Oral Oncology 37 (2001) 103±109
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Evaluation of surgical excision of non-homogeneous oral leukoplakia in a screening intervention trial, Kerala, India M. Pandey a,*, G. Thomas a, T. Somanathan a, R. Sankaranarayanan b, E.K. Abraham a, B.J. Jacob a, B. Mathew for the Trivandrum Oral Cancer Screening Study Group 1 a Regional Cancer Centre, Medical College Campus, Trivandrum, Kerala 695011, India Unit of Descriptive Epidemiology, International Agency for Research on Cancer, 150 Cours Albert Thomas, 69372, Lyon Cedex 08, France
b
Received 14 April 2000; accepted 18 May 2000
Abstract It is well established that most invasive oral cancers arise from precancerous lesions such as leukoplakia, erythroplakia and oral submucous ®brosis. One of the approaches for control of oral cancer is to detect oral precancerous lesions early in their development and prevent their malignant transformation to invasive cancer either by chemoprevention or by surgical excision of the lesions, with concurrent control of tobacco and alcohol use and other speci®c aetiological factors. However, the value of speci®c approaches such surgery in long-term control of lesions and prevention of malignant transformation is not known. We describe our experience with cold knife surgical excision of 59 cases of non-homogeneous leukoplakia of the oral cavity diagnosed in the context of a community-based oral cancer cluster randomised oral cancer screening trial in Kerala, India. Two-thirds of these revealed dysplasia on histology. After a minimum follow-up of 12 months (range 12-37 months) after surgical excision, 44 (74.8%) were remaining disease free with no evidence of recurrent/new lesions; during follow-up, three (5%) developed new luekoplakic lesions, and six (10.1%) developed recurrent lesions, while six (10.1%) could not be traced after treatment. There was no event of malignant change during follow-up. The proportion of subjects remaining with no evidence of disease at 3 years by Kaplan±Meier method of analysis was 62.1% (95% CI: 0.36±0.87). Accrual and long-term follow-up of large number of surgically treated cases may provide valuable leads to management policies of oral leukoplakia, since, as of now, the added value of speci®c treatments over and above primary prevention by tobacco and alcohol control remains to be established. # 2001 Elsevier Science Ltd. All rights reserved. Keywords: Leukoplakia; Treatment; Surgery; Prevention; Oral cancer; Screening; Intervention
1. Introduction Oral Cancer (ICD-10 C00-C06) is an important oncological public health problem in India where it ranks among the most common cancers in both sexes in regions where reliable data are available. The incidence rates for cancers of the oral cavity in India for both sexes are among the highest reported world-wide [1]. * Corresponding author. Tel.: +9l-471-442541; fax. +91-471447454. E-mail address:
[email protected] (M. Pandey). 1 The members of the Trivandrum Oral Cancer Screening Study (TOCS) Group are: R. Sankaranarayanan, D.M. Parkin, Paola Pisani, International Agency for Research on Cancer, Lyon, France; S. Najeeb, Kerala State Health Services, Trivandrum, India; Babu Mathew, Elizabeth Abraham, Iqbal Ahamed, Binu Jose Jacob, M. Krishnan Nair, Manoj Pandey, K. Ramadas, Paul Sebestian, Thara Somanathan, Gigi Thomas, Regional Cancer Centre, Trivandrum, India.
For instance, the age-standardised incidence rate of oral cancer in males was 16.3 per 100,000 and 7.7 in females during 1991±1992 in Trivandrum, Kerala, India [2]. The role of various tobacco habits and alcohol as causative factors for oral precanceous lesions and cancer has been well established. It is also well-accepted that most invasive oral cancers arise from precancerous lesions such as leukoplakia, erythroplakia and oral submucous ®brosis and the incidence of oral cancer in persons with no tobacco habits is negligible [3,4]. The malignant potential of these lesions is well established. One of the approaches for control of oral cancer is to detect oral precancerous lesions early in their development and prevent their malignant transformation to invasive cancer either by chemoprevention or by surgical excision of the lesions, with concurrent control of tobacco and alcohol use and other speci®c aetiological factors. While chemoprevention is still very much
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experimental, the experience and the evidence of bene®t with surgical management of these lesions are even more limited. Speci®c approaches to treat oral precancers are seldom emphatically undertaken in routine clinical practice in contrast to the frequency with which these lesions are diagnosed in high risk settings. Thus, surgical treatment of oral precancers is still not a widely practised approach for a variety of reasons, contrary to well-accepted and evaluated surgical management procedures for cervical intraepithelial lesions. In this paper, we describe our experience with surgical excision of oral leukoplakias in subjects diagnosed in the context of a community-based cluster randomized intervention trial of oral cancer screening in Kerala, India [5].
2. Materials and methods Trivandrum Oral Cancer Screening Study (TOCS) is a community-based cluster randomized controlled trial of oral cancer screening by visual inspection of the oral cavity provided by trained health workers in two rural development blocks (an administrative structure) of Kazhakuttam and Chirayinkil, Trivandrum District, Kerala, India. The study methodology, organisation and the outcome of ®rst round of screening have already been described [5] (Figs. 1 and 2). In brief, 13 geographic administrative sub-units called `panchayats' in the two rural development blocks have been randomised to the intervention (n=7) and the
Fig. 1. Flow chart depicting the management protocol for screen-detected oral premalignant lesions at Trivandrum Oral Cancer Screening Study [5]. SMF, submucous ®brosis.
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Fig. 2. Details of precancerous lesions screen detected in the Trivandrum Oral Cancer Screening Study [5].
control group (n=6). Of the 59,894 eligible individuals (aged 35 years and above) in the intervention group, 49,179 were screened by visual examination of the oral cavity by trained health workers, in the ®rst round carried out between October 1995 and May 1998. Of the 3585 (7.3%) screen-positive subjects referred, 1877 (52.4%) had further con®rmatory examination by dentists or physicians and 1310 subjects were subsequently diagnosed with oral precancerous lesions. The clinical appearance of the lesions were that of homogeneous leukoplakia in 635, non-homogeneous leukoplakia in 519 and submucous ®brosis (SMF) in 175 (Fig. 2). Of the 102 subjects with non-homogenous leukoplakias agreeing for cold knife surgical excision, 76 underwent the same between January 1997 and May 1998. Others did not report for surgery. The criteria for selection of subjects for surgical excision are described in Table 1. The surgical excision was carried out on a day care basis. Patients willing for excision were called for surgery after a light breakfast. The excisions were carried out after injecting local anesthesia (1%
Table 1 Selection criteria for surgical excision of oral premalignant lesion at Trivandrum Oral cancer screening study 1 2 3 4
Non-homogenous lesions Discrete lesions <3 cm in size Localised lesions at one or two distant sites Patients willing for surgical excision and able to give written consent
Xylocaine1) around and under the lesion. Haemostasis was achieved using diathermy coagulation after the excisions. If small, the wound was closed primarily using 3/0 Monocryl1 and if large they were left to granulate and regenerate epithelium. Patients were send home 1 h after the excision and were advised to take oral antibiotics (cipro¯oxacillin and tinidazole) and analgesics (paracetamol and Ibuprofen combination) for 3 days. They were advised to discontinue tobacco or alcohol habits. Of the 76 subjects with clinically non-homogenous lesions undergoing surgical excision, 17 (22%) found to
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have either in situ or invasive squamous cell carcinoma on histology were excluded from further analysis. Thus, 59 subjects were eligible for ®nal analysis. The stage distribution of the lesions in the eligible individuals were carried out using the recently proposed staging system for oral leukoplakia [6]. Clinical follow-up of the subjects was carried out initially every week for the ®rst month and, thereafter, every 3±6 months depending upon histopathology. Eight subjects were lost to followup and the remaining 51 were followed-up for a minimum period of 12 months (range 12±37 months) and their disease status at last follow-up was established. Kaplan±Meier product-limit method was used to calculate the probability of remaining disease free at various follow-up intervals [7]. For this purpose, both recurrences and new lesions were designated as failure. 3. Results Of the 59 eligible cases, 40 were males and 19 females. The age distribution of the subjects were: <35 years; three (5%); 35±44 years: eight (13.5%), 45±54 years; 11 (18.6%); 55±64 years; 24 (40.6%); and >65 years, 12 (20.3%). The pre-operative clinical appearance of the lesions were as follows: ®ve were (8.5%) verrucous leukoplakia; two (3.4%) were erythroleukoplakia; six (10.2%) were cases of nodular leukoplakia; 39 (66.0%) had ulcerated leukoplakia; and seven (11.9%) were cases of leukoplakia not otherwise speci®ed (NOS). Most of the lesions (39.7%) were located in the buccal mucosa, followed by commissure (20.3%) and tongue (13.6%). Histologically, dysplasia was detected in 40 (67.7%) of the cases, which comprised of four mild, 27 moderate and seven cases of severe dysplasia (Table 2). The stage distribution of cases were as follows: III, 52 (88.1%); and IV, seven (11.9%). At last follow-up, 44 (74.6%) were remaining disease free with no evidence of recurrent/ new lesions; during follow-up, three (5%) developed new luekoplakic lesions, and six (10.1%) developed recurrent lesions, while six (10.1%) could not be traced after Table 2 Histology of excised non-homogenous lesions Histology
n
%
Hyperkeratosis Leukoplakia Atypia Dysplasia Mild Moderate Severe NOSa Not available
4 5 5 40 4 27 7 2 5
6.8 8.5 8.5 67.7 6.8 45.8 11.8 3.3 8.5
a
Not otherwise speci®ed.
treatment. The distribution of recurrence/relapse by stage was as follows: stage III, 8/52 (15.3%); stage IV, 1/7 (14.2%). There was no event of malignancy diagnosed during follow-up. The proportion of subjects remaining with no evidence of disease at 3 years by Kaplan±Meier method of analysis was 62.1% (95% CI: 0.36±0.87; Fig. 3). 4. Discussion Leukoplakia, the most common oral precancerous lesion, has evolved as a clinico-pathologic concept over many years. According to World Health Organisation, it is a white patch or plaque that cannot be characterised, clinically or pathologically, as any other disease [8]. This is often used as a clinical descriptive term with no histological connotation. Recently, the de®nition of leukoplakia was rephrased as ``a predominantly white lesion of the oral mucosa that cannot be characterised as any other de®nable lesion; some oral leukoplakias will transform into cancer'' [9]. Though a distinction was made between a provisional `clinical' and more `de®nite' diagnosis based on aetiology and histopathology, the diagnosis of `leukoplakia' in most settings remain clinical. We have used the later clinical de®nition to diagnose leukoplakia in our screening intervention trial. The treatment of oral leukoplakia is based on the premise that early detection and active management of patients with oral leukoplakia may prevent the development of oral squamous cell carcinoma, as some of these lesions are potentially malignant. There have only been a few population-based studies on the natural history of oral leukoplakia, many others based on selected series of patients from hospitals [3,10±14]. The reported risk of malignant transformation of oral leukoplakia vary widely between 0.5 and 20% in many reported studies, with generally high annual malignant transformation percentages reported from hospital-based case series [4,15±18]. It is generally accepted that the nonhomogeneous subtype of leukoplakia, especially the ones with epithelial dysplasia, and those located in the tongue and ¯oor of mouth, are associated with an increased risk of malignant transformation. While treatment modalities and their ecacy of preventing progression of cervical intraepithelial lesions are well established, no standard approaches or their ecacy in reducing the risk of malignant transformation have been de®ned for oral leukoplakia. Thus, what should be the best management of leukoplakia and what is the impact of management on cancer incidence are yet not clear. Various management approaches has been used ranging from behaviour modi®cation, elimination of the possible cause, chemoprevention with retinoids and carotenoids, cold knife excision, laser, or cryosurgery,
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Fig. 3. Relapse-free survival in 59 patients with non-homogenous leukoplakia by Kaplan±Meier's method.
photodynamic therapy and topical application of bleomycin and 5-¯uorouracil. In research settings, oral leukoplakia is being used as a model to study the value of chemoprevention as a strategy to prevent cancer. However, the role of each of these approaches in reducing oral cancer incidence is far from clear. Nevertheless, surgical excision is a feasible management approach in subjects with accessible, localised oral leukoplakia and it may prove useful if it results in the removal of a potential malignant nidus in the lesion, thereby supplementing the eect of primary prevention eorts. However, the treatment of oral leukoplakia poses several challenges for the surgeon. Often the lesions are diuse and large to allow sucient tissue margins for excision, necessitating radical excision procedures with cosmetic implications, which are generally not acceptable for subjects with precancerous lesions. Since the oral precancers are symptomless, subjects may not be willing for any form of excisional procedures at all, let alone radical procedures. While the eect of stopping or reducing tobacco habits on the regression of oral leukoplakia is well established, the added value of surgical excision in preventing malignant transformation is not known. In limited series of treated subjects with
leukoplakia, malignant transformation was observed for 2.9±7.1% of patents within 5 years of follow-up [19± 23]. It is the consensus among surgeons that the frequency of malignant transformation is lower among surgically treated series of patients than in untreated subjects [20]. However, one should consider several caveats. There have been no randomised trials of surgery versus no treatment in the case of oral leukoplakia. Moreover, the case series of treated and untreated subjects in literature are not strictly comparable. It is also not possible to infer on the contribution of reduced exposure to causative agents on the control of lesions in surgically treated patients. Relapse and occurrence of new lesions after excision has been a problem associated with surgical excision [16±18, 21±23]. In a series of 61 surgically treated patients with oral leukoplakia, recurrences were found in 12 (20%) of patients and malignant transformation in three (5%) subjects, over an average follow-up period of 3.9 years [21]. In another series of 167 patients treated by CO2 laser excision, 31 (18.6%) relapsed, 27 (16.2%) developed new lesions, ®ve (3.0%) developed oral cancer, while six (3.6%) developed tumors at other locations over a 5-year period of follow-up [22]. In a recently
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reported series of 70 patients treated with CO2 and Nd:YAG lasers, 21 (30%) developed local recurrences and ®ve (7.1%) developed squamous cell carcinoma [23]. In our study, after a median follow-up of 22 months, lesions recurred in six (10.1%) subjects, while three (5%) developed new lesions. Malignant transformations were not observed in any case. The high frequency of relapse in treated cases stresses the importance of the control of tobacco and alcohol habits and the need for close follow-up after treatment. Our experience with surgical excision of localised leukoplakic lesions has so far been satisfactory in the context of our screening intervention trial. There was no surgical morbidity and the lesions healed within 15 days without scaring and no functional disability (Figs. 4 and 5). However, the sample size studied is small and the follow-up period is rather limited. However, further accrual of cases for excision and continuing follow-up over a long period may give us an opportunity to study the role of surgical excision in preventing invasive oral cancer in subjects with oral leukoplakia.
Fig. 5. Clinical photograph of a patient with non-homogenous leukoplakia: (a) before excision, (b) after excision.
Acknowledgements
Fig. 4. Clinical photograph of a patient with non-homogenous leukoplakia: (a) before excision, (b) after excision.
The Trivandrum Oral Cancer Screening Study (TOCS) is supported by a grant from the Association for International Cancer Research (AICR), St. Andrews, UK. Additional data collection in the study is supported by the Imperial Cancer Research fund (ICRF), UK. The results reported here were presented
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