Study

Epidemiological and clinicopathological study of oral

Minati Mishra, Janardan Mohanty*, Sujata Sengupta, Satyabrata Tripathy Department of & Venereology, S.C.B. Medical College, *Department of Oncopathology, A. H. Regional Cancer Institute, Cuttack, Orissa, India

Address for correspondence: Dr. Minati Mishra, 698, Nayapalli, (Behind Kasturba Women’s College), Bhubaneswar - 12, Orissa, India. E-mail: [email protected]

ABSTRACT

Background: Oral white lesions that cannot be clinically or pathologically characterized by any specific disease are referred to as leukoplakia. Such lesions are well known for their propensity for malignant transformation to the extent of 10-20%.Exfoliative cytology is a simple and useful screening tool for detection of malignant or dysplastic changes in such lesions. Aims: A clinicoepidemiological and cytological study of oral leukoplakia was undertaken to detect their malignant potential and value of cytology in diagnosis. Methods: This 2 year duration multicentre study was undertaken on all patients presenting with oral white lesions to the out patient department of the two institutions. Those cases in which a specific cause (infective, systemic disease or specific disease entity) for the white lesions were elicited were excluded from the study. The group with idiopathic white lesions was included in the study and was subjected to periodic exfoliative cytological study at three monthly intervals to detect any malignant change. Patients presenting less than two times for follow up were excluded from the final analysis of the study. Results: Out of total 2920 patients studied, 89.53% showed benign, 9.93% showed dysplastic and, 0.72% showed malignant cells on exfoliative cytological study. All the dysplastic and malignant lesions were subjected to histopathological study by incisional biopsy. Among the dysplastic lesions 13.79% proved benign and the rest true dysplastic. Among the cytologically malignant group 4.76% showed dysplasia and the rest true malignant lesions. Conclusion: Persistent leukoplakia has a potential for malignant transformation and exfoliative cytology could be a simple method for early detection of dysplastic and malignant changes.

KEY WORDS: Leukoplakia, Dysplasia

INTRODUCTION Barr virus), , erythematosus, dyskeratosis congenita, white sponge , In 1978 a World Health Organization (WHO) group submucosal fibrosis and frank carcinomas.[1-3] It is defined oral leukoplakia as: “A white patch or plaque common in adults beyond 40 years of age, and affects that cannot be characterized clinically or pathologically 1% of the total population.[4] as any other disease”.[1] It is therefore a diagnosis of exclusion from other oral white lesions such as The present study aims to explore the possible leukokeratosis, infective lesions (, syphilitic etiological factors responsible for oral leukoplakia and oral lesion, oral hairy leukoplakia caused by Epstein assess the utility of exfoliative cytology in the detection

How to cite this article: Mishra M, Mohanty J, Sengupta S, Tripathy S. Epidemiological and clinicopathological study of oral leukoplakia. Indian J Dermatol Venereol Leprol 2005;71:161-5. Received: April, 2004. Accepted: October, 2004. Source of Support: Nil. Conflict of interest: None declared.

161 Indian J Dermatol Venereol Leprol May-June 2005 Vol 71 Issue 3 Mishra M, et al: Clinicopathological study of oral leukoplakia of malignant changes. Table 1: Sites of Involvement Site of lesion Male Female No. of Total no METHODS Malignant of lesions lesions Buccal mucosa of Cheek 810 716 10 1526 This prospective study was carried out from November (52.26%)* 1999 to October 2001 in joint collaboration between Tongue Dorsal surface 130 112 2 912 (31.23%) the Department of Dermatology, S.C.B. Medical College Ventral surface 75 73 1 Cuttack and Department of Oncopathology, AH Lateral surface 181 170 4 Floor of mouth 107 64 2 Regional Cancer Institute, Cuttack. Both the institutes Lips 192 150 1 342 are tertiary referral centers of the State Orissa. During (11.71%) Palate 75 65 0 140 this period all cases presenting to the dermatology out (2.22%) patient department with white lesions in the oral cavity Total 1570 1350 20 2920 (53.78%) (46.22%) (0.68%) (100%) were subjected to detailed dermatological and systemic *P<0.05 examination followed by microbiological study of lesions for yeast, and serology for . Cases of and 2nd decades. In the younger age groups, males oral white lesions found to be of any infective etiology tended to outnumber the females. But above the age or a part of any other systemic disease were excluded of 40 years, females were more in number. The duration from the study. The rest of the cases with no of the disease varied from 1 month to 3 years with a demonstrable cause, except tobacco use, were mean disease duration of 1 year 5 months. subjected to histopathological examination to exclude conditions like lichen planus, , The sites involved included the lips, tongue, inner side white sponge nevus, etc. Total number of patients with of the cheeks and palate [Table 1]. In both sexes, the oral white lesions that we came across during the two commonest site involved was the buccal mucosa on year study period numbered 3748. Only the idiopathic the inner side of the cheek (52.26%, P<0.05) followed cases of white lesions were considered for the study. by the tongue in 31.23%. The lips and palate showed Such cases of leukoplakia numbered 2920, excluding lesions in 11.7% and 2.22% cases respectively. the cases lost to follow-up. All the cases were subjected to clinical examination and scrape cytology at an A detailed history was taken to elicit any incriminating interval of three months. Those cases reporting for less factors and in 94.62% patients, a possible causal agent than two times for cytology study during the 2-year could be elicited. As seen in Table 2, in 3.2% males and period (numbering 205) were considered lost to follow- 7.85% females, no definite incriminating factor was up and they were excluded from the final analysis of found. Betel leaf (Paan) was found to be the commonest the study. At the end of the study period the results were compiled, tabulated and analyzed using suitable Table 2: Incriminating factors for Leukoplakia statistical tools like percentages and Student’s t-test. Causal Agents Male Female Total No. of Malignant Lesions RESULTS Betel (Paan) 319 505 824 (28.21) 7(35) Cigarette 327 15 342 (11.71) 4(20) During the time span of the study, 2920 cases were Gutkha 166 74 240 (9.34) 2(10) Bidi/Chutka 242 31 273 (9.34) 2(10) diagnosed to have oral leukoplakia, excluding the cases Khaini snuff (Nasa) 90 395 475 (16.26) 2(10) lost to follow up. This constituted 0.78% of all new cases Gudakhu 175 111 286 (9.79) 2(10) Hyperacidity with 85 0 85 (2.91) 0 attending the outpatient department of Dermatology. smoking Out of these 1570 (53.76%) were male and 1350 (46.24%) Hyperacidity without 10 21 31 0 smoking female [Table 1]. Their ages ranged from 9 years to 84 Denture / infected gum 105 87 192 (16.57) 0 years with a mean of 40.8 years. The maximum Lipstick 0 15 15 (0.51) 0 Unknown 51 106 157 1(5) percentage of patients (55.47%) were seen in the 21-30 Total 1570 1350 2920 (100) 20(100) years age group (3rd decade) followed by the 4th, 5th All parenthesis are in percentage

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Table 3: Cytological and Histopathological profile of the Table 4: Morphological types of Leukoplakia based on their lesions clinical appearance Character Cytology (%) Histopathology Morphological Total No. No. of cases No. of cases type of lesion of cases of confirmed of confirmed Benign 2609 (89.35) Not done dysplasia malignancy Dysplastic 290 (9.93) Dysplastic Benign 250 40 Thin leukoplakia 1705 (58.39) 3 (0.17) 0 Malignant 21 (0.72) Malignant Dysplastic Thick homogeneous 758 (25.95) 96 (12) 0 20 1 leukoplakia Total 2920 (100) Granular (nodular) 367 (12.56) 95 (25.8) 2 (0.54) leukoplakia Verrucous leukoplakia 46 (1.57) 26 (56.8) 7 (15.72) associated addiction, seen in 28.2% patients, and the Speckled leukoplakia 35 (1.19) 23 (65.7) 7 (20) use of snuff (khaini) was seen in 16.26% patients. Both Proliferative verrucous 9 (0.3) 7 (77.7) 4 (44.4) these were found to be more common in females than leukoplakia All parenthesis are in percentage males. Of the total, 11.7% cases reported cigarette smoking. Tobacco in some form or other was observed occurring in response to chronic irritation. Tobacco in as the most common associated factor in development different forms has been described as the most common of leukoplakia. So far as the malignant lesion are incriminating factor for such lesions.[5-7] However, other considered betel quid was the commonest association factors, depending on the socio-cultural habits of the (35% of all malignant lesions) followed by smoking (20%), patients that lead to chronic irritation of oral and buccal guthka, bidi/chutka, khaini and gudakhu (10% each). In mucosa may also be contributory. It starts as a thin one case (5%) of the malignant leukoplakia no homogeneous grayish white plaque either well defined incriminating factor was detected. or blending with the surrounding tissue. The lesion enlarges to leathery appearance with surface fissures On scrape cytology [Table 3] 2609 (89.35%) cases (thick homogeneous leukoplakia). Some lesions showed evidence of being benign, in the form of non- develop surface irregularities (granular or nodular specific inflammatory changes whereas 290 cases leukoplakia), warty papillary surface projections (9.93%) showed dysplasia, and frank malignancy was (verrucous leukoplakia), or mixed red and white lesions recorded in 0.72% cases. Histopathology of these cases (speckled leukoplakia or erythroplakia). The uncommon showed that 40 out of the 290 cases (13.79%) showing variant viz. proliferative verrucous leukoplakia is dysplasia on scrape cytology were actually benign. Out characterized by widespread multifocal sites of of the 21 cases reported to be malignant on cytology, involvement, often in patients with known risk factors. 18 (85.7%) proved to be invasive squamous cell Patients with idiopathic leukoplakia have the highest carcinoma, 2 (9.5%) in situ carcinoma and 1 (4.8%) risk of developing cancer.[8-12] The frequency of dysplastic leukoplakia. Thus there was an agreement dysplastic or malignant change varies from 15.6-39.2% between cytology and histopathological diagnosis in in different studies.[9,11-14] The risk of developing 86.2% cases of dysplastic lesions and 95.2% in the malignancies at lesion sites is 5 times greater in patients malignant lesions. Different morphological types of with leukoplakia than in patients without them. leukoplakia [Table 4] was observed, among which thin Erythroleukoplakia, verrucous leukoplakia, and nodular homogenous leukoplakia was the commonest (58.39%) leukoplakia show an increasing frequency of dysplastic followed by thick homogeneous leukoplakia (25.95%), histological changes or aneuploidy. Frequently oral granular type (12.56%), verrucous (1.57%) speckled white patches are noted secondary to some identifiable (1.19%), and proliferative verrucous (0.3%). The last local irritation. For example, thickened hyperkeratotic mentioned type i.e. proliferative verrucous although lesions are frequently seen over edentulous areas of least common, had the highest rate of malignant alveolar ridges (ridge ), chronic tongue changes (44.4%). chewing (morsicatio linguarum) or chronic cheek chewing (morsicatio buccarum). All such lesions are DISCUSSION secondary responses to a chronic irritation leading to compensatory of the epithelium Idiopathic leukoplakias are mostly benign lesions developing as a protective phenomenon, similar to the

163 Indian J Dermatol Venereol Leprol May-June 2005 Vol 71 Issue 3 Mishra M, et al: Clinicopathological study of oral leukoplakia development of a callus over skin of hand or feet. Such exempted whereas several other studies worldwide[4,7- lesions do not show any dysplasia and are reversible 9] have shown preponderance of leukoplakia in a later on eliminating the causative factor. These lesions are age group beyond 40 years. The discrepancy could be better termed as leukokeratosis rather than leukoplakia due to the use of tobacco, lime and betel quite as agreed by most experts.[7] The usage of the term prevalent among the younger population in our leukoplakia continues to undergo refinement.[7] country. The male to female ratio was found to be 1.16:1. Even though a study on world leukoplakia A retrospective study of 3,300 biopsies of oral prevalence showed[9] a significant male predominance, leukoplakia by Waldron and Shafer determined that we found females outnumbering males in the older age 19.9% of all leukoplakia showed some degree of group, which could be explained by the widespread epithelial dysplasia. In this group 3.1% were use of tobacco in elderly females. As seen in a recent unsuspected squamous cell carcinomas, 4.6% showed study in Kerala, in India and another study in Gujarat, severe dysplasia or carcinoma in situ, and 12.2% showed India, among industrial workers, tobacco chewing in mild to moderate dysplasia.[9] Silverman et al in a the form of betel nut, “pan” “or “supari” was found to clinicopathological study of 57,518 industrial workers be most important implicating factor.[15,17,21,22] This is in over 35 years of age from Gujarat elucidated the natural contrast to a study in the US population, where smoking history and malignant transformation of oral of tobacco was found to be the strongest independent leukoplakia.[15] They followed up this group and showed risk factor.[23] Other forms of tobacco, hyperacidity, that leukoplakia was the oral lesion that proved to be lipstick, and ill-fitting dentures were found to be a precancerous, with a transformation rate of 0.13% in a causative factor, which shows that socioeconomic 2-year interval.[16] status and lifestyle are involved in causing premalignant lesions.[5] Ramesh et al assessed the efficacy of exfoliative cytology in the detection of oral premalignant and In our study, 0.54% of granular or nodular, 15.2% of malignant lesions. They concluded that exfoliative verrucous, 20% of speckled and 44.4% of proliferative cytology is a useful method for detecting oral verrucous leukoplakia were confirmed histologically to premalignant and malignant lesions. Anucleated be malignant lesions. This suggests that certain squames in a smear are non-diagnostic.[17] A correlative morphologic types of leukoplakia are particularly prone study of exfoliative cytology and histopathology of oral for malignancy and need to be closely followed up. Also, carcinoma was conducted by Reddy et al and they lesions at the buccal mucosa were of more malignant commented that oral exfoliative cytology should only potential, accounting for 50% of the total malignant be used as an adjunctive measure and not as a lesions detected in the study. In contrast, Western substitute for biopsy.[18] Exfoliative cytological study of studies have shown lesions of lateral tongue and floor the leukoplakia has shown sensitivity of 77% and of mouth to be at greatest risk.[10-14] This discrepancy specificity of 100% in the detection of dysplastic or may be due to the typical habit of betel quid chewing malignant changes.[18,19] in our population.

Oral cancer is the commonest malignancy in Indian In our study, premalignant changes were seen in 9.93% males.[20] Leukoplakia is the most common cases which is similar to other studies done before.[5,8] precancerous lesion of the oral mucosa.[10-15,21] Its Frank malignancy was seen in 0.72% of our leukoplakia implicating factors, like chewing and smoking of cases. We found that of the 21 cases reported to be tobacco is widely prevalent in our country. However, malignant on scrape cytology 18 (85.7%) proved to be few Indian studies have been published on this topic. invasive squamous cell carcinoma on histopathological The total number of cases of leukoplakia i.e. 2920 study. Hence cytology is an important diagnostic tool formed 0.78% of the total new attendees at the OPD of for detecting in situ anaplastic changes and further the two institutions where the study was conducted. confirmation (by conventional biopsy) will substantiate The age range was wide showing that no age was the dysplasia and the type of malignancy. Different

Indian J Dermatol Venereol Leprol May-June 2005 Vol 71 Issue 3 164 Mishra M, et al: Clinicopathological study of oral leukoplakia studies were done on exfoliative cytology, DNA 6. International collaborative Group on Oral White Lesions. J Oral cytometric diagnosis, and histopathology on oral Pathol Med 1996;25:49-54. 7. Bouquot JE, Gorlin RJ. Leukoplakia, lichen planus, and other leukoplakia and there was an agreement between the oral keratoses in 23,616 white Americans over the age of 35 cytological and histological results in 76.6% of all years. Oral Surg Oral Med Oral Pathol 1986;61:373-81. cases.[2,10,16,17] Frank carcinoma was encountered in 8. Dictrich T, Reichart PA, Scheifele C. Clinical risk factors of oral 32.9% of erosive leukoplakia, 3.2% of verrucous leukoplakia in representative sample of the U.S. population. leukoplakia and none in the leukoplakia simplex Oral Oncol 2004;40:158-63. 9. Waldron CA, Shafer WG. Leukoplakia revisited: A [2,10] group. Moreover, cytology was highly effective in clinicopathologic study of 3256 oral leukoplakias. Cancer detecting malignancy in the erosive leukoplakia 1975;36:1386-92. group.[16,17] 10. Einhorn J, Wersäll J. Incidence of oral carcinoma in patients with leukoplakia of the oral mucosa. Cancer 1967;20:2189- 93. However, interobserver reliability in the cytological and 11. Bánóczy J. Follow-up studies in oral leukoplakia. J Maxillofac [24] histologic diagnosis of leukoplakia is a matter of Surg 1977;5:69-75. concern and, at the slightest clinical suspicion, 12. Pindborg JJ, Jlst O, Renstrup G, Roed-Peterson B. Studies on particularly in elderly patients with longstanding lesions oral leukoplakia: A preliminary report on the period prevalence and multiple risk factors, conventional biopsy followed of malignant transformation in leukoplakia based on a follow- up study of 248 patients. J Am Dent Assoc 1968;76:767-71. by histopathological study at a specialist referral 13. Roed-Petersen B. 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