Analysis of oral lesion biopsies identified and evaluated by visual examination, chemiluminescence and toluidine blue
Introduction
Approximately 30,000 patients per year are diagnosed with oral cavity or oropharyngeal squamous cell carcinoma (OSCC) in the United States, accounting for 3% of all cancers.1, 2, 3 The baseline annual risk is approximately 1/10,000 of the total adult USA population.4 While 84% of patients with oropharyngeal cancers will survive at least one year following diagnosis, overall, 40% of newly diagnosed patients will die within five years.5, 6
Ninety-five percent of OSCC cases occur in patients over 40 years of age and well known risk factors include tobacco and alcohol use.6, 7 Tobacco has been implicated in 90% of all oral and pharyngeal cases and increases the relative risk by 8–20 times for developing squamous cell cancer.7 As a synergistic cofactor with tobacco, alcohol can increase the risk of OSCC by 80 times7 and as an etiologic agent, alone alcohol increases relative risk by a factor of six.8 Human papillomavirus (HPV 16 and 18) has been reported in 18.9% of oropharyngeal cancers and 3.9% of oral cavity cancers9 and represents an additional risk factor.
Eighty-five percent of oral premalignant lesions (OPLs) and/or malignancies may present as leukoplakias.10, 11, 12 Leukoplakias examined microscopically may show hyperkeratosis with some degree of dysplasia in 20% of cases.13 Lesions of the tongue and floor of the mouth are the most likely to be dysplastic (25% and 50%, respectively).13 Although more rare, erythroplakia is clinically significant. Ninety-one percent of erythroplakic lesions represent severe dysplasia or carcinoma.14 Generally, erythroplakia is seen in elderly males (average age = 70) with the most common sites being the lateral border of the tongue, floor of mouth, soft palate, and retromolar pad.15
Although the risk profile of those at risk for developing oral cancer has been well-studied, the rate of death has remained virtually unchanged over the past three decades.5 Five year survival rates are expected to improve if OSCC is detected earlier.5, 6 Discovering and appropriately treating OPLs and OSCC (Stage I, or Stage II tumor)10 is anticipated to result in less aggressive treatment, reduced morbidities and improvement in the rates of survival.
Visual examination continues to be the gold-standard for the detection of early epithelial changes. The criteria for suspicion of an OPL or OSCC include changes in surface texture, loss of surface integrity, color, size, contour deviations or mobility of intraoral or extraoral structures.
A comprehensive head and neck and oral cancer examination is a practical part of routine office visits. Numerous articles have recently been published emphasizing the importance of performing a standard, reproducible, and frequent soft tissue head and neck examination that can be satisfactorily performed in 90 s to 3 min.16, 18, 19 Unfortunately, this comprehensive examination may not be performed as routinely or as frequently as recommended,17, 29 even though a standard visual examination for suspicious lesions is critical for identifying and diagnosing mucosal disease.
The use of acetic acid followed by chemiluminescent illumination for the identification of superficial lesions and improvement in visual lesion parameters has been previously described by Huber et al. 20 and Epstein et al.21 It’s predicate device and application, Speculoscopy (an adjunct to Pap smear of the uterine cervix), utilizes the same chemiluminescent light source (with peak outputs near 430, 540 and 580 nm) to detect cervical lesions after an acetic acid wash.22, 23, 24 In one study24 of 3300 female patients, negative predictive values (NPV) for SCC of 94.7% and 99.1% were demonstrated using Pap smears alone and Speculoscopy followed by Pap smear, respectively. Because visual presentation of cervical and oral/pharyngeal lesions, including SCC, are nearly identical under chemiluminescence,20 this approach has been applied to the oral cavity examination.
The clinical application of toluidine blue has been shown to be selective for staining of premalignant and malignant lesions.25, 26, 27, 28, 29, 30 In the oral cavity, toluidine blue has been shown to be related to genetic changes (allelic loss or loss of heterozygosity [LOH]) that are associated with progression of OPLs to cancer even in histologically benign lesions and lesions with mild dysplasia.28, 29 Biopsy specimens were assessed for LOH and toluidine blue positive specimen harbored LOH changes associated biopsy even in cases with benign histology, suggesting that toluidine blue positive specimen is related to at risk LOH profiles, that may be present prior to histologic phenotypic change.29 Further, a longitudinal study showed that Toluidine blue identified LOH positive lesions that progressed to cancer.28 The reported sensitivity of toluidine blue positive staining in one meta-analytical study ranged from 93.5% to 97.8% and the specificity ranged from 73.3% to 92.9% in patients at high risk for OSCC.25 In the highest risk population of prior upper autodigestive tract cancer patients, Epstein et al. demonstrated sensitivity improvement to detect carcinoma in situ (CIS) and OSCC with the use of toluidine blue when compared to a conventional visual exam (96.7% and 40%, respectively).26 False positive staining (when lesions stain blue, but no carcinoma is identified after a biopsy is taken) occurred in 8–10% of cases associated with keratotic lesions and the regenerating edges of ulcers and erosions.27 These studies show the potential utility of toluidine blue to identify both OPLs and SCC. Here, the probability of a false negative finding for invasive carcinoma is very low and the absolute number of false positive tests is expected to be reduced given the high sensitivity of the toluidine blue in high risk populations.
This study is the first report of the use of a chemiluminescent light source (ViziLite®) and the additive value of an application of pharmaceutical grade toluidine blue (TBlue630™) applied to lesions previously identified by visual examination with histologic outcomes. We postulated chemiluminescence would enhance the lesion characteristics used in identification in a majority of the cases and that due to preferential uptake of toluidine blue by pathological tissues, the total number of biopsies could be reduced for lesions which were identified, but did not retain the dye.
Section snippets
Materials and methods
Patients were identified in clinics at three study sites: the University of California San Francisco (UCSF), the University of Illinois Chicago (UIC), and the British Columbia Cancer Agency (BCCA) and were enrolled after completing institutionally approved informed consent.
Results
Eighty-four patients enrolled in the study, in which 97 lesions were observed. Sixty-seven patients (79.8%) in this study reported a prior diagnosis of oral cancer or white lesions, 16 (19.0%) reported information on the preliminary questionnaire which identified them as high risk (tobacco and/or alcohol use), and one (1.2%) had missing data. The average patient age was 59.64 (Standard deviation =12.53) and female patients represented 51.19% of the sample.
The majority of patients were either
Discussion
We assessed the adjunctive utility of a chemiluminescent exam and application of a toluidine blue stain for detecting serious pathology when compared with the traditional visual exam of the oral cavity. The figures show clinical examples of examination with incandescent light, chemiluminescence and toluidine blue (Figure 1, Figure 2, Figure 3). This is the first report assessing chemiluminescence illumination and toluidine blue with histologic outcomes.
The chemiluminescent exam identified all
Conflict of Interest Statement
Clinical funding was supported by Trylon Corp Inc, Torrance, CA. Drs. Silverman and Epstein are members of the Medical Advisory Board for Zila, Inc.
Acknowledgements
The authors acknowledge the clinical assistance of Dr. M. Yao at the University of Illinois, Department of Otolaryngology and Head and Neck Surgery, Chicago; Dr. P.M. Williams and Dr. A. Hovan at the British Columbia Cancer Agency, Vancouver; Dr. D. Keiles, Dr. N. Chainani-Wu at the University of California at San Francisco, and Dr. W. Carpenter at the University of the Pacific San Francisco.
References (30)
Demographics and occurrence of oral and pharyngeal cancers. The outcomes, the trends, the challenge
J Am Dent Assoc
(2001)- et al.
Perform a death-defying act: the 90-second oral cancer examination
J Am Dent Assoc
(2001) - et al.
Tobacco smoking history and presentation of oral squamous cell carcinoma
J Oral Maxil Surg
(2004) - et al.
Use of meta-analysis to evaluate tolonium chloride in oral cancer screening
Oral Surg Oral Med Oral Pathol
(1989) - Silverman S Jr. Oral Cancer. 5th ed. Hamilton, ON: BC Decker [hard cover; sponsored by the American Cancer Society]...
- et al.
Head and neck cancer
- Jemal A, Murray T, Ward E, Samuels A, Tiowari RC, Ghafoor A et al. Cancer statistics, 2005. CA Cancer J Clin.Jan–Feb...
- et al.
Evaluation of oral cancer screening
J Cancer Educ
(1997) - American Cancer Society. Cancer Facts and Figures 2006. Atlanta: American Cancer Socity; 2006. Available at:...
- et al.
Smoking and drinking in relation to oral and pharyngeal cancer
Cancer Res
(1988)
for the IARC Multicenter Oral Cancer Study Group. Human papillomavirus and oral cancer: the international agency for research on cancer multicenter study
J Natl Cancer Inst
Early diagnosis of asymptomatic oral and oropharyngeal cancer
CA: Cancer J Clin
Oral and maxillofacial pathology
Cited by (126)
Oral squamous cell carcinoma
2023, Biomarkers in Cancer Detection and Monitoring of Therapeutics: Diagnostic and Therapeutic Applications: Volume 2Efficacy of non-invasive diagnostic methods in the diagnosis and screening of oral cancer and precancer
2022, Brazilian Journal of OtorhinolaryngologyCitation Excerpt :Linear regression test of funnel plot asymmetry also showed no significant publication bias (p > 0.05). Conventional visual assessment and tactile examination of the oral cavity remains the gold standard for the identification of oral mucosal lesions.15 However, an adjunctive method to detect OPMD has been reported showing a proper diagnostic yield.25
Comparative study of effectiveness of colposcopic examination versus visual examination for determining the biopsy site of potentially premalignant oral epithelial lesions
2022, Journal of Stomatology, Oral and Maxillofacial SurgeryEfficacy of chemiluminescence in the diagnosis and screening of oral cancer and precancer: a systematic review and meta-analysis
2022, Brazilian Journal of OtorhinolaryngologyCitation Excerpt :These results indicated that, in a patient with an obvious neoplastic lesion, there is no difference in diagnostic accuracy between chemiluminescence and toluidine blue; however, when toluidine blue screening generates negative neoplasm findings, chemiluminescence is more sensitive for identification of suspicious lesions. The high sensitivity of chemiluminescent illumination can be attributed to the increased brightness and clarity of oral lesions, which improves the likelihood of identifying a lesion that may be missed in a standard examination performed by general practitioners.9 Thus, chemiluminescence would be more effective than toluidine blue in identifying non-symptomatic and clinically obscure lesions.5