Advances in Fluorescence Imaging Techniques to Detect Oral Cancer and its Precursors

Dongsuk Shin; Nadarajah Vigneswaran; Ann Gillenwater; Rebecca Richards-Kortum


Future Oncol. 2010;6(7):1143-1154. 

In This Article

Abstract and Introduction


Oral cancer is a significant health problem in the USA and throughout the world. Most oral cancer patients are diagnosed at a late stage, when treatment is less successful and treatment-associated morbidity is more severe. A number of new diagnostic aids to conventional oral examination have recently been introduced to assist in the early detection of oral neoplasia. In particular, autofluorescence imaging has emerged as a promising adjunctive technique to improve early identification of oral premalignant lesions. Direct visual inspection of tissue autofluorescence has shown encouraging results in high-prevalence populations, but the technique requires subjective interpretation and depends on the visual recognition skills of the examiner. Capturing and analyzing digital fluorescence images can reduce subjectivity and potentially improve sensitivity of detection of precancerous changes. Recent studies of wide-field autofluorescence imaging in low-prevalence populations suggest that benign lesions such as inflammation may give rise to false-positive results. High-resolution fluorescence imaging is a new modality that can be used in conjunction with wide-field imaging to improve specificity by imaging subcellular detail of neoplastic tissues. The combination of wide-field and high-resolution fluorescence imaging systems with automated image analysis should be investigated to maximize overall diagnostic performance for early detection of oral neoplasia.


Oral cancer is the eighth most common cancer worldwide, with approximately 274,000 new cases reported annually.[1] In the USA alone, it was estimated that 35,000 new cases were reported in 2009, and 7600 deaths were expected.[2] The majority of patients diagnosed with oral cancer live in developing countries.[3] In India, for example, oral cancer ranks number one in prevalence among all cancers in male patients and number three among cancers in female patients. In south central Asia, oral cancer ranks among the three most common types of cancer. Recent epidemiologic data show sharp increases in the incidence of oral cancer reported in European countries and, to a lesser extent, the USA.[4]

Oral cancer survival rates are strongly dependent on the stage at diagnosis. Patients diagnosed with oral cancer at a localized stage have a substantially greater chance of successful treatment and less treatment-associated morbidity[2] than those diagnosed at a late stage. Improving early detection represents one of the best ways to improve survival and quality of life for oral cancer patients worldwide. In the USA, there has been only marginal improvement in the relative 5-year survival rates for oral cancer since 1975. The modest improvement in survival is due to a combination of earlier diagnosis and improved treatment.[4] In developing countries, oral cancer patients tend to be diagnosed at a later stage than in developed countries.[5] Thus, there remains an important need to improve early detection of oral cancer and its precursors.

Challenges in Oral Cancer Diagnosis & Treatment

The current goal of the International Agency for Research on Cancer, American Cancer Society and the WHO is to reduce the predicted 15 million cancer cases by a third by diagnosing and treating these cancers at their pre-neoplastic levels. Oral cancer is an ideal choice for this strategy because the oral cavity provides easy access for clinical inspection, and oral cancer development is preceded by visible mucosal changes.[6] However, only 40% of oral cancers are currently diagnosed as localized disease, which is the same rate as that of colon cancers.[6]

Despite recent diagnostic and therapeutic advances, the 5-year survival rate for oral cancer has remained less than 50% over the last 50 years owing to the following reasons:

  • The majority of oral cancer cases (60%) present with advanced stages (III and IV) at diagnosis;

  • Oral cancer has the highest risk for the development of second primary tumors ('field cancerization phenomenon') of any cancer.

The 5-year recurrence-free survival rate is 80% for stage I oral cancer patients, whereas only 20% of patients with stage IV oral cancer survive after 5 years.[7–9] Moreover, early diagnosis of oral cancer significantly reduces treatment-related morbidity and improve overall long-term survival.[10,11] Patients with a history of oral cancers are at risk of developing second primary tumors at a rate of 3.7% per year because of 'field cancerization', and a quarter of all oral cancer-related deaths are caused by second primary tumors.[12] Hence, patients who are successfully treated for oral cancer should be closely monitored, preferably using a noninvasive diagnostic test.

Diagnosis of oral cancer at an early stage or at the pre-neoplastic level is critical to improve survival in oral squamous cell carcinoma patients. However, screening via clinical examination alone by general dentists during the patients' routine dental examination has resulted in poor detection rates. Dentists frequently detect white or red patches during routine screening of an asymptomatic patient. Based on analysis of biopsies of potentially malignant oral mucosal lesions (n = 926) submitted to an UT-Dental Branch Houston oral pathology biopsy service in 2009, more than 75% of these lesions are confounding lesions, which will be microscopically diagnosed as benign, except for a small proportion (<25%) being diagnosed as oral cancer or its precursor.

General dental practitioners do not have the clinical training and experience to distinguish potentially malignant lesions from confounding lesions; hence, many of these patients need to be referred to a specialist clinic for scalpel biopsy for a definitive diagnosis.

Referring patients with potentially malignant oral lesions to specialist centers is plagued by a long waiting time leading to significant diagnostic delays.[13] A recent study conducted in the USA reported that the mean time from the initial detection of a potentially malignant lesion by a primary healthcare provider and referral to a specialist for evaluation was 35.9 days.[14] In some cases, this delay exceeded 10 months.[14] For patients with newly diagnosed oral cancer, the median delay in initial diagnosis in Canada was 4.5 weeks, which is significantly shorter than in the USA, which is reported to be 18.4 weeks.[14,15] This longer delay is attributed to the disparity in healthcare systems and health insurance-related issues in the USA.[14] It should be noted that for patients with oral cancer, delays in diagnosis by even 1 month may contribute to a diagnosis of a later stage disease.[16] Moreover, treatment delays of more than 40 days in early-stage oral cancer were associated with an increased risk of locoregional failure impacting their survival.[17] In addition, scalpel biopsy is time consuming, uncomfortable and stressful for the patient and is a relatively expensive procedure.

Therefore, developing and validating an acceptable noninvasive diagnostic test that can discriminate benign oral mucosal lesions from oral cancers and its precursors with minimal false-positive and false-negative results would be beneficial not only for the patient but also to society by reducing heathcare costs through avoiding unnecessary scalpel biopsies.

Current Oral Cancer Screening & Diagnostic Methods

The standard method for oral cancer screening has long been conventional oral examination and palpation, usually performed by dentists or physicians. Visual inspection of the oral cavity is performed under normal white light illumination, followed by palpation of suspicious lesions. Downer et al. has systematically reviewed the performance of visual examination for oral cancer detection.[18] Across the eight studies reviewed by Downer et al., sensitivity values ranged from 60 to 97% and specificity values from 75 to 99%.[18] Oral cancer specialists can often recognize subtle visual changes associated with early lesions, but community practitioners or general dentists may lack the experience to identify early lesion development.

Several visualization adjuncts to standard oral examination are now commercially available. Toluidine blue is a vital dye that has been used in the oral cavity for decades to improve the visibility of lesions during visual exam. In a recent review of the performance of visual exam with toluidine blue, sensitivity ranged from 38 to 98%, while specificity varied from 9 to 93%.[19] In general, examination with toluidine blue is associated with low specificity, and this has prevented toluidine blue from becoming a standard component of early oral cancer detection efforts in the USA.

The ViziLite® (Zila Pharmaceuticals, Inc., AZ, USA) system offers an alternative to white light illumination for visual examination; a disposable chemiluminescent light source illuminates tissue with blue light. Providers view reflected blue light to detect abnormal changes in oral cavity. Initial studies conducted by Epstein et al.[20] and Kerr et al.[21] indicated that the ViziLite could potentially aid in the detection of oral premalignant lesions by improving brightness and sharpness. Epstein et al. examined 134 patients who had identified oral lesions using conventional white light and ViziLite illumination.[20] The study showed that two lesions became clinically visible only after ViziLite examination. Kerr et al. examined 501 patients who had a positive tobacco history using conventional white light, followed by ViziLite illumination.[21] The study reported that six lesions not previously seen by conventional examination were identified by ViziLite examination. However, other studies have reported that the ViziLite does not aid in the identification of oral lesions.[22–24] In a study conducted by Ram and Siar, 40 patients in a high prevalence population were examined with the ViziLite, following conventional examination of the oral cavity.[22] Farah and McCullough examined 55 patients referred for assessment of an oral white lesion with the ViziLite, following conventional oral examination.[23] Both studies concluded that examination with the ViziLite did not change the diagnosis. The authors noted that ViziLite examination could not discriminate between benign or inflammatory and premalignant or malignant oral lesions. In a study conducted by Oh and Laskin,[24] 100 patients who presented for dental screening were examined with the ViziLite, following conventional examination. Results demonstrated that all of the lesions were detected during standard oral examination, and no additional lesions were detected by the ViziLite. Thus, there remains an important need for alternative diagnostic methods that can enhance the visualization of oral lesions and particularly help discriminate benign and premalignant lesions.


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