A New Look At Oral Dysplasia

Approximately 300,000 cases of oral cancer are diagnosed annually worldwide1 with an overall mortality of approximately 40 percent in the United States2, predominately because of diagnosis at a late stage3 (Fig. 1). Early diagnosis of localized disease significantly reduces the mortality rate.

FIGURE 1. Carcinoma on the right maxillary tuberosity.

Carcinoma on the right maxillary  tuberosity.

The most common form of oral cancer, squamous cell carcinoma of the mucosa, generally develops in a stepwise fashion from normal through stages of premalignancy to invasive carcinoma.5 The premalignant stages can have various presentations including white lesions, red lesions or white/red lesions. They may be flat, verrucous or even papillary. These premalignant oral lesions occur in approximately 2.5 percent of the population and are usually asymptomatic.5,6 They are generally detected as an incidental finding during a routine dental examination (Fig. 2).

FIGURE 2. Oral dysplasia of the right tongue.
Renick Fig2 Oral dysplasia

Whereas, treatment for a premalignant lesion or an early oral squamous cell carcinoma might involve only minor surgical excision and careful follow-up monitoring, more advanced disease requires extensive resection, often including neck dissection and/or radiotherapy (Fig. 3). These treatments result in considerable morbidity and expense. Patients suffer from both functional and cosmetic deficits, experience dysgeusia, dysphagia, dysphonia, xerostomia and difficulty with mastication. If radiotherapy is employed, patients are prone to future dental caries and osteoradionecrosis. Those patients with advanced metastatic disease generally have a poor response to interceptive chemotherapy and treatment is primarily palliative.

FIGURE 3. Roger Ebert (Left) after undergoing surgeries to remove oral cancer tissue near his right jaw. (Right) A portrait of Roger before his surgeries.
Renick Fig3 Ebert

The dental community of hygienists, dentists and dental specialists has the opportunity to play a significant role in the early diagnosis and treatment of oral cancer. The majority of the general public does not tend to see their physician on as a regular basis as their dentist. When they do the see their physician, the oral examination at the physician’s office is rarely as detailed as that when they see their dentist. Dentists are much more alert to oral disease and potentially premalignant lesions (Fig. 4). A number of screening products are available but studies have questioned their usefulness. The use of Toluidine Blue and various examination lights are of questionable value over a properly executed oral examination for the detection of malignant or premalignant oral lesions.7-11 Ultimately, a biopsy is necessary to establish a diagnosis.

FIGURE 4. Oral dysplasia  on the floor of the mouth. 
Renick Fig4 white patch

At present, the standard care for assessment of premalignant lesions is dysplasia grading using routine histopathology. Lesions are graded as mild, moderate, or severely dysplastic. The grading system, while based on objective guidelines, is largely subjective in nature.12 There can be considerable overlap between grades and pathologists do not in every case arrive at the same diagnostic conclusion.13 Dysplasia grading is not always reliable and has limited value in predicting the risk of future malignant transformation in patients who have been biopsied. Patients want to know if they will develop intraoral cancer and clinicians would like some objective direction regarding frequency for patient follow-up reassessment. The limitations of our current practice has led to a widely recognized urgent need for more effective prognostic biomarkers, which might assign a risk for cancer development in patients diagnosed with oral premalignant lesions. This risk assessment would provide some clarity for patients and guidance for care providers.

Patients who have a dysplastic and potentially premalignant epithelial lesion or have treated for oral SCC face another concern. Premalignant molecular changes may have occurred in tissue distant from the original lesion or distant from the resection margins without apparent clinical changes. When the margins of biopsied tissue are examined under the microscope using conventional histopathology, they may appear normal and the lesion may seem to be adequately excised, when in fact there are precancerous changes at the margins or remote from the original lesion. Conventional histopathology can confirm that the resection margins are free of microscopic dysplastic change but cannot detect molecular changes or offer advice regarding possible recurrence at the resection site.

Researchers at York University and Mount Sinai Hospital in Toronto, Canada, studying proteins in tissue from oral-pharyngeal cancers identified a number of proteins associated with malignant change. One of several potential protein biomarkers, which the scientists thought might precede neoplastic transformation was the protein S100A7.16 When S100A7 was assessed in sequential biopsies from patients with oral dysplastic lesions, increasing levels of S100A7 were associated with malignant change. S100A7 proved to be an excellent prognostic marker for cancer progression in mucosal precancerous lesions (dysplasia; Fig. 5).17,18


It now appears possible to identify which dysplastic lesions are most at risk for developing oral squamous cell carcinoma. To further improve the sensitivity and specificity, using retrospective data from the world’s largest repository of oral premalignant/malignant tissues at Mount Sinai Hospital, an algorithm was developed, which assigned the relative risk for malignant change in a biopsy sample, using digitally scanned S100A7 stained sections (Fig. 6). This was further refined in the most recent version of the program to include morphometric cellular assessment to determine which patients with oral precancerous lesions were most likely to develop oral carcinoma and inform them of their risk for future oral cancer. No additional biopsy material is required from the patient as the assessment is performed on tissue submitted for conventional histopathology.


Renick Fig7 Flow
This new assessment service, which provides for patients an individualized five-year cancer progression risk, is now available from Proteocyte Diagnostics Inc. of Toronto, under the trade name Straticyte (Fig. 7). It is currently being beta clinically tested in Ontario and will be widely available shortly and the reliability of the service will be further improved as more data is collected with expansion of the service. Finally, we have an assessment that provides some objective input for the rational management of patients with oral premalignant disease. Straticyte may revolutionize how we care for these patients. OH


Barrie M. Renick, South Lake Hosptial and Private Practice, Newmarket. Unpaid advisor to Proteocyte Diagnostics, Toronto.

Oral Health welcomes this original article.

1. Ferlay J, S.I., Ervik M, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, Bray, F., GLOBOCAN 2012 v1.0, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11. 2012, International Agency for Research on Cancer.

2. 2Siegel, R., D. Naishadham, and A. Jemal, Cancer statistics, 2012. CA Cancer J Clin, 2012. 62(1): p. 10-29.

3. 3Lingen, M.W., et al., Critical evaluation of diagnostic aids for the detection of oral cancer. Oral Oncol, 2008. 44(1): p. 10-22.

4. Jacobson, J.J., et al., The cost burden of oral, oral pharyngeal, and salivary gland cancers in three groups: commercial insurance, Medicare, and Medicaid. Head Neck Oncol, 2012. 4: p. 15.

5. McCullough, M.J., G. Prasad, and C.S. Farah, Oral mucosal malignancy and potentially malignant lesions: an update on the epidemiology, risk factors, diagnosis and management. Aust Dent J, 2010. 55 Suppl 1: p. 61-5.

6. Weir, J.C., W.D. Davenport, and R.L. Skinner, A diagnostic and epidemiologic survey of 15,783 oral lesions. J Am Dent Assoc, 1987. 115(3): p. 439-42.

7. Warnakulasuriya, K.A., Johnson, N.W. Sensitivity and specificity of OraScan ® toluidine blue mouthrinse in the detection of oral cancer and precancer. J Oral Pathol Med (1996) 25:97-103.

8. Martin, I.C., Kerawala, C.J., Reed, M. The application of toluidine blue as a diagnostic adjunct in the detection of epithelial dysplasia. Oral Surg Oral Med Oral pathol Oral Radiol Endod (1998) 85:444-6.

9. Oh, E.S., Laskin, D.M. Efficacy of the ViziLite system in the Identification of oral lesions. J Oral Maxillofac Surg 2007; 65:424-426.

10. Mark W. Lingen, M.W., Kalmar, J.R., Karrison, T. Speight, P.M. Critical evaluation of diagnostic aids for the detection of oral cancer. Oral Oncology (2008) 44, 10–22.

11. Kristin K. McNamara, K.K., Brent D. Martin, B.D., Evans, E.W., Kalmar, J.R. The role of direct visual fluorescent examination (VELscope) in routine screening for potentially malignant oral mucosal lesions. Oral Surg Oral Med Oral Pathol Oral Radiol 2012;114:636-643.

12. Warnakulasuriya, S., et al., Oral epithelial dysplasia classification systems: predictive value, utility, weaknesses and scope for improvement. J Oral Pathol Med, 2008. 37(3): p. 127-33.

13. McGurk, M. and S.E. Scott, The reality of identifying early oral cancer in the general dental practice. Br Dent J, 2010. 208(8): p. 347-51.

14. Lingen, M.W., Screening for oral premalignancy and cancer: what platform and which biomarkers? Cancer Prev Res (Phila), 2010. 3(9): p. 1056-9.

15. Smith, J., et al., Biomarkers in dysplasia of the oral cavity: a systematic review. Oral Oncol, 2009. 45(8): p. 647-53.

16. Ralhan, R., et al., Discovery and verification of head-and-neck cancer biomarkers by differential protein expression analysis using iTRAQ labeling, multidimensional liquid chromatography, and tandem mass spectrometry. Mol Cell Proteomics, 2008. 7(6): p. 1162-73.

17. Kaur, J., et al., S100A7 overexpression is a predictive marker for high risk of malignant transformation in oral dysplasia. Int J Cancer, 2014. 134(6): p. 1379-88.

18. Tripathi, S.C., et al., Nuclear S100A7 is associated with poor prognosis in head and neck cancer. PLoS One, 2010. 5(8): p. e11939.