 kV/10 mA/100 mAs/10 s [11, 12] 476.6 557.6 569

CBMercuRay/FOV19 cm/120 kV/15 mA/150 mAs/10 s [11, 12] 846.9 1025.4 1073

CBMercuRay/FOV19 cm/100 kV/15 mA [6] 415 479





Iluma/FOV19 cm/120 kV/1 mA/20 mAs/20 s [11] 50 98

Iluma/FOV19 cm/120 kV/3.8 mA/152 mAs/40 s [11] 252 498

Kodak9500/FOV18 cm/80 kV/86.4 mAs [29] 52 93

Kodak9500/FOV18 cm/85 kV/108 mAs [29] 92 163


Kodak9500/FOV18 cm/90 kV/108 mAs [17] 136

SkyView/FOV17 cm/90 kV/51 mAs [17] 87

MEDIUM FOV CONE BEAM CT

Classic i-CAT/FOV13 cm/120 kV/3–8 mA [27] 39.5 110.5

Classic i-CAT/FOV13 cm/120 kV/5.7 mA [12] 68.7 104.5

Classic i-CAT/FOV13 cm/120 kV/23.87 mA [15] 61.1

Classic i-CAT/FOV13 cm/120 kV/3–8 mA/10 s [28] 48


Classic i-CAT/FOV13 cm/120 kV/5 mA/19 mAs/20 s [11] 29 69

Next Generation i-CAT/FOV13 cm/120 kV/5 mA/19 mAs/8.9 s [11] 36 87

Next Generation i-CAT/FOV13 cm/120 kV/18.5 mAs [17] 83

NewTom9000/FOV13 cm/110 kV/3.2 mA [30] 36.9 77.9

NewTom9000/FOV13 cm/110 kV/3.5 mA/18 s [26] 50.3

NewTom9000/FOV13 cm/110 kV/3.4 mA/17 s [22] 35 64

NewTom9000/FOV13 cm/110 kV/3.4 mA/17 s/Thyroid Protector [22] 23 52

NewTom3G/FOV15 cm/110 kV/<15 mA [28] 57

NewTom5Gi/FOV15 cm/110 kV/8.8 mAs [17] 194

CBMercuRay/FOV15 cm/120 kV/15 mA/120/mAs/10 s [11] 288.9 435.5 560



Galileos/FOV15 cm/85 kV/5 mA/21 mAs/14 s [11] 28 70

Galileos/FOV15 cm/85 kV/7 mA/42 mAs/14 s [11] 52 128

GalileosComfort/FOV15 cm/85 kV/28 mAs [17] 84

Kodak9500/FOV15 cm/80 kV/86.4 mAs [29] 39 76


Kodak9500/FOV15 cm/90 kv/108 mAs [29] 76 166

IlumaElite/FOV14 cm/120 kV/76 mAs [17] 368

Scanora3D/FOV13.5 cm/85 kV/48 mAs [17] 68

SMALL FOV CONE BEAM CT

Classic i-CAT/FOV6 cmMx/120 kV/3–8 mA [27] 9.7 36.5

Classic i-CAT/FOV6 cmMx/120 kV/3–8 mA/HighResolution [27] 18.5 68.3

Classic i-CAT/FOV6 cmMx/120 kV/3–8 mA/20 s [28] 45

Classic i-CAT/FOV6 cmMx/120 kV/3–8 mA/40 s [28] 77


Table 2: Continued.



ICRP 60-1990ICRP 2005 ICRP 103-2007

ExcGland IncGland

Classic i-CAT/FOV6 cmMd/120 kV/3–8 mA [27] 23.9 75.3

Classic i-CAT/FOV6 cmMd/120 kV/3–8 mA/HighResolution [27] 47.2 148.5

Classic i-CAT/FOV6 cmMd/120 kV/3–8 mA/20 s [28] 34

Classic i-CAT/FOV6 cmMd/120 kV/3–8 mA/40 s [28] 64


Next Generation i-CAT/FOV6 cmMd/120 kV/18.5 mAs [17] 45

NewTom9000/FOVMx [30] 19.9 41.5

NewTom9000/FOVMd [30] 34.7 74.7

NewTom5G/FOV10 cm/110 kV/10.4 mAs [17] 83

NewTom5Gi/FOV8 cm/110 kV/43 mAs [17] 265

CBMercuRay/FOV10 cmMx/120 kV/15 mA/150 mAs/10 s [11, 12] 168.4 283.3 407



CBMercuRay/FOV10 cm/120 kV/15 mA [23] 451.8 510.5

Promax3D/FOV8 cm/84 kVp/12 mA/6 s [41] 269 674

Promax3D/FOV8 cm/84 kV/12 mA/72 mAs/18 s [11] 151 488

Promax3D/FOV8 cm/84 kV/16 mA/96 mAs/18 s [11] 203 652

Promax3D/FOV8 cm/84 kV/8 mA/12 s/NormalResolution [42] 102





Promax3D/FOV8 cm/84 kV/8 mA/2.8 s/LowDose [42] 30

Promax3D/FOV8 cm/84 kV/16 mA/12 s/HighDose [42] 306

Promax3D/FOV8 cm/84 kV/8 mA/8.3 s/LowDose [42] 87

Promax3D/FOV8 cm/84 kV/169 mAs/HighDose [17] 122

Promax3D/FOV8 cm/84 kV/19.9 mAs/LowDose [17] 28

PreXion3D/FOV8.1 cm/90 kV/4 mA/76 mAs/19 s [11] 66 189

PreXion3D/FOV8.1 cm/90 kV/4 mA/148 mAs/37 s [11] 154 388

3D Accuitomo 170/FOV5 cmMx/90 kV/87.5 mAs [17] 54

Kodak9500/FOV8 cm/90 kV/108 mAs [17] 92

PicassoTrio HighDose/FOV7 cm/85 kV/127 mAs [17] 123

PicassoTrio LowDose/FOV7 cm/85 kV/91 mAs [17] 81

Scanora 3D/FOV7.5 cmMx/85 kV/30 mAs [17] 46

Scanora 3D/FOV7.5 cmMd/85 kV/30 mAs [17] 47

Scanora 3D/FOV7.5 cmMxMd/85 kV/30 mAs [17] 45

Veraviewpocs3D/FOV8 cm/70 kV/51 mAs [17] 73

CONVENTIONAL CT

SomatomVolumeZoom4/Scan22.6 cmFullHead/120 kV/90 mA/44.12 s/Slice0.75 mm [28]

1110

SomatomSensation16/Scan22.5 cmFullHeadl/120 kV/90 mA/29.48 s/slice0.75 mm [28]

995

Mx8000IDTPhilips/Scan22.5 cmFullHead/120 kV/140 mA/29.6 s/Slice0.75 mm [28] 1160

Somatom64/Scan12 cm/120 kV/90 mA [11] 453 860

Somatom64CareDose4D/Scan12 cm/120 kV/90 mA [11] 285 534

SomatomPlusVolumeZoom4/ScanMx+Md/Slice1.25 mm/21.25 s/120 kVp/150 mA [18]

2110


Table 2: Continued.



ICRP 60-1990ICRP 2005 ICRP 103-2007

ExcGland IncGland

SomatomSensation/Scan10 cm/120 kV/90 mA [15] 429.7

ExcelTwin/Scan9.6 cm/120 kV/300 mAs/Slice2 mm/2sporslice [39] 314 924

HiSpeedQX/i/Scan7.7 cmMx+Md/120 kV/100 mA [23] 595.6 768.9

SomatomVolumeZoom4/Scan7.2 cmMd/120 kV/90 mA/15.16 s/ Slice0.75 mm [28] 494

SomatomSensation16/Scan6.3 cmMd/120 kV/90 mA/7.87 s/Slice0.75 mm [28] 474

Mx8000IDTPhilips/Scan6 cmMd/120 kV/140 mA/7.89 s/ Slice0.75 mm [28] 541

SomatomPlus4VolumeZoom Scan5.2 cmMd/120 kV/100 mAs [24] 250

ElscintExcel2400/ScanMd/120 kVp/315 mAs [43] 2426 3324

SomatomPlus4VolumeZoom/ScanMd/Slice1.25 mm/12.64 s/ 120 kVp/150 mA [18] 1320

SomatomPlusVolumeZoom4/ScanMx/Slice1.25 mm/9.47 s/ 120 kVp/150 mA [18] 1400

ElscintExcel2400/ScanMx/120 kVp/315 mAs [43] 1031 1202

for the i-CAT, the kV, mA, and exposure time are establishedby the manufacturer and do not vary from patient to patient.That is, the same dose is used for patients of different sizesand different ages. In children, this may be higher thanneeded for a diagnosis. For the NewTom 3G, exposure is alsoset by the manufacturer, but a dynamic process identifiesthe radiation needed, and the mA is adjusted during theexposure. For the CB MercuRay, the operator defines kV andmA. Inexperienced operators tend to increase kV and mAbecause the overexposed images appear to be adequate withreduced noise, which increases the risk of overexposure [12].

For CBCT, smaller FOV normally generates lower radia-tion doses, similar to the action of collimators [6, 12, 17, 27–29]. In general, the mandibular FOV has a larger dose thanthe maxillary [27, 30], because the salivary glands, thyroid,and esophagus are more irradiated in this exam. The chosenFOV must be the smallest that will encompass the region ofinterest [6]. For example, the medium FOV (13 cm) fromthe NewTom/i-CAT is often enough to reach the regionsrequired in many children for orthodontics. With the largeFOV, unnecessary areas are irradiated in these “minor”children, increasing the effective dose. On the other hand,the large FOV is always necessary in adults. The operatoris responsible for choosing the appropriate FOV, large ormedium, according to the size of the child.

4.2. CBCT versus CT. The effective dose generated by CT isgenerally higher than that of CBCT. When analyzing the doseaccording the 2007 ICRP, the head CT requires doses between995 and 1160 µSv, whereas the large FOV CBCT requires 30to 68 µSv for the NewTom 3G, 74 µSv for the Next Generationi-CAT, 82 to 182.1 µSv for the Classic i-CAT, 87 µSv forthe SkyView, 93 to 260 µSv for the Kodak 9500, and 98 to498 µSv for the Iluma. The CB MercuRay approaches theradiation levels of standard CT, with doses between 569 and1073 µSv. High doses are observed for CT even when areasare reduced, ranging between 534 and 860 µSv for the maxillaand mandible. This represents a higher dose emitted by CT,

especially in relation to the NewTom 3G and i-CAT CBCTdevices. The CT dose is also high in relation to radiographs,which emit doses of 14.2 to 24.3 µSv for the panoramicradiograph, 5.4 µSv for the lateral cephalometric radiographand 34.9 to 170.7 µSv for a complete intraoral examination.

4.3. CBCT versus Conventional Radiographs. In this tran-sition phase of image diagnosis, a question frequentlyarises: “to how many radiographs is the radiation dose ofCBCT equivalent?” Despite the straightforward nature of thequestion, the answer involves many nuances.

The characteristics of an intraoral radiograph influenceits effective dose, such as film sensitivity (when not digital)and, especially, the type of collimation (rectangular orcircular). Intraoral radiographs with circular collimation andfilms that are not sensitive (D-speed) yielding doses that aremuch greater than sensitive (E/F-speed) and digital filmswith rectangular collimation. The dose for the digital/F-speed complete intraoral exam with rectangular collimation(34.9 µSv) is close to 4.9 times lower than one with circularcollimation (170.7 µSv) [13]. The NCRP [31] and theAmerican Dental Association [32] recommend rectangularcollimation for periapical and bitewing radiographs, the useof a thyroid protector and the avoidance of using filmslower than E-speed (preferably F-speed/digital). In termsof extraoral radiographs, according to ICRP 2005/2007, thedoses are between 2.7 and 24.3 µSv for the panoramic and5.6 µSv for the lateral cephalometric.

Many orthodontists do not request a full-mouth seriesof intraoral radiographs for orthodontic planning and thispractice greatly reduces the dose of radiation imparted tothe patient when compared to CBCT exposure. This isparticularly important when dealing with young childrenthat are more susceptible to radiation [4]. However, in someinstances, it hampers the diagnosis since the panoramicradiograph shows large distortions that prevent the diagnosisof more subtle changes, such as caries and root resorptionin early stages. Thus, these radiographs should be taken in


patients with permanent dentition that will begin full bracesorthodontic treatment to search for dental diseases and toserve as a precise record of each teeth and adjacent boneduring and posttreatment. Panoramics should also be takenduring comprehensive orthodontic treatment to visualize theentire maxilla and mandible including the teeth, maxillarysinuses, nasal cavity, and condyles.

Therefore, in the initial orthodontic radiographic doc-umentation (ORD), which often includes full mouth seriesof intraoral radiographs (FMX), panoramic, and lateralcephalometric radiographs, the total dose varies between43.2 and 200.6 µSv, depending on the collimation of intraoralradiographs. The large FOV of most CBCT scanners provideslower doses than the ORD with FMX using circular colli-mation. If rectangular collimation is used, the ORD presentslower effective dose.

It is not enough to compare doses between diagnosticprocedures, because diagnostic quality cannot be separatedfrom the dose used. Objective studies of the impact of CBCTimage quality on diagnostic performance must be conductedbefore any definitive conclusions are drawn about the differ-ences generated by reduced doses [12]. Current data describethe reconstructions of lateral teleradiography of CBCT ashaving similar precision to conventional radiographs [33]in addition to high intra- and interexaminer reproducibil-ity [34]. Comparisons between CBCT images, periapicalradiography, and clinical evaluations have not demonstratedsignificant differences in the extent of periodontal defects,but CBCT allows for the observation of all bone defectsand better inspection of craters and furcation defects [35].However, delicate structures such as the trabecular bone andthe periodontal ligament display lower visibility and highervariability between CBCT and CT than do other structures[36]. Conventional radiography has advantages in terms ofcontrast, the quality of the bone image and delineation of thelamina dura, in addition to superior performance in the eval-uation of the periodontal space compared to CBCT [37] andis, therefore, indispensable for accurate periapical diagnosis.

4.4. Differences between CBCT Devices. The CBCT dose var-ies according to the CBCT device. Among the better knownlarge FOV CBCT, the CB MercuRay provides the greatestradiation, followed by the Classic i-CAT, the Kodak 9500,the Iluma, the Next Generation i-CAT, and the NewTom 3G.Considering the large FOV (ICRP2005) [12], the radiationdoses of the Classic i-CAT and the CB MercuRay are 3.3 and9.5 to 17 times greater, respectively, than that of the NewTom3G. The Next Generation i-CAT comes close to the NewTom3G (ICRP 2007) in terms of radiation level because it scansmore quickly than the Classic i-CAT.

Considering the large FOV CBCT, a general conclusion,based on values described in Table 2, is that the effectivedoses from most devices are found in the 30–200 µSv range.Although the geometry of image acquisition is basicallythe same, the differences in collimation of the cone beam,as well as the X-ray exposure factors, lead to considerabledifferences in absorbed dose for all organs in the head andthe neck regions. A single effective dose is not a conceptthat should be used for CBCT when compared to alternative

radiographic methods such as panoramic, intraoral radio-graphy, and conventional CT. The range of doses amongdevices is too large to consider them as a single modality[17].

In addition to controlling the settings of tomographs,radiation levels can vary due to exposure times and radiationbeams. The NewTom 3G scans in 36 s but emits X-ray foronly 5.4 s. Similarly, the Classic i-CAT (FOV 13 cm) scans in20 s, but the X-ray tube is only activated for 3.3 s. The largeFOV in the i-CAT involves two FOV 13 cm scans, performedsequentially and interlaced to create a greater volume. Dou-ble scanning preserves the quality of FOV 13 cm but requiresalmost double the exposure time. The CB MercuRay scans in11 s and emits for 10 s. Thus, the exposure for the CB Mer-cuRay is continuous, whereas for the NewTom 3G and thei-CAT it is pulsed; consequently, the latter two use radiationmore efficiently because the detector is only exposed whileit registers photons and because radiation is not emittedwhile the detector transfers the image signal to the computer[12].

The results of the CBCT devices expressed in Table 2should be interpreted carefully due to the interplay amongimage quality, the size of the scanned volume, and theabsorbed radiation dose in different tissues. Comparisonsof the performances of CBCT devices cannot be donebased on dosimetric results alone. The radiation dose fromthese devices can be seen as a function of the diagnosticapplication. The two key factors for an acceptable imageare an appropriate size and positioning of the FOV and anacceptable quality of the reconstructed image [17], a pointthat was not evaluated in this revision. Further study isrequired to bring the image quality into play, on a technicaland diagnostic level. By investigating technical image quality,the relation between the exposure from CBCT devices andthe image quality performance can be quantified [17].

5. Conclusions

(1) Increases in kV, mA, exposure time, and FOV in-crease the dose of radiation, regardless of the type ofexam.

(2) The effective dose for CT is greater than for CBCT orconventional radiographs.

(3) When the FMX is performed with round collimation,the ORD issues higher doses than most of the largeFOV CBCT. Radiation dose for ORD can be lowerthan large FOV CBCT if rectangular collimation isused in FMX. Despite the image quality, CBCT doesnot replace the FMX and most orthodontic caseswill be properly handled with conventional 2D radio-graphs. CBCT should be required for more complexcases.

(4) The orthodontists have the duty to preserve thehealth of the patient and always seek the best treat-ment. This quest begins with exams that require theleast amount of radiation dose to treat the patientappropriately.


References

[1] A. M. Bollen, J. Cunha-Cruz, and P. P. Hujoel, “Secular trendsin preadult orthodontic care in the United States: 1942–2002,”American Journal of Orthodontics and Dentofacial Orthopedics,vol. 132, no. 5, pp. 579–585, 2007.

[2] P. Hujoel, L. Hollender, A. M. Bollen, J. D. Young, M. McGee,and A. Grosso, “Head-and-neck organ doses from an episodeof orthodontic care,” American Journal of Orthodontics andDentofacial Orthopedics, vol. 133, no. 2, pp. 210–217, 2008.

[3] E. D. M. M. Cerqueira, J. R. C. Meireles, M. A. Lopes et al.,“Genotoxic effects of X-rays on keratinized mucosa cells du-ring panoramic dental radiography,” Dentomaxillofacial Radi-ology, vol. 37, no. 7, pp. 398–403, 2008.

[4] L. Hagmar, S. Bonassi, U. Stromberg et al., “Chromosomal ab-errations in lymphocytes predict human cancer: a report fromthe European study group on cytogenetic biomarkers andhealth (ESCH),” Cancer Research, vol. 58, no. 18, pp. 4117–4121, 1998.

[5] A. Memon, S. Godward, D. Williams, I. Siddique, and K. Al-Saleh, “Dental x-rays and the risk of thyroid cancer: a case-control study,” Acta Oncologica, vol. 49, no. 4, pp. 447–453,2010.

[6] J. M. Palomo, P. S. Rao, and M. G. Hans, “Influence of CBCTexposure conditions on radiation dose,” Oral Surgery, OralMedicine, Oral Pathology, Oral Radiology and Endodontology,vol. 105, no. 6, pp. 773–782, 2008.

[7] International Commission on Radiological Protection, “1990recommendations of the international commission on radio-logical protection,” Annals of the ICRP, vol. 21, no. 1–3, pp.1–201, 1991.

[8] M. A. Garcia Silva, U. Wolf, F. Heinicke, K. Grundler, H. Visser,and E. Hirsch, “Effective dosages for recording Veraviewepocsdental panoramic images: analog film, digital, and panoramicscout for CBCT,” Oral Surgery, Oral Medicine, Oral Pathology,Oral Radiology and Endodontology, vol. 106, no. 4, pp. 571–577, 2008.

[9] National Council on Radiation Protection and Measurements,“Ionizing radiation exposure of the population of the UnitedStates,” National Council on Raditation Protection Reportnumber 160, National Council on Radiation Protection andMeasurements, Bethesda, Md, USA, 2009.

[10] J. Valentin, “The 2007 recommendations of the InternationalCommission on Radiological Protection. ICRP publication103,” Annals of the ICRP, vol. 37, no. 2–4, pp. 1–332, 2007.

[11] J. B. Ludlow and M. Ivanovic, “Comparative dosimetry ofdental CBCT devices and 64-slice CT for oral and maxillofacialradiology,” Oral Surgery, Oral Medicine, Oral Pathology, OralRadiology and Endodontology, vol. 106, no. 1, pp. 106–114,2008.

[12] J. B. Ludlow, L. E. Davies-Ludlow, S. L. Brooks, and W. B.Howerton, “Dosimetry of 3 CBCT devices for oral and maxi-llofacial radiology: CB Mercuray, NewTom 3G and i-CAT,”Dentomaxillofacial Radiology, vol. 35, no. 4, pp. 219–226, 2006.

[13] J. B. Ludlow, L. E. Davies-Ludlow, and S. C. White, “Patientrisk related to common dental radiographic examinations: theimpact of 2007 International Commission on RadiologicalProtection recommendations regarding dose calculation,”Journal of the American Dental Association, vol. 139, no. 9, pp.1237–1243, 2008.

[14] W. De Vos, J. Casselman, and G. R. J. Swennen, “Cone-beamcomputerized tomography (CBCT) imaging of the oral andmaxillofacial region: a systematic review of the literature,”

International Journal of Oral and Maxillofacial Surgery, vol. 38,no. 6, pp. 609–625, 2009.

[15] M. A. G. Silva, U. Wolf, F. Heinicke, A. Bumann, H. Visser, andE. Hirsch, “Cone-beam computed tomography for routineorthodontic treatment planning: a radiation dose evaluation,”American Journal of Orthodontics and Dentofacial Orthopedics,vol. 133, no. 5, pp. 640.e1–640.e5, 2008.

[16] S. Gavala, C. Donta, K. Tsiklakis, A. Boziari, V. Kameno-poulou, and H. C. Stamatakis, “Radiation dose reduction indirect digital panoramic radiography,” European Journal of Ra-diology, vol. 71, no. 1, pp. 42–48, 2009.

[17] R. Pauwels, J. Beinsberger, B. Collaert et al., “Effective doserange for dental cone beam computed tomography scanners,”European Journal of Radiology, vol. 81, no. 2, pp. 267–271,2012.

[18] D. C. Ngan, O. P. Kharbanda, J. P. Geenty, and M. A.Darendeliler, “Comparison of radiation levels from computedtomography and conventional dental radiographs,” AustralianOrthodontic Journal, vol. 19, no. 2, pp. 67–75, 2003.

[19] H. Visser, T. Rodig, and K. P. Hermann, “Dose reduction bydirect-digital cephalometric radiography,” Angle Orthodontist,vol. 71, no. 3, pp. 159–163, 2001.

[20] F. Gijbels, G. Sanderink, J. Wyatt, J. Van Dam, B. Nowak, andR. Jacobs, “Radiation doses of collimated vs non-collimatedcephalometric exposures,” Dentomaxillofacial Radiology, vol.32, no. 2, pp. 128–133, 2003.

[21] F. Gijbels, G. Sanderink, J. Wyatt, J. Van Dam, B. Nowak,and R. Jacobs, “Radiation doses of indirect and direct digitalcephalometric radiography,” British Dental Journal, vol. 197,no. 3, pp. 149–152, 2004.

[22] K. Tsiklakis, C. Donta, S. Gavala, K. Karayianni, V.Kamenopoulou, and C. J. Hourdakis, “Dose reduction in max-illofacial imaging using low dose Cone Beam CT,” EuropeanJournal of Radiology, vol. 56, no. 3, pp. 413–417, 2005.

[23] T. Okano, Y. Harata, Y. Sugihara et al., “Absorbed and effectivedoses from cone beam volumetric imaging for implant plan-ning,” Dentomaxillofacial Radiology, vol. 38, no. 2, pp. 79–85,2009.

[24] A. Ohman, L. Kull, J. Andersson, and L. Flygare, “Radiationdoses in examination of lower third molars with computedtomography and conventional radiography,” Dentomaxillofa-cial Radiology, vol. 37, no. 8, pp. 445–452, 2008.

[25] R. A. Danforth and D. E. Clark, “Effective dose from radi-ation absorbed during a panoramic examination with a newgeneration machine,” Oral Surgery, Oral Medicine, Oral Path-ology, Oral Radiology, and Endodontics, vol. 89, no. 2, pp. 236–243, 2000.

[26] J. K. Mah, R. A. Danforth, A. Bumann, and D. Hatcher, “Radi-ation absorbed in maxillofacial imaging with a new dentalcomputed tomography device,” Oral Surgery, Oral Medicine,Oral Pathology, Oral Radiology, and Endodontics, vol. 96, no. 4,pp. 508–513, 2003.

[27] J. A. Roberts, N. A. Drage, J. Davies, and D. W. Thomas, “Effec-tive dose from cone beam CT examinations in dentistry,”British Journal of Radiology, vol. 82, no. 973, pp. 35–40, 2009.

[28] M. Loubele, R. Bogaerts, E. Van Dijck et al., “Comparisonbetween effective radiation dose of CBCT and MSCT scannersfor dentomaxillofacial applications,” European Journal of Radi-ology, vol. 71, no. 3, pp. 461–468, 2009.

[29] J. B. Ludlow, “A manufacturer’s role in reducing the doseof cone beam computed tomography examinations: effect ofbeam filtration,” Dentomaxillofacial Radiology, vol. 40, no. 2,pp. 115–122, 2011.


[30] J. B. Ludlow, L. E. Davies-Ludlow, and S. L. Brooks, “Dosime-try of two extraoral direct digital imaging devices: newTomcone beam CT and Orthophos Plus DS panoramic unit,”Dentomaxillofacial Radiology, vol. 32, no. 4, pp. 229–234, 2003.

[31] D. A. Miles and R. P. Langlais, “NCRP Report No. 145: newdental x-ray guidelines: their potential impact on your dentalpractice,” Dentistry Today, vol. 23, no. 9, pp. 128–134, 2004.

[32] American Dental Association Council on Scientific Affairs,“The use of dental radiographs: update and recommenda-tions,” The Journal of the American Dental Association, vol. 137,no. 9, pp. 1304–1312, 2006.

[33] V. Kumar, J. B. Ludlow, A. Mol, and L. Cevidanes, “Compari-son of conventional and cone beam CT synthesized cephalo-grams,” Dentomaxillofacial Radiology, vol. 36, no. 5, pp. 263–269, 2007.

[34] A. E. F. de Oliveira, L. H. S. Cevidanes, C. Phillips, A.Motta, B. Burke, and D. Tyndall, “Observer reliability ofthree-dimensional cephalometric landmark identification oncone-beam computerized tomography,” Oral Surgery, OralMedicine, Oral Pathology, Oral Radiology and Endodontology,vol. 107, no. 2, pp. 256–265, 2009.

[35] K. A. Misch, E. S. Yi, and D. P. Sarment, “Accuracy of conebeam computed tomography for periodontal defect measure-ments,” Journal of Periodontology, vol. 77, no. 7, pp. 1261–1266, 2006.

[36] X. Liang, R. Jacobs, B. Hassan et al., “A comparative evaluationof cone beam computed tomography (CBCT) and multi-sliceCT (MSCT) Part I. On subjective image quality,” EuropeanJournal of Radiology, vol. 75, no. 2, pp. 265–269, 2010.

[37] N. Ozmeric, I. Kostioutchenko, G. Hagler, M. Frentzen, andP. -M. Jervøe-Storm, “Cone-beam computed tomography inassessment of periodontal ligament space: in vitro study onartificial tooth model,” Clinical Oral Investigations, vol. 12, no.3, pp. 233–239, 2008.

[38] A. R. Lecomber, S. L. Downes, M. Mokhtari, and K. Faulkner,“Optimisation of patient doses in programmable dental pano-ramic radiography,” Dentomaxillofacial Radiology, vol. 29, no.2, pp. 107–112, 2000.

[39] A. R. Lecomber, Y. Yoneyama, D. J. Lovelock, T. Hosoi, and A.M. Adams, “Comparison of patient dose from imaging pro-tocols for dental implant planning using conventional radiog-raphy and computed tomography,” Dentomaxillofacial Radiol-ogy, vol. 30, no. 5, pp. 255–259, 2001.

[40] F. Gijbels, R. Jacobs, R. Bogaerts, D. Debaveye, S. Verlinden,and G. Sanderink, “Dosimetry of digital panoramic imaging.Part I: patient exposure,” Dentomaxillofacial Radiology, vol. 34,no. 3, pp. 145–149, 2005.

[41] A. Suomalainen, T. Kiljunen, Y. Kaser, J. Peltola, and M.Kortesniemi, “Dosimetry and image quality of four dentalcone beam computed tomography scanners compared withmultislice computed tomography scanners,” Dentomaxillofa-cial Radiology, vol. 38, no. 6, pp. 367–378, 2009.

[42] X. M. Qu, G. Li, J. B. Ludlow, Z. Y. Zhang, and X. C. Ma,“Effective radiation dose of ProMax 3D cone-beam comput-erized tomography scanner with different dental protocols,”Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiologyand Endodontology, vol. 110, no. 6, pp. 770–776, 2010.

[43] G. Scaf, A. G. Lurie, K. M. Mosier, M. L. Kantor, G. R.Ramsby, and M. L. Freedman, “Dosimetry and cost of imagingosseointegrated implants with film-based and computed to-mography,” Oral Surgery, Oral Medicine, Oral Pathology, OralRadiology, and Endodontics, vol. 83, no. 1, pp. 41–48, 1997.


Research Article

Supernumerary Teeth in Indian Children: A Survey of 300 Cases

Amita Sharma1 and Varun Pratap Singh2

1 Department of Pediatric Dentistry, College of Dental Sciences, BPKIHS, Dharan, Nepal2 Department of Orthodontics, College of Dental Sciences, BPKIHS, Dharan, Nepal

Correspondence should be addressed to Varun Pratap Singh, [email protected]

Received 11 July 2011; Revised 19 December 2011; Accepted 10 January 2012

Academic Editor: Preetha Kanjirath

Copyright © 2012 A. Sharma and V. P. Singh. This is an open access article distributed under the Creative Commons AttributionLicense, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properlycited.

The aim of this investigation was to study children with supernumerary teeth who visited the Department of Pedodontics andPreventive Dentistry, Government Dental College and Hospital, Rohtak, Haryana, India. Only children with supernumerary teethwere included in the study while patients having supernumerary teeth with associated syndromes were excluded. Supernumerarieswere detected by clinical and radiographic examination. The results indicated that males were affected more than females witha sex ratio of 2.9 : 1. Single supernumerary tooth was seen in 79% of the patients, 20% had double, and 1% had three or moresupernumeraries. Premaxillary supernumeraries accounted for 93.8% of the cases. Conical shaped supernumerary teeth werethe most common type (59.7%). Majority of supernumeraries remained unerupted (65%). Fusion of supernumerary tooth witha regular tooth was observed in 4% of the patients. Talon cusp, an associated dental anomaly, was seen in 5% of the cases.Simultaneous hypodontia occurred in 2.3% of patients with supernumeraries.

1. Introduction

Supernumerary teeth (hyperdontia) may be defined as extrateeth—more than twenty in the deciduous dentition or morethan thirty-two in the permanent dentition [1]. The etiologyof supernumerary teeth is not well understood. Several the-ories have been put forward to explain the anomaly. Onetheory suggests that supernumeraries are formed as a resultof local, conditioned hyperactivity of dental lamina whileanother theory proposes dichotomy of tooth bud. Heredityplays an important role in the occurrence of supernumeraryteeth but does not follow a simple Mendelian pattern. Afamilial tendency and sex-linked inheritance (males beingaffected twice as frequently as females) has been demon-strated [2–4].

Supernumerary teeth occur in 0.3 to 3.8 percent of dif-ferent populations and appear to be on the rise. Out ofthese 90 to 98 percent occur in the maxilla with a particularpredilection for the premaxilla. Supernumerary teeth may besingle or multiple, unilateral or bilateral, erupted or impact-ed and in one or both jaws. Multiple supernumerary teethare rare and usually seen in association with cleft lip/palate,

Cleidocranial dysplasia, Gardner’s syndrome, and so forth[5, 6].

Supernumerary teeth may be classified according to theirform/morphology (supplemental or rudimentary includingconical, tuberculate, and molariform types) and location(mesiodens, paramolar, and distomolar). Detection of super-numerary teeth is best achieved with a thorough clinicaland radiographic examination. Many complications canbe associated with supernumeraries like crowding, delayederuption, impaction, abnormal diastema, cystic lesions, ec-topic eruption, root resorption of adjacent teeth, and soforth. An early diagnosis allows an early intervention, a morefavourable prognosis, and minimal complications [7].

The purpose of this study was to investigate the charac-teristics of supernumerary teeth among children who report-ed to our specialty clinic and compare the data with othersimilar studies.

2. Material and Method

A survey was performed on 21,824 patients (11,218 femalesand 10,606 males) attending the Department of Pedodontics


Table 1: Distribution of supernumerary teeth by dentition and sex.∗Denotes statistically significant values (P < 0.01).

Type of dentition Male Female Total P Value

Deciduous 15 5 20 0.002∗

Mixed 142 39 181 0.001∗

Permanent 67 32 99 0.017

Total 224 76 300 0.002∗

Table 2: Distribution of supernumerary teeth by number perpatient.

Number of teethper patient

Number of patientsPercentage of

supernumerary teeth

One 237 79.0

Two 60 20.0

Three or more 03 01.0

Total 300 100.0

Table 3: Type of supernumerary tooth.

Type Number Percentage

Supplemental (Eumorphic) 70 18.2

Rudimentary (Dysmorphic): Conical 230 59.7

Tuberculate 55 14.3

Molariform 30 07.8

Total 385 100.0

and Preventive Dentistry, Government Dental College andHospital, Rohtak, Haryana, India over a period of six years.Out of the total population, 300 children with ages rangingfrom 4 to 14 years were diagnosed with supernumerary teethin different regions of the dental arches. Reasons for visitingincluded caries, malocclusion, lack of eruption of permanentteeth, and routine dental check up. The characteristics ofsupernumerary teeth were noted and diagnosis made duringclinical and radiographic examination with help of occlusal,periapical, and panoramic radiographs. The horizontal shifttechnique was used to determine the sagittal position of theimpacted supernumerary teeth. Surgical removal of teethwhen and where indicated further confirmed the character-istics of supernumeraries. Patients with syndromes known tobe predisposed to supernumerary teeth such as Cleidocranialdysplasia, Gardner’s syndrome, clefts of lip, and palate werenot included in the study. All the radiographs were reviewedin a negatoscope and interexaminer discrepancies weresolved by mutual consensus. The Pearson chi-square test wasused to determine potential differences in the distribution ofsupernumerary teeth when stratified by gender. P value ofless than 0.01 was considered statistically significant.

3. Results

Out of 300 patients, 224 were male, and 76 were female, thesex ratio was 2.9 : 1 (Table 1).

The total number of supernumerary teeth was 385among the 300 patients. Majority of the patients had single

Figure 1: Radiographic appearance of an erupted supplemental21 along with an unerupted tuberculate supernumerary tooth inmaxillary central incisor region.

Figure 2: Two unerupted normally oriented conical supernumer-ary teeth causing failure of eruption of 11 and 21.

supernumerary tooth (Table 2) which was conical in form(Table 3).

Supernumerary teeth located in the premaxilla were 361(93.8%), and out of these, 293 (81.2%) supernumerarieswere located in the central incisor region (Figure 1), of which88 (30.0%) were in midline (mesiodens). Sixty-eight super-numerary teeth were seen in maxillary lateral incisor region(18.8%). The remaining teeth were located in premolar(3.6%), canine (1.0%), and mandibular incisor (1.5%)regions. A large percentage of supernumerary teeth remainedunerupted (65%), while 35% were partially or fully erupted(Figures 2 and 3).

Rotation/displacement of adjacent permanent teeth wasthe most frequently found complication. Three cases ofdentigerous cyst associated with supernumerary teeth weredetected (Figure 4).

In 4% of the patients fusion of supernumerary tooth withthe adjacent normal tooth occurred. Talon cusp, an associ-ated dental anomaly was seen in 5% of the cases (Figure 5).

Talon cusp on supernumerary teeth was observed in 2%of the patients (Figure 6).

Seven patients with supernumerary teeth were foundhaving simultaneously congenitally absent teeth (excludingthird molars), that is, concomitant hypohyperdontia wasobserved in 2.3% of the cases (Figure 7).


Figure 3: Bilateral unerupted (inverted) conical mesiodentes ob-served during radiographic examination of fractured anterior teeth.

Figure 4: Maxillary occlusal radiograph showing two impactedsupernumerary teeth. One on the right side is associated with aradiolucency having sclerotic border suggestive of dentigerous cyst.

Figure 5: Occlusal radiograph showing talon cusp on 12 and 22;fusion of 22 and supplemental supernumerary 22.

4. Discussion

Table 4 provides an overview of studies done on supernu-merary teeth in different populations. Supernumerary teethmost commonly involved the premaxilla which has also beenestablished as the predominant location by others [2, 5,11–13]. Supernumeraries appeared in a variety of forms(size and shape). Most common was conical, followed bysupplemental, then by tuberculate and molariform type

Figure 6: A well-developed mesiodens with talon cusp: a typicalsuperimposed inverted V-shaped radiopaque structure.

Figure 7: Panoramic radiograph showing bilaterally erupted sup-plemental mesiodentes; fusion of 61 and 62 and missing 22.

(Table 3). Koch et al. reported 56% conical, 12% tubercular,and 11% supplemental and 12% other configurations amongtheir patients [14]. In this study, 35% of the supernumeraryteeth were erupted which is higher than that reportedin Mckibben’s study but comparable to Liu’s study [2,12]. Few authors have reported around 20% of eruptedsupernumeraries [13, 15].

The association of talon cusp with other odontogenicanomalies reported in the literature includes peg-shaped lat-eral incisors, supernumerary teeth, and dens invaginatus,megadont [16, 17]. Very few cases of talon cusp on super-numerary teeth have been reported [18, 19]. Concomitanthypohyperdontia is a rare condition of mixed numericvariation in human dentition. It is usually mentioned asindividual case reports in the literature [20]. Its prevalencein orthodontic patients (including third molars) has beenreported to be 0.4% [21, 22]. In the present survey on Indianchildren, a high incidence of other dental anomalies liketalon cusp and concomitant hypodontia were seen to be asso-ciated with supernumerary teeth while Celikoglu et al. foundno such associated dental anomalies in Turkish population[23]. Dentists should take cognizance of associated dentalanomalies during the examination for supernumerary teethso that a comprehensive treatment can be rendered.

Furthermore as supernumerary teeth are often associatedwith delayed eruption or impaction of permanent teeth,early removal is recommended to facilitate the spontaneouseruption of impacted permanent teeth [24]. In one interest-ing study Ashkenazi et al. demonstrated that spontaneous


Table 4: Summary of various studies carried out on supernumerary teeth in different populations.

Authors Sample size Country Age MethodTypes of

supernumeraryincluded

Male : Female

Present study

300 childrendiagnosed withsupernumerary

teeth

India 4–14 YerasClinical

Examination andradiographs

All 2.9 : 1

Tyrologou et al.(2005) [8]

97 children withdiagnosedmesiodens

Sweden 3–15 yearsClinical examination

and radiographsMesiodens 2 : 1

Huang et al.(1992) [9]

152 children withdiagnosed

supernumeraryteeth

Jordan 5–15 yearsClinical examination

and radiographsAll 2.2 : 1

Liu (1995) [2]

112 children withdiagnosed

supernumeraryteeth in the

premaxillaryregions

Taiwan 4–14 yearsClinical examination

and radiographsIn the Premaxillary

region.2.8 : 1

von Arx (1992)[10]

90 patients withanterior maxillary

supernumerarySwitzerland 6–10 years

Clinical examinationand radiographs

In the AnteriorMaxillary region

2.6 : 1

eruption of permanent teeth depends on various variableslike apex distance of the impacted tooth relative to its fi-nal position, extent of vertical impaction, morphology ofsupernumerary teeth, angle of impaction relative to midline,and time of surgery. However the authors recommended im-mediate orthodontic traction at the time of removal of su-pernumerary teeth [25].

References

[1] C. Schulze, “Developmental abnormalities of the teeth andjaws,” in Thoma’s Oral Pathology, R. J. Gorlin and H. M. Gold-man, Eds., The CV Mosby Co., St Louis, Mo, USA, 6th edition,1970.

[2] J. F. Liu, “Characteristics of premaxillary supernumerary teeth:a survey of 112 cases,” ASDC Journal of Dentistry for Children,vol. 62, no. 4, pp. 262–265, 1995.

[3] A. H. Brook, “A unifying aetiological explanation for anoma-lies of human tooth number and size,” Archives of Oral Biology,vol. 29, no. 5, pp. 373–378, 1984.

[4] M. J. Kinirons, “Unerupted premaxillary supernumeraryteeth. A study of their occurrence in males and females,”British Dental Journal, vol. 153, no. 3, p. 110, 1982.

[5] M. M. Nazif, R. C. Ruffalo, and T. Zullo, “Impacted supernu-merary teeth: a survey of 50 cases,” The Journal of the AmericanDental Association, vol. 106, no. 2, pp. 201–204, 1983.

[6] R. E. Primosch, “Anterior supernumerary teeth—assessmentand surgical intervention in children,” Pediatric Dentistry, vol.3, no. 2, pp. 204–215, 1981.

[7] F. N. Hattab, O. M. Yassin, and M. A. Rawashdeh, “Supernu-merary teeth: report of three cases and review of the literature,”ASDC Journal of Dentistry for Children, vol. 61, no. 5-6, pp.382–393, 1994.

[8] S. Tyrologou, G. Koch, and J. Kurol, “Location, complicationsand treatment of mesiodentes—a retrospective study inchildren,” Swedish Dental Journal, vol. 29, no. 1, pp. 1–9, 2005.

[9] W. H. Huang, T. P. Tsai, and H. L. Su, “Mesiodens in theprimary dentition stage: a radiographic study,” ASDC Journalof Dentistry for Children, vol. 59, no. 3, pp. 186–189, 1992.

[10] T. von Arx, “Anterior maxillary supernumerary teeth: a clinicaland radiographic study,” Australian Dental Journal, vol. 37, no.3, pp. 189–195, 1992.

[11] J. R. Luten, “The prevalence of supernumerary teeth in pri-mary and mixed dentitions,” Journal of Dentistry for Children,vol. 34, no. 5, pp. 346–353, 1967.

[12] D. R. McKibben and L. J. Brearley, “Radiographic deter-mination of the prevalence of selected dental anomalies inchildren,” ASDC Journal of Dentistry for Children, vol. 28, no.6, pp. 390–398, 1971.

[13] L. D. Rajab and M. A. M. Hamdan, “Supernumerary teeth:review of the literature and a survey of 152 cases,” InternationalJournal of Paediatric Dentistry, vol. 12, no. 4, pp. 244–254,2002.

[14] H. Koch, O. Schwartz, and B. Klausen, “Indications for sur-gical removal of supernumerary teeth in the premaxilla,”International Journal of Oral and Maxillofacial surgery, vol. 15,no. 3, pp. 273–281, 1986.

[15] C. De Oliveira Gomes, S. N. Drummond, B. C. Jham, E. N.Abdo, and R. A. Mesquita, “A survey of 460 supernumeraryteeth in Brazilian children and adolescents,” InternationalJournal of Paediatric Dentistry, vol. 18, no. 2, pp. 98–106, 2008.

[16] C. L. Mader, “Talon cusp,” The Journal of the American DentalAssociation, vol. 103, no. 2, pp. 244–246, 1981.

[17] P. J. Davis and A. H. Brook, “The presentation of talon cusp:diagnosis, clinical features, associations and possible aetiol-ogy,” British Dental Journal, vol. 160, no. 3, pp. 84–88, 1986.


[18] M. A. O. Al-Omari, F. N. Hattab, A. M. G. Darwazeh, and P.M. H. Dummer, “Clinical problems associated with unusualcases of talon cusp,” International Endodontic Journal, vol. 32,no. 3, pp. 183–190, 1999.

[19] F. S. Salama, C. M. Hanes, P. J. Hanes, and M. A. Ready, “Taloncusp: a review and two case reports on supernumerary pri-mary and permanent teeth,” ASDC Journal of Dentistry forChildren, vol. 57, no. 2, pp. 147–149, 1990.

[20] J. Zhu, M. Marcushamer, D. L. King, and R. J. Henry, “Super-numerary and congenitally absent teeth: a literature review,”Journal of Clinical Pediatric Dentistry, vol. 20, no. 2, pp. 87–95,1996.

[21] A. C. Gibson, “Concomitant hypo-hyperodontia,” BritishJournal of Orthodontics, vol. 6, no. 2, pp. 101–105, 1979.

[22] I. B. O’Dowling, “Hypo-hyperdontia in an Irish population,”Journal of the Irish Dental Association, vol. 35, no. 3, pp. 114–117, 1989.

[23] M. Celikoglu, H. Kamak, and H. Oktay, “Prevalence andcharacteristics of supernumerary teeth in a non-syndromeTurkish population: associated pathologies and proposedtreatment,” Medicina Oral, Patologia Oral y Cirugia Bucal, vol.15, no. 4, pp. e575–e578, 2010.

[24] L. Leyland, P. Batra, F. Wong, and R. Llewelyn, “A retrospectiveevaluation of the eruption of impacted permanent incisorsafter extraction of supernumerary teeth,” Journal of ClinicalPediatric Dentistry, vol. 30, no. 3, pp. 225–232, 2006.

[25] M. Ashkenazi, B. P. Greenberg, G. Chodik, and M. Rakocz,“Postoperative prognosis of unerupted teeth after removalof supernumerary teeth or odontomas,” American Journal ofOrthodontics and Dentofacial Orthopedics, vol. 131, no. 5, pp.614–619, 2007.


Review Article

Oral Leukoplakia as It Relates to HPV Infection: A Review

L. Feller and J. Lemmer

Department of Periodontology and Oral Medicine, University of Limpopo, Medunsa Campus, Medunsa, South Africa

Correspondence should be addressed to L. Feller, [email protected]

Received 13 July 2011; Revised 2 September 2011; Accepted 19 December 2011

Academic Editor: Neil S. Norton

Copyright © 2012 L. Feller and J. Lemmer. This is an open access article distributed under the Creative Commons AttributionLicense, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properlycited.

Leukoplakia is the most common potentially malignant lesion of the oral cavity and can be categorised according to itsclinical appearance as homogeneous or nonhomogenous. Tobacco and areca nut use, either alone or in combination are themost common risk factors for oral leukoplakia, but some oral leukoplakias are idiopathic. Some leukoplakias arise withinfields of precancerized oral epithelium in which the keratinocytes may be at different stages of cytogenetic transformation.Leukoplakias may unpredictably regress, may remain stable, or may progress to carcinoma. There is a greater risk of carcinomatoustransformation of idiopathic leukoplakia, of non-homogenous leukoplakia, of leukoplakia affecting the floor of the mouth; theventrolateral surface of the tongue and the maxillary retromolar and adjoining soft palate (collectively called high-risk sites),of leukoplakia with high-grade epithelial dysplasia, and of leukoplakia in which the keratinocytes carry cytogenetic alterationsassociated with carcinomatous transformation. Although there appears to be some link between human papillomavirus (HPV)and oral leukoplakia, there is little evidence to support a causal relationship either between HPV infection and oral leukoplakia orbetween HPV-infected leukoplakic keratinocytes and their carcinomatous transformation.

1. Introduction

Leukoplakia is the most common potentially malignantlesion of the oral cavity [1, 2]. Leukoplakia is a term describ-ing “a white lesion of the oral mucosa that cannot be char-acterized clinically or microscopically as any other definedoral disease entity” [3, 4]. At a World Health Organisation(WHO) workshop held in 2005, it was recommended thatoral leukoplakia be defined as “a white plaque of questionablerisk having excluded (other) known diseases or disorders thatcarry no increased risk for cancer” [5–7]. Oral leukoplakianeeds to be distinguished from other predominantly whitekeratotic lesions including frictional keratosis and stomatitisnicotina, which do not have malignant potential [1, 2, 5–8].

About 70–90% of oral leukoplakias are related to smok-ing and areca nut use, either alone or in combination, andthere is a direct relationship between the frequency andthe duration of cigarette, pipe, or cigar smoking and theprevalence of oral leukoplakia [8, 9]. The factors implicatedin the pathogenesis of idiopathic leukoplakia are unknown.

However it is possible that infection of the oral epithe-lium with human papillomavirus (HPV) and excessiveconsumption of alcoholic beverages may be associated with

oral leukoplakia, but there is little evidence of a causalrelationship between either HPV infection or alcohol, andoral leukoplakia [6].

It has been suggested that a definitive diagnosis oforal leukoplakia must be established by histopathologicalexclusion of other keratotic oral lesions that are recognisedas specific entities, and by exclusion of any aetiological agentsother than tobacco/areca nut use [7].

It is the opinion of the authors that these criteria areunrealistically limiting, ignoring as they do the possibleroles of HPV, alcohol, chronic inflammation, and low-grade chronic frictional trauma in the pathogenesis of oralleukoplakia. Referring to the WHO definition of 2005 above,it is difficult to understand how such a definition couldgain any useful currency since it is so “exclusive” that itleaves no rational guidance for the everyday diagnosis of oralleukoplakia.

2. Oral Leukoplakia: Clinical Aspects

According to its clinical appearance, oral leukoplakia canbe categorised into two main clinical types: homogeneous


and non-homogeneous. Either type may occur as an isolatedlesion or as multiple lesions. The leukoplakic lesion can varyin size from a few millimetres to several centimeters [1, 2, 5–12].

Homogeneous leukoplakia is a uniformly white flatplaque with a smooth or relatively smooth surface; non-homogeneous leukoplakia may be nodular or verrucoushaving a wrinkled or corrugated surface or may be a minglingof white and red areas termed erythroleukoplakia [7, 10, 11].

The clinical appearance of oral leukoplakia may changeover time. Some homogeneous lesions may become larger, ornon-homogeneous, but most oral leukoplakias will remainstable or will regress, while some few will undergo carcino-matous transformation [13–15].

Oral erythroplakia, of all precancerous oral lesions,carries the greatest threat of malignant transformation. Ithas a velvety-red appearance, and about 50% of all casesof erythroplakia are already squamous cell carcinomata atthe time of diagnosis. The erythroplakic component of oralerythroleukoplakia is identical to erythroplakia [16].

Proliferative verrucous leukoplakia, considered to beeither a clinical subtype of non-homogeneous oral leuko-plakia or to be a distinct clinical entity, is not strongly associ-ated with smoking, is characterized by multiple leukoplakiclesions that affect wide areas of the oral epithelium, and mayprogress either to verrucous carcinoma or to squamous cellcarcinoma [17–20]. In most cases, proliferative verrucousleukoplakia is recognised only late in its course since in itsinitial stages it is identical to an isolated leukoplakia [17–24].

3. Epidemiology of Oral Leukoplakia

The data from epidemiological studies on oral leukoplakiais inconsistent, most probably owing to differences in caseselection criteria (house-to-house surveys, hospital surveys,age, gender, race, ethnicity, and tobacco use) and in method-ology (diagnostic criteria, time of follow-up and whether ornot the leukoplakia had previously been treated) [1, 10, 11].

Estimates of the global prevalence of oral leukoplakiarange from 0.5% to 3.46%, and of the rates of carcinomatoustransformation of oral leukoplakia from 0.7% to 2.9% [25].Oral leukoplakia is more prevalent in India where personssmoke and practice the habit of tobacco and areca nutchewing more than elsewhere [26].

Oral leukoplakia is usually diagnosed in middle age, andits prevalence increases with age. About 10% of oral leuko-plakias are idiopathic and the greater part of the remaining90% is associated with the use of tobacco/areca nut [26].Males are more often affected than females probably owingto the greater prevalence of tobacco use by males [8]. Thebuccal mucosa is affected in 25% of cases, the mandibulargingiva in 20%, the tongue in 10%, the floor of the mouth in10%, and other oral sites account for the remainder [13].

The literature on the relationship between race and oralleukoplakia is sparse. In a South African study of archivedhistopathological material, 86% of oral leukoplakias werefrom whites, 9% from blacks, and 5% from Asians, despitethe fact that the vast majority of South Africans are black

[27]. This is not easy to explain. Bearing in mind that thestudy was on histopathological material, an explanation maybe that blacks tend to postpone seeking medical treatmentuntil the leukoplakia has already undergone carcinomatoustransformation, thus skewing the statistics away from theleukoplakia [27], or because black people in South Africamay smoke less than white people.

4. Epithelial Dysplasia and Oral Leukoplakia

The reported prevalence of epithelial dysplasia in oral leuko-plakia ranges from 5% to 25% [8]. Dysplasia is more frequentin non-homogeneous than in homogeneous leukoplakia[11], and it is probable that dysplasia is the histopathologicalexpression of genomic and molecular alterations in a field ofkeratinocytes [28, 29].

The presence of epithelial dysplasia is a marker of themalignant potential of oral leukoplakia, and the risk ofan individual leukoplakic lesion to progress to carcinomaincreases with the increase of the grade of the epithelialdysplasia [11, 12, 14, 30].

However, some dysplastic oral leukoplakias can remainstable or even regress, while some oral leukoplakias withoutepithelial dysplasia will indeed progress to carcinoma [5,11, 12]. In one study 36% of dysplastic oral leukoplakiasprogressed to squamous cell carcinoma, but a substantialproportion of 16% of oral leukoplakias without epithelialdysplasia at the time of initial biopsy also progressed tocarcinoma [31]. The risk of progression to carcinoma ofleukoplakias with moderate and severe dysplasia is estimatedto be twice as great as for oral leukoplakias with simpleepithelial hyperplasia or with mild dysplasia [14].

Treatment of dysplastic oral leukoplakia by excision, bylaser or by cryosurgery, or by topical or systemic chemo-therapy does not eliminate either the risk of relapse orrecurrence, or the risk of carcinomatous transformation[1, 5, 6]. The estimated recurrence rate of oral leukoplakiamay be as high as 30% [32], and squamous cell carcinomadevelops at 12% of sites of treated leukoplakia [15]. In a studyinvestigating the pattern of carcinomatous transformation oforal leukoplakia and oral erythroplakia, 36% of carcinomatadeveloped at the same site, 49% at contiguous sites, and 15%at oral sites remote from the preexisting lesions [33].

It is evident from this data that some cases of treatedoral leukoplakia are unpredictably destined to recur orto undergo carcinomatous transformation, and that thereare not yet any diagnostic methods available (clinical,histological or molecular), to confidently identify these cases[1].

Epithelial dysplasia in oral leukoplakia is a useful markerof the risk of carcinomatous transformation and is an impor-tant guide to clinical management [1, 11, 28]. However, sincedysplasia can remain stable for long periods, it cannot beused with confidence as a predictor of carcinomatous trans-formation [14, 29]. Moreover, as the histological exercise ofgrading of epithelial dysplasia is highly subjective with lowinterpersonal and intrapersonal reproducibility [16, 34, 35],and as an incisional biopsy cannot be representative of an


entire lesion [34, 36], a histopathological report of any degreeof epithelial dysplasia or of the absence of epithelial dysplasiamust be viewed with caution.

5. The Natural Course and the MalignantPotential of Oral Leukoplakia

The progression of oral leukoplakia to carcinoma is unpre-dictable but is relatively infrequent with an estimated overallrisk of less than 2% per year [5, 6, 13, 26]; if progressionoccurs, it may take a few months or many years [8]. Thecarcinomatous transformation of oral leukoplakia is notpredictably associated with tobacco smoking [33], and thefrequency of carcinomatous transformation of idiopathicleukoplakia is higher than that of tobacco-associated leuko-plakia [11, 26].

In populations where smoking, the use of smokelesstobacco, reverse smoking, and the use of areca nut arevery prevalent, most squamous cell carcinomata arise frompreexisting leukoplakias; while in populations with a lowerprevalence of these habits, most squamous cell carcinomataarise de novo in normal-looking epithelium [26]. It hasbeen suggested that squamous cell carcinoma arising denovo usually runs a more aggressive course and has a lessfavourable prognosis than squamous cell carcinoma arisingfrom preexisting leukoplakia [12, 26], but a recent studyhas demonstrated little difference [37]. Sometimes squamouscell carcinoma arises de novo in close proximity to oralleukoplakias [8].

Non-homogeneous leukoplakia has a greater risk of car-cinomatous transformation (20–25%) than homogeneousleukoplakia (0.6–5%) [11, 13]. Most leukoplakias eitherremain stable or will regress [13, 15]. However, if proliferativeverrucous leukoplakia is considered as a distinct entity, mostsuch cases progress to carcinoma [18, 24].

The rates of progression of large oral leukoplakias(>5 mm) and of leukoplakias at sites in the mouth knownto be at most risk of developing carcinoma (floor ofmouth, ventrolateral surface of tongue, and maxillaryretromolar/soft palate region) are greater than for smallerleukoplakias or for leukoplakias at other sites in the mouth[1, 11, 13, 33, 38]. The increased risk of carcinomatoustransformation of oral leukoplakia at high-risk sites is notentirely a function of the degree of dysplasia. It is alsodependent upon as yet undefined characteristics of thelocation of the leukoplakia since the rate of carcinomatoustransformation of dysplastic leukoplakias at high-risk sites isgreater than the rate of transformation of equally dysplasticleukoplakias at other sites [38].

There is evidence that clearly suggests that some leuko-plakias arise from cytogenetically altered transformed ker-atinocytes within fields of precancerized oral epithelium.Keratinocytes of oral leukoplakia show cytogenetic changesincluding alterations in the p53 tumour suppressor gene,aberrations in their DNA content, and loss of heterozy-gosity (LoH) at chromosomal regions of candidate tumoursuppressor genes [20, 33, 39–45]. LoH at either 3p or at9p occurs frequently in keratinocytes of oral leukoplakia

and is associated with carcinomatous transformation ofthese lesions [33, 41, 42, 44, 45]. Additional cytogeneticalterations to the keratinocytes in the precancerized fieldreferred to above may result in the evolution of one orseveral keratinocytes containing a complete set of cytogeneticalterations of a cancerous phenotype, and in the subsequentdevelopment of squamous cell carcinoma [41, 46, 47].

However, some precancerous oral leukoplakias in whichcytogenetic alterations in the keratinocytes cannot bedemonstrated, nevertheless undergo carcinomatous trans-formation [41, 42]. The pathogenic mechanisms that bringabout the progressive transformation of these keratinocytesto carcinomatous cells are yet to be elucidated. Most oralleukoplakias are benign in nature and will remain stableor will regress [28, 32]. These leukoplakias probably havea different aetiopathogenesis to precancerous leukoplakiasand probably do not have the cytogenetic characteristics ofprecancerous leukoplakias. What is certain, however, is thatleukoplakias with malignant potential and those withoutmalignant potential cannot be distinguished clinically [1].

6. Human Papillomavirus and Oral Leukoplakia

Human papilloma viruses (HPVs) are strictly epitheliotropicand infect either cutaneous or mucosal squamous epithe-lium, depending upon their genotype [48, 49]. Those thatinfect mucosal epithelium have been categorized into high-risk types (e.g., HPV-16, 18, 31, 33, and 35) based on theirepidemiological association with carcinoma of the cervixuteri, or into low-risk types (HPV-6, 11, 13, and 32) [50].These categories have been universally adopted for use instudies of the oncogenic significance of HPV infection at allanatomical regions of the upper aerodigestive tract.

Low-risk HPV genotypes have been implicated in thepathogenesis of the benign oral proliferative epitheliallesions, squamous cell papilloma, common wart (verru-cous vulgaris), condyloma acuminatum, and focal epithe-lial hyperplasia (Heck disease); while high-risk types havebeen associated with precancerous and cancerous oral andoropharyngeal epithelial lesions [49, 51–56].

There is an extreme variation in the reported prevalenceof HPV infection in oral precancerous and cancerous lesionsranging from 0% to 100% [57, 58]. This is owing todifferences in sampling and HPV detection methods, todifferences in ethnicity, geographic locations, and sample sizeof the subjects examined, and to the inappropriate group-ing together of different lesions from different anatomicallocations of the mucosa of the upper aerodigestive tract[49, 51, 58–64].

Many studies investigating the association of HPV andsquamous cell carcinoma of the mucosa of the upperaerodigestive tract used PCR techniques for detection ofHPV DNA without also quantifying the DNA viral load.PCR can detect extremely small fragments of DNA that mayrepresent either contamination of the sample or biologicallyinsignificant HPV infection [51, 57, 58]. These findings havebeen reported as if they were pathogenically significant.


Whether these are legitimate findings or are the resultsof inconsistencies and errors in methodology, several HPVgenotypes have been detected in precancerous oral lesions.High-risk HPV genotypes, in particular HPV-16, have beenreported to be the most prevalent in oral leukoplakias,including proliferative verrucous leukoplakia [55, 65]. Otherreports implicated low-risk rather than high-risk HPVgenotypes in oral leukoplakia [54, 63], and yet others assertthat oral leukoplakia is coinfected with a variety of HPVgenotypes [49, 55, 66]. In a meta-analysis of data from 94studies of a total of 4580 specimens, Miller and Johnstone[63] determined that the likelihood of HPV being detectedin precancerous oral lesions is 2 to 3 times greater and inoral squamous cell carcinoma is 4 to 5 times greater thanin normal oral mucosa. The prevalence of HPV in normaloral mucosa, in nondysplastic leukoplakias, in dysplasticleukoplakias and in other precancerous intraepithelial oralneoplasms, and in oral squamous cell carcinoma is likely tobe 10%, 20.2%, 26.2%, and 46.5%, respectively [63].

This suggests that there may be some link between HPVinfection and oral precancerous and cancerous lesions. AsE6 and E7 oncoproteins of high-risk HPV genotypes havethe capacity to mediate carcinomatous transformation ofinfected keratinocytes by inactivating cellular p53 and Rbtumour suppressor pathways [50, 52], HPV may play eitheran oncogenic or a co-oncogenic role in some HPV-infectedprecancerous and cancerous epithelial neoplasms.

In fact, HPV-16 has been found to be causally associatedprimarily with squamous cell carcinoma of the palatal tonsils[67–70] in a subset of subjects who are younger, consumeless tobacco, are more engaged in high-risk sexual behaviour(great number of lifetime sexual partners and practicingoral-genital sex), have higher HPV-16 serum antibody titers,and have a better disease-free survival and overall survivalrates than subjects with HPV-cytonegative oropharyngealsquamous cell carcinoma [51, 64, 67–70]. The cells of HPV-cytopositive oropharyngeal carcinoma in these subjects havea distinct molecular profile [50]. The cells of squamouscell carcinoma causally associated with HPV express E6/E7oncoproteins. They frequently demonstrate viral integrationwithin the cellular genome with the presence of intactE6 gene. They exhibit high viral load, reduced expressionof Rb proteins, functional overexpression of p16 INK4A,unmutated p53 gene, and loss of heterozygosity (LoH) atchromosomal loci 3p, 9p and 17p is infrequent [51, 68–74]. In contrast, HPV-cytonegative oropharyngeal squamouscell carcinoma is characterized by p53 gene mutations, byfrequent LoH at 3p, 9p, and 17p, by decreased levels ofp16INK4A and by normal or increased levels of Rb proteins[50, 51, 71].

Recent meta-analyses and comprehensive studies [60, 62,67, 75] show little or no causal association between HPVand oral squamous cell carcinoma in contrast to the strongassociation between HPV and oropharyngeal squamous cellcarcinoma. HPV-16 cytopositive oral squamous cell carci-noma is characterized by a low viral load, by infrequent viralintegration, and the cancerous cells seldom contain activetranscriptional E6/E7 mRNA [72, 76]. However, it is possiblethat, in HPV-cytopositive oral squamous cell carcinomata

that do not express E6/E7 mRNA, E6/E7 oncoproteins maywell have participated or have had a complementary role inthe initial transformation, but then phased out [77].

With oropharyngeal carcinoma as the model, a causalassociation between HPV and cancerization in oral epithe-lium is likely if the cells of the lesion contain HPV DNAexpressing E6 and/or E7 mRNA [71], if there is viralintegration within the cellular genome [74], and if there isa high viral load (>1 copies per cell). A limited biologicalsignificance of the virus in the process of transformationcan be deduced if there is a low-copy number (<1 copy percell), or if there is no transcriptional activity of E6 and/orE7 mRNA [60, 71]. Nevertheless, although integration ofHPV DNA into the cellular genome is a strong indication ofthe oncogenic potential of the virus, transcription of HPV-16 E6/E7 mRNA has been shown to occur in oropharyngealcarcinoma without integration of viral DNA, the virus beingin an episomal form [69].

It is well established that non-homogeneous leukoplakiasmore frequently undergo malignant transformation thanhomogeneous leukoplakias, yet it appears that HPV isfound more commonly in homogeneous than in non-homogeneous leukoplakia [54, 78]. Nevertheless the roleof HPV in the pathogenesis of oral leukoplakia and in itsprogression to carcinoma is unclear since there is a low viralload in HPV-cytopositive precancerous and cancerous orallesions, and viral integration is seldom found [72, 76]. Itis possible that HPV DNA in oral leukoplakia and in oralsquamous cell carcinoma may be oncogenically insignificant.Alternatively the HPV may have superinfected keratinocytesalready initially transformed and may thus additively orsynergistically promote later stages of transformation [49, 51,69].

Little is known about the E6 and E7 proteins of low-risk HPV either with regard to their role in the patho-genesis of HPV-infected oral leukoplakias, or with regardto their role in the carcinomatous transformation of someleukoplakias. It is possible that as in other HPV-associatedbenign proliferative oral epithelial lesions, E6 and E7 proteinsof low-risk HPV types found in oral leukoplakia maystimulate suprabasal postmitotic infected keratinocytes toreenter the S-phase of the cell cycle resulting in epithelialproliferation and disturbed maturation, without causing thegenomic instability possibly associated with subsequent celltransformation. This mechanism may be a co-determinant ofthe development of the leukoplakia, but there is no concreteevidence to support this.

7. Treatment

As oral leukoplakia is potentially malignant, and as someleukoplakias will unpredictably progress to carcinoma, ide-ally all oral leukoplakias should be treated. When dealingwith two or three accessible circumscribed lesions, the treat-ment of choice is surgical excision. For multiple or for largeleukoplakias where surgical treatment would be impracticalbecause it would result in unacceptable deformities or infunctional disabilities, treatment can be by cryosurgery,


laser surgery, or by the use of topical bleomycin. However,regardless of the extent of the lesion or of the modality oftreatment, in as many as 30% of treated cases, leukoplakiaswill recur and treatment will not prevent the progression ofsome leukoplakias to squamous cell carcinoma [5, 15, 21,32].

Idiopathic leukoplakia, non-homogeneous leukoplakia,leukoplakia affecting high-risk oral sites, and leukoplakiashowing moderate or severe grades of epithelial dysplasiaand particularly leukoplakias, in which a combination ofthese factors affect the risk of carcinomatous transformation,should be treated aggressively. Any changes in colour, textureor size, and appearance of additional leukoplakias at new oralsites are advance warning of the possibility of carcinomatoustransformation.

8. Summary

Leukoplakia is the most common potentially malignantlesion of the mouth. It may unpredictably regress, mayremain stable, or may undergo carcinomatous transforma-tion. Those leukoplakias that are committed to a cancerouspathway most probably arise within a field of precancerizedepithelium consisting of keratinocytes at different stages ofcytogenetic transformation. This may explain the high rateof recurrence of oral leukoplakia despite treatment, and whysome leukoplakias progress to carcinoma.

Many studies have reported the presence of HPV DNAin oral leukoplakias. However, there is not enough evidenceto prove any casual association either between HPV and thedevelopment of oral leukoplakia, or between HPV and theprogression of oral leukoplakia to carcinoma. The nature ofthe link between HPV infection and oral leukoplakia is as yetunknown.

References

[1] L. Feller and J. Lemmer, “Field cancerization and oralleukoplakia,” in Field Cancerization: Basic Science and ClinicalApplications, G. D. Dakubo, Ed., pp. 95–111, Nova Science,Ontario, Canada, 2011.

[2] J. J. Sciubba, “Oral cancer: the importance of early diagnosisand treatment,” American Journal of Clinical Dermatology, vol.2, no. 4, pp. 239–251, 2001.

[3] A. Roosaar, L. Yin, A. L. V. Johansson, G. Sandborgh-Englund,O. Nyren, and T. Axell, “A long-term follow-up study on thenatural course of oral leukoplakia in a Swedish population-based sample,” Journal of Oral Pathology and Medicine, vol. 36,no. 2, pp. 78–82, 2007.

[4] T. Amagasa, M. Yamashiro, and N. Uzawa, “Oral premalignantlesions: from a clinical perspective,” International Journal ofClinical Oncology, vol. 16, no. 1, pp. 5–14, 2011.

[5] I. van der Waal, “Potentially malignant disorders of the oraland oropharyngeal mucosa; terminology, classification andpresent concepts of management,” Oral Oncology, vol. 45, no.4-5, pp. 317–323, 2009.

[6] I. van der Waal, “Potentially malignant disorders of the oraland oropharyngeal mucosa; present concepts of manage-ment,” Oral Oncology, vol. 46, no. 6, pp. 423–425, 2010.

[7] S. Warnakulasuriya, N. W. Johnson, and I. van der Waal,“Nomenclature and classification of potentially malignantdisorders of the oral mucosa,” Journal of Oral Pathology andMedicine, vol. 36, no. 10, pp. 575–580, 2007.

[8] B. Neville, D. Damm, C. Allen, and J. Bouquot, Oral andMaxillofacial Pathology, Saunders/Elsevier, St. Louis, Mo,USA, 3rd edition, 2009.

[9] T. Dietrich, P. A. Reichart, and C. Scheifele, “Clinical riskfactors of oral leukoplakia in a representative sample of the USpopulation,” Oral Oncology, vol. 40, no. 2, pp. 158–163, 2004.

[10] G. Lodi, A. Sardella, C. Bez, F. Demarosi, and A. Car-rassi, “Interventions for treating oral leukoplakia,” CochraneDatabase of Systematic Reviews, no. 4, Article ID CD001829,2006.

[11] J. Reibel, “Prognosis of oral pre-malignant lesions: significanceof clinical, histopathological, and molecular biological charac-teristics,” Critical Reviews in Oral Biology and Medicine, vol. 14,no. 1, pp. 47–62, 2003.

[12] I. van der Waal and T. Axell, “Oral leukoplakia: a proposal foruniform reporting,” Oral Oncology, vol. 38, no. 6, pp. 521–526,2002.

[13] S. S. Napier and P. M. Speight, “Natural history of potentiallymalignant oral lesions and conditions: an overview of theliterature,” Journal of Oral Pathology and Medicine, vol. 37, no.1, pp. 1–10, 2008.

[14] C. Scully, J. Sudbø, and P. M. Speight, “Progress in determin-ing the malignant potential of oral lesions,” Journal of OralPathology and Medicine, vol. 32, no. 5, pp. 251–256, 2003.

[15] P. Holmstrup, P. Vedtofte, J. Reibel, and K. Stoltze, “Long-term treatment outcome of oral premalignant lesions,” OralOncology, vol. 42, no. 5, pp. 461–474, 2006.

[16] P. A. Reichart and H. P. Philipsen, “Oral erythroplakia—areview,” Oral Oncology, vol. 41, no. 6, pp. 551–561, 2005.

[17] L. S. Hansen, J. A. Olson, and S. Silverman Jr., “Proliferativeverrucous leukoplakia. A long-term study of thirty patients,”Oral Surgery, Oral Medicine, Oral Pathology, vol. 60, no. 3, pp.285–298, 1985.

[18] J. M. Zakrzewska, V. Lopes, P. Speight, and C. Hopper,“Proliferative verrucous leukoplakia a report of ten cases,” OralSurgery, Oral Medicine, Oral Pathology, Oral Radiology, andEndodontology, vol. 82, no. 4, pp. 396–401, 1996.

[19] S. Silverman Jr. and M. Gorsky, “Proliferative verrucousleukoplakia: a follow-up study of 54 cases,” Oral Surgery, OralMedicine, Oral Pathology, Oral Radiology and Endodontology,vol. 84, no. 2, pp. 154–157, 1997.

[20] D. Greenspan and R. C. K. Jordan, “The white lesionthat kills—aneuploid dysplastic oral leukoplakia,” The NewEngland Journal of Medicine, vol. 350, no. 14, pp. 1382–1384,2004.

[21] J. V. Bagan, Y. Jimenez, J. M. Sanchis et al., “Proliferativeverrucous leukoplakia: high incidence of gingival squamouscell carcinoma,” Journal of Oral Pathology and Medicine, vol.32, no. 7, pp. 379–382, 2003.

[22] L. Feller, N. H. Wood, and E. J. Raubenheimer, “Proliferativeverrucous leukoplakia and field cancerization: report of acase,” Journal of the International Academy of Periodontology,vol. 8, no. 2, pp. 67–70, 2006.

[23] R. J. Cabay, T. H. Morton Jr., and J. B. Epstein, “Proliferativeverrucous leukoplakia and its progression to oral carcinoma:a review of the literature,” Journal of Oral Pathology andMedicine, vol. 36, no. 5, pp. 255–261, 2007.

[24] J. V. Bagan, J. Murillo, R. Poveda, C. Gavalda, Y. Jimenez,and C. Scully, “Proliferative verrucous leukoplakia: unusual


locations of oral squamous cell carcinomas, and field cancer-ization as shown by the appearance of multiple OSCCs,” OralOncology, vol. 40, no. 4, pp. 440–443, 2004.

[25] S. Petti, “Pooled estimate of world leukoplakia prevalence: asystematic review,” Oral Oncology, vol. 39, no. 8, pp. 770–780,2003.

[26] P. Suarez, J. G. Batsakis, and A. K. El-Naggar, “Leukoplakia:still a gallimaufry or is progress being made?—a review,”Advances in Anatomic Pathology, vol. 5, no. 3, pp. 137–155,1998.

[27] L. Feller, M. Altini, and H. Slabbert, “Pre-malignant lesions ofthe oral mucosa in a South African sample–a clinicopathologi-cal study,” The Journal of the Dental Association of South Africa,vol. 46, no. 5, pp. 261–265, 1991.

[28] S. Warnakulasuriya, J. Reibel, J. Bouquot, and E. Dabelsteen,“Oral epithelial dysplasia classification systems: predictivevalue, utility, weaknesses and scope for improvement,” Journalof Oral Pathology and Medicine, vol. 37, no. 3, pp. 127–133,2008.

[29] S. Warnakulasuriya, “Histological grading of oral epithelialdysplasia: revisited,” Journal of Pathology, vol. 194, no. 3, pp.294–297, 2001.

[30] S. Silverman Jr., M. Gorsky, and F. Lozada, “Oral leuko-plakia and malignant transformation. A follow-up study of257 patients,” Cancer, vol. 53, no. 3, pp. 563–568, 1984.

[31] S. Silverman Jr., M. Gorsky, and G. E. Kaugars, “Leukoplakia,dysplasia, and malignant transformation,” Oral Surgery, OralMedicine, Oral Pathology, Oral Radiology, and Endodontology,vol. 82, no. 2, article 117, 1996.

[32] G. Lodi and S. Porter, “Management of potentially malignantdisorders: evidence and critique,” Journal of Oral Pathologyand Medicine, vol. 37, no. 2, pp. 63–69, 2008.

[33] M. Partridge, S. Pateromichelakis, E. Phillips, G. G. Emilion,R. P. A’Hern, and J. D. Langdon, “A case-control studyconfirms that microsatellite assay can identify patients at riskof developing oral squamous cell carcinoma within a field ofcancerization,” Cancer Research, vol. 60, no. 14, pp. 3893–3898,2000.

[34] H. Lumerman, P. Freedman, and S. Kerpel, “Oral epithelialdysplasia and the development of invasive squamous cellcarcinoma,” Oral Surgery, Oral Medicine, Oral Pathology, OralRadiology, and Endodontology, vol. 79, no. 3, pp. 321–329,1995.

[35] M. P. Tabor, B. J. M. Braakhuis, J. E. van der Wal et al.,“Comparative molecular and histological grading of epithelialdysplasia of the oral cavity and the oropharynx,” Journal ofPathology, vol. 199, no. 3, pp. 354–360, 2003.

[36] P. Holmstrup, P. Vedtofte, J. Reibel, and K. Stoltze, “Oralpremalignant lesions: is a biopsy reliable?” Journal of OralPathology and Medicine, vol. 36, no. 5, pp. 262–266, 2007.

[37] M. Weijers, I. Ten Hove, R. H. B. Allard, D. P. D. Bezemer, andI. van der Waal, “Patients with oral cancer developing frompre-existing oral leukoplakia: do they do better than those withde novo oral cancer?” Journal of Oral Pathology and Medicine,vol. 37, no. 3, pp. 134–136, 2008.

[38] L. Zhang, K. J. Cheung, W. L. Lam et al., “Increased geneticdamage in oral leukoplakia from high risk sites: potentialimpact on staging and clinical management,” Cancer, vol. 91,no. 11, pp. 2148–2155, 2001.

[39] S. Warnakulasuriya, “Lack of molecular markers to predictmalignant potential of oral precancer,” Journal of Pathology,vol. 190, no. 4, pp. 407–409, 2000.

[40] J. Sudbø, W. Kildal, B. Risberg, H. S. Koppang, H. E. Danielsen,and A. Reith, “DNA content as a prognostic marker in patientswith oral leukoplakia,” The New England Journal of Medicine,vol. 344, no. 17, pp. 1270–1278, 2001.

[41] M. P. Rosin, X. Cheng, C. Poh et al., “Use of allelic loss topredict malignant risk for low-grade oral epithelial dysplasia,”Clinical Cancer Research, vol. 6, no. 2, pp. 357–362, 2000.

[42] L. Mao, J. S. Lee, Y. H. Fan et al., “Frequent microsatellitealterations at chromosomes 9p21 and 3p14 in oral premalig-nant lesions and their value in cancer risk assessment,” NatureMedicine, vol. 2, no. 6, pp. 682–685, 1996.

[43] M. P. Tabor, R. H. Brakenhoff, V. M. M. van Houten et al.,“Persistence of genetically altered fields in head and neckcancer patients: biological and clinical implications,” ClinicalCancer Research, vol. 7, no. 6, pp. 1523–1532, 2001.

[44] J. Califano, P. van der Riet, W. Westra et al., “Geneticprogression model for head and neck cancer: implications forfield cancerization,” Cancer Research, vol. 56, no. 11, pp. 2488–2492, 1996.

[45] J. J. Lee, W. K. Hong, W. N. Hittelman et al., “Predicting cancerdevelopment in oral leukoplakia: ten years of translationalresearch,” Clinical Cancer Research, vol. 6, no. 5, pp. 1702–1710, 2000.

[46] L. Zhang and M. P. Rosin, “Loss of heterozygosity: a potentialtool in management of oral premalignant lesions?” Journal ofOral Pathology and Medicine, vol. 30, no. 9, pp. 513–520, 2001.

[47] M. M. Kim and J. A. Califano, “Molecular pathology of head-and-neck cancer,” International Journal of Cancer, vol. 112, no.4, pp. 545–553, 2004.

[48] M. J. Conway and C. Meyers, “Replication and assembly ofhuman papillomaviruses,” Journal of Dental Research, vol. 88,no. 4, pp. 307–317, 2009.

[49] L. Feller, R. A. Khammissa, N. H. Wood, and J. Lemmer,“Epithelial maturation and molecular biology of oral HPV,”Infectious Agents and Cancer, vol. 4, no. 1, article 16, 2009.

[50] L. Vidal and M. L. Gillison, “Human papillomavirus inHNSCC: recognition of a distinct disease type,” Hematol-ogy/Oncology Clinics of North America, vol. 22, no. 6, pp. 1125–1142, 2008.

[51] L. Feller, N. H. Wood, R. A. G. Khammissa, and J. Lemmer,“Human papillomavirus-mediated carcinogenesis and HPV-associated oral and oropharyngeal squamous cell carcinoma—part 2: human papillomavirus associated oral and oropharyn-geal squamous cell carcinoma,” Head & Face Medicine, vol. 6,article 15, 2010.

[52] L. Feller, N. H. Wood, R. A. G. Khammissa, and J. Lemmer,“Human papillomavirus-mediated carcinogenesis and HPV-associated oral and oropharyngeal squamous cell carcinoma—part 1: human papillomavirus-mediated carcinogenesis,”Head & Face Medicine, vol. 6, article 14, 2010.

[53] V. E. Furrer, M. B. Benitez, M. Furnes, H. E. Lanfranchi, andN. M. Modesti, “Biopsy vs. superficial scraping: detection ofhuman papillomavirus 6, 11, 16, and 18 in potentially malig-nant and malignant oral lesions,” Journal of Oral Pathology andMedicine, vol. 35, no. 6, pp. 338–344, 2006.

[54] H. Nielsen, B. Norrild, P. Vedtofte, F. Prætorius, J. Reibel, andP. Holmstrup, “Human papillomavirus in oral premalignantlesions,” European Journal of Cancer B, vol. 32, no. 4, pp. 264–270, 1996.

[55] C. Ostwald, K. Rutsatz, J. Schweder, W. Schmidt, K. Gundlach,and M. Barten, “Human papillomavirus 6/11, 16 and 18 inoral carcinomas and benign oral lesions,” Medical Microbiologyand Immunology, vol. 192, no. 3, pp. 145–148, 2003.


[56] F. Praetorius, “HPV-Associated diseases of oral mucosa,”Clinics in Dermatology, vol. 15, no. 3, pp. 399–413, 1997.

[57] P. T. Hennessey, W. H. Westra, and J. A. Califano, “Humanpapillomavirus and head and neck squamous cell carcinoma:recent evidence and clinical implications,” Journal of DentalResearch, vol. 88, no. 4, pp. 300–306, 2009.

[58] P. K. Ha and J. A. Califano, “The role of human papillomavirusin oral carcinogenesis,” Critical Reviews in Oral Biology andMedicine, vol. 15, no. 4, pp. 188–196, 2004.

[59] G. Campisi and L. Giovannelli, “Controversies surroundinghuman papilloma virus infection, head & neck vs oral cancer,implications for prophylaxis and treatment,” Head & NeckOncology, vol. 1, p. 8, 2009.

[60] C. G. L. Hobbs, J. A. C. Sterne, M. Bailey, R. S. Heyderman,M. A. Birchall, and S. J. Thomas, “Human papillomavirus andhead and neck cancer: a systematic review and meta-analysis,”Clinical Otolaryngology, vol. 31, no. 4, pp. 259–266, 2006.

[61] N. Termine, V. Panzarella, S. Falaschini et al., “HPV in oralsquamous cell carcinoma vs head and neck squamous cellcarcinoma biopsies: a meta-analysis (1988–2007),” Annals ofOncology, vol. 19, no. 10, pp. 1681–1690, 2008.

[62] A. R. Kreimer, G. M. Clifford, P. Boyle, and S. Franceschi,“Human papillomavirus types in head and neck squamous cellcarcinomas worldwide: a systemic review,” Cancer Epidemi-ology Biomarkers and Prevention, vol. 14, no. 2, pp. 467–475,2005.

[63] C. S. Miller and B. M. Johnstone, “Human papillomavirus as arisk factor for oral squamous cell carcinoma: a meta-analysis,1982–1997,” Oral Surgery, Oral Medicine, Oral Pathology, OralRadiology, and Endodontology, vol. 91, no. 6, pp. 622–635,2001.

[64] L. Feller, N. H. Wood, R. A. G. Khammissa et al., “Epidemiol-ogy and transmission of HPV infection: vaccination for HPVinfection,” South African Dental Journal, vol. 65, pp. 478–481,2010.

[65] J. M. Palefsky, S. Silverman Jr., M. Abdel-Salaam, T. E. Daniels,and J. S. Greenspan, “Association between proliferative ver-rucous leukoplakia and infection with human papillomavirustype 16,” Journal of Oral Pathology and Medicine, vol. 24, no. 5,pp. 193–197, 1995.

[66] M. Bouda, V. G. Gorgoulis, N. G. Kastrinakis et al., ““Highrisk” HPV types are frequently detected in potentially malig-nant and malignant oral lesions, but not in normal oralmucosa,” Modern Pathology, vol. 13, no. 6, pp. 644–653, 2000.

[67] J. Pintos, M. J. Black, N. Sadeghi et al., “Human papillo-mavirus infection and oral cancer: a case-control study inMontreal, Canada,” Oral Oncology, vol. 44, no. 3, pp. 242–250,2008.

[68] L. Charfi, T. Jouffroy, P. de Cremoux et al., “Two types ofsquamous cell carcinoma of the palatine tonsil characterizedby distinct etiology, molecular features and outcome,” CancerLetters, vol. 260, no. 1-2, pp. 72–78, 2008.

[69] P. M. Weinberger, Z. Yu, B. G. Haffty et al., “Molecularclassification identifies a subset of human papillomavirus—associated oropharyngeal cancers with favorable prognosis,”Journal of Clinical Oncology, vol. 24, no. 5, pp. 736–747, 2006.

[70] L. Licitra, F. Perrone, P. Bossi et al., “High-risk humanpapillomavirus affects prognosis in patients with surgicallytreated oropharyngeal squamous cell carcinoma,” Journal ofClinical Oncology, vol. 24, no. 36, pp. 5630–5636, 2006.

[71] B. J. M. Braakhuis, P. J. F. Snijders, W. J. H. Keune et al.,“Genetic patterns in head and neck cancers that contain orlack transcriptionally active human papillomavirus,” Journal

of the National Cancer Institute, vol. 96, no. 13, pp. 998–1006,2004.

[72] W. J. Koskinen, R. W. Chen, I. Leivo et al., “Prevalence andphysical status of human papillomavirus in squamous cellcarcinomas of the head and neck,” International Journal ofCancer, vol. 107, no. 3, pp. 401–406, 2003.

[73] J. P. Klussmann, S. J. Weissenborn, U. Wieland et al., “Preva-lence, distribution, and viral load of human papillomavirus16 DNA in tonsillar carcinomas,” Cancer, vol. 92, no. 11, pp.2875–2884, 2001.

[74] T. Wiest, E. Schwarz, C. Enders, C. Flechtenmacher, and F. X.Bosch, “Involvement of intact HPV16 E6/E7 gene expressionin head and neck cancers with unaltered p53 status andperturbed pRB cell cycle control,” Oncogene, vol. 21, no. 10,pp. 1510–1517, 2002.

[75] X. H. Liang, J. Lewis, R. Foote, D. Smith, and D. Kademani,“Prevalence and significance of human papillomavirus in oraltongue cancer: the Mayo Clinic experience,” Journal of Oraland Maxillofacial Surgery, vol. 66, no. 9, pp. 1875–1880, 2008.

[76] P. K. Ha, S. I. Pai, W. H. Westra et al., “Real-time quantitativePCR demonstrates low prevalence of human papillomavirustype 16 in premalignant and malignant lesions of the oralcavity,” Clinical Cancer Research, vol. 8, no. 5, pp. 1203–1209,2002.

[77] V. M. M. van Houten, P. J. F. Snijders, M. W. M. van den Brekelet al., “Biological evidence that human papillomavirusesare etiologically involved in a subgroup of head and necksquamous cell carcinomas,” International Journal of Cancer,vol. 93, no. 2, pp. 232–235, 2001.

[78] G. Campisi, L. Giovannelli, P. Arico et al., “HPV DNA inclinically different variants of oral leukoplakia and lichenplanus,” Oral Surgery, Oral Medicine, Oral Pathology, OralRadiology and Endodontology, vol. 98, no. 6, pp. 705–711,2004.


Clinical Study

Technical Considerations in Rehabilitation of an EdentulousTotal Glossectomy Patient

Pravin Bhirangi, Priyanka Somani, K. P. Dholam, and Gurmeet Bachher

Department of Dental and Prosthetic Surgery, Tata Memorial Hospital, Mumbai 400 012, India

Correspondence should be addressed to Pravin Bhirangi, [email protected]

Received 5 July 2011; Accepted 14 December 2011

Academic Editor: Pilar Hita-Iglesias

Copyright © 2012 Pravin Bhirangi et al. This is an open access article distributed under the Creative Commons AttributionLicense, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properlycited.

The technician by virtue of his profession plays an important role in fabricating silicone tongue prosthesis for a total glossectomypatient. The technician, with his skills and specialized knowledge in handling material, plays a valuable role as a member of theoncology team. A patient with total glossectomy can be rehabilitated by silicone tongue prosthesis as an aid to improve his speechand swallowing. This paper describes the technical steps involved in fabricating a silicone tongue prosthesis for an edentulous totalglossectomy patient.

1. Introduction

Oncologic management of advanced carcinoma of thetongue is a difficult medical problem that can create serioustreatment dilemmas. Often criticized as a treatment optionbecause of the severe functional sequelae, total glossectomymay sometimes be the treatment of choice.

Tongue prosthesis occupies the space in the floor ofthe oral cavity. It provides the patient with a platform fordirecting food into the esophagus and aids in speaking.

This paper describes the technical steps involved inprosthetic management of an edentulous patient (EP) whounderwent total glossectomy with a prosthesis made ofsilicone tongue (fabricated with molloplast-B) attached tomandibular complete denture.

EP reported with ulceroproliferative growth on tongue(T4N2aMx). He underwent near total glossectomy withmodified neck dissection with pectoralis major myocu-taneous flap reconstruction. Postoperatively, he receivedradiotherapy (4600 Gy) only.

The patient complained of difficulty in eating andswallowing with no complaint of aspiration. He was on liquiddiet without ryles tube. After completion of one year ofradiation, the intraoral tissues healed to withstand prostheticintervention on clinical examination. In view of total surgical

excision of the tongue and completely edentulous state of theupper and lower jaws, tongue prosthesis was planned for thepatient (Figures 1 and 2).

2. Procedure

Step 1. Mucocompressive impression was made of an upperedentulous arch using impression compound and mucostaticimpression was made of lower edentulous arch and floorof the mouth using irreversible hydrocolloid impressionmaterial by a maxillofacial prosthodontist. The disinfectedimpressions were then sent to the dental laboratory.

Step 2. The diagnostic casts/primary casts were obtained.Custom trays were fabricated on upper and lower edentulousprimary casts with autopolymerizing acrylic resin.

Step 3. Border molding using low fusing impression com-pound was done, and secondary impressions of upper andlower edentulous arch with zinc oxide eugenol impressionpaste using selective pressure impression technique weremade (Figure 3). Stock tray was then used to make a pick-upimpression of this (only mandibular arch) and to record floorof the mouth together as a single impression (irreversiblehydrocolloid impression).


Figure 1: Preoperative intraoral view.

Figure 2: Preoperative extraoral view.

Step 4. The impressions were disinfected and poured withtype III dental stone to obtain master cast.

Step 5. On the master cast, temporary record bases weremade using autopolymerizing acrylic resin, which were triedin patient’s mouth to check retention and stability.

Step 6. On the temporary record bases, occlusal rims weremade to record maxilla-mandibular relation and the teetharrangement was done following recording of jaw relation.

Step 7. Wax up of tongue prosthesis [1] was done on thetemporary record bases, which was contoured in the shapeof a tongue that conforms to oral cavity dimensions withrounded edges (Figure 4).

The tongue tip was arched inferiorly to approximatelya 15-degree angle, and the entire pattern was then archedslightly to form the highest point at the anterior one third.

Wax pattern was then folded to form a wide centralV-shaped angle (approximately 160 degrees). The wax wasreduced 4 to 5 mm of thickness at the base and the posteriortwo thirds.

Figure 3: Final Impression.

Figure 4: Wax up trial of tongue prosthesis.

Figure 5: Wax up trial of tongue prosthesis in the patient’s mouth.

Figure 6: Flasking of the tongue prosthesis.


Figure 7: Dewaxing of the tongue prosthesis.

Figure 8: Packing of Molloplast-B material.

The wax pattern was finally sealed to the lower trialdenture.

Step 8. The waxed up prosthesis was then tried in patientsmouth. (Figure 5) The speech therapist evaluated the speecharticulation with the waxed up tongue (WT) for maximumcontact of the dorsum with palate for optimum articulation.

Step 9. Processing of silicone tongue prosthesis: flaskingand dewaxing was done for the waxed up upper and lowerprosthesis in conventional manner (Figures 6 and 7).

At the packing stage, the heat temperature vulcaniz-ing silicone (Molloplast-B, Regneri GmbH & Co.KG, W-Germany) was packed in tongue space (Figure 8).

Trial closure was done and excess molloplast material wasremoved.

Heat cure denture base resin was packed in edentulousridge space (Figure 9).

The flask was closed and kept for overnight bench curing.Curing of the prosthesis was done as per manufacturer

instructions.After deflasking, the prosthesis was trimmed, finished,

and polished (Figures 10 and 11).

Figure 9: Packing of heat cure acrylic resin.

Figure 10: Final tongue prosthesis.

3. Discussion

Swallowing and speaking by prosthodontic management ofglossectomy patient is a difficult undertaking for both theprosthodontist and the patient. Particular considerationsshould be given to the patient’s chief complaints whenplanning treatment for the glossectomy patient. A patientmay be able to accommodate to some dysfunction withoutprosthetic support, while desiring prosthetic treatment helpsto improve or correct other specific problems [2].

A wide buccolingual table, an occlusal table heightmatched to that of the tongue body, and a closely adheringtongue and lingual flange are effective means of preventingthe food from dropping to the oral floor, keeping the foodon the occlusal table, and crushing the food.

When constructed in a systematic manner with theassistance of a speech pathologist, the mandibular tongueprosthesis can achieve the following [3]:

(1) reduction in the size of the oral cavity, therebyimproving resonance characteristics,


Figure 11: Final tongue prosthesis.

Figure 12: Tongue prosthesis in the patient’s mouth.

(2) direction of food into the esophagus with the aid of atrough carved into the prosthetic tongue,

(3) protection of the underlying fragile tissue,

(4) development of a surface for the residual tonguetissue to contact during speech and swallowing,

(5) improvement in appearance and psychosocial adjust-ment.

In this EP, after fabrication of the tongue prosthesis swal-lowing improved. Liquid diet was replaced with semisolidswithout difficulty and apparent aspiration (Figures 12 and13).

Improvement in speech was also observed. Withouttongue prosthesis, he was substituting labiodentals and vow-els for fricative and palatal sounds. After using prosthesis forsix months, fricative and palatal sounds improved audibly.

The material used to fabricate tongue prosthesis, sili-cone (Molloplast-B, Molloplast, Regneri GmbH @ Co, W-Germany), permanent soft relining material, has severaladvantages [4]:

(i) single component, ready to use eliminating mixingand dosing errors,

(ii) easy processing,

(iii) can be polymerized simultaneously with acrylic,

(iv) stands the influences of oral environment withoutdeterioration,

(v) nonirritant and tissue compatible,

(vi) odourless and tasteless.

Figure 13: Postoperative extraoral view.

4. Summary

The paper describes technical steps for the prostheticrehabilitation of an edentulous glossectomy patient, inwhich treatment dentures were constructed with mandibulartongue prosthesis and the appropriate denture form andocclusion was established.

The prosthetic tongue may not replace the intricatelymobile structure of the tongue, which is capable of infinitemovements in swallowing and speech. The silicone tongueprosthesis does provide glossectomy patient with a certaindegree of comfort and function.

References

[1] K. Izdebski, J. C. Ross, W. L. Roberts, and R. G. de Boie,“An interim prosthesis for the glossectomy patient,” Journal ofProsthetic Dentistry, vol. 57, no. 5, pp. 608–611, 1987.

[2] M. A. Pigno and J. J. Funk, “Prosthetic management of a totalglossectomy defect after free flap reconstruction in an edentu-lous patient: a clinical report,” Journal of Prosthetic Dentistry,vol. 89, no. 2, pp. 119–122, 2003.

[3] M. A. Aramany, J. A. Downs, Q. C. Beery, and Y. Aslan, “Prost-hodontic rehabilitation for glossectomy patients,” Journal ofProsthetic Dentistry, vol. 57, pp. 608–111, 1987.

[4] M. A. Aramany, J. A. Downs, Q. C. Beery, and Y. Aslan, “Prost-hodontic rehabilitation for glossectomy patients,” The Journalof Prosthetic Dentistry, vol. 48, no. 1, pp. 78–81, 1982.


Review Article

Cell Transformation and the Evolution of a Field ofPrecancerization As It Relates to Oral Leukoplakia

L. Feller and J. Lemmer

Department of Periodontology and Oral Medicine, University of Limpopo, Medunsa Campus, South Africa

Correspondence should be addressed to L. Feller, [email protected]

Received 13 July 2011; Accepted 10 August 2011

Academic Editor: Paul C. Edwards

Copyright © 2011 L. Feller and J. Lemmer. This is an open access article distributed under the Creative Commons AttributionLicense, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properlycited.

Potentially malignant oral leukoplakias arise within precancerized epithelial fields consisting of cytogenetically alteredkeratinocytes at various stages of transformation. The evolution of a clone of keratinocytes culminating in a precancerousphenotype is a function of the number of mutagenic events, rather than the sequential order in which they occur. The alteredmolecular configurations of the transformed precancerous keratinocytes may confer upon them a growth advantage in relation tothe unaltered neighbouring keratinocytes. Replicative clonal expansion of these keratinocytes results in the progressive replacementof the surrounding normal keratinocytes by the fitter clone or clones of altered cells. The precancerized oral epithelial fieldmay have a clinically normal appearance and microscopically may be normal or may show dysplasia. Oral leukoplakias arisingwithin a precancerized epithelial field in which the keratinocytes show DNA aneuploidy or loss of heterozygosity at certainspecific chromosomal loci have the potential to progress to carcinoma. The pathogenic mechanisms that drive the carcinomatoustransformation of oral leukoplakias, in which cytogenetic alterations in the keratinocytes cannot be detected, are unknown.

1. Introduction

The genome can sustain a number of alterations to its DNAwithout any apparent cellular functional disability, but anycell that has sustained a critical number of DNA alterations,such that one or two additional alterations are likely to resultin malignant change, is regarded as being transformed.

It is evident that potentially malignant oral leuko-plakias arise within fields of precancerization consistingof cytogenetically altered keratinocytes [1, 2]. A field ofprecancerization in the oral cavity can be defined as anarea of clinically normal-looking epithelium which is eithermicroscopically normal or shows dysplasia, but in whichsome keratinocytes have undergone cytogenetic alterations[1–8]. The process of progressive cytogenetic alteration(transformation) can confer upon the keratinocytes in suchan epithelial field a growth advantage in relation to thenormal surrounding keratinocytes [9] so that within anapparently clinically normal stretch of oral mucosa there canbe a pathobiological continuum from normal epithelium toprecancerized epithelium where carcinoma can arise [7].

2. An Oral Field of Precancerization

A field of precancerized oral epithelium comprises a largenumber of cytogenetically altered keratinocytes at variousstages of transformation. It is not yet clear how many geneticevents are necessary to establish cellular transformation,and not all the molecular alterations associated with fieldprecancerization of normal-looking oral epithelium havebeen characterized [1].

The initial transformational events occur in progenitorcells in the basal and/or parabasal cell layers of the oralepithelium [10, 11]. These progenitor cells give rise tocells that maintain the integrity of the basal and parabasalcell layers and to amplifying cells that divide frequently,producing daughter cells that enter the maturation process,and gradually progress to the surface of the epithelium [12].

The initial cytogenetic events leading to cell trans-formation are most probably characterized by molecularand subsequent functional alterations to genes maintainingthe cell’s genomic stability. Such alterations precipitatesequential cytogenetic lesions driving the genetic evolution


of the initially transformed progenitor cell towards a cellwith a complete set of genetic alterations of a malignantphenotype [13–17]. In this regard, the evolution of acancerous keratinocyte is the outcome of a sufficient numberof accumulated cytogenetic alterations rather than of thesequential order in which they occur [15, 18–20].

The cytogenetic alterations in precancerous keratinocytesreflect a noncritical accumulation of molecular events, andthose seen in cancerous keratinocytes are the outcomeof a further critical accumulation of transforming events.The exact sequence of the cytogenetic molecular eventsculminating in carcinogenesis can vary [14, 21].

Most of the cytogenetic and transcriptional alterationsoccur early in the continuum from normality, to precancer-ization, to carcinoma. It is probable that a greater numberof such alterations are required for the transformation of anormal to a precancerous keratinocyte, than for the trans-formation of a precancerous keratinocyte to a keratinocyteexpressing a full cancerous phenotype [22].

The number of sequential cytogenetic alterations nec-essary for a progenitor cell to become a cancer cell isimponderable, but is estimated to be between 3 and 12.The exact number of these singular genetic events is afunction of several factors: loss of DNA repair mechanisms,dysregulation of signal transduction pathways, and blockingof mechanisms leading to apoptosis [23, 24], which togetherwill selectively confer an advantage upon the transformedcells with regard to competitive fitness and growth in relationto the surrounding normal cells [9]. This cytogenetic evolu-tion will promote the clonal expansion of the transformedcell population and their subsequent clonal divergence toform either a single precancerized epithelial field or multiplefields that may be contiguous with or separate from eachother, at the expense of the surrounding normal epithelium[1].

A field of precancerization may comprise a monoclonalcell population originating from one transformed progenitorbasal cell that underwent clonal expansion, and spread later-ally. The molecular profile of the transformed keratinocytesin such a field may be identical if they are all part ofa monoclone. On the other hand, the molecular profileof the transformed keratinocytes may be similar to butnot identical with one another (clonally related) if theyarose from subclones related by descent from the originalmonoclone, but each subclone having experienced episodesof different mutations [1, 25–29].

However, a field of precancerization may also consist ofa polyclonal cell population, several transformed progenitorbasal cells having undergone independent clonal expansionwith subsequent independent clonal divergence. The molec-ular profiles of the transformed keratinocytes in such afield will be dissimilar, but might share some cytogeneticalterations, as the polyclonal cells will have been exposed toidentical carcinogens and to the same microenvironment inthe mouth. Thus, the keratinocytes of a unique precancerousoral leukoplakia or of a unique oral squamous cell carcinomacan show molecular heterogeneity with similar or dissimilarcytogenetic alterations [1, 25–29].

The precancerous field may be clinically normal, whetheror not there is epithelial dysplasia. The presence of a fieldof precancerization may be disclosed by the developmentof a leukoplakia or of an erythroplakia, or the appearanceof squamous cell carcinoma will make the nature of thepreviously unrecognized field of precancerization become alltoo apparent [1].

The cytogenetic events culminating in the developmentof a field of precancerization can be either spontaneousor microenvironmentally induced, or extraneously imposed,but it is possible that some ectodermal stem cells destinedto become progenitor cells in the oral epithelium canactually undergo genetic and/or epigenetic alterations duringorganogenesis, giving rise to cytogenetically altered epithelialprogenitor cells. If during maturation these developmentallyaltered keratinocytes are exposed to further transformingmolecular events, their clonal expansion can culminate in theformation of a precancerized field [1, 10, 11, 25, 30].

It is possible that dysregulation of gene expression in thefibroblasts of the lamina propria, with consequent produc-tion and release of aberrant mediators, may impose uponthe overlying keratinocytes that have already undergoneinitial transformation from whatever cause, dysregulatoryinductive signals contributing to the development of theprecancerized field [1, 31–33].

3. The Failure of the Studies ofPotentially Malignant Lesions to Contributeto Knowledge of Potentially MalignantLesions of the Mouth

There are a number of potentially malignant lesions ofthe upper aerodigestive tract in which the oral cavity,nasopharynx, oropharynx, hypopharynx, and the larynx,are grouped together as if premalignancies of these sitesconstitute a homogeneous group. Potentially malignantlesions from these various sites are, however, site specific, sosuch studies are of limited value in isolating molecular andcytogenetic markers of carcinomatous transformation of oralleukoplakia [1].

Furthermore, although the potentially malignant lesionsof the upper aerodigestive tract have common histologicalfeatures of epithelial dysplasia or hyperplasia, they certainlydo not have similar clinical features or natural courses. Inaddition, in several studies, oral epithelial dysplasia andhyperplasia have been chosen as the inclusion criteria forcategorising oral lesions as being potentially malignant,without differentiating the clinical entities. Moreover, certainreactive and inflammatory lesions of the oral mucosa exhibit-ing epithelial hyperplasia or low-grade dysplasia have beenerroneously included in some of the studies although theselesions will never undergo carcinomatous transformation[1].


4. Molecular Markers of Oral Leukoplakia andIts Progression to Squamous Cell Carcinoma

The development of precancerous oral leukoplakia and itscarcinomatous transformation can be brought about by dys-regulation of the mechanisms controlling the cell cycle, DNArepair, and apoptosis, by activation of proto-oncogenes, byloss of chromosomal regions containing candidate tumour-suppressor genes as a result of loss of heterozygosity (LoH),and by alterations to genomic DNA and to mitochondrialDNA [23–25, 34, 35]. While these molecular and cytogeneticmarkers may not be reliable predictors of carcinomatoustransformation [1, 34, 36–38], there is a good deal ofevidence that LoH at specific chromosomal arms, andaneuploidy, are indeed associated with increased frequencyof carcinomatous transformation of oral leukoplakia [35, 39–43]. However, irrespective of one or more cytogenetic ormolecular changes to the keratinocytes of oral leukoplakia,progression to carcinoma may never occur [1].

LoH at the chromosome arms 3p and 9p occur frequentlyin keratinocytes of precancerous epithelial lesions of theupper aerodigestive tract. This pattern of LoH can be associ-ated with carcinomatous transformation of these lesions [18,35, 40, 44, 45]. In one study, precancerous epithelial lesionswith keratinocytes having LoH limited to 3p and/or 9phad a 3.8-fold higher risk of carcinomatous transformationcompared to precancerous lesions without LoH either at3p or at 9p, while those lesions with keratinocytes carryingLoH at 3p and/or 9p, together with additional losses at anyof the chromosomes 4q, 8p, 11q, and 17p had a 33-foldincreased risk of carcinomatous transformation, comparedto precancerous lesions with keratinocytes retaining thesechromosomal arms, and also progressed to carcinoma morerapidly, although unpredictably [35, 41].

For unknown reasons, keratinocytes of dysplastic oralleukoplakias on the floor of the mouth, on the ventrolateralsurface of the tongue, and at the maxillary retromolar/softpalate region have LoH more frequently than do the ker-atinocytes of dysplastic leukoplakias affecting other regionsof the oral mucosa. This may be one of the factorsputting leukoplakias at the three sites of the oral mucosamentioned, at higher risk of carcinomatous transformationthan leukoplakias at other lower-risk sites [41].

Notwithstanding, the increased risk of carcinomatoustransformation associated with LoH in precancerous epithe-lial lesions, not all oral leukoplakias with keratinocyticLoH, will progress to carcinoma, and as some oral leuko-plakias without keratinocytic LoH will indeed progress tocarcinoma, LoH is certainly not an infallible predictor ofcarcinomatous transformation [1].

It seems that the presence of DNA aneuploidy inkeratinocytes of oral leukoplakia may be a valuable molecularmarker of carcinomatous transformation of oral leukoplakiaand an indicator of poor prognosis. The frequency ofcarcinomatous transformation of dysplastic oral leukoplakiais much greater for those leukoplakias with keratinocytesshowing DNA aneuploidy than for those with keratinocyteswith normal (diploid) DNA content, and subjects withoral carcinoma developing from dysplastic leukoplakia with

keratinocytes manifesting aneuploidy have a lower rate ofsurvival compared to subjects with oral squamous cellcarcinoma evolving from dysplastic leukoplakia with ker-atinocytes with diploid DNA content [43, 46].

5. Field Precancerization and Oral Leukoplakia

The existence of a field or fields of precancerization canexplain why oral leukoplakia may manifest at single or atmultiple sites, synchronously and/or metachronously andmay recur at the same site from which it was previouslyapparently successfully excised [1]

Additional cytogenetic alterations superimposed upontransformed precancerous keratinocytes either within aleukoplakia or within a clinically normal-looking zone ofan epithelial field of precancerization may drive the processof cancerization. This explains why sometimes an oralleukoplakia on microscopical examination is found to havealready become squamous cell carcinoma, and sometimessquamous cell carcinoma arises apparently de novo eithercontiguous to or separated from existing leukoplakia. If asubstantial portion of a field of precancerization arises froma monoclone of cytogenetically transformed keratinocytes,then any leukoplakias, or subsequently developing carcino-mas arising within that field either contiguously or separatelyfrom each other, will be cytogenetically very similar oridentical. On the other hand, if a field of precancerizationcomprises a number of clones of cytogenetically dissimilarlytransformed keratinocytes, then leukoplakias or carcinomasarising within this field (if multiple lesions should occur) willbe cytogenetically dissimilar [1, 30].

The transformed keratinocytes in the precancerized fieldfrom which a leukoplakia had apparently been completelyexcised may give rise to “recurrence” of another leukoplakiafrom cytogenetically related subclones of transformed ker-atinocytes adjacent to the surgical excision or from adjacentcytogenetically unrelated clones [45].

The time of progression of oral leukoplakias withkeratinocytes with molecular profiles associated with car-cinomatous transformation, to squamous cell carcinoma ifit occurs, unpredictably and inexplicably varies from sixmonths to eight years [35, 41]. However, it may sometimestake more than 30 years for oral leukoplakia to progressto squamous cell carcinoma [47], and the average periodfor carcinomatous transformation ranges from 5 to 8 years[47, 48]. Neither the rate of progression of oral leukoplakiato carcinoma nor the mechanisms bringing about theregression of oral leukoplakia, can be explained in terms ofthe cytogenetic characteristics of the precancerous field.

The mechanisms that bring about regression of oralleukoplakia in which the keratinocytes harbour cytogeneticchanges associated with early transformational events areobscure. However, it is possible that a continuous accumula-tion of cytogenetic alterations may give rise to a precancerousclone of cells that is inferior rather than superior in itscompetitive growth and fitness resulting in its replacementby, rather than in its replacing, the normal neighbouring


keratinocytes [1]. Alternatively, or additionally, the accumu-lated cytogenetic alterations may result in failure of DNAreplication and cell viability leading to the extinction of theprecancerous clone [14].

6. Summary

Despite advances in molecular genetic studies, there are nomolecular markers that are reliable predictors of progressionof oral leukoplakia to carcinoma. Although some oralleukoplakias arise within fields of precancerized epitheliumwhere initial cytogenetic alterations have already occurred,their transformed keratinocytes may or may not acquirecomplete malignant phenotypes.

References

[1] L. Feller and J. Lemmer, “Field cancerization and oralleukoplakia,” in Field Cancerization: Basic Science and ClinicalApplications, G. D. Dakubo, Ed., pp. 95–111, Nova Science,Ontario, Canada, 2011.

[2] P. J. Thomson, “Field change and oral cancer: new evidence forwidespread carcinogenesis?” International Journal of Oral andMaxillofacial Surgery, vol. 31, no. 3, pp. 262–266, 2002.

[3] M. P. Tabor, R. H. Brakenhoff, V. M. M. Van Houten et al.,“Persistence of genetically altered fields in head and neckcancer patients: biological and clinical implications,” ClinicalCancer Research, vol. 7, no. 6, pp. 1523–1532, 2001.

[4] M. P. Tabor, R. H. Brakenhoff, H. J. Ruijter-Schippers, J. A.Kummer, C. R. Leemans, and B. J. M. Braakhuis, “Geneticallyaltered fields as origin of locally recurrent head and neckcancer: a retrospective study,” Clinical Cancer Research, vol. 10,no. 11, pp. 3607–3613, 2004.

[5] M. P. Tabor, B. J. M. Braakhuis, J. E. van der Wal et al.,“Comparative molecular and histological grading of epithelialdysplasia of the oral cavity and the oropharynx,” Journal ofPathology, vol. 199, no. 3, pp. 354–360, 2003.

[6] P. K. Ha and J. A. Califano, “The molecular biology of mucosalfield cancerization of the head and neck,” Critical Reviews inOral Biology and Medicine, vol. 14, no. 5, pp. 363–369, 2003.

[7] B. J. M. Braakhuis, M. P. Tabor, J. A. Kummer, C. R.Leemans, and R. H. Brakenhoff, “A genetic explanation ofslaughter’s concept of field cancerization: evidence and clinicalimplications,” Cancer Research, vol. 63, no. 8, pp. 1727–1730,2003.

[8] B. J. M. Braakhuis, R. H. Brakenhoff, and C. R. Leemans, “Sec-ond field tumors: a new opportunity for cancer prevention?”Oncologist, vol. 10, no. 7, pp. 493–500, 2005.

[9] C. Rhiner and E. Moreno, “Super competition as a possiblemechanism to pioneer precancerous fields,” Carcinogenesis,vol. 30, no. 5, pp. 723–728, 2009.

[10] L. Feller, M. Bouckaert, U. M. Chikte et al., “A short account ofcancer—specifically in relation to squamous cell carcinoma,”South African Dental Journal, vol. 65, no. 7, pp. 322–324, 2010.

[11] L. Feller, R. Essop, N. H. Wood et al., “Chemotherapy- andradiotherapy-induced oral mucositis: pathobiology, epidemi-ology and management,” South African Dental Journal, vol. 65,no. 8, pp. 372–374, 2010.

[12] A. Nanci, “Oral mucosa,” in Ten Cate’s Oral Histology.Development structure and function, A. Nanci, Ed., pp. 318–357, Mosby Elsevier, St. Louis, Mo, USA, 7th edition, 2008.

[13] T. D. Tlsty, A. Briot, A. Gualberto et al., “Genomic instabilityand cancer,” Mutation Research, vol. 337, no. 1, pp. 1–7, 1995.

[14] L. A. Loeb, “A mutator phenotype in cancer,” Cancer Research,vol. 61, no. 8, pp. 3230–3239, 2001.

[15] L. A. Loeb, K. R. Loeb, and J. P. Anderson, “Multiple mutationsand cancer,” Proceedings of the National Academy of Sciences ofthe United States of America, vol. 100, no. 3, pp. 776–781, 2003.

[16] L. A. Loeb, J. H. Bielas, and R. A. Beckman, “Cancers exhibita mutator phenotype: clinical implications,” Cancer Research,vol. 68, no. 10, pp. 3551–3557, 2008.

[17] C. Lengauer, K. W. Kinzler, and B. Vogelstein, “Geneticinstabilities in human cancers,” Nature, vol. 396, no. 6712, pp.643–649, 1998.

[18] J. Califano, P. Van Der Riet, W. Westra et al., “Geneticprogression model for head and neck cancer: implications forfield cancerization,” Cancer Research, vol. 56, no. 11, pp. 2488–2492, 1996.

[19] J. J. Sciubba, “Oral cancer: the importance of early diagnosisand treatment,” American Journal of Clinical Dermatology, vol.2, no. 4, pp. 239–251, 2001.

[20] A. M. Mandard, P. Hainaut, and M. Hollstein, “Geneticsteps in the development of squamous cell carcinoma of theesophagus,” Mutation Research, vol. 462, no. 2-3, pp. 335–342,2000.

[21] A. V. Lichtenstein, “On evolutionary origin of cancer,” CancerCell International, vol. 5, 2005.

[22] P. K. Ha, N. E. Benoit, R. Yochem et al., “A transcriptionalprogression model for head and neck cancer,” Clinical CancerResearch, vol. 9, no. 8, pp. 3058–3064, 2003.

[23] P. K. Ha, S. S. Chang, C. A. Glazer, J. A. Califano, and D.Sidransky, “Molecular techniques and genetic alterations inhead and neck cancer,” Oral Oncology, vol. 45, no. 4-5, pp.335–339, 2009.

[24] C. A. Glazer, S. S. Chang, P. K. Ha, and J. A. Califano,“Applying the molecular biology and epigenetics of head andneck cancer in everyday clinical practice,” Oral Oncology, vol.45, no. 4-5, pp. 440–446, 2009.

[25] G. D. Dakubo, J. P. Jakupciak, M. A. Birch-Machin, and R. L.Parr, “Clinical implications and utility of field cancerization,”Cancer Cell International, vol. 7, article 2, 2007.

[26] M. P. Tabor, R. H. Brakenhoff, H. J. Ruijter-Schippers et al.,“Multiple head and neck tumors frequently originate from asingle preneoplastic lesion,” American Journal of Pathology, vol.161, no. 3, pp. 1051–1060, 2002.

[27] V. M. M. van Houten, C. R. Leemans, J. A. Kummer et al.,“Molecular diagnosis of surgical margins and local recurrencein head and neck cancer patients: a prospective study,” ClinicalCancer Research, vol. 10, no. 11, pp. 3614–3620, 2004.

[28] B. J. M. Braakhuis, M. P. Tabor, C. R. Leemans, I. Van DerWaal, G. B. Snow, and R. H. Brakenhoff, “Second primarytumors and field cancerization in oral and oropharyngealcancer: molecular techniques provide new insights and defi-nitions,” Head and Neck, vol. 24, no. 2, pp. 198–206, 2002.

[29] B. J. M. Braakhuis, E. Bloemena, C. R. Leemans, and R. H.Brakenhoff, “Molecular analysis of surgical margins in headand neck cancer: more than a marginal issue,” Oral Oncology,vol. 46, no. 7, pp. 485–491, 2010.

[30] L. Feller, “Cancer metastasis: a short account,” South AfricanDental Journal, vol. 66, no. 4, pp. 180–183, 2011.

[31] F. Weber, Y. Xu, L. Zhang et al., “Microenvironmental genomicalterations and clinicopathological behavior in head and necksquamous cell carcinoma,” Journal of the American MedicalAssociation, vol. 297, no. 2, pp. 187–195, 2007.

[32] S. G. Baker and B. S. Kramer, “Paradoxes in carcinogenesis:new opportunities for research directions,” BMC Cancer, vol.7, article 151, 2007.


[33] L. Feller, R. A. G. Khammissa, N. H. Wood, Y. Jadwat, R.Meyerov, and J. Lemmer, “Sunlight (actinic) keratosis: anupdate,” Journal of Preventive Medicine and Hygiene, vol. 50,no. 4, pp. 217–220, 2009.

[34] C. Scully, J. Sudbø, and P. M. Speight, “Progress in determin-ing the malignant potential of oral lesions,” Journal of OralPathology and Medicine, vol. 32, no. 5, pp. 251–256, 2003.

[35] M. P. Rosin, X. Cheng, C. Poh et al., “Use of allelic loss topredict malignant risk for low-grade oral epithelial dysplasia,”Clinical Cancer Research, vol. 6, no. 2, pp. 357–362, 2000.

[36] S. Warnakulasuriya, “Lack of molecular markers to predictmalignant potential of oral precancer,” Journal of Pathology,vol. 190, no. 4, pp. 407–409, 2000.

[37] S. Warnakulasuriya, “Histological grading of oral epithelialdysplasia: revisited,” Journal of Pathology, vol. 194, no. 3, pp.294–297, 2001.

[38] J. Reibel, “Prognosis of oral pre-malignant lesions: significanceof clinical, histopathological, and molecular biological charac-teristics,” Critical Reviews in oral Biology and Medicine, vol. 14,no. 1, pp. 47–62, 2003.

[39] M. M. Kim and J. A. Califano, “Molecular pathology of head-and-neck cancer,” International Journal of Cancer, vol. 112, no.4, pp. 545–553, 2004.

[40] L. Mao, J. S. Lee, Y. H. Fan et al., “Frequent microsatellitealterations at chromosomes 9p21 and 3p14 in oral premalig-nant lesions and their value in cancer risk assessment,” NatureMedicine, vol. 2, no. 6, pp. 682–685, 1996.

[41] L. Zhang, M. Williams, C. F. Poh et al., “Toluidine bluestaining identifies high-risk primary oral premalignant lesionswith poor outcome,” Cancer Research, vol. 65, no. 17, pp.8017–8021, 2005.

[42] L. Zhang and M. P. Rosin, “Loss of heterozygosity: a potentialtool in management of oral premalignant lesions?” Journal ofOral Pathology and Medicine, vol. 30, no. 9, pp. 513–520, 2001.

[43] J. Sudbø, W. Kildal, B. Risberg, H. S. Koppang, H. E. Danielsen,and A. Reith, “DNA content as a prognostic marker in patientswith oral leukoplakia,” New England Journal of Medicine, vol.344, no. 17, pp. 1270–1278, 2001.

[44] J. J. Lee, W. K. Hong, W. N. Hittelman et al., “Predicting cancerdevelopment in oral leukoplakia: ten years of translationalresearch,” Clinical Cancer Research, vol. 6, no. 5, pp. 1702–1710, 2000.

[45] M. Partridge, S. Pateromichelakis, E. Phillips, G. G. Emilion,R. P. A’Hern, and J. D. Langdon, “A case-control studyconfirms that microsatellite assay can identify patients at riskof developing oral squamous cell carcinoma within a field ofcancerization,” Cancer Research, vol. 60, no. 14, pp. 3893–3898,2000.

[46] J. Sudbo, S. M. Lippman, J. J. Lee et al., “The influence ofresection and aneuploidy on mortality in oral leukoplakia,”New England Journal of Medicine, vol. 350, no. 14, pp. 1405–1413, 2004.

[47] S. Silverman, M. Gorsky, and F. Lozada, “Oral leukoplakia andmalignant transformation,” Cancer, vol. 53, no. 3, pp. 563–568, 1984.

[48] W. F. C. Hogewind, W. A. M. Van Der Kwast, and I. VanDer Waal, “Oral leukoplakia, with emphasis on malignanttransformation,” Journal of Cranio-Maxillo-Facial Surgery, vol.17, no. 3, pp. 128–133, 1989.

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