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A survey of the current approaches to diagnosis and management of oral premalignant lesions
Joel B. Epstein, DMD, MSD, FRCD(C), FDSRCSE; Meir Gorsky, DMD; Dena Fischer, DDS, MSD, MS; Anurag Gupta, BDS, MPH; Matthew Epstein, BSc; Sharon Elad, DMD, MSc

n 2006, approximately 31,000 new cases of oropharyngeal cancer were diagnosed in the United States and more than 7,400 people died of this disease.1 Most oropharyngeal cancers are oral squamous cell carcinoma (OSCC). The overall five-year relative survival rate in the United States is approximately 57 percent,1-4 and it has been shown that if the disease is less advanced at diagnosis, the five-year survival rate increases.2,3 Furthermore, patients who receive a diagnosis at an earlier stage of the disease require less aggressive treatment and experience less morbidity and lower costs. Risk factors for developing OSCC are multifactorial and include tobacco use; chronic alcohol consumption; older age; having human papillomavirus infection, immunosuppression or nutritional deficiencies; and genetics.4-7 Morbidity, mortality and incidence of OSCC may decrease if oral premalignant lesions (OPLs) are detected and effectively treated.

ABSTRACT

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DISCLOSURE: Dr. Epstein is on the medical advisory board of Zila, Phoenix.

Background. Early diagnosis of oral premalignant lesions (OPLs) and oral squamous cell carcinoma facilN C itates treatment with less aggressive approaches and A U I N U G ED 2 R results in a better prognosis. The authors conducted a TICLE study to identify current practices in the diagnosis and management of these oral lesions by oral medicine professionals. Methods. The authors sent a questionnaire to 176 diplomates of the American Board of Oral Medicine and asked them to complete the questionnaires and return them by mail. Results. The initial clinical approach taken by most of the responders included visual examination, elimination of possible local causes and twoweek follow-up. Adjuvant clinical tests included toluidine blue, oral brush biopsy and exfoliative cytology. If there was no clinical improvement after two weeks, most responders recommended that a biopsy be performed. Induration, red component, nonhomogeneous surface and ulceration were characteristics of lesions that increased the responders decisions to perform a biopsy. Lesion symptoms and location also contributed to their decisions to perform a biopsy. Follow-up more frequently than twice a year was recommended for red lesions, lesions with histologically confirmed dysplasia or both. Most clinicians recommend a biopsy during follow-up of an OPL whenever the lesion changes in appearance. Conclusions. The findings of this survey may provide background for initial guidelines to be used by oral practitioners to diagnose and manage OPL. Clinicians awareness of the complexity of OPL diagnosis and management is important, and referral to an experienced provider is recommended. Key Words. Oral premalignant lesions; leukoplakia; erythroplakia; diagnosis; management. JADA 2007;138(12):1555-62.
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Dr. Epstein is a professor and the head, Department of Oral Medicine and Diagnostic Sciences, College of Dentistry, University of Illinois at Chicago; a professor, Department of Oral Medicine and Diagnostic Sciences, College of Dentistry, University of Illinois at Chicago; and the director, Interdisciplinary Program in Oral Cancer Prevention, Detection and Treatment, Chicago Cancer Center, University of Illinois at Chicago. Address reprint requests to Dr. Epstein at Department of Oral Medicine and Diagnostic Sciences, College of Dentistry, University of Illinois at Chicago, 801 S. Paulina St., Room 556 (M/C 838), Chicago, Ill. 60612-7213, e-mail jepstein@uic.edu. Dr. Gorsky is a professor, Department of Oral Pathology and Oral Medicine, the Maurice and Gabriella Goldschleger School of Dental Medicine, Tel Aviv University, Israel, and a visiting professor, Department of Oral Medicine and Diagnostic Sciences, College of Medicine, University of Illinois at Chicago. Dr. Fischer is an assistant professor, Department of Oral Medicine and Diagnostic Sciences, College of Dentistry, University of Illinois at Chicago. Dr. Gupta is a research assistant, Department of Oral Medicine and Diagnostic Sciences, College of Dentistry, University of Illinois at Chicago. Mr. Epstein is a research assistant, Fred Hutchinson Cancer Research Center, Seattle. Dr. Elad is a lecturer, Department of Oral Medicine, Hebrew University-Hadassah School of Dental Medicine, Jerusalem.

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Unfortunately, the detection of early, localized OSCC has remained unchanged during the past three decades4; two-thirds of cases are diagnosed at advanced stages (Stages III and IV), even though OPL and OSCC are surface lesions that can be detected by visual inspection and palpation. Change in color (white or red), texture, size or contour; ulceration; or limited mobility of intraoral or perioral tissue may be a sign of OPL or OSCC. Although a comprehensive clinical head and neck and oral cancer examination requires less than 90 seconds to conduct,8 it may not be performed routinely or as frequently as it should, and deviations from normal tissue may not be clinically obvious or symptomatic. The key to diagnosis is the early detection of mucosal changes that may represent disease and not variations of normal. White and red lesions of the oral mucosa are the most common precancerous clinical lesions. Many oral cancers are preceded by clinically evident premalignant mucosal changes that give a warning of risk and present an opportunity for detection and preventive measures. Leukoplakia (clinically detected white lesions) occurs more frequently than does erythroplakia (clinically detected red lesions), but lesions with a red component are associated with a higher risk of dysplasia and cancer.9 The clinical approach to the detection, diagnosis and management of OPL may vary among health care providers, including oral health care professionals and medical care professionals, and evidenced-based guidelines do not exist. The introduction of new technology is increasing awareness of the need to identify oral cancer and OPLs.10-19 OPL and the early stages of oral malignant disease are detected more commonly by dental care providers, while medical care providers identify more late-stage disease.10,11 Providers with experience in oral health care may manage OPL better. We conducted a study to identify the current clinical steps taken to diagnose OPL and OSCC and the current approaches taken by experienced oral medicine professionals to manage these lesions.
MATERIAL AND METHODS

included multiple-choice questions and closedended questions with five-point rating scales, which was pretested by eight faculty members in the College of Dentistry at the University of Illinois at Chicago. The universitys institutional review board approved the project. Using a 2004 membership list, we mailed the survey to all 176 diplomates of the American Board of Oral Medicine (ABOM) and asked them to complete the questionnaire and return it by mail. We sent two follow-up mailings to nonresponders at approximately two-month intervals. We used statistical software (Stata Statistical Software, Version 8, College Station, Texas) to summarize the responses, and we collapsed responses obtained on five-point Likert scales into three levels: increase, decrease or no change in the variable assessed.
RESULTS

Sixty-five ABOM diplomates (36.9 percent) responded to the questionnaire. Eighty percent of the responders were men, with a mean age of 54.7 years. Thirty-nine responders (65 percent) defined leukoplakia as a white lesion that could not be characterized clinically as any other disease, but nine (13.8 percent) classified such a lesion as being at risk of becoming cancerous. First assessment of mucosal lesions. The initial clinical approach used by 53 responders (81.5 percent) was visual examination, elimination of possible local causes of tissue irritation and a follow-up visit in two weeks (Figure). Thirty-three of those responders (62.3 percent) reported frequently using adjuvant clinical tests in their initial assessment of oral lesions. Of these responders, 19 (57.6 percent) used toluidine blue vital staining, 15 (45.5 percent) used brush biopsy (OralCDx, CDx Laboratories, Suffern, N.Y.), and seven (21.2 percent) used exfoliative cytology. One responder (3.0 percent) used other diagnostic tests such as Lugols iodine or chemiluminescent light. After a two-week follow-up of a lesion suspected to be leukoplakia, 47 of 53 responders (88.7 percent) said they would perform a biopsy if they noted no change in the lesion (Figure). Nineteen (40.4 percent) of those who said they would ABBREVIATION KEY. ABOM: American Board of Oral Medicine. FDA: U.S. Food and Drug Administration. OPL: Oral premalignant lesion. OSCC: Oral squamous cell carcinoma. WHO: World Health Organization.

By means of consensus, we developed a questionnaire that included demographic information, questions about the first assessment of oral mucosal lesions and queries about the guiding principles for follow-up of OPL. The questionnaire
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perform a biopsy said they would use an adjuvant test, most frequently toluidine Time Leukoplakia blue, to guide biopsy site selection. In addi(n = 65) tion, seven clinicians (14.9 percent) said they would use an oral brush biopsy test and four clinicians (8.5 percent) said they would use exfoliative cytology before per81.5% (n = 53) First 18.5% (n = 12) forming biopsies on suspected leukoplakia Assessment Visual Examination, lesions. Although all biopsy specimens are Elimination Visual Examination of Possible Causes Biopsy sent for hematoxylin and eosin staining, Adjuvant Tests four responders (4.6 percent) said they also 62.3% (n = 33) send the biopsy specimens for immunofluorescence to rule out possible immunemediated vesiculoulcerative disease. Based on the clinical nature of the lesion, a biopsy performed at first assessment or at the two-week follow-up visit is considered a part of the initial approach to TwoAdjuvant Tests diagnosing a persisting oral lesion that Week 40.4% (n = 19) Followmay be an OPL. Responders rated up patients characteristics that affect their decisions to perform a biopsy of the mucosal lesion (Table 1). Findings in the 88.7% (n = 47) patients medical histories that accelerated the decision to perform a biopsy include Figure. Flowchart of initial clinical approach. past malignancies (90.8 percent), tobacco smoking (89.2 percent) and alcohol use (86.2 pergreatest concern were the floor of the mouth cent). Immunosuppression or use of chewing or (89.2 percent), lateral or ventral surface of the smokeless tobacco increased most responders tongue (89.2 percent) and the tonsillar fossa decisions to perform a biopsy (83.1 percent and (70.8 percent). 80.0 percent, respectively), whereas 3.1 percent of Follow-up of OPL lesions. The responders the responders reported that such findings recommended follow-up schedule was made on decreased their intention to perform a biopsy. the basis of the clinical appearance of the oral The anatomical location of the lesion and lesions (Table 2, page 1559). Twenty-six responlesions characteristics also affect clinicians deciders (40.0 percent) recommended a biannual sions to perform a biopsy of a potential OPL. follow-up for uniform white lesions, and 35 Induration and a red component were the leading responders (53.9 percent) recommended an clinical signs accelerating responders decisions to increase in frequency of follow-up for uniform red perform a biopsy (92.3 percent each), followed by lesions. Although 27 responders (41.5 percent) nonhomogeneous surface (89.2 percent), ulcerarecommended one follow-up visit per year for strition in the lesion (86.2 percent) and verrucous ated white lesions (most of which probably are surface (83.1 percent). Unilateral lesions and lichen planus), an increase in the number of those with a size greater than 15 millimeters follow-up visits per year was suggested by 46 were considered a cause for increased concern by responders (70.8 percent) when a red component 67.7 percent and 66.2 percent of responders, is present in the striated lesion. Thirty-eight respectively. Pedunculated white lesions (30.8 responders (58.5 percent) recommended at least percent) and a homogeneous clinical surface (18.5 three follow-up visits per year for mixed-patched percent) had the least effect on responders decilesions. Different assessment utilities are used in sions. Symptoms associated with oral leukoplakia follow-up examinations of oral lesions, depending that caused an increase in responders concern on lesion characteristics. Biopsy and photographic leading to biopsy include numbness (86.2 perdocumentation are the leading clinical methods cent), regional sensory changes (78.5 percent) and used by the responders. pain (61.5 percent). The three oral sites of Management of OPL lesions. We found that
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TABLE 2 (73.8 percent) addressed reduction or elimination of Recommended frequency of follow-up for oral alcohol use, regardless of mucosal lesions on the basis of clinical parameters. the patients lesions clinUNIFORM UNIFORM WHITE MIXEDMIXEDFREQUENCY OF ical characteristics. RED LESION WHITE LESION STRIATED STRIATED PATCHED FOLLOW-UP Via the questionnaire, (N [%]) (N [%]) LESION LESION LESION (N [%]) (N [%]) (N [%]) we asked the responders opinions regarding sur3 (4.6) 2 (3.1) 1 (1.5) 1 (1.5) More Than One 1 (1.5) Year gical and nonsurgical treatment modalities for 22 (33.8) 27 (41.5) 10 (15.4) 10 (15.4) Once Per Year 5 (7.7) the management of OPLs. 26 (40.0) 22 (33.8) 11 (16.9) 21 (32.3) Twice Per Year 13 (20.0) Surgical removal of lesions 5 (7.7) 5 (7.7) 12 (18.5) 12 (18.5) Three Times by means of scalpel exci13 (20.0) Per Year sion was suggested by 45 3 (4.6) 2 (3.1) 23 (35.4) 13 (20.0) Four Times Per responders (69.2 percent), 25 (38.5) Year laser removal was sug6 (9.2) 7 (10.8) 8 (12.3) 8 (12.3) Other gested by 13 responders 8 (12.3) (20.0 percent), and TABLE 3 cryosurgery or other combined surgical modality Estimated frequency of biopsy performed during with more than one follow-up for oral premalignant lesions. removal method was sugUNIFORM MIXEDUNIFORM WHITE MIXEDBIOPSY gested by two responders WHITE LESION RED LESION STRIATED STRIATED PATCHED FREQUENCY (N [%]) (N [%]) LESION LESION LESION (3.1 percent). If lesions (N [%]) (N [%]) (N [%]) recur after excision, 43 (66.2) 48 (73.8) 43 (66.2) 46 (70.8) 46 (70.8) Whenever the responders reported that Lesion Changes they would consider addi3 (4.6) 5 (7.7) 0 (0) 0 (0) 0 (0) Every Five tional or different Years approaches (Table 4). The 10 (15.4) 8 (12.3) 5 (7.7) 4 (6.2) 7 (10.8) Every Two most commonly recomYears mended treatments were 6 (9.2) 1 (1.5) 8 (12.3) 7 (10.8) 5 (7.7) Once Per Year performing another biopsy by 60 responders (92.3 per- Twice Per Year 3 (4.6) 2 (3.1) 6 (9.2) 5 (7.7) 5 (7.7) cent) and re-excision by 54 0 (0) 0 (0) 1 (1.5) 2 (3.1) 1 (1.5) Three Times responders (84.4 percent). Per Year Management of oral 0 (0) 0 (0) 2 (3.1) 1 (1.5) 1 (1.5) Four Times Per lesions by using topical or Year systemic therapies also was recommended. Eight according to a structured hierarchy. Although responders (12.3 percent) recommended use of white and red oral lesions have been recognized topical vitamin A and derivatives for uniform by the World Health Organization (WHO) as prewhite lesions. Thirty-four responders (52.3 permalignant lesions,12 no evidence-based guidelines cent) recommended use of topical steroids for for diagnosis, management and follow-up have lesions with a red component. In cases in which been published. In addition, new technologies are systemic treatment was considered, 27 respondbecoming available that may make guidelines for ers (41.5) recommended systemic steroids for early detection even more complex. Our survey of mixed-striated lesions, and 17 responders (26.2 current clinical approaches used by experienced percent) recommended the same for both white health care providers may represent a summary and red lesions. of nationwide experience. Sharing the practices of DISCUSSION experienced professionals with the broad dental In the era of evidence-based health care, multiple community may provide dental clinicians with a sources of scientific information are categorized view of the clinical decision-making process used

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TABLE 4

approach for lesions suspected to be leukoplakia, erythroplakia or mixed Preferred treatment for oral premalignant leukoerythroplakia was to determine lesions that recur after excision.* the nature of the lesion. They treated a RECOMMEND NO OPPOSE (N [%]) TREATMENT lesion they thought may have repre(N [%]) PREFERENCE APPROACH sented inflammatory conditions by (N [%]) eliminating potential causes and re60 (92.3) 3 (4.6) 2 (3.1) Perform Another evaluating the lesion after two weeks. Biopsy If the lesion persisted, they performed a 54 (84.4) 6 (9.4) 4 (6.2) Re-excision biopsy. 21 (36.2) 25 (43.1) Adjuvant tests may help evaluate 12 (20.7) Laser Removal the lesion, select the biopsy site or both. 17 (27.0) 23 (36.5) 23 (36.5) Topical Therapy Toluidine blue has been shown in 15 (23.4) 14 (21.9) 35 (54.7) Follow-up Only single-center and multicenter studies to * Response totals do not always add up to 65 (100 percent), as some responses were missing. help identify OPLs and OSCC, to provide information about lesion margins in diagnosing and managing oral mucosal lesions and to aid in biopsy site selection.14,16-22 Toluidine and help providers assess their approach to the blue appears to be retained in cells that have care of patients with oral mucosal lesions. The genetic changes associated with OPLs and results of our survey reflect the opinions of ABOM OSCC,20-23 and it is the most common adjuvant diplomates who were involved actively in the care technique used clinically to assess oral lesions. of such patients at the time the survey was conThe introduction of the minimally invasive oral ducted. The results, however, do not provide a brush biopsy test used to collect oral mucosal review of the approaches to diagnosis and treattransepithelial samples for a computerized cytoment used by general dental care providers or logic examination and pathologist review24,25 has other specialists in dentistry or medicine. increased the attention given to early detection. The definition of leukoplakia proposed by WHO Cytology, an initial diagnostic approach used to in 197812 is a white patch or plaque that cannot enhance early diagnosis of OPL and cancer, was be characterized clinically or pathologically as used by 24 percent of responders to diagnose any other disease, and it was accepted by 60.0 white lesions. The diagnostic value of the oral percent of responders in our study. Three percent brush biopsy test has been studied, and a sensiof responders extended this definition by adding, tivity of 92.3 percent and a specificity of 94.3 pernot associated with any physical or chemical cent were recorded in one study24; however, the causative agent except the use of tobacco. The variable false-positive and false-negative results fact that leukoplakic lesions are associated with reported with the oral brush biopsy test26-32 and some risk of malignant transformation was the fact that use of the oral brush biopsy test may endorsed by 13.8 percent of the responders. delay performance of a biopsy may be reasons Although most white lesions represent benign why responders used it infrequently. hyperkeratosis, the clinical diagnosis of leukoDevices that may promote detection by means plakia may be associated with a continuum of of enhancing the visibility of oral lesions have histopathologically defined diagnoses ranging been introduced, although the U.S. Food and from benign lesions to dysplastic lesions and to Drug Administration had not cleared some at the OSCC.13 Dysplasia within a lesion represents an time we conducted our survey. The oral lesion increased risk of malignant transformation to identification and marking system uses a lowcancer.13 Erythroplakia is defined as a red patch energy wavelength chemiluminescent disposable that cannot be clinically or pathologically diaglight source (ViziLite, Zila, Phoenix) to improve nosed as any other condition and is associated the visibility of oral mucosal lesions.32 Using the with dysplastic or malignant change more frechemiluminescent light with toluidine blue swabs quently than is leukoplakia.12 Red lesions attrib(ViziLite Plus TBlue630, Zila) has been cleared by utable to known causes such as inflammatory or the FDA.33,34 In single-center and multicenter immune conditions are excluded from the definistudies, the oral lesion identification and marking tion of erythroplakia. system has been shown to help clinicians detect For most ABOM diplomates, the initial clinical abnormal mucosal lesions early and to guide prac1560 JADA, Vol. 138 http://jada.ada.org December 2007 Copyright 2007 American Dental Association. All rights reserved.

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titioners when performing biopsies, as well as reduce the number of required biopsies by approximately 50 percent and diagnose all significant tissue pathology.34 The VELscope mucosal examination system (LED Dental, White Rock, British Columbia, Canada) produces tissue autofluorescence, which helps detect abnormal oral mucosal lesions suspected as cancer.35-37 It recently was cleared by the FDA, but it was not available at the time we conducted our survey. The mucosal examination system has support in reports from one center.35,36 Early identification of a lesion or a suspicious area is paramount to the success of any method designed to accelerate early diagnosis of OPL or OSCC. OPL is managed according to patients clinical characteristics. Close surveillance, including multiple follow-up visits per year, is mandatory and may require the need for another biopsy to be performed for tissue diagnosis, treatment or both to manage symptoms and signs. Unfortunately, it has not been determined whether chemoprevention38-40 or surgical removal of dysplastic lesions39,41 prevents malignant transformation of the lesion in the long term, and, therefore, close follow-up is recommended. If striated white lesions manifest bilaterally, they most likely represent oral lichen planus or lichenoid reactions; however, such a diagnosis requires histologic confirmation or response to local therapy. Almost all responders in our study endorsed a follow-up visit at least once a year, owing to a 2 to 3 percent risk of malignant transformation of such lesions.42 A unilateral striated appearance may be suggestive of a lichenoid lesion that may be at risk of developing histologic dysplasia. If histologic dysplasia is confirmed, appropriate management for dysplasia is recommended, including frequent follow-up and more biopsies if changes develop in the lesion. Most responders believed that immunosuppression increases the need to perform a biopsy to obtain a tissue diagnosis. Although immunosuppressive agents commonly are used to reduce inflammation and restore comfort in patients with immune-mediated inflammatory diseases, this therapy can suppress local cell-mediated immunity and promote the risk of dysplastic lesions progressing, while reducing symptoms associated with the lesion.40 Medical therapy associated with immunosupression increases the risk of oral cancer,43-45 and more frequent follow-up is recommended in these patients.

Our study provides opinions regarding diagnosis and management of OPL, but it has limitations. First, the response to the survey was relatively low, and approximately one-third of the surveys were returned unopened, owing to the addressees change in address or retirement from practice or other unknown reasons. We did not have access to the nonresponders demographic information. A second limitation was that we used a questionnaire as a survey tool to determine consensus opinions. One should use caution in generalizing these opinions to all clinical cases, as case diagnosis and management should be assessed on an individualized basis.
CONCLUSIONS

As there are no evidence-based guidelines for early detection, treatment and follow-up of OPL, the development of guidelines for approaches to diagnosis and use of adjuvant tests is needed. Our study characterizes the lines of consensus of ABOM diplomates and may demonstrate to general health care providers the complexity of the evidence-based management of OPL. Dental care providers and other health care providers should be aware of the current lack of evidence-based guidelines and note that referring patients with suspect lesions to experienced dental care providers is recommended, owing to the subjective nature of detecting abnormalities and of assessing changes in the appearance and behavior of a lesion, the lack of a recommended schedule of follow-up visits and the lack of established management guidelines for OPL.
A copy of the survey instrument used in this study is posted on JADA Online (http://jada.ada.org). Interested readers may link to this article online, then click on the link in the Supplemental Data box. The authors would like to express their appreciation to the diplomates of the American Board of Oral Medicine who completed the survey. The authors would like to thank Dr. Cyril Meyerowitz for his constructive advice with the study design. 1. American Cancer Society. Cancer facts and figures 2006. Atlanta: American Cancer Society; 2006. 2. Silverman S Jr. Demographics and occurrence of oral and pharyngeal cancers: the outcomes, the trends, the challenge. JADA 2001; 132(supplement):7S-11S. 3. National Cancer Institute. Surveillance, epidemiology, and end results program public-use data, 1973-1998. Rockville, Md.: National Cancer Institute, Division of Cancer Control and Population Sciences, Surveillance Research Program, Cancer Statistics Branch; 2001. 4. Shiboski CH, Shiboski SC, Silverman S Jr. Trends in oral cancer rates in the United States, 1973-1996. Community Dent Oral Epidemiol 2000;28(4):249-56. 5. Bouquot JE, Meckstroth RL. Oral cancer in a tobacco-chewing US population: no apparent increased incidence or mortality. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1998;86(6):697-706. 6. Martin-Granizo R, Rodriguez-Campo F, Naval L, Diaz Gonzalez FJ. Squamous cell carcinoma of the oral cavity in patients younger than 40 years. Otolaryngol Head Neck Surg 1997;117(3 pt 1):268-75.

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