Temporal epidemiological profile of oral potentially malignant disorders in southern BrazilAbstract
The study aimed to investigate oral potentially malignant disorders (OPMDs) diagnosed in an Oral Pathology service in southern Brazil over a span of 56 years and to assess the factors influencing their severity and outcomes. A retrospective analysis of histopathological records from 1965 to 2021 was performed. Lesions diagnosed as leukoplakia, erythroplakia, leukoerythroplakia, or actinic cheilitis were included. Data on age, sex, race, tobacco smoking, alcohol drinking, clinical characteristics, biopsy type, and histopathological diagnosis were collected. Among 32.698 histopathological reports, 2.10% were classified as OPMD. The study included 689 specimens from 602 patients, with a predominance of cases affecting men aged over 51 years, particularly in anatomical sites considered of low risk. White lesions, with leukoplakia as the most common clinical diagnosis were observed. Over time, there was an increase in the incidence of OPMDs among females and in high-risk anatomical sites. The mean follow-up period was 30.28 ± 29.86 months, during which 9.6% of cases exhibited malignant transformation. Lesions diagnosed as leukoerythroplakia and those presenting epithelial dysplasia exhibited a higher risk of malignant transformation, particularly when located in high-risk sites. This underscores the importance of identifying clinical and microscopic features, as well as lesion’s anatomical location, as crucial factors in determining the risk of malignant transformation. These findings provide valuable insights for clinicians managing OPMDs and contribute to the improvement of oral cancer prevention.
Precancerous Conditions; Leukoplakia; Cheilitis; Squamous Cell Carcinoma of Head and Neck
Introduction
Lip and oral cavity cancer ranks 15th in global cancer incidence, with an estimated 377,000 new cases and over 177,000 deaths reported in 2020.1 In Brazil, oral cancer is the fifth most prevalent cancer among men, with 15,190 new cases in 2022, resulting in 6,192 deaths. The incidence and mortality rates vary across different geographical regions in Brazil.2 Late detection remains the primary factor that negatively affects the overall survival and prognosis of patients with oral cancer.3
Oral potentially malignant disorders (OPMDs) often precede oral cancer, presenting as morphological and molecular alterations in the oral mucosa that may progress to the development of malignant tumors. OPMDs include different lesions and conditions,4 including leukoplakia, erythroplakia, and actinic cheilitis, which are most prevalent in the Western world.5 Identification of OPMDs by health professionals is of paramount importance, as early diagnosis improves the prognosis of affected patients and may decrease mortality and morbidity of oral cancer.6 The use of tobacco and alcohol is considered the main etiological factor of OPMD. However, idiopathic lesions can also occur.4
Actinic cheilitis is an OPMD that affects only the lips due to prolonged exposure to ultraviolet rays, appearing as dryness, erosion, and loss of definition of the lip contour. Its prevalence ranges from 0.24% to 2.4%, reaching up to 43.2% in specific populations with outdoor activities.7,8Leukoplakia is characterized by a white patch or plaque that cannot be removed by scraping and is not clinically or histopathological associated with other diseases.4The global prevalence of oral leukoplakia is about 2%.8 Currently, the rate of malignant transformation varies between 1.1% and 40.8%.9,10Erythroplakia is characterized by a red spot or patch that cannot be clinically or microscopically associated with other pathologies.5 Its reported prevalence varies from 0.02% to 0.83%.11 Erythroplakia has the highest risk of malignant transformation compared to all other OPMDs. Mixed white and red lesions are known as leukoerythroplakia or speckled leukoplakia.10
The microscopic features of OPMDs can be categorized into dysplastic and non-dysplastic epithelial alterations. Non-dysplastic alterations include epithelial hyperplasia, hyperkeratosis, and acanthosis. Conversely, dysplastic alterations are characterized by the presence of cellular atypia and loss of epithelial maturation and stratification. OPMDs exhibiting epithelial dysplasia have a higher risk of malignant transformation.12
Currently, no reliable diagnostic tool is available to predict which OPMDs will evolve into neoplasia.13 A temporal study of OPMD involves analyzing the epidemiological profile over time. This study aimed to examine OPMD cases diagnosed by a pathology service in southern Brazil over the past 50 years. This study aimed to gain insights into the profiles of patients with OPMD and assess the factors that influence the severity and prognosis of these lesions.
Methods
Study design and sample
This study followed the STROBE guidelines and was approved by the Research Ethics Committee of the Federal University of Rio Grande do Sul (UFRGS), Brazil (protocol number 4.095.472). This retrospective study was conducted by analyzing records from the Oral Pathology Laboratory at the School of Dentistry (UFRGS) in Porto Alegre. Data were collected from histopathological examinations performed between 1965 and 2021 by four calibrated researchers.
Lesions were selected based on clinical diagnostic hypotheses and microscopic findings. Selected lesions included OPMD with a clinical diagnosis of leukoplakia, erythroplakia, leukoerythroplakia, or actinic cheilitis. Microscopically, the lesions should present epithelial proliferation and maturation alterations, with a histopathological diagnosis of hyperplasia, hyperkeratosis, acanthosis, or epithelial dysplasia. Cases with microscopic diagnosis of squamous cell carcinoma (SCC) were included only when the clinical description of the lesions was compatible with OPMD and not ulcers.14 Lesions with different histopathological diagnoses were excluded from the study.
A total of 32,698 reports were reviewed and data from 602 patients with OPMDs were identified. Some patients presented multifocal lesions, resulting in the inclusion of 689 specimens in this study. Information on age, sex, race, smoking habits, and alcohol consumption was extracted from biopsy records. Information related to the lesions such as anatomical location, clinical appearance, biopsy type, clinical diagnosis, and histopathological diagnosis was also recorded.
For data analysis, the location of the lesions was grouped into high risk (tongue border, floor of mouth, and palate) and low risk (all other intraoral locations) groups.15,16 Histopathological diagnoses of epithelial hyperplasia, hyperkeratosis/hyperparakeratosis, and acanthosis were defined as non-dysplastic.
Follow-up data were available for 93 patients. Evolution data were registered and classified as favorable if there was no recurrence of an excised lesion or no alteration of an incised lesion. An unfavorable evolution was defined as if the lesion recurred, became more severe clinically or histologically, or if new oral OPMD lesions developed over time. Malignant transformations were independently recorded. To avoid misdiagnosis, malignant transformation was only considered if it occurred at least 6 months after the previous biopsy.17 The time of follow-up was registered in months.
Statistical analysis
Associations between the studied variables and clinical and histopathological diagnoses were analyzed using the Chi-squared test. When significant, the local analysis was verified using an adjusted standardized residual analysis. The significance level was set at p < 0.05.
The effect of each factor on the malignant transformation outcome was assessed using univariate Cox regression. Variables with significance ≤ 0.10 were included as candidates in the multivariable model. The variables for the histopathological diagnosis outcome, using the “non-dysplastic” category as the reference and analyzing the effect of the epithelial dysplasia category, were assessed by a binary logistic regression model to estimate the Odds Ratio (OR) and their respective 95% CIs. All statistical analyses were performed using SPSS version 25 software.
Results
After assessing 32,698 histopathological reports from the Oral Pathology Service spanning 56 years, we observed that 689 cases from 602 patients could be categorized under the selected OPMD, comprising 2.10% of all oral biopsies. Notably, most OPMD cases affected men (60.63%) aged > 51 years (69.26%). Regarding lesion site, most were found in low-risk sites (80.84%) and clinically presented as white lesions (79.4%). Clinically, these lesions were most frequently diagnosed as leukoplakia (75.32%) and histopathologically determined to be non-dysplastic (73.58%).
OPMDs distribution over the decades
The number of OPMD among the total number of samples from the pathology service is illustrated in Figure. An increase was observed regarding OPMD frequency among the total lesions, rising from 0.07% to 7.18% The temporal analysis (Table 1) revealed a notable increase in the diagnosis of lesions classified as Erythroplakia/Leukoplakia and Actinic Cheilitis. Additionally, there was a discernible increase in the incidence of these lesions among participants aged >50 years. Regarding anatomical site, the analysis demonstrated a decrease in the number of lesions located in low-risk areas and a concurrent increase in the number of lesions located at high-risk sites.
Number and frequency of OPMD cases in relation to total number of cases in the Oral Pathology Service.
OPMDs clinical and histopathological characteristics
Sample analysis based on clinical diagnosis (Table 2) showed that leukoplakia was predominantly found in the low-risk regions (64.9%). In contrast, erythroplakia lesions showed an even distribution between high- and low-risk locations, whereas leukoerythroplakia lesions were more frequently located at high-risk sites (58.8%). In terms of biopsy type, a similar distribution was observed for leukoplakia lesions, whereas incisional biopsies were preferred for erythroplakia, leukoerythroplakia, and actinic cheilitis. No significant association was observed between smoking and drinking habits with clinical diagnosis; however, it is worth noting that most individuals with OPMD were either smokers or former smokers, whereas alcohol use was not predominant. Information regarding the amount and duration of use of both smoke and alcohol was absent from more than 95% of the records; therefore, these analyses were not performed.
When comparing histopathological diagnoses (Table 3), it was observed that in lesions clinically diagnosed as leukoplakia, the most frequently encountered histopathological diagnosis was non-dysplastic, observed in 80.15% of cases. In contrast, among those clinically diagnosed with actinic cheilitis, a histopathological diagnosis of epithelial dysplasia was predominant, occurring in 47.05% of the cases. Notably, OPMD in high-risk locations exhibited a higher proportion of severe microscopic diagnoses, with epithelial dysplasia diagnosed in 32.55% of cases and SCC in 6.04% of cases, compared to low-risk site lesions, where epithelial dysplasia was detected in 19.21% of cases and SCC in 1.96% of cases (p = 0.019). Additionally, cases with a non-dysplastic histopathological diagnosis were more frequently observed in women (77.5%).
Factors associated to OPMDs malignant transformation
Of the 602 patients included in this study, follow-up data were available for 93 (Table 4). Among this subgroup, 47 (50.53%) were men, and the majority were aged > 51 years (60.2%). In terms of habits, 65 (69.9%) were current smokers or former smokers and 49 (52.68%) reported alcohol consumption or were former alcoholics. During the follow-up period, 43 (46.23%) patients exhibited favorable progression, characterized by no recurrence following excisional biopsy, stable lesion size and clinical appearance, and even regression in size. In contrast, 41 (44.08%) patients experienced unfavorable progression, marked by an increase in lesion size and the emergence of new lesions, and in 9 cases (9.67%), malignant transformation occurred. The mean duration of the follow-up period was 30.28 months (± 29.86).
Cox regression analysis revealed that the only variables associated with malignant transformation in this sample of OPMDs were clinical and microscopic diagnoses as well as the anatomic site of the lesion (Table 5). Lesions diagnosed as leukoerythroplakia presented a 8.98 higher risk (95%CI: 1.85–43.67, p = 0.007) of evolving into cancer than leukoplakia lesions. OPMDs with epithelial dysplasia showed a 5.19 higher risk (95%CI 1.87–14.43, p = 0.002) of malignant transformation than non-dysplastic lesions. High risk location was also a risk factor for malignant transformations (HR: 12.43, 95%CI 1.65–93.51, p = 0.014). However, multivariate analysis failed to confirm these as independent risk factors for the malignant transformation of OPMDs.
Considering that epithelial dysplasia is an important risk factor for OPMD progression, a logistic regression analysis was performed to assess the variables significantly associated with this feature (Table 6). Compared to leukoplakia, all other OPMDs showed higher risk for dysplastic findings (p < 0.05) and location at a high-risk site increased the epithelial dysplasia risk by 2.14 times than when located at low-risk anatomical sites (95%CI 1.34–3.42, p = 0.001).
Discussion
This study revealed the demographic characteristics of individuals affected by OPMDs over decades and assessed the clinical and pathological factors related to evolution and malignant transformation. These analyses aims to enable early detection and development of preventive measures against progression to malignancy. This study investigated the epidemiological characteristics of patients afflicted with OPMDs over five decades. From 1965 to 2021, a 2.10% OPMD frequency was observed. A systematic review and meta-analysis encompassing 22 studies conducted in various geographical regions revealed a 4.47% (95%CI: 2.43–7.08) global prevalence of OPMDs. This prevalence displayed significant geographical heterogeneity, ranging from 0.11% in North America to 10.54% in Asia. South America and the Caribbean had a prevalence of 3.94% (95%CI: 2.43–5.77). These variations can be attributed to differences in environmental factors and exposure to risk factors.8
An increase in the sample size and diagnosis of OPMDs was observed over the decades in this study. This observation can be explained by the increase in access to the Brazilian Unified Health System in recent decades. Since 2004, the implementation of the National Oral Health Policy and the 2005 National Oncology Care Policy organized a line of care to reduce the incidence and morbidity of oral cancer. The implementation of Dental Specialty Centers and public health services responsible for providing dental care has increased the diagnosis of oral mucosal lesions, particularly oral cancer and OPMDs.18
Between 1965 and 1990, the prevailing demographic predominantly comprised men aged ≥ 51 years. In the subsequent decade, a notable shift occurred, with women within the same age group exhibiting the highest frequencies. This phenomenon can, in part, be explained by heightened health consciousness and proactive health-seeking behavior among women.5,19 Longitudinal analysis further revealed an increase in the incidence of OPMDs among older individuals. Despite documented increases in the incidence of oral cancer among younger patients, there is no compelling evidence suggesting a similar trend in OPMDs.13,20
In the samples examined in this investigation, oral leukoplakia emerged as the prevailing lesion, with actinic cheilitis and erythroplakia following in frequency. These findings align with the prevailing trends observed in most existing studies.21,22 The meta-analysis mentioned previously identified oral submucosal fibrosis as the most prevalent lesion worldwide, followed by leukoplakia (the most prevalent in Latin America), actinic cheilitis, and erythroplakia.8 Oral submucosal diseases (caused by chewing tobacco and inverted smoking) are not usual in Brazil; therefore, leukoplakia being the most common OPMD is expected. In this study, 77.4% of the OPMDs were diagnosed as leukoplakia, representing a total prevalence of 1.38% among all oral biopsies. This frequency is in agreement with other studies conducted in the Brazilian population, which reported a prevalence ranging from 0.63% to 2.88%.11,19,23,24
Actinic cheilitis was predominant in white men, which can be explained by this lesion usually affecting people with fair skin and by the predominant type of professional activity in the southern region of Brazil, such as agriculture and livestock farming, in which individuals are chronically exposed to sunlight.11,25 Unfortunately, there were no significant records of sun exposure in the studied sample, which may be a limitation because of the importance of this variable in cases of actinic cheilitis. Our samples only included 51 cases of actinic cheilitis because, unlike leukoplakia and erythroplakia, where biopsy is mandatory, only more severe clinical cases of cheilitis or refractory lesions undergo biopsies. This was confirmed by the strong association observed with a more severe histopathological diagnosis, with epithelial dysplasia or SCC being more prevalent in individuals with biopsied actinic cheilitis than in those with leukoplakia. This finding was also reported in another Brazilian study.19 Currently, predicting which cases of actinic cheilitis will undergo malignant transformation remains challenging; however, a previous study reports a malignant transformation rate of 3.07%.26
The demographic profile of erythroplakia lesions in our study closely mirrored previously published data, with a higher incidence observed among men aged >50 years.5 Histologically, a significant majority (70%) of erythroplakia lesions were diagnosed as epithelial dysplasia or SCC.19,27,28 Within our cohort of 689 cases of OPMDs, the diagnosis of erythroplakia was exceedingly rare, constituting only six instances (0.87%). This observation aligns with the findings of Mehta,29 who conducted a comprehensive survey involving 50.915 Indian patients and identified only nine cases of erythroplakia (0.02%), as well with a Brazilian study which detected a 0.8% frequency of erythroplakia among OPMDs.19 The scarcity of erythroplakia cases is attributed to the inherent diagnostic challenge associated with this lesion. Erythroplakia, a distinctive red hue, diminishes its visual contrast with the adjacent oral mucosa when compared to the more conspicuous white lesions, frequently resulting in misclassification as inflammatory reactions. Furthermore, it is plausible that many erythroplakia cases are diagnosed at a more advanced stage, possibly already having progressed to cancer, because a substantial proportion of these lesions undergo malignant transformation.30
Cases of clinical lesions diagnosed as OPMDs that already presented with infiltrative carcinoma were included to assess the frequency of lesions that were diagnosed and had already progressed. As expected, the incidence was higher in lesions presenting as erythroplakia and actinic cheilitis. However, leukoplakia can also underscore SCC, as observed in 2.69% of our cases. This was already shown in the classic study by Waldron and Shafer14 assessing 3256 leukoplakia, of which 3.1% presented an infiltrative SCC.
OPMDs in high-risk anatomical locations demand particular attention due to their elevated association with a heightened incidence of SCC, as corroborated by findings from Mello.8 Consistent with existing literature, our study identified an increase in the risk of malignant transformation associated with OPMDs located in anatomically high-risk regions (OR 12.4, 95%CI: 1.65–93.51). Anatomical location is an essential factor to be considered by clinicians, as it is an important risk factor associated with the development and progression of OPMDs.13Furthermore, clinical and microscopic diagnoses are significant variables associated with the malignant transformation of OPMDs. This reaffirms the importance of these factors in assessing the risk of progression to SCC. The lack of identification of independent risk factors in the multivariate analysis demonstrates the complexity of OPMDs and the multifactorial nature of their progression. This suggests that factors other than the variables analyzed in this study may contribute to the development of malignant transformations in OPMDs. Consistent with other studies, this highlights the need for further research to explore additional factors and their contributions to OPMD progression and the development of oral cancer.4,31
Additionally, logistic regression analysis demonstrated a heightened risk of dysplastic findings in all other OPMDs compared to leukoplakia, consistent with findings from prior literature.19 This highlights the significance of considering various types of OPMDs and their distinct characteristics when evaluating the risk of epithelial dysplasia and the potential for malignant transformation.
A limitation of this study is the source of information for the cases, which was obtained from biopsy records that were frequently incomplete, specifically with regard to habits and risk factors, particularly in older records. Additionally, follow-up data were accessible for a limited number of cases and the occurrence of malignant transformation was relatively rare, which hindered the possibility of conducting more robust statistical analyses. However, it’s important to note that the study has several strengths, including a substantial sample size and an extended data collection period for the cases. These factors enable a more precise temporal analysis of the data.
Conclusion
The profile of patients affected by OPMD in our cohort was similar to that demonstrated in studies from different demographic regions, with leukoplakia being the most frequent lesion, mainly located in low-risk areas and microscopically diagnosed as non-dysplastic. However, lesions diagnosed as leukoerythroplakia and those exhibiting epithelial dysplasia showed a higher risk of progression to cancer. Moreover, lesions located in high-risk areas were also identified as risk factors for malignant transformation.
The findings of this study emphasize the need for the long-term monitoring and management of OPMDs to detect and address potential malignant changes in a timely manner. Overall, these findings contribute to our understanding of OPMDs and provide valuable information for clinicians involved in their diagnosis, treatment, and follow-up of patients with OPMDs. Continued research in this field will enhance our knowledge and improve patient outcomes in the prevention and management of oral cancer.
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Publication Dates
-
Publication in this collection
20 Dec 2024 -
Date of issue
2024
History
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Received
2 Nov 2023 -
Accepted
5 May 2024 -
Reviewed
10 Sept 2024
