December 11, 2018
by M.R. Darling, BChd, MSc (Dent), MSc (Med), MChD; A. Hassan, BMedSci (Hons Pathology) Candidate; L. McLean, DDS. Oral and Maxillofacial Surgery Resident
Approximately 90% or more of oral cancers are squamous cell carcinomas (OSCCs). These often begin as potentially malignant oral lesions such as a white patch (leukoplakia; Fig. 1), or red patch (erythroplakia; Fig. 2), 1 which progress to an invasive cancer.1 Although the term “premalignant” is widely used for such lesions, the term “potentially malignant” is now more acceptable, as it means that not all such lesions will inevitably become malignant, and the progression to cancer is only a potential risk. 2,3
The term “oral potentially malignant disorders” (OPMD) as an umbrella term for potentially malignant lesions and disorders is used in the latest World Health Organization (WHO) classification. 1 The WHO defines OPMD as “clinical presentations that carry a risk of cancer development in the oral cavity, whether in a clinical definable precursor lesion or in clinically normal oral mucosa”. 1 In this classification, OPMD are listed as follows in Table 1: 1
Several factors increase the risk for progression of OPMD to cancer. Key risk factors include age, gender, habits (tobacco and alcohol consumption), site of lesion development, clinical appearance of the lesion, and size. Chronic inflammation may also be a possible cofactor. 3
Older age is associated with a high risk of malignant transformation. 4 In general, lesions tend to progress soon after initial diagnosis, and the risk of transformation into cancer is higher within the first five years after diagnosis. 4,5
In studies that have examined a relationship between gender and malignant transformation, the rate of transformation is greater in females. The reasons for greater risk in females are not clear. 4
As for OSCC, tobacco and alcohol consumption are well-established risk factors for the development of OPMD, as well as for the progression and transformation of lesions. 3 However, non-homogenous lesions in female non-smokers carry a higher risk for transformation than in tobacco and alcohol users. 3,5 Areca nut use (“Betel nut chewing”) causes oral submucous fibrosis. 6
In developed countries, the most common sites of OPMD and OSCC are the lateral tongue, ventral tongue and floor of mouth, typically in tobacco smokers and alcohol users. 1,3 These sites generally represent the highest risk of transformation. In Asian countries where betel quid chewing is popular, OPMD and OSCC most commonly affect the buccal mucosa. 1
OPMD can present with a variety of appearances, ranging from homogenous white (leukoplakia) to nodular, verrucous, speckled (with red patches) and red (erythroplakia). The non-homogenous irregularly surfaced lesions carry the highest risk of transformation to OSCC. 3
Larger lesions, specifically those greater than 200mm 2, and those that extend over several anatomic sites, carry a greater risk for transformation to OSCC. 4
Histopathology of Lesion And Dysplasia Grading
Dysplasia grading from the microscopic examination of biopsied tissues is used to determine the risk of malignant transformation of oral lesions. 1 The usefulness of dysplasia grading as a prognostic tool has been challenged due its low predictive value and lack of objectivity as a result of intraobserver and interobserver variations. 1 At least one study has shown that calibration exercises may help decrease variation in the assessment of dysplasia. 7
Increasing grade of dysplasia (mild to severe) has generally been associated with a higher rate of malignant transformation. However, some dysplastic regions may remain static or even regress while some non-dysplastic lesions may become malignant. 8 This discrepancy presents a clinical challenge in the identification of lesions at high risk of malignant transformation 9 as well as lesions that have dysplasia but are unlikely to progress to cancer. 10 A binary system of dysplasia grading using a combination of four architectural and four cytologic features with addition of smoking and alcohol consumption has been shown to improve rater/observer correlation and prognostication (Table 2). 1
Due to the low progression rate of oral lesions, clinicians typically choose to monitor patients. Consequently, many high risk lesions are not diagnosed or treated appropriately, enabling these lesions to transform to cancer. 1
Individuals affected by OPMD are less likely to seek consultation unless they present with symptoms or persistent pain, making early detection of precancers and cancers difficult. 5 As a result, diagnoses are made at advanced stages of malignancy, contributing to the high mortality rate of oral carcinomas. 1 Diagnosis at early stages would significantly lower mortality rate. To some degree, poor clinical outlook can be attributed to the lack of biomarkers to facilitate early diagnosis and consequently improve survival rate.
The high mortality rate of oral carcinomas along with the low rate of transformation create a strong demand for reliable early detection diagnostics. 10 Early detection through biomarkers should lead to more effective disease management as they have potential in evaluating risk of malignant transformation accurately and objectively.
A comprehensive systematic review suggests that genetic events such as loss of heterozygosity (loss of one copy of an entire gene) and DNA content, expression of proteins survivin and MMP 9 are the best potential markers for increased risk of progression from oral dysplasia to cancer. 11 Measurement of DNA aneuploidy (abnormal number of chromosomes) stands out as a relatively rapid and reliable non-invasive test for risk assessment of oral lesions. 11 A recent review concluded that DNA hyper-methylation (methyl groups added to DNA which alter function of a gene) of tumor suppressor genes involved in pathways including cell-cycle control, DNA repair and cell-cycle signaling had potential utility as a diagnostic biomarker for oral pre-cancer progression. 12 Most of these studies have focused on a qualitative rather than a quantitative approach to evaluation.
Recent studies have identified psoriasin (S100A7) expression in oral epithelium as a risk factor corresponding with poor prognosis of OSCC patients. 13 Psoriasin is a member of the multigenic Ca2+-modulated S100 family of proteins, the majority of which are found on the epidermal differentiation complex on human chromosome 1q21. Psoriasin was originally identified in skin cells of patients with psoriasis and is associated with inflammatory responses in the skin. It has since been found to be overexpressed in several epithelial malignancies including lung, bladder, head and neck, gastric, breast, cervical and ovarian cancers. 14
Overexpression of psoriasin has been observed in the majority of cases where oral dysplasia progressed to malignancy, highlighting its potential for stratifying patients that present with dysplastic oral lesions at high risk for malignant transformation. Psoriasin overexpression has also been detected in squamous epithelial hyperplasia with no evidence of dysplasia. 13 It can also potentially predict patients at a higher risk for post-operative recurrence. 10
The secretion of psoriasin by tumour cells induces the secretion of factors by surrounding stromal tissue cells (tissue cells surrounding the tumour cells) which act back on the tumour cells. These factors are involved in tumour invasion, matrix remodeling, angiogenesis, inflammation and immune cell differentiation, all of which support tumour growth and metastasis. The use of antibodies directed against psoriasin in a therapeutic approach has demonstrated significant reduction in tumour growth and complete inhibition of metastasis. 15
The loss of psoriasin is thought to reduce cell-to-cell adhesion through decreased E-cadherin (an epithelial adhesion molecule) expression, allowing migration of cancer cells through normal boundaries and dispersion to distant sites via epithelial-mesenchymal transition (EMT). Cancer cells decrease E-cadherin expression to allow for migration through EMT. Interestingly, this suggests a protective role of psoriasin against malignancy and can explain why it is overexpressed in premalignant lesions at early stages of tumour disease. 16
The ß-catenin signaling pathway is a protein cascade involved in promoting cell proliferation and migration. Activation of the ß-catenin signaling pathway plays a role in the initiation and progression of cancer by promoting proliferation of cancer cells over differentiation. Psoriasin also has a protective role as a negative modulator of ß-catenin signaling by targeting its degradation thereby inhibiting its proliferative functions and promoting cell differentiation. 16 Psoriasin overexpression is significantly correlated with well differentiated OSCC. 13 This is also consistent with results that showed psoriasin promotes tumour differentiation and suppresses tumour growth in experimental OSCC tumour models. This suggests that psoriasin plays more of a role in tumour differentiation rather than tumour growth.
In conclusion, a recent study has shown promise that psoriasin expression in oral dysplastic lesions could be used as a risk predictor for the progression to OSCC. An algorithmic application, called Straticyte, which is based on image analysis of immunhistochemical staining of the psoriasin protein (Figs. 3A & B), shows potential to provide a five-year risk assessment for progression of dysplastic lesions in a quantitative fashion. 10 Additional benefits would include more careful individual follow up and therefore translate to improved patient care. OH
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About the Authors
Dr. Mark Darling is Professor, Division of Oral Pathology in the Department of Pathology and Laboratory Medicine, Schulich School of Medicine and Dentistry at Western University. He graduated from the University of the Western Cape in Cape Town, South Africa, with a BChD degree in 1985. He has also received an MSc (Dent) from the University of the Western Cape in 1990, an MSc (Med) in Experimental Oral Pathology from the University of London, United Kingdom in 1991, and an MChD (Oral Pathology) from the University of Stellenbosch, South Africa in 1998. He is a member of the International Association of Oral Pathologists, the American Association for Oral Medicine and Pathology and the International Association for Dental Research. He has 62 publications in peer reviewed Journals, 29 published abstracts and 84 presentations at scientific meetings.
Ahmed Hassan is currently a 4th year undergraduate student enrolled in the Bachelor of Medical Science, Honours in Pathology course, at Western University, London, Ontario.
Dr. Lachlan McLean is currently Oral and Maxillofacial Surgery resident at Western University, London, Ontario. He obtained his Doctor of Dental Medicine degree from the University of British Columbia in 2013, and completed an internship in Oral Surgery at the John Peter Smith Hospital, Fort Worth, Texas in 2014.