The aim of this essay is to describe the link between dysplasia and the accumulation of events that leads into cancer; and to critically appraise selected studies that have provided evidence that oral dysplasia transforms into a malignant lesion and need long-term monitoring.
2. INTRODUCTION
2.1 Oral dysplasia
Dysplasia is defined as abnormal development and growth of cells or tissues [6]. Dysplasia is usually graded as mild, moderate and severe [6] based on the degree of cytological and architectural changes in the epithelium. Mild epithelial shows only a few cytological irregularities, while severe dysplasia shows significant cytological abnormalities [3]. Many studies have shown that cancer could develop from dysplasia in a varying degree from 4.4% to 36% when dysplasia is moderate or severe [22,25].
Any oral mucosal lesions that are at risk of malignant transformation may exhibit some degree of dysplasia. They include: oral leukoplakia, oral erythroplakia, oral lichen planus, and oral submucous fibrosis [20]. Oral leukoplakia is one of the most common diagnosed premalignant lesions in the oral cavity and its prevalence is higher [15, 20, 25].
2.2 Oral leukoplakia
Leukoplakia is a clinical diagnosis defined as 'a white patch or plaque that cannot be characterized clinically or histopathologically as any other disease' [14,26]. Leukoplakias could be with or without dysplastic epithelial cells, and the ones that show dysplasia histologically may display a range of dysplasia from mild to severe [6]. The tendency for malignant transformation of leukoplakia lesions has been stated in several studies [11,14,27,28], especially if moderate or severe dysplasia is present in the leukoplakia lesion [8].
The accumulation of events that leads to development of cancer is reviewed to link the progression of dysplasia to oral cancer.
2.3 Development of cancer (carcinogenesis)
In general it is believed that cancer is a disease process [2,27] and models such as the 'two stage model' by Knudson and the 'multiple stage model' by Armitage and Doll suggest that development of cancer occurs by an accumulation of events [1,2,27,33]. This essay will concentrate on the development of oral squamous cell carcinoma (OSCC), which is one of the 10th most common cancers [5,18] and its prevalence is 1 in 20,000 [9,6].
Stem cells within the oral epithelium are more susceptible to genetic mutations that result in formation of cancer, as they self-renew and differentiate continuously to repair the damage tissue and are the long-term residents of the epithelium [2].
In the initiation event, a single susceptible cell undergoes a genetic mutation, which occurs in any gene responsible for cellular regulatory mechanisms such as oncogenes (growth enhancing genes) and tumour suppressor genes (growth inhibiting genes) [31,33]. This allows the cell to proliferate abnormally and escape the cellular regulatory mechanisms [4,27,31]. The carcinogenic agents that cause mutation are found in cigarettes, viruses, inonising and non-inonising radiation, diet, bacteria, fungi and miscellaneous agents [27]. In the promotion event the altered cell is exposed to a tumour promoter, which could either be an external or internal stimuli, causes a rapid proliferation of the mutated cell resulting in an abnormal clone of cells [27]. This step produces relatively benign growths. In the malignant transformation event further mutations alter the organization, structure, and adhesion of the cells that allows them to replace the normal epithelium and infiltrate adjacent tissues and ultimately develop into carcinoma [2]; this is termed malignant behavior [4,27].
Mild dysplasia shows cytological irregularities [3] suggesting that cells in mild dysplasia could be at the initiation stage. Severe dysplasia shows significant cytological irregularities [3] suggesting that cells in severe dysplasia could be at the promotion stage.
3. METHOD
Four recent studies (2001-2010) with similar aim to investigate progression of oral dysplasia into oral cancer were selected to provide evidence that management of oral dysplasia should include careful monitoring. In the result section the selected studies were mentioned and in discussion the strength, limitation, results and conclusion of each study was discussed.
4. RESULTS (Selected Studies)
4.1: Cowan CG, Gregg TA, Napier SS, McKenna SM, Kee F. 2001.[8]
This study was based on Northern Ireland's population of 1.6 million, to investigate the potential for malignant transformation of oral mucosal lesions. They selected all biopsied cases from all laboratories within a 20-year period. Their sample size of patients with dysplasia was 165. They included a control group, consists of patients with non-dysplastic lesions, to compare with patients with dysplastic lesions.
4.2: Mishra M, Mohanty J, Sengupta S, Tripathy S. 2005[14]
One of the aims of this study was to detect malignant potential of oral leukoplakia. They selected all the cases that presented with oral white lesion during a 2-year study. They excluded cases with any infective aetiology and cases that failed to follow-up; ultimately ending up with a sufficient sample size of 2920. They did not use any control groups to compare with the studied group.
4.3: Hsue SS, Wang WC, Chen CH, Lin CC, Chen YK, Lin LM. 2007.[11]
This study was a follow-up investigation, for 10 year, of patients with premalignant oral lesions, to estimate the rate of the malignant transformation within these lesions. A sufficient number of patients were recruited (numbered 1458) and were divided into six histological categories including the ones that were dysplastic. This study did not have a control group to compare with the premalignant lesion group.
4.4: Wei L, Wang YF, Zhou HW, Shi P, Zhou ZT, Tnag GY. 2010[32]
This was a retrospective cohort study of 218 patients with oral leukoplakia that were followed-up for 5.3 years to investigate the malignant transformation of these lesions. They classified the lesions as low-risk dysplasia and high-risk dysplasia. They excluded any patient with diagnosis of oral leukoplakia that coexisted with OSCC at the first visit. They did not use any control groups to compare with the selected group.
5. DISCUSSION
Different literature provided evidence to illustrate the potential transformation of oral dysplasia into a malignant lesion [13,16,19,23,24,30]. On the other hand not many literatures were found to investigate the events that took place while oral dysplasia was progressing to oral cancer. Thus it was difficult to verify that oral dysplasia followed the same events in carcinogenesis mentioned by the two models. Accordingly, recent studies (from 2001-2010) that showed progression of dysplasia to a malignant lesion were selected; to bring evidence that oral dysplasia could in fact progress to oral cancer and needs careful monitoring. Each study had its strength and limitation in terms of their methods. The topics that were compared within the studies include: control groups, selection of oral biopsies, criteria to diagnosis malignant transformation, results and their conclusion.
To see if the rate of malignant transformation in dysplasia is significantly different from a normal mucosa, a control group with normal mucosa needs to be monitored at the same time. None of the studies included a control group to compare with the dysplastic lesions except the first study, which considered patients with non-dysplastic lesions as their control group but they did not monitor any group with normal mucosa.
Selection of biopsies is important, as it will indicate if the study considered all dysplastic lesions that occur within the oral cavity. The first study included all oral biopsies (dysplasia and non-dysplasia group), minimising selection bias and reducing errors that could arise from tissue selection [8]. The third study also considered all premalignant oral lesions and subgroup them into different histological features including the ones that were dysplastic [11]. The second study included only oral leukoplakia lesions and did not subgroup the lesions into dysplastic or non-dysplastic [14]. Therefore, it is more difficult to discuss whether the malignant transformation was from dysplastic lesions or non-dysplastic lesions. The fourth study included only leukoplakia lesions and subgroup them into low-risk dysplasia and high-risk dysplasia. This increases tissue selection bias and considers only a percentage of dysplasia that occurs in the oral cavity.
Another limitation that the selected studies had in their biopsy selection was that they did not indicate if the number of biopsies corresponds to the number of each patient or if they had multiple biopsies from the same patient. The first study indicated that occasionally multiple biopsies were taken from the same patient and they were grouped depending on the histological diagnosis [8]. However, their result was based on the total number of patients rather than the total number of biopsies.
Two criteria are important in order for the study to claim that oral dysplasia progressed into oral cancer after a certain time. The first criterion is that the oral cancer must have developed from the same site as the initial lesion [11]. The second is that the progression was after 6 months from the initial diagnosis to exclude an already formed oral cancer [11]. The first, third and fourth study followed the two important criteria to diagnose a progression of dysplasia into a malignant lesion. In contrast, the second study did not include any of these criteria and it made an assumption that if a white lesion exhibits dysplasia and malignancy, the malignant lesion was originally dysplastic.
The results of the first study showed that malignant transformation occurred in 15% of dysplasias, after 48 months of initial diagnosis, and in 1% of 'non-dysplastic' lesions, after 65 months of initial diagnosis. The fourth study showed a similar malignant transformation rate in 17.9% of oral leukoplakia with dysplasia, after a longer duration of 5.2 years [32]. In addition, they showed that high-risk dysplastic oral leukoplakia had a 4.57-fold increased risk of malignant transformation, compared with low-risk dysplasia [32]. The third study showed that malignant transformation occurred in 4.82% of dysplasisas [11], which is low compared with the two studies. This may be due to the fact that this study contained a much wider range of oral premalignant epithelial lesions [11]. The second study showed that 9.93% of the white lesions were dysplastic and 0.72% showed malignant cells [14]. However, this study was not as convincing as the other studies, as they assumed if oral leukoplakia shows dysplasia and malignancy this indicates that the malignant lesion was originally dysplastic.
The first study concluded that there might be more than one pathway for the development of OSCC since the majority arises from 'clinically normal' mucosa while a lesser number develop from white lesions [8]. To conclude that they need to monitor a control group with normal mucosa to see the rate of their progression into oral cancer. The second study concluded that use of simple methods such as biopsy and exfoliative cytology from oral lesions will detect early dysplastic and malignant changes and a periodic follow up is important [14]. The third study also concluded that the management of oral pre-malignancy includes careful follow up since there is a risk of malignant transformation [11]. The fourth study concluded that high-risk dysplasia could be used as a significant indicator for malignant transformation risk in patients when they are being followed up in the first 2-3 years [32].
6. CONCLUSION
From the studies selected the first, third and the fourth study provided evidence that oral dysplasia could progress to cancer and implied that management of oral dysplasia therefore needs long-term monitoring [8,11,32]. However, more studies are required to compare the malignant transformation of normal mucosa with dysplastic lesions to detect if the rate of transformation is significantly different. Meanwhile monitoring these lesions seems beneficial for detection of early oral caner. The second study did not contribute enough evidence that oral dysplasia progresses to cancer but showed that clinically diagnosed oral leukoplakia could be malignant when biopsied on the first visit and implied that early biopsy of these lesions could detect early malignant changes [14].
There is no effective treatment in preventing malignant transformation of oral dysplasia or eradicating its occurrence. Various treatments such as surgical excision, cryosurgery, CO2 laser surgery, retinoids and other drugs are available, which reduce the transformation rate, however, relapses and side effects are common [28].
Further experiments on molecular level will increase our understanding of the accumulating events that occurs within dysplastic lesions when its transforming into cancer and will help improve treatments needed to prevent progression of oral dysplasia into oral cancer.
