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J Am Dent Assoc, Vol 138, No 12, 1555-1562.
© 2007 American Dental Association
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CLINICAL PRACTICE

JADA Continuing Education

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 and Sharon Elad, DMD, MSc


   ABSTRACT
TOP
 ABSTRACT
MATERIAL AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
Background. Early diagnosis of oral premalignant lesions (OPLs) and oral squamous cell carcinoma facilitates treatment with less aggressive approaches and results in a better prognosis. The authors conducted a 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 two-week 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

Abbreviations: 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

In 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.

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 intra-oral 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
TOP
 ABSTRACT
 MATERIAL AND METHODS
RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
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 included multiple-choice questions and closed-ended 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 university’s 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
TOP
 ABSTRACT
 MATERIAL AND METHODS
 RESULTS
DISCUSSION
 CONCLUSIONS
 REFERENCES
 
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 (FigureGo). 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 Lugol’s iodine or chemiluminescent light.


Figure 1
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  		Figure. Flowchart of initial clinical approach.

 
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 (FigureGo). Nineteen (40.4 percent) of those who said they would perform a biopsy said they would use an adjuvant test, most frequently toluidine blue, to guide biopsy site selection. In addition, 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 performing biopsies on suspected leukoplakia lesions. Although all biopsy specimens are sent for hematoxylin and eosin staining, four responders (4.6 percent) said they also send the biopsy specimens for immunofluorescence to rule out possible immune-mediated 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 diagnosing a persisting oral lesion that may be an OPL. Responders rated patients’ characteristics that affect their decisions to perform a biopsy of the mucosal lesion (Table 1Go). Findings in the patients’ medical histories that accelerated the decision to perform a biopsy include past malignancies (90.8 percent), tobacco smoking (89.2 percent) and alcohol use (86.2 percent). Immunosuppression or use of chewing or smokeless tobacco increased most responders’ decisions to perform a biopsy (83.1 percent and 80.0 percent, respectively), whereas 3.1 percent of the responders reported that such findings decreased their intention to perform a biopsy.


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  		TABLE 1 Patients’ characteristics affecting responders’ decisions to perform a biopsy.*

 
The anatomical location of the lesion and lesion’s characteristics also affect clinicians’ decisions to perform a biopsy of a potential OPL. Induration and a red component were the leading clinical signs accelerating responders’ decisions to perform a biopsy (92.3 percent each), followed by nonhomogeneous surface (89.2 percent), ulceration in the lesion (86.2 percent) and verrucous surface (83.1 percent). Unilateral lesions and those with a size greater than 15 millimeters were considered a cause for increased concern by 67.7 percent and 66.2 percent of responders, respectively. Pedunculated white lesions (30.8 percent) and a homogeneous clinical surface (18.5 percent) had the least effect on responders’ decisions. Symptoms associated with oral leukoplakia that caused an increase in responders’ concern leading to biopsy include numbness (86.2 percent), regional sensory changes (78.5 percent) and pain (61.5 percent). The three oral sites of greatest concern were the floor of the mouth (89.2 percent), lateral or ventral surface of the tongue (89.2 percent) and the tonsillar fossa (70.8 percent).

Follow-up of OPL lesions. The responders’ recommended follow-up schedule was made on the basis of the clinical appearance of the oral lesions (Table 2Go, page 1559). Twenty-six responders (40.0 percent) recommended a biannual follow-up for uniform white lesions, and 35 responders (53.9 percent) recommended an increase in frequency of follow-up for uniform red lesions. Although 27 responders (41.5 percent) recommended one follow-up visit per year for striated white lesions (most of which probably are lichen planus), an increase in the number of follow-up visits per year was suggested by 46 responders (70.8 percent) when a red component is present in the striated lesion. Thirty-eight responders (58.5 percent) recommended at least three follow-up visits per year for mixed-patched lesions. Different assessment utilities are used in follow-up examinations of oral lesions, depending on lesion characteristics. Biopsy and photographic documentation are the leading clinical methods used by the responders.


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  		TABLE 2 Recommended frequency of follow-up for oral mucosal lesions on the basis of clinical parameters.

 
Management of OPL lesions. We found that the frequency of follow-up for patients with a biopsy-confirmed potential OPL was variable and influenced by a number of findings. The histopathologic diagnosis of moderate or severe dysplasia was the most influential finding leading to an increase in frequency of follow-up visits for 63 (96.9 percent) and 65 (100 percent) of responders, respectively. The patient’s use of alcohol, smoking more than 10 cigarettes per day and having a history of chronic immunosuppressive treatment led to an increase in follow-up frequency for 61 responders’ (93.8 percent), followed by clinical texture changes for 58 responders (89.2 percent) and symptomatic lesions for 43 responders (66.2 percent). A total of seven responders (10.1 percent) and 14 responders (21.2 percent) did not recommend an increase in frequency of follow-up for lesions with benign histopathologic findings or asymptomatic lesions, respectively.

The majority of responders (66.2 percent) recommended an additional biopsy during follow-up of an OPL whenever the lesion changes in appearance rather than performing biopsies at predetermined intervals (Table 3Go). Seventeen responders (26.1 percent) recommended at least one biopsy per year for uniform red lesions, and 12 responders (18.4 percent) recommended the same for mixed-striated white and red lesions.


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  		TABLE 3 Estimated frequency of biopsy performed during follow-up for oral premalignant lesions.

 
We asked responders to grade the elements that influenced their recommendation of biopsy during follow-up. Sixty-three clinicians (96.9 percent) indicated that an initial biopsy performed when moderate or severe dysplasia was present played a major role in their decision to perform another biopsy for persisting lesions at follow-up visits. We also found that a change in the texture of the lesions and a patient’s regularly using alcohol and smoking more than 10 cigarettes per day influenced the decisions of 60 responders (92.3 percent) and 58 responders (89.2 percent), respectively, to perform biopsies at follow-up visits.

Responders reported that management during follow-up appointments included evaluations of lifestyle changes. Reinforcement of reduction or cessation of tobacco use was recommended by 54 responders (83.0 percent) for patients with white uniform lesions, red uniform lesions, or mixed-striated or mixed-patched white or red lesions. Thirty-four responders (52.3 percent) used aids for tobacco-use cessation. Forty-eight responders (73.8 percent) addressed reduction or elimination of alcohol use, regardless of the patients’ lesions’ clinical characteristics.

Via the questionnaire, we asked the responders’ opinions regarding surgical and nonsurgical treatment modalities for the management of OPLs. Surgical removal of lesions by means of scalpel excision was suggested by 45 responders (69.2 percent), laser removal was suggested by 13 responders (20.0 percent), and cryosurgery or other combined surgical modality with more than one removal method was suggested by two responders (3.1 percent). If lesions recur after excision, responders reported that they would consider additional or different approaches (Table 4Go). The most commonly recommended treatments were performing another biopsy by 60 responders (92.3 percent) and re-excision by 54 responders (84.4 percent).


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  		TABLE 4 Preferred treatment for oral premalignant lesions that recur after excision.*

 
Management of oral lesions by using topical or systemic therapies also was recommended. Eight responders (12.3 percent) recommended use of topical vitamin A and derivatives for uniform white lesions. Thirty-four responders (52.3 percent) recommended use of topical steroids for lesions with a red component. In cases in which systemic treatment was considered, 27 responders (41.5) recommended systemic steroids for mixed-striated lesions, and 17 responders (26.2 percent) recommended the same for both white and red lesions.


   DISCUSSION
TOP
 ABSTRACT
 MATERIAL AND METHODS
 RESULTS
 DISCUSSION
CONCLUSIONS
 REFERENCES
 
In the era of evidence-based health care, multiple sources of scientific information are categorized according to a structured hierarchy. Although white and red oral lesions have been recognized by the World Health Organization (WHO) as pre-malignant lesions,12 no evidence-based guidelines for diagnosis, management and follow-up have been published. In addition, new technologies are becoming available that may make guidelines for early detection even more complex. Our survey of current clinical approaches used by experienced health care providers may represent a summary of nationwide experience. Sharing the practices of experienced professionals with the broad dental community may provide dental clinicians with a view of the clinical decision-making process used in diagnosing and managing oral mucosal lesions and help providers assess their approach to the care of patients with oral mucosal lesions. The results of our survey reflect the opinions of ABOM diplomates who were involved actively in the care of such patients at the time the survey was conducted. The results, however, do not provide a review of the approaches to diagnosis and treatment used by general dental care providers or other specialists in dentistry or medicine.

The definition of leukoplakia proposed by WHO in 197812 is "a white patch or plaque that cannot be characterized clinically or pathologically as any other disease," and it was accepted by 60.0 percent of responders in our study. Three percent of responders extended this definition by adding, "not associated with any physical or chemical causative agent except the use of tobacco." The fact that leukoplakic lesions are associated with some risk of malignant transformation was endorsed by 13.8 percent of the responders. Although most white lesions represent benign hyperkeratosis, the clinical diagnosis of leukoplakia may be associated with a continuum of histopathologically defined diagnoses ranging from benign lesions to dysplastic lesions and to OSCC.13 Dysplasia within a lesion represents an increased risk of malignant transformation to cancer.13 Erythroplakia is defined as a red patch that cannot be clinically or pathologically diagnosed as any other condition and is associated with dysplastic or malignant change more frequently than is leukoplakia.12 Red lesions attributable to known causes such as inflammatory or immune conditions are excluded from the definition of erythroplakia.

For most ABOM diplomates, the initial clinical approach for lesions suspected to be leukoplakia, erythroplakia or mixed leukoerythroplakia was to determine the nature of the lesion. They treated a lesion they thought may have represented inflammatory conditions by eliminating potential causes and reevaluating the lesion after two weeks. If the lesion persisted, they performed a biopsy.

Adjuvant tests may help evaluate the lesion, select the biopsy site or both. Toluidine blue has been shown in single-center and multicenter studies to help identify OPLs and OSCC, to provide information about lesion margins and to aid in biopsy site selection.14,16–22 Toluidine blue appears to be retained in cells that have genetic changes associated with OPLs and OSCC,20–23 and it is the most common adjuvant technique used clinically to assess oral lesions. The introduction of the minimally invasive oral brush biopsy test used to collect oral mucosal transepithelial samples for a computerized cytologic examination and pathologist review24,25 has increased the attention given to early detection. Cytology, an initial diagnostic approach used to enhance early diagnosis of OPL and cancer, was used by 24 percent of responders to diagnose white lesions. The diagnostic value of the oral brush biopsy test has been studied, and a sensitivity of 92.3 percent and a specificity of 94.3 percent were recorded in one study24; however, the variable false-positive and false-negative results reported with the oral brush biopsy test26–32 and the fact that use of the oral brush biopsy test may delay performance of a biopsy may be reasons why responders used it infrequently.

Devices that may promote detection by means of enhancing the visibility of oral lesions have been introduced, although the U.S. Food and Drug Administration had not cleared some at the time we conducted our survey. The oral lesion identification and marking system uses a low-energy wavelength chemiluminescent disposable light source (ViziLite, Zila, Phoenix) to improve the visibility of oral mucosal lesions.32 Using the chemiluminescent light with toluidine blue swabs (ViziLite Plus TBlue630, Zila) has been cleared by the FDA.33,34 In single-center and multicenter studies, the oral lesion identification and marking system has been shown to help clinicians detect abnormal mucosal lesions early and to guide practitioners 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 addressee’s 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
TOP
 ABSTRACT
 MATERIAL AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
REFERENCES
 
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.


   FOOTNOTES
 

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


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{at}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.


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.


   REFERENCES
TOP
 ABSTRACT
 MATERIAL AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 

  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.[Medline]

  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.[Medline]

  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.[Medline]

  7. National Cancer Institute. Oral cancer (PDQ): Prevention. Available at: "www.cancer.gov.cancertopics/pdq/prevention/oral/healthprofessional/allpages". Accessed Sept. 10, 2006.

  8. Horowitz AM, Alfano MC. Perform a death-defying act: the 90-second oral cancer examination. JADA 2001;132(supplement):36S–40S.

  9. Silverman S Jr, Gorsky M, Lozada F. Oral leukoplakia and malignant transformation: a follow-up study of 257 patients. Cancer 1984; 53(3):563–8.[Medline]

  10. Gorsky M, Dayan D. Referral delay in diagnosis of oro/oropharyngeal cancer in Israel. Eur J Cancer B Oral Oncol 1995; 31B(3):166–8.

  11. Gellrich NC, Suarez-Cunqueiro MM, Bremerich A, Schramm A. Characteristics of oral cancer in a central European population: defining the dentist’s role. JADA 2003;134(3):307–14.

  12. Kramer IR, Lucas RB, Pindborg JJ, Sobin LH. Definition of leukoplakia and related lesions: an aid to studies on oral precancer. Oral Surg Oral Med Oral Pathol 1978;46(4);518–39.[Medline]

  13. Reibel J. Prognosis of oral pre-malignant lesions: significance of clinical, histopathological, and molecular biological characteristics. Crit Rev Oral Biol Med 2003;14(1):47–62.[Abstract/Free Full Text]

  14. Epstein JB, Oakley C, Millner A, Emerton S, van der Meij E, Le N. The utility of toluidine blue application as a diagnostic aid in patients previously treated for upper oropharyngeal carcinoma. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1997;83(5):537–47.[Medline]

  15. Epstein JB, Scully C, Spinelli J. Toluidine blue and Lugol’s iodine application in the assessment of oral malignant disease and lesions at risk of malignancy. J Oral Pathol Med 1992;21(4):160–3.[Medline]

  16. Epstein JB, Feldman R, Dolor RJ, Porter SR. The utility of tolonium chloride rinse in the diagnosis of recurrent or second primary cancers in patients with prior upper aerodigestive tract cancer. Head Neck 2003;25(11):911–21.[Medline]

  17. Onofre MA, Sposto MR, Navarro CM. Reliability of toluidine blue application in the detection of oral epithelial dysplasia and in situ and invasive squamous cell carcinomas. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2001;91(5):535–40.[Medline]

  18. Portugal LG, Wilson KM, Biddinger PW, Gluckman JL. The role of toluidine blue in assessing margin status after resection of squamous cell carcinomas of the upper aerodigestive tract. Arch Otolaryngol Head Neck Surg 1996;122(5):517–9.[Abstract]

  19. Kerawala CJ, Beale V, Reed M, Martin IC. The role of vital tissue staining in the marginal control of oral squamous cell carcinoma. Int J Oral Maxillofac Surg 2000;29(1):32–5.[Medline]

  20. Epstein JB, Zhang L, Poh C, Nakamura H, Berean K, Rosin M. Increased allelic loss in toluidine blue-positive oral premalignant lesions. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2003;95(1): 45–50.[Medline]

  21. Zhang L, Williams M, Poh CF, et al. Toluidine blue staining identifies high-risk primary oral premalignant lesions with poor outcome. Cancer Res 2005;65(17):8017–21.[Abstract/Free Full Text]

  22. Epstein JB, Sciubba J, Silverman S Jr, Sroussi HY. Utility of toluidine blue in oral premalignant lesions and squamous cell carcinoma: continuing research and implications for clinical practice. Head Neck 2007;29(10):948–58.[Medline]

  23. Guo Z, Yamaguchi K, Sanchez-Cespedes M, Westra WH, Koch WM, Sidransky D. Allelic losses in OraTest-directed biopsies of patients with prior upper aerodigestive tract malignancy. Clin Cancer Res 2001;7(7):1963–8.[Abstract/Free Full Text]

  24. Sciubba JJ; for U.S. Collaborative OralCDx Study Group. Improving detection of precancerous and cancerous oral lesions: computer-assisted analysis of the oral brush biopsy. JADA 1999; 130(10):1445–57.

  25. Scheifele C, Schmidt-Westhausen AM, Dietrich T, Reichart PA. The sensitivity and specificity of the OralCDx technique: evaluation of 103 cases. Oral Oncol 2004;40(8):824–8.[Medline]

  26. Pektas ZO, Keskin A, Günhan O, Karslio lu Y. Evaluation of nuclear morphometry and DNA ploidy status for detection of malignant and premalignant oral lesions: quantitative cytologic assessment and review of methods for cytomorphometric measurements. J Oral Maxillofac Surg 2006;64(4):628–35.[Medline]

  27. Poate TW, Buchanan JA, Hodgson TA, et al. An audit of the efficacy of the oral brush biopsy technique in a specialist oral medicine unit. Oral Oncol 2004;40(8):829–34.[Medline]

  28. Rick GM. Oral brush biopsy: the problem of false positives. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2003;96(3):252.[Medline]

  29. Potter TJ, Summerlin DJ, Campbell JH. Oral malignancies associated with negative transepithelial brush biopsy. J Oral Maxillofac Surg 2003;61(6):674–7.[Medline]

  30. Svirsky JA, Burns JC, Carpenter WM, et al. Comparison of computer-assisted brush biopsy results with follow up scalpel biopsy and histology. Gen Dent 2002;50(6):500–3.[Medline]

  31. Christian DC. Computer-assisted analysis of oral brush biopsies at an oral cancer screening program. JADA 2002;133(3):357–62.

  32. Kerr AR, Sirois DA, Epstein JB. Clinical evaluation of chemiluminescent lighting: an adjunct for oral mucosal examinations. J Clin Dent 2006;17(3):59–63.[Medline]

  33. Epstein JB, Gorsky M, Lonky S, Silverman S Jr, Epstein JD, Bride M. The efficacy of oral lumenoscopy (ViziLite) in visualizing oral mucosal lesions. Spec Care Dentist 2006;26(4):171–4.[Medline]

  34. Epstein JB, Silverman S Jr, Epstein JD, Lonky SA, Bride MA. Analysis of oral lesion biopsies identified and evaluated by visual examination, chemiluminescence and toluidine blue. Oral Oncology (in press).

  35. Lane PM, Gilhuly T, Whitehead P, et al. Simple device for the direct visualization of oral-cavity tissue fluorescence. J Biomed Opt 2006;11(2):024006.[Medline]

  36. Poh CF, Zhang L, Anderson DW, et al. Fluorescence visualization detection of field alterations in tumor margins of oral cancer patients. Clin Cancer Res 2006;12(22):6716–22.[Abstract/Free Full Text]

  37. De Veld DC, Witjes MJ, Sterenborg HJ, Roodenburg JL. The status of in vivo autofluorescence spectroscopy and imaging for oral oncology. Oral Oncol 2005;41(2):117–31.[Medline]

  38. Epstein JB, Gorsky M, Wong FL, Millner A. Topical bleomycin for the treatment of dysplastic oral leukoplakia. Cancer 1998;83(4):629–34.[Medline]

  39. Lodi G, Sardella A, Bez C, Demarosi F, Carrassi A. Interventions for treating oral leukoplakia. Cochrane Database Syst Rev 2004;(3): CD001829.

  40. Gorsky M, Epstein JB. The effect of retinoids on premalignant oral lesions: focus on topical therapy. Cancer 2002;95(6):1258–64.[Medline]

  41. Zhang L, Poh CF, Lam WL, et al. Impact of localized treatment in reducing risk of progression of low-grade oral dysplasia: molecular evidence of incomplete resection. Oral Oncol 2001;37(6):505–12.[Medline]

  42. Epstein JB, Wan LS, Gorsky M, Zhang L. Oral lichen planus: progress in understanding its malignant potential and the implications for clinical management. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2003:96(1):32–7.[Medline]

  43. Curtis RE, Rowlings PA, Deeg HJ, et al. Solid cancers after bone marrow transplantation. N Engl J Med 1997;336(13):897–904.[Abstract/Free Full Text]

  44. Demarosi F, Lodi G, Carrassi A, Soligo D, Sardella A. Oral malignancies following HSCT: graft versus host disease and other risk factors. Oral Oncol 2005;41(9):865–77.[Medline]

  45. Scheifelle C, Reichart PA, Hippler-Benscheidt M, Neuhaus P, Neuhaus R. Incidence of oral, pharyngeal, and laryngeal squamous cell carcinomas among 1515 patients after liver transplantation. Oral Oncol 2005;41(7):670–6.[Medline]





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