|Year : 2016 | Volume
| Issue : 1 | Page : 29-34
A clinicopathological study of oral potentially malignant disorders
Subodh Hosagadde, Jyoti Dabholkar, Nitish Virmani
Department of ENT and Head-Neck Surgery, Seth G.S. Medical College, KEM Hospital, Mumbai, Maharashtra, India
|Date of Web Publication||23-May-2016|
Department of ENT and Head.Neck Surgery, Seth G.S. Medical College, KEM Hospital, Mumbai - 400 012, Maharashtra
Source of Support: None, Conflict of Interest: None
Introduction: Oral cancer is the leading cause of cancer in India accounting for approximately 40% of the cancer burden. A significant number of these are preceded by precancerous lesions and conditions, together referred to as potentially malignant disorders (PMDs). It is important to screen patients for these conditions as they allow physicians to intervene early for prevention as well as early diagnosis of oral cancer. Aims: To study the demographic profile, etiology, clinical profile, and histopathology of oral PMDs. Materials and Methods: Patient evaluation was done in the outpatient department of a tertiary referral center, and those who complained of oral mucosal lesions were examined between March 2011 and March 2012. They were evaluated and treated according to their diagnosis and were observed for 1½ years, with minimum of 4 follow-ups. Results: Of the 23,380 patients who attended the outpatient department between March 2011 and March 2012, 70 (0.29% incidence) patients had oral potentially malignant lesions. Age group most commonly affected was 21–30 years (28.57%). Males were affected more than females (m = 50; f = 20). Smokeless tobacco was the most common risk factor (58.57%). Among single site lesions, buccal mucosa was most commonly affected. Based on histopathology, “leukoplakia without atypia” was the most common lesion followed by oral submucous fibrosis. Conclusions: There is a change in the trend of the age distribution of the oral potentially malignant lesions with younger generation and females being involved more and also a definite relation between tobacco-related abuses and oral lesions.
Keywords: Conventional oral examination, oral potentially malignant disorders, screening
|How to cite this article:|
Hosagadde S, Dabholkar J, Virmani N. A clinicopathological study of oral potentially malignant disorders. J Head Neck Physicians Surg 2016;4:29-34
|How to cite this URL:|
Hosagadde S, Dabholkar J, Virmani N. A clinicopathological study of oral potentially malignant disorders. J Head Neck Physicians Surg [serial online] 2016 [cited 2021 Sep 18];4:29-34. Available from: https://www.jhnps.org/text.asp?2016/4/1/29/182853
| Introduction|| |
Oral cavity cancer is the sixth most common cancer in the world. It is the most common cause of cancer in India accounting for up to 40% of all cancers, and its incidence is on the rise., Oral cancer has multiple etiologies, the most important of which are tobacco and alcohol. Most of the cancers in the oral cavity are amenable to early detection owing to easy accessibility of oral sites by routine screening examination by healthcare workers or by mouth self-examination.
A precancerous lesion is a morphologically altered tissue in which oral cancer is more likely to occur that its apparently normal counterpart whereas a precancerous condition is a generalized state associated with a significantly increased risk of cancer. However, in a workshop coordinated by World Health Organization, it was decided to use the term “potentially malignant disorders (PMD)” to convey that not all disorders described under this term may transform into cancer rather this is a family of morphological alterations among which some may have an increased potential for malignant transformation. These lesions are not only site specific predictors of malignancy but also indicate an increased risk of future malignancies elsewhere in (clinically normal appearing) oral mucosa. The following were identified as PMD s by the World Health Organization's working group on oral cancer: Leukoplakia, erythroplakia, palatal lesion of reverse cigar smoking, oral lichen planus, oral submucous fibrosis (OSMF), discoid lupus erythematosus. In the last few years, a disturbing new trend has been observed with a greater predilection of younger age groups to oral PMDs. This can be mainly attributed to increase in substance abuse among the youth.
Most PMDs are asymptomatic, and the main aim of treatment is to prevent and/or to detect cancer development early. Etiological factors can be identified and patients can be warned of the potential of malignancy. Abstinence from tobacco and alcohol, even after many years of use, significantly reduces the risk of developing cancer. The knowledge of susceptibility to cancer among the general population must be imparted by awareness programs and publications in media. Oral PMDs may be considered a blessing in disguise as they can help in early diagnosis and prevention of oral malignancies which can decrease the burden of cancer prevalence, especially in the youth and working class of the society.,
| Materials and Methods|| |
The 1 year prospective study was conducted in the ENT division of our hospital, a tertiary care referral center. Patients presenting to the outpatient department with oral potentially malignant lesions were included in the study. A detailed clinical workup including personal history and habits was done. Patients were observed for resolution of the lesions with 2 weeks of medications; those which persisted despite treatment were biopsied to diagnose the underlying pathology.
Medical treatment was instituted in the form of oral antioxidants and multivitamins. Patients were counseled about the potential of malignancy and advised complete abstinence from tobacco and alcohol. They were followed up for 1½ years, with a minimum of four follow-up visits at 1 month, 6 months, 1 year, and 1½ years. Photo-documentation of the lesions was done for better comparison and assessment in each visit.
| Results|| |
Of a total of 23,380 patients who attended the outpatient department of ENT division during the period between March 2011 and March 2012 (1 year), 70 patients were diagnosed with oral PMDs. Thus, the incidence was 0.29%.
The age range of the study group was 18–70 years; mean 42.39 years. The age group most commonly affected was 21–30 years comprising 28.57% of the total burden [Table 1]. The increased incidence in younger age groups was found to be statistically significant (P< 0.05). Males were affected more often with an M: F ratio of 2.5:1. All the patients belonged to lower or middle socioeconomic class.
Among the predisposing risk factors, smokeless tobacco was the most common (58.57%) followed by betel nut and dental abnormalities. Mishri addiction was found exclusively in females. Other factors are as shown in [Table 2]. No predisposing factor could be identified in 18 patients.
|Table 2: The risk factors predisposing to oral potentially malignant disorders|
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The most common clinical presentation of patients with oral cavity lesions was a white patch on oral mucosa (70%) [Figure 1]. Other presentations included red patch, a combination of red and white patch, pain, burning sensation, and decreased mouth opening.
Multiple site involvement was observed in 28 patients (40%). Among the patients with single site lesions, buccal mucosa was the most commonly affected site [Table 3].
“Leukoplakia without atypia” was the commonest underlying pathology comprising 45.71% of the study population. It was followed by OSMF (21.43%) [Figure 2]. Leukoplakia with atypia/dysplasia was seen in 10% of the patients. Oral lichen planus was seen in 8.57% [Figure 3] and verrucous leukoplakia and erythroplakia [Figure 4] were both seen in 2.86% of patients. Only 1 patient had well differentiated squamous cell carcinoma which clinically presented like a leukoplakia.
| Discussion|| |
The incidence of oral PMDs in our hospital-based study was 0.29% per year. Roy and Varshney (2013) in their study from Dehradun, India, had a similar incidence rate of 0.29% for Oral potentially malignant lesions per year.
The maximum numbers of patients with oral PMDs were seen in the third decade, an alarming finding.
Scott et al. (1989) and Waldron et al. (1975) in their studies found the sixth and seventh decades as the commonest age of occurrence. According to studies by Mehrotra et al. and Dietrich et al., potentially malignant lesions were commonly seen in the 6th decade. However, Liu et al. in 2011 reported the highest incidence of potentially malignant lesions in 5th decade, a decade earlier than the previously mentioned studies. Misra et al. in their hospital-based study found that the mean age of patients in the prospective group of 2003–2004 was less than in the retrospective group over the previous decade. The increased predilection for younger age groups is probably due to a decrease in the age of patients taking gutkha/pan masala, smoking, increased substance abuse, early screening, and increased awareness about the problem. Easier access, peer pressure, and advertisements of the substances in the media contribute significantly to this disturbing change in age distribution.
Males were affected more often than females (M:F ratio 2.5:1). This finding is in concordance with Dietrich et al., Mishra et al. and Liu et al. showing increased incidence among males. This can be explained by a higher incidence of substance abuse in males.
Among the etiological factors, smokeless tobacco was found to be the most common abuse in various forms such as supari, gutkha. Mishri abuse was mainly noted among females. Dental factors that are responsible for the formation of premalignant lesions include sharp cusps, malocclusion, loose tooth, or ill-fitting dentures. Multiple factors are contributory in a significant number of patients and include combinations such as smokeless tobacco with betel chewing, smokeless tobacco with cigarettes, smokeless tobacco with dental irritation and dental irritation with mishri. Our findings are in concordance with the existing literature.
Iype et al. reported that 56.4% of patients with oral PMDs were habituated to either tobacco chewing, smoking, or alcohol while Kandekar et al. observed that 71.3% of patients were habituated to tobacco. 63.3% were habituated to tobacco in the form of cigarettes or beedis. In a number of other studies ,, tobacco abuse, as well as alcoholic consumption, was found to be a causative factor for both oral premalignant lesions as well as oral cancer.
We relied on conventional oral examination (COE) to diagnose as well as to decide the site of biopsy in patients with oral PMDs.
A meta-analysis of different studies undertaken to assess the reliability of conventional oral examination showed a weighted pooled sensitivity of 0.848 (95% confidence interval [95% CI]: 0.73, 0.92) and specificity of 0.965 (95% CI: 0.93, 0.98) indicating a satisfactory test performance for an oral examination. Sankarnarayan et al., conducted a population-based randomized controlled trial (RCT) in the Trivandarum district, Kerala, from 1995 to 2004. Long-term results at 9 years showed that though, there was no increase in survival in the overall population, a significant increase in survival was seen among males with high-risk habits, such as tobacco use. This was the first clear evidence to support the efficacy of an oral cancer screening program in high-risk population, as measured by reduced mortality.
Several adjuncts are available to aid in the detection of PMDs such as toluidine blue, brush cytology, tissue chemiluminescence, and autofluorescence. Vital staining by toluidine blue has been used to demarcate the lesion prior to excision. A recent review by Epstein et al. suggests that toluidine blue has utility as an adjunct in the in the assessment and management of oral mucosal lesions by accelerating the decision to biopsy and guiding in selection of biopsy site. Chaturvedi et al. in a recent review on screening methods concluded that there is no evidence that supports the use of reflective tissue fluorescence systems to help in the detection of oral premalignant lesions. They also concluded that while clinical examination and histopathology remain the “gold standard” for the detection of oral cancer, other than visual examination, no single method for screening seems to be applicable and cost-effective in the general population.
We found buccal mucosa to be the commonest site involved in single site lesions followed by the lateral border of the tongue. Even among patients with multiple site involvement, buccal mucosa was the most common site involved.
This pattern of involvement is similar to the findings of Mishra et al., Lee et al., Misra et al. but is discordant with the study done by Liu et al. where the tongue was the most common site for the potentially malignant lesions. We also did not find any lesions in the high-risk sites commonly mentioned in the western literature like ventral surface of tongue or floor of mouth. This may be explained by differences in the substance abuse pattern and needs further evaluation.
Leukoplakia without atypia was the most common underlying histopathology followed by OSMF. Other pathologies observed were leukoplakia with atypia or dysplasia, oral lichen planus, erythroleukoplakia, and one case of squamous cell carcinoma.
Roy and Varshney  reported that out of their 35 OPL patients, 4 (11.4%) had leukoplakia, 12 (34.2%) had oral lichen planus, 6 (17.1%) had OSMF and 13 (37%) had discoid lupus erythematosus. In another Indian study by Ranganathan et al., oral soft tissue lesions were found in 4.1% of the study subjects. The prevalence of leukoplakia, oral submucous fibrosis (OSF), and oral lichen planus was 0.59%, 0.55%, and 0.15%, respectively.
In a study by Holmstrup et al., 2006 a total of 269 lesions in 236 patients were included. 39 lesions (41%) being homogenous and 46 (49%) nonhomogenous leukoplakias whereas nine (5%) were erythroplakias. Seventy-three percent of the lesions were associated with tobacco habits. 71% of the lesions showed a degree of epithelial dysplasia. Nonhomogenous leukoplakia accounted for highest frequency of malignant development, i.e. 20%, whereas 3% of the homogenous leukoplakias developed carcinomas.
This is in agreement with our results that leukoplakia is the most common oral potentially malignant lesion while erythroplakia is found in very less number of cases. There was a positive correlation with tobacco abuse, both chewable form and smoking.
The incidence of malignancy in our study was 2.86%. One patient who had 15 years history of smokeless tobacco consumption and had presented with a white patch in the oral cavity for 9 months was diagnosed with well-differentiated squamous cell carcinoma on histopathological examination. Another patient who was diagnosed with OSF initially developed malignancy during the observation period.
A large-scale study by Lee et al., which analyzed 1046 patients with oral leukoplakia between 1997 and 2004 of which 408 cases were only epithelial hyperplasia, and/or hyperkeratosis showed 477 cases (45.6%) of epithelial dysplasias of various degrees. Mild dysplasia was seen in 200 cases (19.12%), moderate in 234 (22.37%), and severe in 43 (4.11%) cases were observed. Invasive SCC was present in 135 oral leukoplakia cases, resulting in a 12.9% prevalence rate of carcinoma among all oral leukoplakia lesions which is much higher than our study.
A follow-up study of a hospital-based population by Schepman et al. 1998, of 166 patients with oral leukoplakia revealed a 2.9% annual malignant transformation rate over a median follow-up period of 29 months. Leukoplakias in Stage IV, consisting of lesions with moderate or severe epithelial dysplasia, were associated with an increased risk of malignant transformation (P< 0.01). There were no oral subsites associated with an increased risk. Patients who had any form of intervention did not have a significantly lower chance for malignant transformation than patients who were kept under surveillance without intervention.
These studies show varied rates of conversion to malignancy. Our study is in concordance with the study by Schepman et al., but the observation period in our study was much shorter. Hence, a significant comparison cannot be done and short duration is found to be a limitation in studies on oral potentially malignant lesions.
Most PMDs are asymptomatic, and the main aim of treatment is to prevent and/or to detect cancer development early. Treatment of PMD can be in three categories namely close observation, surgical excision/ablation, and medical treatment. Patients with early, small lesions that are clinically benign looking and appear at favorable sites can be observed. Although conservative surgical excision with negative margins remains the treatment of choice for leukoplakia to remove areas at high risk, attempts to remove all clinically apparent areas of leukoplakia or histologically diagnosed areas of dysplasia, are impractical in most circumstances and produce scarring and contracture that result in more morbidity than benefit to the patient. Furthermore, excision is associated with high recurrence rates.,
A Cochrane review published by Lodi et al. studied the effectiveness of different interventions for leukoplakia. The possible effectiveness of surgical interventions, including laser and cryotherapy, has never been studied by means of an RCT with a no treatment/arm. Nine RCTs of nonsurgical interventions studies were included in the analysis. Malignant transformation was recorded in just two studies: None of the treatments tested showed a benefit when compared with the placebo. Treatment with beta carotene, lycopene, and vitamin A or retinoids, was associated with significant rates of clinical resolution, compared with or absence of treatment. Whenever reported, a high rate of relapse was a common finding. It was concluded that till date there is no evidence of effective treatment in preventing malignant transformation of leukoplakia. Treatments may be effective in the resolution of lesions, however, relapses and adverse effects are common.
In case of erythroplakia, surgery, either by cold knife or by laser, is the recommended treatment modality., Without therapy, this disease transforms into invasive carcinoma in 60–90% of the cases within 5–10 years after initial diagnosis. There are no data, however, from the literature about the recurrence rate after excision of erythroplakia.
| Conclusion|| |
There is a definite relation between tobacco-related abuses and oral PMD. There is a recent and disturbing change in the distribution of the oral PMD with a higher predilection for younger age group due to a decrease in the age of patients indulging in substance abuse. Easier access, peer pressure and advertisements of the substances in the media contribute significantly to this trend.
Although, surgical and nonsurgical interventions may be effective in the resolution of lesions, there is no evidence to suggest that they prevent malignant transformation. Relapses and adverse effects are common.
Abstinence from substance abuse with elimination of other risk factors such as dental abnormalities seem to be the best way forward to reduce the burden of PMD as well as oral cancer. Proper counseling and strict follow-up can ensure early diagnosis and treatment of any malignant changes that may occur in patients with PMD. Overall, prevention is the best way to deal with oral PMD. Awareness in health care workers, dentists, general practitioners, ENT surgeons and self-examination by the patient will go a long way to reduce the burden of oral cancer by taking timely action and, in turn, reducing the economic burden of treating oral cancer, on the country.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Greenlee RT, Hill-Harmon MB, Murray T, Thun M, Cancer statistics 2001, CA Cancer J Clin 2001;51;15-36.
Saranath D, Bhoite LT, Deo MG. Molecular lesions in Human Oral Cancer. The Indian scene. Euro J Cancer B Oral oncol 1993; 29B: 107-12.
Van der Waal I, Shepman KP, Van der Meij EH, et al.
Oral Leukoplakia: a clinicopathological review. Oral onco 1997;33; 291-301.
Neville BW, Day TA, Oral cancer and Precancerous lesions. Cancer journal of Clinicians, 2002;52:195.
Warnakulasuriya, S, Johnson, Newell W, Van Der Waal, I. Nomenclature and classification of potentially malignant disorders of the oral mucosa. Journal of Oral Pathology & Medicine 2007;36:575-80.
Misra V, Singh PA, Lal N, Agarwal P, Singh M. Changing Pattern of Oral Cavity Lesions and Personal Habits Over a Decade: Hospital Based Record Analysis from Allahabad. Indian Journal of Community Medicine: Official Publication of Indian Association of Preventive & Social Medicine 2009;34:321-5.
Pindborg JJ, Daftary DK, Mehta FS, A follow-up study of sixty-one oral dysplastic precancerous lesions in Indian villagers. Oral surg Oral med Oral patho 1977;43:383-90.
Roy S, Varshney S. Oral Dermatological Conditions: A Clinical Study. Indian Journal of Otolaryngology and Head & Neck Surgery. 2013;65:97-101.
Scott J, Cheah SB. The prevalence of Oral mucosal lesions in the elderly in Surgical biopsy population. Gerodontology 1989;8:73-8.
Waldron CA, Shafer WG. Leukoplakia revisited. A Clinico Pathologic study of 3256 Oral leukoplakia. Cancer 1975;36:1386-92.
Mehrotra R, Singh M, Kumar D, Pandey AN, Gupta RK, Sinha US. Age specific incidence rate and pathological spectrum of oral cancer in Allahabad. Indian Journal of Medical Sciences 2003;57:400-4.
Dietrich AT, Reicharta PA, Scheifelea C. Clinical risk factors of oral leukoplakia in a representative sample of the US population. Oral Oncology 2004;40:158-63.
Liu W, Wang YF, Zhou HW, Shi P, Zhou ZT, Tang GY. Malignant transformation of oral leukoplakia: A retrospective cohort study of 218 Chinese patients. Cancer 2010;10:685.
Mishra M, Mohanty J, Sengupta S, Tripathy S. Epidemiological and clinicopathological study of oral leukoplakia. Indian J Dermatol Venereol Leprol 2005;71:161-5.
Iype EM, Pandey M, Mathew A, Thomas G, Sebastian P, Nair MK. Oral cancer among patients under the age of 35 years. J postgrad Med 2001;47:171-6.
Khandekar SP, Bagdey PS, Tiwari RR. Oral cancer and some epidemiological factors: A hospital based study. Indian J Community Med 2006;31:157-9.
Durazzo MD, Araujo CEN, Brandao Neto JS, Potenza AS, Costa P, Takeda F, et al
. Clinical and epidemiological features of oral cancer in a medical school teaching hospital from 1994 to 2002: increasing incidence in women, predominance of advanced local disease, and low incidence of neck metastases. Clinics 2005;60:293-8.
Dias GS, Almeida AP. A histological and clinical study on oral cancer: Descriptive analyses of 365 cases. Med Oral Patol Oral Cir Bucal 2007;12:474-8.
Balaram Prabha, Sridhar H, Rajkumar T, Vaccarella S, Herrero R, Nandakumar A. et al
. Oral cancer in Southern India: the influence of smoking, drinking, pan chewing and oral hygiene. Int J Cancer 2002;98:440-45.
Downer MC, Moles DR, Palmer S, Speight PM. A systematic review of test performance in screening for oral cancer and precancer. Oral Oncol 2004;40:264-73.
Sankaranarayanan R, Mathew B, Jacob BJ, Thomas G, Somanathan T, Pisani P, et al
. Early findings from a community-based, cluster-randomized, controlled oral cancer screening trial in Kerala, India. The Trivandrum Oral Cancer Screening Study Group. Cancer 2000;88:664-73.
Ramadas K, Sankaranarayanan R, Jacob BJ, Thomas G, Somanathan T, Mahe C, et al
. Interim results from a cluster randomized controlled oral cancer screening trial in Kerala, India. Oral Oncol 2003;39:580-8.
Epstein JB, Güneri P. The adjunctive role of toluidine blue in detection of oral premalignant and malignant lesions. Curr Opin Otolaryngol Head Neck Surg 2009;17:79-87.
Nair DR, Pruthy R, Pawar U, Chaturvedi P. Oral cancer: Premalignant conditions and screening--an update. J Cancer Res Ther. 2012 Jan;8 Suppl 1:S57-66.
Lee JJ, Hung HC, Cheng SJ, Chen YJ, Chiang CP, Liu BY, et al
. Carcinoma and dysplasia in oral leukoplakias in Taiwan: Prevalence and risk factors. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2006;101:472-80.
Ranganathan K, Devi MU, Joshua E, Kirankumar K, Saraswathi TR. Oral submucous fibrosis: a case-control study in Chennai, South India. J Oral Pathol Med 2004;33:274-7.
Holmstrup P, Vedtofte P, Reibel J, Stoltze K. Long-term treatment outcome of oral premalignant lesions. Oral Oncol 2006;42:461-74.
Schepman KP, Bezemer PD, van der Meij EH, Smeele LE, van der Waal I. Tobacco usage in relation to the anatomical site of oral leukoplakia. Oral Dis 2001;7:25-27.
van der Hem PS, Nauta JM, Van der Wal JE, Roodenburg JL. The results of CO2 laser surgery in patients with oral leukoplakia: A 25 year follow up. Oral Oncol 2005;41:31-7.
Vedtofte P, Holmstrup P, Hjorting-Hansen E, Pindborg JJ. Surgical treatment of premalignant lesions of the oral mucosa. Int J Oral Maxillofac Surg 1987;16:656-64.
Lodi G, Sardella A, Bez C, Demarosi F, Carrassi A. Interventions for treating oral leukoplakia. Cochrane Database Syst Rev 2006;4:CD001829.
van der Waal I. Potentially malignant disorders of the oral and oropharyngeal mucosa; terminology, classification and present concepts of management. Oral Oncol 2009;45:317-23.
Reichart PA, Philipsen HP. Oral erythroplakia--a review. Oral Oncol 2005;41:551-61.
[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2], [Table 3]
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