Current and Emerging Oral Cancer Clinical Diagnostic Approaches

Current and Emerging Oral Cancer Clinical Diagnostic Approaches
Student’s Name
Affiliation
Course
Professor
Due Date
Chapter Summary
Oral cancer remains one of the most common cancers but still records a survival rate that is below 50 percent. The survival rate could be significantly enhanced through the early detection and diagnosis of oral cancer in patients. In the initial stages, the cancer is preceded by the emergence of oral potentially malignant disorders (OPMDs), but it is highly challenging for one to determine whether OPMDs will eventually translate into oral cancer. While a physical examination is still applied in the patient examination, the current main approaches used for the clinical diagnosis of cancer are vital staining, oral cytology, and optical imaging. Notably, the three methods can discriminate between lesions and normal cells but they have differing levels of specificity and sensitivity. In addition, the three approaches are mainly dependent upon the experience of the pathologists. With this in mind, there have been efforts to develop detection and diagnosis methods that rely on biomarkers for the detection of oral cancer in various specimens. Biomarkers are considered more reliable given that they offer molecular evidence on the existence of a given process in a cell. The potential molecules that are currently being researched for the development of biomarkers are proteins, mRNAs, and DNA methylation products.
In addition, there are indications that future technologies will have a significant impact on the early detection and diagnosis of cancer. Nanotechnology will yield novel imaging approaches to facilitate the generation of accurate images of normal and cancerous cells and complement clinical decision-making. AI-based systems will revolutionize the detection and prediction of oral cancer as machines use data to predict the likelihood of OPMDs translating to oral cancer. Notably, LOC shows the most promise among future technologies as it will ease the detection of oral cancer while ensuring the cost-effectiveness of the process.
Contents Chapter Summary. 1 Introduction. 3 Current Clinical Diagnostic Methods. 6 Vital Staining. 6 Oral Cytology. 8 Optical Imaging. 9 Methods under Development 11 DNA Methylation Biomarker 11 mRNA Biomarker 12 Protein Biomarkers. 13 Future Technologies. 14 Nanotechnology. 14 AI-Based Systems. 19 Lab-on-Chip. 21 Conclusion. 21 References. 24
Emerging Oral Cancer Clinical Diagnostic Approaches
Introduction
Oral cancer remains one of the most common forms of head and neck cancer globally, with an estimated 350,000 new cases recorded every year worldwide. The number of deaths reported globally every year due to oral cancer is roughly 170,000. In definition, oral cancer describes the various malignant lesions that are observed in the oral structure including the mouth floor, anterior parts of the tongue, the lips, gingiva, buccal mucosa, and in retromolar trigone (figure 1). Ninety percent of cancer manifest as squamous cell carcinoma, with the use of multidisciplinary oncological treatment that combines the use of surgery, and radiation therapy being reliably used to facilitate the treatment stage. Notably, the risk factors for the development of cancer are significantly variable based on the geographical and lifestyle habits of the patient. Smoking and drinking are the main risk factors for oral cancer in Western countries, with betel-nut chewing and smoking increases the risk of oral cancer development in South Asia and Pacific countries. In addition, HPV infection is also another significant risk factor in the development of oral cancer.
Figure SEQ Figure \* ARABIC 1: Oral cavity anatomy
The development of oral potentially malignant disorders (OPMD), a group of heterogeneous oral mucosal lesions, usually precedes the development of oral cancer. Detection and evaluation of OPMD in the early stages of their emergence is considered essential to the treatment of oral cancer. Notably, visual oral examination (VOE) remains a significant approach to the screening of oral mucosal lesions. VOE involves an intraoral and extraoral examination of the patient. The intraoral examination involves the systematic observation and feeling of the oral structures that are susceptible to oral cancer such as mouth floor and retromolar trigone among others using a strong headlight and a tongue depressor. The extraoral examination involves the observation and palpitation of the scalp and the facial skin including the evaluation of the major neck glands and lymph nodes. Notably, VOE is highly limited as its effectiveness depends on the physician’s experience given that some OPMDs are indistinguishable from persistent ulcers. Notably, the biopsy of suspected tissue remains one of the most reliable approaches to the differentiation and diagnosis of OPMDs and oral cancers. Nonetheless, an accurate clinical diagnosis remains a significant challenge given that OPMDs are not localized and tend to scatter in multiple areas. The invasive nature of biopsy means that most patients are fearful of multiple biopsies despite the presence of suspicious lesions. Consequently, an accurate histopathological diagnosis is based on the extent to which the biopsied specimen is retrieved using the right approach and the experience of the physician.
Given that the five-year survival rate of oral cancer is 15-50 percent (Chin & Mayers, 2015), the early detection of oral cancer and OPMD is essential to the treatment and management of the disease. At a clinical level, it is of utmost importance for the physician to identify the mucosal lesions with high transformation rates as they have a significant influence on the treatment process of oral cancer. As such, a biopsy of oral tissue is mainly insufficient especially when attempting to differentiate OPMDs. The use of intracellular biomarkers offers a better chance for the precise evaluation and prediction of the likelihood of mucosal lesions transforming into oral cancer so that treatment can commence. The present chapter offers an overview of the current oral cancer diagnostic approaches and reviews methods under development as well as future technologies.
Diagnostic Approaches to Oral Cancer
Current
Under Development
Future
Vital staining
Protein biomarkers
Artificial Intelligence
Oral cytology
mRNA biomarkers
Lab-on-a-Chip
Optical Imaging
DNA Methylation biomarkers
Nanotechnology
Figure SEQ Figure \* ARABIC 2: Approaches to Clinical diagnosis of Oral cancer
Current Clinical Diagnostic Methods
The three commonly clinically used oral cancer diagnostic approaches are vital staining, oral cytology, and optical imaging.
Vital Staining
Bisht et al. (2021) describe vital staining as the application of a dye such as tolonium chloride to facilitate the staining and the highlighting of abnormal regions of the oral cavity. The most commonly used dye is toluidine blue (TB), a dye that binds to the nucleic acid content of the dysplastic and anaplastic cells (see figure 3). The use of TB vital staining is largely informed by the high content of nucleic acids in mucosal lesions, which makes it easy for the physician to identify mucosal changes after staining. In addition to nucleic acid content, the effectiveness of TB dyeing is informed by wider intracellular canals in the malignant epithelium that make it easy for TB to penetrate the cells with lesions (Nambiar et al., 2016). The degree of TB staining can provide information on the degree of the epithelial surface involvement in the sense that benign lesions will have fainter coloration and carcinomas will show intense coloration. Bisht et al. (2021) note that the use of TB vital staining is effective for asymptomatic patients.
Figure SEQ Figure \* ARABIC 3: A mucosal lesion (A) viewed after TB staining (B)
Notably, TB staining has varying diagnostic efficacy with studies indicating that the staining approach has a high level of sensitivity but low levels of specificity. In a study conducted to examine the diagnostic accuracy of TB staining, Vijayakumar et al. (2019) recruited fifty-five subjects who had malignant lesions. The participants were adequately screened and subjected to TB staining of their lesions. A comparison of the TB staining result and the histopathological examination showed that TB staining had a 92.6 percent accuracy in malignancy detection and a 69.7 specificity. Overall, the diagnostic accuracy of TB staining in the study was 80 percent. The researcher noted that TB staining can be considered a valuable diagnostic approach for oral and oropharyngeal cancers (Vijayakumar et al., 2019).
Lugol iodine staining is another effective vital staining approach that can be reliably used in clinical settings to identify OPMDs. In normal oral mucosa, Lugol iodine reacts with glycogen and presents a mahogany color. Comparatively, Lugo iodine returns a pale or clear appearance when reacting with carcinomas. As such, Su et al. (2021) note that TB dye can be combined with Lugol iodine to distinguish between normal and abnormal epithelium. In such a way, the two dyes can be effectively used to facilitate the selection of sites that can provide biopsy tissues, especially in cases where the patient has a wide field of mucosal lesions.
Oral Cytology
Exfoliative cytology is one of the reliable diagnostic tools that can be effectively used to assess malignant changes in the oral cavity. The process involves the collection of OPMDs with the help of a brush or a tongue blade that scraps, rinses, or brushes the exfoliative cells. One should then fix and stain the collected mucosal cells to facilitate the examination of the morphology of the cells. Using a microscope, a pathologist interprets the images that are produced after the staining of the cells. The method that is used in oral cytology parallels the one used in cervical Pap smear. Despite its use since 1963, oral cytology has not been widely accepted as an oral cancer diagnostic tool as is the case with cervical pap smears. Su et al. (2021) note that oral cytology is not preferred as a screening method mainly because of its low sensitivity when diagnosing oral cancer as a result of the non-representative sampling nature of the collected oral smear, the risk of procedural errors, and the high levels of subjectivity reported during the pathological interpretations.
Nonetheless, research and development have resulted in significant improvement in its application in clinical diagnosis for the diagnosis of suspicious lesions. Brush cytology has emerged as a potential approach that can be reliably used to confirm lesion sites in instances where an individual has trouble opening their mouth to facilitate scalpel biopsies (Su et al., 2021). OralCDx® Brush Test is a brush cytology that adds artificial intelligence to enhance the effectiveness of brush cytology in the analysis of oral lesions in the early stages (Su et al., 2021). Nonetheless, the application of the technology in the clinical setting remains a controversial subject given that the test results have been shown to vary with some studies reporting high sensitivity and specificity in the identification of precancerous lesions, while other studies questioning the findings reporting the high performance of the OralCDx® Brush Test (SU et al., 2021).
Optical Imaging
In clinical diagnosis, oral imaging involves the use of the color of light reflected from the oral epithelium to assess the condition of the oral epithelium to detect oral cancer and OPMDs. The two optical imaging approaches common in clinical settings are autofluorescence-based and chemiluminescence-based.
Autofluorescence-Based: Autofluorescence-based optical imaging involves the use of a specific light wavelength to cause cell excitation and reemission of different wavelengths of light. The naturally occurring fluorophores such as collagen, elastin, and keratin among others in human tissue emit autofluorescence. In OPMDs and cancerous lesions, the number and density of fluorophores are altered resulting in changes in regards to how a given light interacts with normal light. Using medical devices, a pathologist can be able to effectively detect OPMDs and cancerous cells by detecting the alterations in fluorophores in tissues. VELScope®Vx is one of the most commonly used non-invasive medical devices that detects alterations in the autofluorescence in the oral mucosal. The handheld device emits 400nm and 460nm blue light that is coupled with optical filtering systems to facilitate the visualization of oral abnormalities. In a normal cell, green autofluorescent light is produced when the device is used while dark areas appear in areas with mucosal lesions. Notably, the device is effective in the identification of OPMDs presence and other disorders (Awan, Morgan, & Warnakulasuriya, 2011) but lacks the discriminatory power to distinguish between low and high-risk lesions. Consequently, the use of autofluorescence-based optical imaging in clinical settings should be accompanied by highly experienced pathologists or other diagnostic methods.
Chemiluminescence-Based: The approach involves the use of a chemical in place of light to excite the electrons in the cell and incite the emission of light photons. It is based on the reflectance phenomenon whereby the proportion of incident light reflected by a given surface is captured. ViziLite® Blue oral examination kit is one of the medical devices that is based on the reflectance phenomenon and is used in the examination of mucosal lesions. The device illuminates the oral cavity with the light of 430nm, 540nm, and 580nm and gives a diagnosis based on the color of the light reflected. Mucosal lesions produce a light that is white in appearance, while normal cells give backlight that is light blue (Ram & Siar, 2005). Notably, Chemiluminescence-Based optical imaging has been described as effective in the identification of mucosal lesions missed by VOE, especially when detecting leukoplakia. However, the approach has limitations in the sense that it fails to effectively detect cancerous lesions. In addition, the approach lacks discriminatory power to distinguish between keratosis, OPMDs, inflammation, lichen planus, and ulcerated lesion.
Identafi® is an optical imaging device that facilitates the multispectral screening of OPMDs. To this end, the device combines, white, violet, and green-amber lights at differing wavelengths to conduct a sequential oral examination. The white light in the device offers an optimal view and the violet light is used for the autofluorescence of the cells. The green-amber light facilitates the discrimination of benign and malignant lesions based on the visualization of dilated vasculature. To this end, abnormal tissues show high levels of vascularity than normal tissues. Notably, the device has a high level of specificity but lacks sensitivity, making the device an effective complement to VOE in the detection and visualization of oral mucosal lesions.
Methods under Development
Most of the oral cancer diagnostics methods under development seek to leverage the effectiveness of biomarkers in the detection and diagnosis of oral cancer. To this end, Su et al. (2021) report that biomarkers can effectively assist a pathology to determine whether oral cancer is present or absent in a given human tissue. Some of the common biomarkers that can be used to diagnose oral cancer include enzymatic changes, antibodies, nucleic acids, lipids, and carbohydrates among others (Su et al., 2021). The biomarkers are advantageous in clinical diagnosis due to their ease of availability and non-invasiveness of the procedures that rely upon biomarkers for patient diagnosis (Santosh, Jones, & Harvey, 2016). A valid biomarker should facilitate objective, precise, reliable, and quantitative assessments of the disease, facilitate estimation of disease risk, and facilitate the discrimination of benign and malignant cells. Nonetheless, it is important to note that biomarkers introduce the likelihood of measurement errors and the potentially destabilizing influence of confounding factors on the measurements based on biomarkers. The three biomarkers that have been identified as potentially effective in the clinical diagnosis of oral cancer include DNA Methylation mRNA, and protein-based expression biomarkers (Su et al., 2021).
DNA Methylation Biomarker
The DNA methylation biomarkers developed for oral cancer diagnosis are ZNF582 and PAX1. ZNF581 is a member of the transcriptional factors that are used to code for zinc finger proteins (Su et al., 2021). Zhao et al. (2020) conducted a study that showed the role of ZNF582 as a tumor-repression molecule for nasopharyngeal carcinoma. To this end, ZNF582 regulates the transcription and expression of the adhesion molecules and its hypermethylation promotes the metastasis of nasopharyngeal carcinoma. Consequently, ZNF582 has significant potential to act as a biomarker for the detection of oral cancer. PAX1 is a transcriptional regulator that plays a significant role during embryogenesis and plays a role in the suppression of tumors. Its methylation at high levels has been shown to result in the tumorigenesis of oral cancer (Su et al., 2021).
The two biomarkers are mainly used as an in-vitro diagnostic kit that facilitates the detection of the risk levels of development of oral cancer in an individual. To achieve this, the kit measures the methylation levels of the two biomarkers. Consequently, a kit based on ZNF582 and PAX1 can help pathologists to complete VOE in the sense that they can assist the doctor to decide on whether to conduct a histopathological examination after a VOE. Consequently, the two biomarkers are highly effective in making sure that there are no cases of misdiagnosis when using VOE for oral cancer diagnosis (Zhao et al., 2020).
mRNA Biomarker
The mRNA biomarkers whose potential has been realized in the diagnosis of oral cancer are OAZ1, SAT, and DUSP1. OAZ1 is a product of a polyamine-dependent process and plays a key role in DNA repair as well as in determining the metastatic potential of cell lines of oral squamous cell carcinoma (OSCC) patients (Tsuji et al., 2007). SAT is an enzyme that is mainly involved in the acetylation of spermidine and spermine, thus regulating the concentration of polyamine in the cells as well as their transportation in the cells. SAT has been observed to be highly expressed in a patient with oral cancer. DUSP1 is a type-1 protein that plays a role in a signaling pathway. Salivary DUSP1 is elevated in a patient with oral cancer than in normal patients. The combination of the three mRNA biomarkers with housekeepi...