APPROACH TO THE DIAGNOSIS OF PREMALIGNANT LESIONS IN CLINICAL PRACTICE

Review Article APPROACH TO THE DIAGNOSIS OF PREMALIGNANT LESIONS IN CLINICAL PRACTICE Authors: Mayura Paul*, Rohit Paul**, Kalyani Bhargava***, Deepak Bhargava****, Kanika Sethi***** ABSTRACT Dentists who encounter a change in the oral mucosa of a patient must decide whether the abnormality requires further investigation. In this paper, we describe a systematic approach to the assessment of oral mucosal conditions that are thought likely to be premalignant or an early cancer. These steps, which include a comprehensive history, step-by-step clinical examination (including use of adjunctive visual tools), diagnostic testing and formulation of diagnosis can be routinely used by dentists for use in daily practice. Keywords : Clinical, Diagnosis, premalignancy, tools Introduction Over the course of a typical practice day, a dentist will examine the oral cavity of many patients. On occasion, a change in the oral mucosa will be detected. The challenge is to decide whether the abnormality requires further investigation. If the answer is yes, a systematic approach to the evaluation of the lesion that includes methodical gathering of background information and a step-by-step clinical [2] examination is required.(table 1). Methodical process is important as many mucosal conditions have a similar appearance. A quick look provides insufficient information and may result in misdiagnosis and improper care. Although the recommended approach is appropriate for use in evaluating any mucosal condition, the focus of this article will be limited to one that can be used to evaluate the lesions that are more likely to be premalignant or an early cancer. Table 1. A systematic approach to the assessment of [2] a suspicious oral mucosal lesion 1. History of current illness Address for Correspondence: Dr. Mayura Paul C-113, Preet Vihar, Delhi -110092. drmayurapaul@live.in onset, location, intensity, frequency, duration aggravating and/or relieving variables better, unchanged or worse over time 2. Medical, tobacco and alcohol history medical conditions medications and allergies tobacco and alcohol (type, frequency, duration) 3. Clinical examination extraoral examination intraoral examination lesion inspection (adjunctive visual tools such as toluidine blue and direct fluorescence) 4. Differential diagnosis 5. Diagnostic tests biopsy 6. Definitive diagnosis 7. Suggested management Approach The diagnostic process begins with a history that includes a review of the patient's chief complaint followed by completion of a thorough medical history. Once this has been obtained, a comprehensive clinical examination including extraoral, intraoral and mucosal lesion assessments *Reader, *****Senior Lecturer, *** Professor & Head of Department, Department of Oral Pathology, Inderprastha Dental College & Hospital, Sahibabad. **Professor, Department of Conservative Dentistry & Endodontics, K. D Dental College, Mathura ****Professor & Head of Department, Department of Oral Pathology, School of Dental Sciences, Sharda University, Greater Noida. 57

should be completed. Only then can a diagnosis or a decision about the need for further investigation be rendered and appropriate decisions made regarding patient care. History of the Current Illness When inquiring about the condition of concern, the dentist needs to have an appreciation of the symptom profile. In some situations, the patient will have no complaints. If symptoms are present, then information about onset, location, intensity, frequency and duration should be obtained. If the condition has been resent for any length of time, inquire about changes that might have occurred has the symptom improved, remained unchanged or worsened over time? Identifying significant aggravating or relieving variables may also be helpful. It is important to remember that most oral premalignant lesions or early cancers have few if any symptoms. Persistent oral sensitivity or a sense of mucosal roughness may be warning signs. If a lesion has persisted over time or if it has become larger or more symptomatic, it is of concern and warrants prompt and thorough investigation. Medical, Tobacco and Alcohol History A comprehensive medical history that includes attention to tobacco and alcohol use should be obtained at the time of all new patient examinations and updated at general dental recall. Information to be collected should include habit type, frequency [3] and duration. Review of the medical history should include a list of current medications, as certain drugs may cause oral tissue changes with characteristics similar to premalignant or early cancer changes. Notable examples of such drugs include immunosuppressive, anti-inflammatory and antihypertensive medications. Also, steroids delivered in inhaler, topical or oral form and other medications that dry the mouth increase risk of development of oral candidiasis, which often appears as whitish, nonadherent plaques. Finally, information regarding previous cancer history (type and associated treatment) and any known dermatologic conditions should be gathered. Certain dermatologic conditions, such as lichen planus, can manifest cutaneously and as white [4] lesions intraorally. Clinical Examination The clinical examination should always include [5] extraoral and intraoral components. If a mucosal lesion is identified, a systematic approach to lesion assessment is recommended. Extraoral Examination Complete the extraoral examination first. This includes inspection of the head and neck region for asymmetry or swelling. Palpate the submental, submandibular, cervical and supraclavicular regions paying particular attention to size, number, tenderness and mobility of lymph nodes. A bimanual approach is recommended as it enhances the examiner's ability to appreciate the characteristics of any mass and to make comparisons with the contralateral side. In patients who have had a prior dental infection or surgical procedure in the head and neck region, it is common to find small, painless, freely mobile residual lymph nodes. However, if a lymph node is enlarged (i.e., > 1 cm in diameter) and palpably firm or fixed to adjacent structures, referral or further investigation is indicated. To complete the extraoral examination, inspect and palpate the lips and perioral tissues for [6] abnormalities. Intraoral Examination Systematically inspect and palpate all oral soft tissues, as oral cancer can develop at any anatomical site. Particular attention should be given to highrisk sites, which include the lateral and ventral aspects of the tongue, floor of mouth and the soft palate complex. Lesion Inspection If a mucosal lesion is identified, additional attention to its characteristics is recommended. Oral premalignant lesions and early oral cancers are quite varied in appearance (Figure 1, 2 3 & 4); clinical characteristics can be used to help raise the level of suspicion that a lesion may be premalignant or an early cancer. However, remember that a biopsy of the lesion is required to establish a definitive 58

diagnosis, as seemingly benign lesions may still pose a risk. Mucosal lesions can be predominantly white or red and have variable thickness and texture. A speckled red and white appearance, nonhealing ulceration or induration should signal a priority need for biopsy or referral. Figure 4. A diffuse, raised, speckled, indurated lesion. Histopathological diagnosis confirmed squamous cell carcinoma. Figure 1 : A smooth, white, discrete, homogeneous lesion. Histopathological diagnosis confirmed mild dysplasia. Figure 2. A predominantly red, diffuse, granular lesion. Histopathological diagnosis confirmed moderate to severe dysplasia The terminology and characteristics commonly used to describe lesions suspected of being premalignant or early cancer: location [anatomic site(s)], size [length and width], colour [ white, speckled, red; homogeneous vs. nonhomogeneous], outline [ discrete vs. diffuse] and texture [smooth, flat, raised, dome shaped; granular, verrucous, ulcerated, indurated]. Figure 5 is an example of a lesion at the left labial commissure. A leukoplakia is a white patch that cannot be rubbed off and cannot be characterized clinically or histologically as any [7,8] other lesion. Leukoplakias can be classified as homogeneous or nonhomogeneous. Homogeneous leukoplakias are white lesions that are uniform in both colour and texture. They are predominantly white and have a smooth, thin or slightly wrinkled texture. Nonhomogeneous leukoplakias usually have a rough (leathery or granular) or speckled surface. Figure 3. A diffuse, red ulcerated lesion. Histopathological diagnosis confirmed carcinoma in situ. Figure 5. Example of a single lesion at the left labial commissure discrete, nonhomogeneous, raised, white lesion (2.5 cm 1.0 cm) with a verrucous texture. 59

If a nonhomogeneous leukoplakia contains a red component, it is called an erythroleukoplakia. In general, homogeneous leukoplakias are believed to carry a lower risk of transforming into cancer than [ 9 ] n o n h o m o g e n e o u s l e u ko p l a k i a s. O ra l Erythroplakia can be defined as A fiery red patch that cannot be characterized clinically or 10 pathologically as any other definable disease. These have the greatest potential for malignant 9 transformation in the mouth. The outline or borders of the lesion should also be considered. Diffuse lesions, with irregular or ill-defined edges are more worrisome than discrete lesions. The presence of multiple lesions is considered more worrisome than a solitary lesion. As mentioned, the presence of a mucosal lesion at selected anatomic sites (lateral and ventral aspects of the tongue, floor of mouth and the soft palate complex) is of greater concern. Finally, leukoplakia size is also correlated with cancer risk, although the cutoff size for risk level remains speculative. Most oral lesions are < 2 cm and have a low cancer risk. Table 2: Disorders that need exclusion to 9 diagnose leukoplakia No. Disorder Diagnostic Feature 1. White sponge nevus 2. Frictional keratosis 3. Morsicatio buccarum 4. Chemical injury 5. Acute pseudomembra nous candidosis Noted in early life, family history, large areas involved, affected genital mucosa may be History of trauma, mostly along the occlusal plane, an etiological cause apparent, mostly reversible on removing the cause Habitual cheek lip biting known, irregular whitish line flakes with jagged out Known history, site of lesion corresponds to chemical rapidly injury, painful, resolves The membrane can be scraped off leaving an erythematous/raw surface 6. Leukoedema Bilateral on buccal mucosa, could be 7. Lichen planus (plaque type) 8. Lichenoid reaction 9. Discoid lupus erythematosus made to disappear (retracting), racial on stretching Other forms of lichen planus (reticular) found in association Drug history, e.g. close to an amalgam restoration 10. Skin graft Known history 11. Hairy leukoplakia Circumscribed lesion with central erythema, white lines radiating Bilateral tongue keratosis White Patch Provisional clinical diagnosis of leukoplakia BIOPSY Other known disorder excluded Leukoplakia with dysplasia Leukoplakia without dysplasia Schematic representation of the steps in diagnosis of oral leukoplakia. Differential Diagnosis Oral mucosal lesions can usually be simply grouped into 5 categories, known as the 5 I's: inherent (congenital or hereditary, e.g., white sponge nevus), inflammation (e.g., oral lichen planus, some variants of geographic tongue), infection (e.g., oral candidiasis), iatrogenic (e.g., drug-induced lichenoid reaction, frictional hyperkeratosis) and idiopathic (e.g., oral premalignant lesion or neoplasm). The first 4 categories must be ruled out before classifying a lesion as a leukoplakia or an erythroplakia. An atlas of clinical lesions is a useful office reference. Adjunctive tools for diagnosis 1. Supravital staining Excluded other known conditions/disorders/ diseases based on history and examination Other known disorder confirmed Revise diagnosis to other disease/disorder Toluidine blue (TB) is an acidophilic dye designed to stain acidic cellular components such as DNA and RNA. Its use in the detection of precancerous/ cancerous tissue is based on the fact that dysplastic tissue contains quantitatively more DNA and RNA than nondysplastic tissue. To perform the staining, a 1% solution is placed on the oral mucosa and removed after 1-2 minutes with 2% acetic acid. The clinician then examines the oral mucosa for areas of [11] increased cellular staining. In the evaluation of potentially malignant oral 60

lesions, TB staining may provide better demarcation of lesion margins, may guide biopsy site selection, and may be valuable in the identification and visualization of lesions in high- 12,13,14 risk patients. Although useful as an adjunct to clinical examination, the specificity of TB staining is limited because cells undergoing inflammatory changes and benign hyperplasia may also retain dye leading to false-positive results. Overall, the sensitivity of TB staining ranges from 0.78 to 1.00, [12] and the specificity ranges from 0.31 to 1.00. 2. Oral cytology Oral cytology describes a diagnostic technique used to sample oral tissue for histomorphological analysis. To obtain a tissue sample, the clinician applies a stiff brush to the oral mucosa with enough pressure to induce pinpoint bleeding, which ensures a full-thickness or trans-epithelial tissue sample. These cellular samples can then be analyzed by a variety of unique diagnostic measures, including cytomorphometry, DNA cytometry, and [11,15] immunocytochemical analysis. Computerized image analysis of brush biopsy samples (OralCDx) uses a computer program to perform morphological and cytological analysis of tissue samples. The computerized analysis ranks cells based on the amount of abnormal morphology, which are then presented to a pathologist for further distinction and classification. The sensitivity of the OralCDx ranges from 0.71 to 1.00, and the specificity [11] is as low as 0.32. DNA cytometry uses a DNA-specific Feulgen dye to quantify and identify deviations in DNA content in sampled tissue. Although data are still limited, the addition of DNA measurements to cytological analysis has been shown to increase the sensitivity [11] and specificity of brush biopsies. The use of oral cytology in the detection of dysplastic lesions shows considerable promise but has been limited thus far by variable false-positive [11,12,15,16] and false-negative results. 3. Chemiluminescent light Chemiluminescent light based systems (ViziLite Plus, MicroLux DL) use the application of a diffuse chemiluminescent light source to visualize abnormal oral mucosa not visible under normal incandescent light. A 1% acetic acid oral rinse is used to remove surface debris and slightly desiccate the oral mucosa before direct examination with the light source. Under illumination, normal epithelium absorbs the light (appearing light blue) while abnormal tissue reflects the light (appearing white, with sharper, distinct margins). The ViziLite system then uses a toluidine blue stain to aid in further lesion assessment. There is insufficient evidence that supports the use of chemiluminescent light modalities in discovering pathology that would not have been identified using incandescent light alone. However, the potential ability to identify pathologic tissue not visible under conventional examination may support the use of c h e m i l u m i n e s c e n t l i g h t a s a s c re e n i n g [11,12,16,17,18] technique. 4. Tissue autofluorescence Tissue autofluorescence describes the exposure of epithelial tissue to specific wavelengths of light that results in the excitation of cellular fluorophores and emission of energy in the form of fluorescence. With the disruption of normal tissue morphology in dysplastic lesions, tissue fluorescence is scattered and absorbed, resulting in characteristic alterations [19] in color that can be visually interpreted. The VELscope is an early detection device based on these principles. Under excitation with the VELscope device, normal mucosa emits a pale green light, whereas abnormal mucosa appears dark. The initial evidence suggests that the VELscope may be useful as both an adjuvant method of margin determination during surgical procedures as well as a screening technique to identify premalignant lesions not visualized during conventional [12,16] examination. Diagnostic Biopsy for Definitive Diagnosis Once the dentist has completed a thorough history and comprehensive clinical examination, he or she will need to decide which mucosal lesions can appropriately be monitored and which require biopsy. A great disservice and burden to the health care system is done unnecessarily if a biopsy is 61

performed on every mucosal abnormality seen. During an oral cancer screening examination, if a suspicious mucosal lesion persists for more than 3 weeks following removal of local irritants, such as trauma, infection or inflammation, diagnostic biopsy(ies) or referral to an oral health care provider with expertise in the evaluation and management of premalignant or potentially [20] malignant conditions is recommended. Tissue biopsy remains the gold standard for diagnosing an oral premalignant lesion or oral cancer. A carefully selected, performed and interpreted biopsy is [21] critical in rendering an accurate diagnosis. Appropriate management decisions are made through the described approach to the evaluation of any mucosal lesion. A definitive diagnosis is an opinion based on critical analysis of all pertinent information obtained. Once the practitioner arrives at this conclusion, a decision about optimum patient care can be made. Conclusion In this paper, we describe a methodical approach to the assessment of oral mucosal condition that are thought likely to be premalignant or an early cancer. The various techniques described for the diagnosis of precancer lesions have certain advantages and limitations. However, many possibilities are available and it is concluded that the most reliable method of diagnosis is still the biopsy followed by histopathological diagnosis and can be done with ease in a dental office. References 1. Williams PM, Poh CF, Allan JH, Ng S, Miriam PR. Evaluation of a suspicious oral mucosal lesion. J Can Dent Assoc 2008;74(3):275-80. 2. The Early Detection of Oral Cancer Working Group. Guideline for the early detection of oral cancer in British Columbia 2008. BC Oral Cancer Prevention Program of the BC Cancer A g e n c y. M a r c h 2 0 0 8. A v a i l a b l e : www.cdsbc.org/pdf/oc_guideline_final_200 8.pdf. 3. Laronde Dm, Hislop TG, Elwood JM, Rosin MP. Oral cancer: just the facts. J Can Dent Assoc 2008;74(3):269-72. 4. Neville BW, Damm DD, Allen CM, Bouqout JE. Allergic mucosal reactions to systemic drug administration. In: Oral and maxillofacial pathology. Philadelphia: WB Saunders; 2002.p.300-2. 5. Poh CF, Williams PM, Zhang L, Rosin MP. Heads up! A call for dentists to screen for oral cancer. J Can Dent Assoc 2006;72(5):413-6. 6. Kademani D. Oral cancer. Mayo Clin Proc 2007;82(7):878-87. 7. Axell T, Pindborg JJ, Smith CJ, Waal van der I. Oral white lesion with special reference to precancerous and tobacco-related lesions: conclusions of an international symposium held in Uppsala, Sweden, May 18-21 1994. International Collaborative Group on Oral W h i t e L e s i o n s. J O ra l Pa t h o l M e d 1986;25(2):49-54. 8. Report of a meeting of investigators on the histological definition of precancerous lesions. Geneva; World Health Organization; 1973. 9. Warnakulasuriya S, Johnson NW, Waal van der I. Nomenclature and classification of potentially malignant disorders of the oral mucosa. J Oral Pathol Med 2007;36:575-80. 10. Axell T, Holmstrup P, Kramer IRH, Pindborg JJ, Shear M. International seminar on oral leukoplakia and associated lesions related to tobacco habits. Community Dent and Epidemiol 1984;12:145-54. 11. Driemel O, Kunkel M, Hullmann M, et al. Diagnosis of oral squamous cell carcinoma and its precursor lesions. J Dtsch Dermatol Ges. Dec 2007;5(12):1095-100. 12. Lingen MW, Kalmar JR, Karrison T, et al. Critical evaluation of diagnostic aids for the detection of oral cancer. Oral Oncol. Jan 2008;44(1):10-22. 13. Epstein JB, Silverman S Jr, Epstein JD, et al. Analysis of oral lesion biopsies identified and e v a l u a t e d b y v i s u a l e x a m i n a t i o n, chemiluminescence and toluidine blue. Oral Oncol. Jun 2008;44(6):538-44. 62

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