The role of interventional surgery in oral potentially malignant disorders by Peter Thomson

84 Peter Thomson DOI 10.1308/204268514X13939420839142 The role of interventional surgery in oral potentially malignant disorders by Peter Thomson Oral potentially malignant disorders are mucosal diseases with a significantly increased risk of squamous carcinoma development a lethal and deforming disease with rising incidence, especially in young people. Despite the ability to recognise pre-cancer disorders in patients, clinicians remain unable to predict individual mucosal lesion behaviour or quantify the risk of malignant transformation. No clear management guidelines exist and the available scientific literature is unable to answer the fundamental question: does early diagnosis and interventional management treat pre-cancer effectively and prevent malignant transformation? Author: Peter Thomson, Professor of Oral & Maxillofacial Surgery, School of Dental Sciences, Newcastle University, Framlington Place, Newcastle upon Tyne NE2 4BW E: peter.thomson@ncl.ac.uk Keywords: interventional surgery, potentially malignant disorders, guidelines

85 The progression model for oral carcinogenesis proposes that, following irreversible genetic mutation, various phenotypic epithelial tissue disorganisation and dysmaturation changes occur which, if allowed to progress, lead to carcinoma development and invasive disease. Often resulting from excessive tobacco and alcohol exposure, these features are identifiable at the microscopic level and collectively termed epithelial dysplasia. Assessment of the degree of dysplasia is made following incision biopsy and classification into mild, moderate or severe categories. The more severe the dysplasia, the higher the risk of malignant change although there is a strong subjective element in grading, and biopsy sampling error and fluctuations in the severity of lesionsy over time may confound diagnostic accuracy. 1,2 It has been recognised for many years that a spectrum of mucosal abnormalities accompanies dysplastic change and may be identified clinically, albeit somewhat nonspecifically, as potentially malignant disorders during oral examination. There is an opportunity therefore for both early diagnosis and therapeutic intervention during this oral pre-cancer window. Potentially malignant limited understanding of [potentially malignant disorders] has resulted in a variety of proposed treatments, including clinic observation, medical treatment and surgical excision, many of which are simply based upon an individual clinician s preference

86 Peter Thomson disorders encompass localised lesions, classic oral leukoplakia or erythroplakia, or more generalised multi-focal conditions, including immunodeficiency, oral submucous fibrosis and more controversially lichenoid lesions. 3 Estimates of the prevalence of potentially malignant disease suggest an overall figure of between 2 3%, with the vast majority appearing as leukoplakia on the floor of the mouth, ventro-lateral tongue and buccal mucosa. 4,5 The concept that such disorders represent a potentially malignant state has arisen following the observed transformation of precursor lesions into invasive cancers, the recognition that leukoplakic or erythroplakic lesions often co-exist with squamous carcinoma and the identification of histopathological and biomolecular changes common to both cancer and pre-cancer. 6 The identification of a mucosal lesion in an individual patient does not mean that malignant transformation is inevitable, however, because many do not progress over time and others may regress, particularly with cessation of risk factor behaviour. It is impossible in contemporary clinical practice to predict the behaviour of any individual lesion and patients must be considered to be at an increased risk of cancer development. There are no clear management guidelines or agreed treatment strategies for potentially malignant disorders. Limited understanding of their natural history and a lack of meaningful, randomised controlled clinical trials has resulted in a variety of proposed treatments, including clinic observation, medical treatment and surgical excision, many of which are simply based upon an individual clinician s preference. 7,8 In the absence of evidence-based treatment protocols this paper will argue, using data from a series of longitudinal patient cohort studies carried out in Newcastle upon Tyne, that a structured and coordinated diagnosis and interventional management strategy based upon initial incision biopsy diagnosis, patient education on risk factor behaviour, CO 2 laser surgery to facilitate precise pre-cancerous lesion excision, and full histopathological assessment of tissue specimens, facilitates a definitive, efficacious and low morbidity management protocol 9 13 (Figure 1). Publication Number of upgraded Percentage lesions Thomson 11/55 20% (2002) 9 Hamadah 11/78 14% (2009) 12 Goodson (2011) 19 48/169 28% Table 1 Up-grading of dysplasia following laser excision of potentially malignant lesions.... Figure 1 CO2 laser in use in theatre for oral potentially malignant lesion excision.... Cohort studies, although ranking less highly in the hierarchy of clinical research trials, offer important opportunities for longitudinal observation of a defined patient population sharing a common clinical presentation, similar risk factor behaviour and undergoing standardised diagnostic and management protocols. Objectives of potentially malignant disorder treatment The objectives of treatment intervention for potentially malignant disorders are poorly defined and rarely discussed in the literature, although most authors agree that prevention of malignancy is the main priority. It is important, however, to define a number of salient management goals in treating oral pre-cancer: Accurate and definitive diagnosis Early recognition of malignancy Removal of dysplastic mucosa Prevention of recurrent or further dysplastic lesions Prevention of malignant transformation Minimal patient morbidity Accurate and definitive diagnosis Accurate diagnosis is fundamental but incision biopsies are unlikely to be representative of the true nature of oral dysplastic lesions, particularly large and widespread disorders, 3,14 17 and it is the opinion of the author that it is mandatory that surgical excision and histological examination of the entire clinical lesion is carried out to establish accurate dysplasia grading and definitive diagnosis. Histopathological review of laser excision specimens in our studies has confirmed that initial, diagnostic incision biopsies require up-grading in 14 28% of cases owing to the increased severity of dysplasia seen within excision specimens (Table 1).

87 Balasundaram 1 recently concurred that all potentially malignant disorders, regardless of clinical appearance and incision biopsy diagnosis, should be treated by whole lesion surgical removal. This management shift from clinic observation to surgical intervention supports the treatment philosophy we first proposed more than 10 years ago. 9 Multiple lesion disease, particularly in patients presenting with widespread pan-oral lesions, is of course more difficult to manage but we have shown that field mapping biopsies to determine the most significant foci of dysplasia, together with targeted laser excision is an effective strategy. 18 Publication Clear Mild dysplasia Margin status (%) Moderate dysplasia Hamadah (2009) 12 55% 19% 21% 5% Diajil (2013) 13 48% 23% 14% 15% Severe dysplasia Table 2 Efficacy of laser excision of dysplastic lesions by excision margin analysis.... Early recognition of malignancy Formal surgical excision of pre-cancer lesions also facilitates early recognition of cancer. 15,16 We found preexisting unexpected carcinomas in 15 out of a consecutive series of 169 patients with potentially malignant disorders (9%) treated for lesions diagnosed as dysplasia only on incision biopsy. The true efficacy of interventional treatment was confirmed by the observations that all laser surgery was carried out within six weeks of initial biopsy and the fact that none of the patients required additional post-laser treatment for their excised carcinomas and that all patients remained disease-free at 36 months follow-up. 19 Removal of dysplastic mucosa Oral potentially malignant disorders are, by definition, mucosal conditions and do not require the aggressive treatment necessary for removal and/or destruction of invasive cancer. It seems self-evident, therefore, to intervene early and remove dysplastic mucosa at the preinvasive stage. The effectiveness of dysplastic tissue removal by laser is confirmed in Table 2, which summarises histopathological examination of excision margin status in two patient cohort studies. 12,13 It is notable that in nearly three quarters of cases clear margins or foci of mild dysplasia only were seen. In neither of these studies was there an association between residual dysplasia in resection margins and clinical outcome, probably owing to the standard practice of laser ablating all oral cavity margins for 2 3mm beyond the excision margin during the final stage of treatment (Figure 2). Thermal cytological artefacts, including superficial vacuolation, necrosis, basal cell degeneration and pseudodysplastic epithelial changes, have all been reported following CO 2 laser excision biopsies but these do not appear to adversely affect histopathology assessment by experienced oral pathologists. One important caveat to note, however, is that a trend is seen for lesions exhibiting severe dysplastic foci in excision margins to be at a greater risk of further disease development during prolonged follow-up. 13 Figure 2 Intra-operative views during the excision of a severely dysplastic labial commissure leukoplakia showing: (a) laser excision margins sited 5mm beyond apparent clinical extent of mucosal lesion; (b) full-thickness mucosal excision underway; and (c) post-excision ablation of lesion base and all margins which effectively extends treatment zone beyond resection margin....

88 Peter Thomson Thomson (2002) 9 Stocker (2005) 10 Hamadah (2009) 12 Diajil (2013) 13 Clinical resolution (%) 76 67 64 62 Recurrent disease (%) 6 15 18 18 Further disease (%) 12 14 14 14 Malignant transformation (%) 4 0 0 5 OSCC development (%) 2 4 4 2 Number of patients 57 199 78 100 Study period (years) 4 7 10 10 Table 3 Clinical outcome data for interventional laser surgery (Newcastle cohort studies).... Prevention of recurrent or further dysplastic lesions Patient cohort studies have helped define terminology and classify a range of specific clinical outcomes following treatment: clinical resolution (disease-free status), persistent, recurrent or further dysplastic disease, malignant (same site) transformation, and oral cancer development (at new sites). Interestingly, many authors now concur that consistency among defined diagnosis and treatment outcome categories is essential to inform future studies and to ensure an improved understanding of the natural history of oral potentially malignant disorders. 3,5 Table 3 tabulates outcome data for four Newcastle cohort studies; while follow-up periods ranged from 4 10 years post-treatment, percentage outcomes for the categories remain remarkably similar between studies. Mean outcome data show that 68% of patients are disease-free, 14% develop recurrent disease, 13% further disease, 2% undergo malignant transformation and 3% develop cancers at new oral sites. It is difficult to find meaningful data with which to compare these studies as many of the papers in the literature are anecdotal, observational and retrospective in nature with no defined patient cohorts, heterogeneous lesions, and uncoordinated management and follow-up regimes. An important, consistent observation, however, is that the incidence of recurrent or further disease increases with the length of patient follow-up, and that nonhomogeneous leukoplakias, larger lesions, more severe dysplasias and floor of mouth and ventral tongue sites appear to be at greatest risk. 13 Smoking and alcohol remain persistent risk factors in patients following laser surgery and risk the development of further lesions. It is also important to note the higher rates of further disease seen in non-smokers and non-alcohol drinkers, which emphasises the importance of genetic predisposition and other risk factors in precancer disease. 12,13 Prevention of malignant transformation The risk of malignant transformation for oral potentially malignant disorders remains unpredictable and is highly variable, with quoted rates ranging between 0.13 36.4%. 21 It is a fundamental hypothesis of this paper, and indeed probably the most significant reason for actively treating potentially malignant disease, that surgical excision of dysplastic lesions should reduce the risk of oral malignancy. Mehanna 22 reviewed 14 unrelated, non-randomised studies reporting on 992 potentially malignant disorder patients and quoted an overall malignant transformation rate of 12.1%. While mild-to-moderately dysplastic lesions showed a 10.3% transformation rate, this increased to 24.1% for severe dysplasia. Patients whose lesions were not excised surgically exhibited a much higher transformation rate of 14.6% compared with only 5.4% for patients whose lesions were removed. Perhaps of most significance, however, was the 25% transformation rate observed in a UK specialist dysplasia clinic reported by Ho, 23 in which, despite long-term patient follow-up, there appeared to be no coordinated treatment or interventional protocol in place. Our patient cohort studies of interventional laser surgery for dysplastic lesions have shown much lower malignant transformation rates of between 2 5% (depending on whether same-site or new-site cancer formation was examined) and certainly support this author s opinion that appropriate intervention reduces the risk of cancer development. It is important in contrasting these low transformation rates with those in the literature to emphasise that Newcastle patients were all treated for significant dysplastic disease, with 32 55% of lesions exhibiting severe dysplasia or carcinoma-in-situ in their initial incision biopsies. 9,12,13 Surgical excision of dysplastic lesions decreases the risk of same-site malignant transformation but does not eliminate the risk of new-site oral cancer development. The clinical consequence is therefore the realisation that continued patient surveillance, regular clinic monitoring and risk-factor profiling remain pertinent for all potentially malignant disorder cases following treatment. Minimal patient morbidity As CO 2 laser surgery is recommended as the management of choice for potentially malignant disorders, we have sought to detail any postoperative morbidity and the nature and extent of any complications experienced by patients following intervention. 9,20 Significant complications are rare and, while some patients report postoperative pain, submandibular salivary gland swelling following floor of mouth procedures, and lingual nerve dysaesthesia after tongue surgery, these are all usually transient and self-limiting and rarely require additional treatment. A small number of patients are seen to experience more severe or longer lasting complications and these are usually those who have undergone more extensive surgery or who have continued to smoke and consume alcohol after treatment. 20

89 Intervention versus observation There remains a lack of meaningful, randomised trials in potentially malignant disorder management. We therefore carried out a comparative cohort study by assessing the results of surgical intervention in 78 potentially malignant disorder patients assessed as high risk with observational management in 39 low risk cases; we found 64% of laser-treated patients disease free 3-years post-intervention, while 77% of observed lesions persisted. 24 Clearly limited in significance by its non-randomisation, this study nonetheless emphasises the effectiveness of laser surgery and it seems increasingly difficult to justify a policy of nonintervention. it seems increasingly difficult to justify a policy of nonintervention CO 2 laser surgery is well tolerated and accepted by patients, it is noted to aid haemostasis, promote excellent healing, and produce minimal scarring with little in the way of functional deficit or patient morbidity. 9,12,13,25 A particular advantage of laser surgery is the ability to repeat excisions or ablations at the same site, if required, on a number of occasions without compromising oral healing or function. 25 Increasingly, transoral laser surgery is now applied in head and neck surgery to reduce the morbidity, while maintaining the efficacy, of a range of tumour resection procedures. 11 Conclusion The author s opinion is that interventional surgical management is a readily available, effective and low morbidity treatment that is successful in treating potentially malignant lesions and reducing the risk of malignant transformation at the site of precursor lesions. In contrast to observational or medical treatment, surgical excision facilitates all of the required management objectives. Continued, active surveillance of all potentially malignant disorder patients remains essential to ensure early recognition of recurrent or further dysplasia or the development of new-site carcinoma as a consequence of field cancerisation. Precise data governing the length of patient followup or the optimal time intervals between appointments are not known at present and require further research. Multi-centre, randomised controlled trials are needed to confirm the efficacy of interventional laser surgery. References 1. Balasundaram I, Payne KFB, Al-Hadad I. Is there any benefit in surgery for potentially malignant disorders of the oral cavity? J Oral Pathol Med 2013; doi 10.1111/jop.12088 (epub ahead of print). 2. Rastogi V, Puri N, Mishras S. An insight to oral epithelial dysplasia. Int J Head Neck Surg 2013; 4: 74 82. 3. van der Waal I. Potentially malignant disorders of the oral and oropharyngeal mucosa; terminology, classification and present concepts of management. Oral Oncol 2009; 45: 317 323. 4. Petti S. Pooled estimate of world leukoplakia prevalence: a systematic review. Oral Oncol 2003; 39: 770 780. 5. Napier SS, Speight PM. Natural history of potentially malignant oral lesions and conditions: an overview of the literature. J Oral Pathol Med 2008; 37: 1 10. 6. Warnakulasuriya S, Johnson NW, van der Waal I. Nomenclature and classification of potentially malignant disorders of the oral mucosa. J Oral Pathol Med 2007; 36: 575 580. 7. Kanatas AN, Fisher SE, Lowe D. The configuration of clinics and the use of biopsy and photography in oral premalignancy: a survey of consultants of the British Association of Oral and Maxillofacial Surgeons. Br J Oral Maxillofac Surg 2011; 49: 99 105. 8. Kumar A, Cascarini L, McCaul JA. How should we manage oral leukoplakia? Br J Oral Maxillofac Surg 2013; 51 : 377 383. 9. Thomson PJ, Wylie J. Interventional laser surgery: an effective surgical and diagnostic tool in oral precancer management. Int J Oral Maxillofac Surg 2002; 31:145 153. 10. Stocker J, Thomson PJ, Hamadah O. Laser surgery in oral oncology the Newcastle experience. The Surgeon 2005; 3: S32 33 11. Goodson ML, Banks RJ, Thomson PJ. Partial glossectomy for early stage tongue cancer and precancer the Newcastle experience. Br J Oral Maxillofac Surg 2007 45: e4. 12. Hamadah O, Thomson PJ. Factors affecting carbon dioxide laser treatment for oral precancer: A patient cohort study. Lasers Surg Med 2009; 41: 17 25. 13. Diajil AR, Robinson CM, Sloan P, Thomson PJ. Clinical outcome following oral potentially malignant disorder treatment: a 100 patient cohort study. Int J Dent 2013; 809248 (epub 9 July 2013). 14. Pentenero M, Carrozzo M, Pagano M. Oral mucosal dysplastic lesions and early squamous cell carcinomas: underdiagnosis from incisional biopsy. Oral Dis 2003; 9: 68 72. 15. Holmstrup P, Vedtofte P, Reibel J, Stoltze K. Oral premalignant lesions: is a biopsy reliable? J Oral Pathol Med 2007; 36: 262 266. 16. Lee J-J, Hung H-C, Cheng S-J. Factors associated with underdiagnosis from incisional biopsy of oral leukoplakic lesions. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2007; 104: 217 225. 17. Goodson ML, Kumar A, Thomson PJ. Oral precancer excision is required for definitive diagnosis: incisional vs excisional biopsies in oral leukoplakia management. Oral Oncol 2011; 47: S128 129. 18. Thomson PJ, Hamadah O. Cancerisation within the oral cavity: The use of field mapping biopsies in clinical management. Oral Oncol 2007; 43: 20 26. 19. Goodson ML, Thomson PJ. Management of oral carcinoma benefits of early precancerous intervention. Br J Oral Maxillofac Surg 2011; 49: 88 91. 20. Goodson ML, Sugden K, Kometa S, Thomson PJ. Complications following interventional laser surgery for oral cancer and precancerous lesions. 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