Abstract
Currently there is no definite approved guidelines over the treatment and follow-up required for patients with oral epithelial dysplasia (OED). There are ample controversies based on predicting the malignant transformation potential and deciding the management options solely based on the degree of epithelial dysplasia. The objective of this review was to identify an evidence-based management pathway for OED. The systematic review was conducted using PubMed, EMBASE using PRISMA guidelines. Following applications of inclusion and exclusion criteria, only 12 studies were included in the review. Overall, there were a wide variation in the reported recurrence rate (2.5 %–51.4 %) and the malignant transformation rate (MTR) (2.6–27 %). The degree of dysplasia was not significant in malignant transformation. The mainstay of treatment includes observation, laser ablation and excision with no concrete evidence of resolution. Therefore, there is an urgent need for a multidisciplinary conference to create a consensus for treatment pathway for OED.
1
Introduction
Oral epithelial dysplasia (OED) is a histological diagnosis and is the most important prognostic indicator of a given potentially malignant condition [ ] . The World Health Organization (WHO) defined OED as a “spectrum of architectural and cytological changes, in the mucosa associated with an increased risk of malignant transformation” [ , ] . Clinically, OED may manifest as a white patch, red patch, mixed white or red patch which are collectively identified as oral potentially malignant disorders. (OPMD) [ ]. In 2022, WHO defined OPMD as a group of clinical conditions that has morphologically altered tissue which carries an increased risk of malignant transformation and encompass lesions like leukoplakia, erythroplakia, erythroleukoplakia, lichen planus, proliferative verrucous leukoplakia (PVL) [ ].
Historically, OED were classified into mild, moderate, severe based on the presentation of the architectural and cytological changes observed under the microscope [ ] . In mild OED, cytological changes are limited to the basal third of the epithelium and in moderate epithelial dysplasia, cytological atypia extending into middle third is considered as the initial criterion; with upgrading possible for lesions showing high degree of atypia while severe epithelial dysplasia, cytological atypia extending to the upper third of the epithelium [ , ]. To overcome the short comings of WHO classification, Kujan et al. proposed a binary grading system which classified dysplastic lesions into high-grade and low-grade lesions [ , ] .
Previous studies reported of the malignant transformation rate (MTR) associated with dysplasia range from 0.13 to 34 % [ , ]. Factors associated with the risk of malignant transformation seem to vary and may depend on the study population. There are ample controversies based on predicting the MTR and management pathway solely based on the degree of epithelial dysplasia [ ]. Currently there is no consensus or guidelines over the treatment and follow-up required for patients with oral dysplasia. Management strategies vary from observation, non-surgical management such as topical Vitamin E, bleomycin and surgical management such as laser ablation and excision [ , , ]. The reported follow-up strategies varied from immediate discharge to lifetime follow-up. Hence, we conducted this systematic review to seek into the possibility of formulating a management strategy for patients presenting with OED.
2
Patients and methods
2.1
Search strategy
This systematic review was reported according to the Preferred Reporting Items for Systematic Reviews and Meta Analysis (PRISMA) checklist ( Fig. 1 ). Last search was performed in April 2024. Our core search terms were ‘oral dysplasia, oral epithelial dysplasia, management, histology’ AND ‘follow up, treatment.’
2.2
Inclusion criteria
Only studies reported on patients with histologically confirmed dysplasia either with incision or excision biopsy were included. The lesions needed to be histologically graded either as mild, moderate or severe or based on the binary grading system as high-risk or low risk. Furthermore, included studies should report at least one of the outcome measures and the intervention carried out with a minimum follow-up of 12 months.
2.3
Exclusion criteria
Studies that reported on patients with oral leukoplakia, erythroplakia and PVL without histologically confirmed diagnosis were excluded. Studies which did not include histopathological grading were not included. Cross sectional studies of the prevalence, reviews, letters, personal opinion, book chapters, publications in language other than English were excluded. Data from studies in which patients that could not be extracted for individual at-risk groups were excluded. Studies that included patients with synchronous cancer at or identified within 3 months of the time of diagnosis were also excluded.
2.4
Outcome measures
The following outcomes were extracted from the studies such as the rate of malignant transformation, its time interval to malignancy, recurrence rate and the degree of dysplasia. The potential risk factors associated with oral dysplasia including age, site of the lesion, continuation of smoking and alcohol intake were also extracted. Also, wherever possible we tried to analyse the degree of dysplasia (mild, moderate, severe) for the patients who had malignant transformation.
3
Results
3.1
Search outcomes
The search strategy produced 953 papers in total of which 21 were deemed eligible and subjected to full review following screening through the abstracts. After application of inclusion and exclusion criteria, a total of 12 studies were included for our systematic review. There was no randomized control trial or case-control study in this review.
There was a total of 2213 patients reported in these 12 studies. The mean age ranged from 49.7 to 68.3 years old. All the studies have recorded the continuation of risk habits and the subsite except one study. In terms of level of dysplasia, 505 patients displayed no dysplasia, 787 lesions had mild dysplasia, 410 had moderate dysplasia whilst 511 had severe dysplasia/high-risk dysplasia. In terms of management, 21.4 % lesions were kept under close observation, 48.3 % treated with laser ablation/excision, 28.6 % with surgical excision while remaining 1.7 % had other treatments such as cryotherapy. The reported average follow-up ranged from 2.5 to 11 years.
3.2
Outcome of the individual studies
- 1)
Yang et al. [ ] reported of 114 patients who received CO2 laser ablation regardless of the histological subtype which consisted of 90 mild, 8 moderate and 16 severe lesions. They reported of 17.5 % recurrence and 11.4 % malignant transformation rate. Continuation of cigarette smoking, betel quid use, non-homogenous lesions, higher grade dysplasia were significant predisposing factors for recurrence.
- 2)
Jerjes et al. [ ] reported of 77 patients with dysplastic lesions who underwent laser resection. 17 lesions were mild and 42 moderate dysplasia and 18 severe dysplasia. The reported recurrence rate was 19.5 % and MTR 10.4 %. Rate of recurrence was statistically significant with higher grades of dysplasia, but no association was found with the anatomical site. MT was commonly seen in non-homogenous lesions.
- 3)
Thomsan et al. [ ] included 590 patients with the histological grading based on the most significant finding extracted from either excision or incision biopsy. In his study, 68 patients had no dysplasia, 186 mild dysplasia, 144 moderate dysplasia and rest had severe dysplasia or carcinoma in situ. All the patients underwent laser excision or ablation. 13.1 % patients required further intervention due to recurrence. 4.8 % developed malignant transformation during the follow-up. The recurrence was associated with higher grade of dysplasia and with non-homogenous nature of the lesions.
- 4)
Hamadah et al. [ ] observed 78 patients who had laser excision. Study population included mild, moderate and severe dysplasia with 14 %, 42 % and 44 % respectively. Dysplasia recurrence was mainly seen in lesions arising in the floor of the mouth and ventro-lateral tongue and smokers. But no association was found between recurrence and the histopathological diagnosis.
- 5)
Saito et al. [ ] reported of 142 patients with histologically confirmed dysplasia. In their study smaller lesions had incisional biopsies while larger lesions were subjected to multiple samples from different areas. All dysplastic lesions had active treatment and majority had surgical excision. Lesions were excised with a 3–5 mm margin of clinically normal mucosa. The overall MTR was 6.3 %. The MTR was lower amongst patients who received surgical intervention but there was no obvious relation between the grade of dysplasia and MTR.
- 6)
Arudino et al. [ ] discussed outcome of 207 patients who had 135, 50, 22 of mild, moderate and severe dysplastic lesions respectively. Only 133 patients underwent active treatment. Lesions with moderate to severe dysplasia, along the lateral border of the tongue were strongly recommended for surgical intervention. The recurrence rate was 33.7 % and the MTR was 7.24 %. Malignant transformation was more associated with higher grade of dysplasia. However, interestingly the authors depicted there is no eminent benefit of surgical intervention of OED in prevention of recurrence and malignancy development.
- 7)
Gilveti et al. [ ] reported the outcome of 120 patients with high-grade dysplasia with the overall MTR of 17.8 %. The MTR was 28.6 % in untreated patients while MTR was only 12.3 % in patients who underwent surgical treatment. In addition, older age, non-homogenous nature and incomplete excision were poor prognostic factors.
- 8)
Jayasooriya et al. [ ] study consisted of 93 patients that included 34, 20 and 19 mild, moderate and severe dysplastic lesions respectively. The planned management included excision of high-grade dysplasia and observation of low-grade dysplasia. The recurrence rate was 31 % and MTR was 7.5 %. They concluded lesions with higher grade of dysplasia and non-homogenous lesions were more associated with malignant transformation.
- 9)
Began et al. [ ] reported of 224 patients who underwent surgical or laser treatment. The sample included 50 mild, 15 moderate and one severe dysplasia. The remainder did not show oral dysplasia. Overall MTR was 11.6 %. Both non- and homogenous dysplastic lesions were more likely to develop malignant transformation.
- 10)
Bronus et al. [ ] study included a cohort of 144 patients with oral dysplasia. In his sample 11 % had malignant transformation. No statistical relation was found between the anatomical subsite, clinical appearance, degree of dysplasia, method of management with regards to the malignant transformation.
- 11)
Bernad et al. [ ] in his retrospective study reported clinical outcome of 155 patients.The sample included 71 low grade, 56 high grade and 28 showed no dysplasia. 94 patients had surgical excision and while 61 were kept under observation. The MTR was 27 %. The degree of dysplasia does not affect the management and risk of malignancy.
- 12)
Holmstrup et al. [ ] study reported a total of 236 patients with 207 mild, 37 moderate and 25 severe dysplasia lesions. 94 lesions with majority consisting of severe and moderate dysplasia underwent surgical excision while rest of them were kept under observation. Following surgical treatment, 12 % developed oral squamous cell cancer (OSCC). Surgically treated lesions with mild, moderate and severe dysplasia developed OSCC with similar frequencies. The malignant transformation was more associated with non-homogenous and larger lesions.
Overall, the average recurrence rate in ten studies was 26.5 % (Range 2.5 %–51.4 %). Two studies did not report their recurrence rate. The average overall MTR was 9.9 % (Range 2.6–27 %). Three of twelve studies advocate for surgery to reduce the risk of MTR but two studies concluded that surgery doesn’t influence the MTR. Overall, the evidence for each treatment modality for management of OED was weak. Several studies reported of no significant correlation between the level of dysplasia and MTR and its management. The outcomes of individual studies are summarized in Tables 1–3 .
| Study | Year/Country | Sample size | Type of study | Management | Recurrence rate | Malignant transformation rate | Mean Follow up |
|---|---|---|---|---|---|---|---|
| Yang et al. | 2011 Taiwan |
114 | Retrospective study | C02 laser | 17.5 % (20) | 11.4 % (13) | 3.4 years |
| Jerjes et al. | 2011 UK |
77 | Prospective study | C02 laser | 19.5 % | 10.4 % (8) | 6.4 years |
| Thomson et al. | 2016 Australia |
590 | Retrospective study | CO2 laser | 14.8 % (87) | 4.8 % (28) | 7.3 years |
| Hamadah et al. | 2009 UK |
78 | Prospective study | CO2 laser | 32 % | 4 % | 4.8 years |
| Saito et al. | 2001 Japan |
142 | Retrospective study | Surgery Cryotherapy Observation |
2.8 % | 6.3 % | 4 years |
| Arudino et al. | 2009 Italy |
207 | Retrospective study | Excision Observation |
33.7 % | 7.24 %(15) | 4.5 years |
| Gilvetti et al. | 2021 UK |
120 | Retrospective study | Excision CO2 laser Observation |
34.7 % (34) | 14.1 % | 4.16 years |
| Jayasooriya et al. | 2020 SL |
93 | Retrospective study | Surgery Observation |
31 %(16) | 7.5 % (7) | 2.5 years |
| Bagan et al. | 2022 Spain |
224 | Prospective study | Surgery C02 laser |
51.7 % (116) | 11.6 % (26) | 6.4 years |
| Bronuns et al. | 2013 Netherlands |
144 | Retrospective study | Surgery C02 laser Observation |
27 % (39) | 2.6 % (16) | 4.266 years |
| Bernard et al. | 2023 Canada |
155 | Retrospective study | Surgery Observation |
NR | 27 % (42) | 11 years |
| Holmstrup et al. | 2005 Denmark |
269 | Retrospective study | Surgery Observation |
NR | 12 % (18) | 6 years |
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