|Year : 2021 | Volume
| Issue : 2 | Page : 88-93
Epithelial dysplasia as a predictor of malignant transformation in oral potentially malignant disorders: The concepts, controversies, and challenges
Mahija Janardhanan1, Rakesh Suresh1, Vindhya Savithri1, Thara Aravind1, Mridula Mohan1, KR Biniraj2
1 Department of Oral Pathology and Microbiology, Amrita School of Dentistry, AIMS Campus, Amrita Vishwa Vidyapeetham, Kochi, Kerala, India
2 Department of Periodontology, Royal Dental College, Palakkad, Kerala, India
|Date of Submission||16-Oct-2021|
|Date of Acceptance||20-Oct-2021|
|Date of Web Publication||17-Dec-2021|
Dr. Mahija Janardhanan
Department of Oral Pathology, Amrita School of Dentistry, Amrita Vishwa Vidyapeetham, AIMS Campus, AIMS Ponekkara (P.O), Kochi - 682 041, Kerala
Source of Support: None, Conflict of Interest: None
Oral potentially malignant disorders (OMPDs) are a group of precursor lesions with varied clinical manifestations which exhibit an increased risk of malignant transformation. Early diagnosis and prevention of oral cancer now focuses more on the early recognition of OPMDs and assessment of their risk of malignant transformation. Although epithelial dysplasia is being widely used as a yardstick to assess the malignant potential of OMPDs, the interobserver variability and lack of reproducibility observed in the interpretations had made their efficacy as a predictor of malignant transformation highly questionable. The aim of this paper is to discuss the concept, controversies, and challenges involved in the utility of epithelial dysplasia as a predictor of malignant transformation.
Keywords: Epithelial dysplasia, grade, oral cancer, oral potentially malignant diseases, WHO
|How to cite this article:|
Janardhanan M, Suresh R, Savithri V, Aravind T, Mohan M, Biniraj K R. Epithelial dysplasia as a predictor of malignant transformation in oral potentially malignant disorders: The concepts, controversies, and challenges. J Head Neck Physicians Surg 2021;9:88-93
|How to cite this URL:|
Janardhanan M, Suresh R, Savithri V, Aravind T, Mohan M, Biniraj K R. Epithelial dysplasia as a predictor of malignant transformation in oral potentially malignant disorders: The concepts, controversies, and challenges. J Head Neck Physicians Surg [serial online] 2021 [cited 2022 Jan 18];9:88-93. Available from: https://www.jhnps.org/text.asp?2021/9/2/88/332725
| Introduction|| |
Oral squamous cell carcinoma (OSCC), the common malignancy affecting oral cavity is evolving as a major health concern affecting a good number of people worldwide. It is the 11th most common cancer in the world, and in India where the tobacco habit is quite prevalent, it tops the list as the most common cancer among males. In spite of the advances made in the treatment modalities, little progress had been made in improving the 5-year survival rate of oscc. The malignant transformation of oral epithelium is thought to be the end product of cellular changes which follow the progressive and sequential genetic mutations induced by exposure to carcinogens. The spectrum of cytological and architectural epithelial changes termed as dysplasia evident at the microscopic level manifest clinically as diverse lesions which are collectively referred to as oral potentially malignant disorders (OPMD). Unlike the other less accessible sites, the progressive changes in the color and texture of oral mucosa during the transformation of normal mucosa to carcinoma can be readily observed and had been found to be correlating well with the microscopic progression of dysplasia. Early diagnosis being the main determinant for successful treatment, more focus is given in recognizing and assessing the epithelial dysplasia which is considered the current gold standard to predict malignant transformation in OPMDs. The ultimate goal of having a foolproof grading system for epithelial dysplasia is it to translate the findings into effective management. But one of the major concerns regarding the utility of epithelial dysplasia as a prognostic indicator is the subjectivity associated with the various histological parameters used in grading of dysplasia. Attempts had been made to standardize the oral epithelial dysplasia (OED) grading system with the intention of reducing the interobserver variability and improving the reproducibility. So far, more than twenty classification systems had been proposed which reflects the ambiguity involved in the grading of OEDs.,,,,,,,,,,,,,,, This paper reviews the concept of OEDs that evolved over the years and discusses the challenges associated with grading of oral epithelial dysplasias and their utility as a predictor of malignant transformation.
| Oral Potentially Malignant Disorders|| |
OPMDs are defined by the WHO in 2017 as “clinical presentations that carry a risk of cancer development in the oral cavity, whether in a clinically definable precursor lesion or in clinically normal mucosa.” The very concept of premalignancy stemmed from the understanding that OSCC may arise from precursor lesions and this transformation is a progressive process which passes through varied clinically detectable phases. The entities considered as OPMDs and listed by the WHO are given in [Table 1]. Apart from leukoplakia, erythroleukoplakia and erythroplakia which may occur as a continuum in a transforming epithelium, oral submucous fibrosis, dyskeratosis congenita, smokeless tobacco keratosis, palatal lesions associated with reverse smoking, chronic candidiasis, lichen planus, discoid lupus erythematosus, syphilitic glossitis, and actinic keratosis of the lip also show increased risk of malignant transformation and hence are included under potentially malignant disorders. Clinically OMPDs present as variation in the color (usually as red and white lesions) and/or texture of normal oral mucosa. When it presents as progressive lesions, the changes in the mucosa occur in a sequence and can be appreciated clinically as transition from preleukoplakic phase characterized by greyish translucency in the mucosa, thin leukoplakia, thick fissured leukoplakia, verrucous/nodular leukoplakia, erythroleukoplakia/speckled leukoplakia, erythroplakia and finally to frank malignancy. The red lesions which represent more advanced stage carry more risk of malignant transformation than white lesions, and among the OMPDs, the highest transformation rate had been reported in erythroplakia. But erythroplakia is relatively a rare lesion, with prevalence between 0.02% and 0.83% while the reported prevalence of leukoplakia generally ranges from 1% to 4%.
| Oral Epithelial Dysplasias|| |
OED as defined by the WHO is a spectrum of architectural and cytological epithelial changes caused by accumulation of genetic changes, associated with an increased risk of progression to squamous cell carcinoma. The current reported risk of malignant potential in OEDs remains varied, and there is inconsistency in the literature regarding the usefulness of OED grading in predicting malignant transformation. A risk of malignant transformation ranging from 2.6% to 12.1%, had been reported earlier. A recent meta-analysis conducted to assess malignant transformation in OPMDs and epithelial dysplasias which reviewed 92 studies revealed an overall cumulative malignant transformation rate of 7.9%. The highest transformation rate of 49% was observed in proliferative verrucous leukoplakia, followed by erythroplakia (33.1%) and leukoplakia (9.5%). It was also noted that moderate/severe dysplasia was associated with a much greater risk of MT compared to mild dysplasia with an OR of 2.4. A transformation rate of 17.8% had been reported in a study conducted in 95 cases of high-grade OED where a significant association was observed between malignant transformation rate and age, clinical appearance, site, treatment received, and positive excision margins.
| Criteria for Diagnosing Epithelial Dysplasia|| |
The oral mucosa composed of epithelial compartment and the underlying stroma is a complex structure which shows wide variation between the sites in the thickness, the degree of keratinization, and morphology of rete ridges. The normal oral epithelium consists of many layers of squamous cells arranged in well-organized strata as stratum basale, stratum spinosum, stratum granulosum, and stratum corneum. Functionally the basal layer forms the proliferating compartment and the superficial layers represent the maturing compartment. The cells in the maturing compartment show progressive stages of maturation from deeper layers to the superficial layer, each layer representing cells with different levels of maturation. The lining mucosa is nonkeratinized stratified squamous epithelium and exhibits slight regional variations. The epithelium is thicker than keratinized mucosa at the labial and buccal mucosa, while it is thin at the ventral surface of the tongue and the floor of the mouth. The masticatory mucosa, which consists of gingiva and hard palate, on the other hand is relatively thin and parakeratinized or lightly orthokeratinized. Generally, rete ridges are absent in nonkeratinized epithelium and shorter in keratinized epithelium. These structural variations noticed in various intra-oral sites can be misinterpreted and hence need to be considered while assessing dysplasia in OPMDs.
The relevance of recognizing features of dysplasia in oral potentially malignant lesions lies in their utility in predicting the risk of malignancy and in assessing the extent of the risk involved. Hence, while reporting a case of OPMD, it becomes the responsibility of the pathologist to identify the features of epithelial dysplasia in the tissue sections and to assess the amount of risk it carries. The changes observed at the cellular and tissue level in the epithelial compartment during the malignant transformation are used as the criteria for recognizing epithelial dysplasias, and the prognosis is assessed based on the grading of dysplastic features. The WHO criteria for the diagnosis of OED are given in [Table 2]. The dysplasia of oral epithelium is characterized by abnormal proliferation, maturation, and differentiation and hence identification of dysplastic features in tissue sections depends mainly on the recognition of normal and abnormal process involved and not on the individual features. Most of the features mentioned when taken individually may be seen in benign hyperplasias and hence need to be analyzed in different combination and in correct clinical context to be regarded as dysplasia. Although the cellular atypia and architectural changes are discussed separately, they are closely linked and hence atypical changes always need to be considered in the context of tissue architecture. The variation in the size and shape of cell and nuclei can occur in benign hyperplasia hence need to be evaluated in the background of architectural maturation. Increased nuclear–cytoplasmic ratio indicates the expansion of basaloid proliferative compartment where smaller cells with larger nuclei appear prominent in upper layers or it could represent true nuclear enlargement in severe dysplasia. Nuclear hyperchromatism reflects chromosomal instability leading to excessive DNA content within the nuclei and almost always indicates severe dysplasia. Mitotic figures alone are not a reliable indicator of dysplasia as more mitotic figures can be seen in benign hyperplasia. The architectural changes in dysplasias are related to disturbances in maturation and stratification of the epithelium. In dysplasias, the epithelium loses it arrangement in strata due to change in the differentiation pattern along the length of epithelium. The normal stratification characterized by similarly sized nuclei, with similar nucleolar characteristics, at the same level throughout the epithelium and evenly spaced with equivalent cytoplasmic maturation in all cells at the same level will be lost during the malignant transformation. The abnormal maturation in dysplasias may also present as either early and single-cell keratinization or loss of keratinization. Oral epithelial basal cells lack a defined polarity, and loss of polarity of epithelium is not readily defined. But the cuboidal basal cells become elongated, vertically oriented, and crowded, and these changes can be observed both in hyperplasia and dysplasia. The rounded bulbous rete ridges which are drop shaped and filled with basaloid cells are usually associated with expansion of proliferative compartment and considered a feature of severe dysplasia and loss of cohesion of cells is seen as an increase in the intercellular space and is a common feature of moderate or severe dysplasia.
| Dysplasia Grading-Three Tier System Versus Binary System|| |
In-depth reviews had been done previously on the merits and demerits of the various OED grading systems., Ever since the first grading system put forth by Smith and Pindborg that classified OED as mild, moderate, or severe based on the epithelial characteristics which took into account both cellar atypia and tissue level architectural changes, around twenty oral epithelial grading systems which attempted to address the limitations of inter-observer variability and lack of reproducibility involved had been proposed. Most of these classifications followed the three-tier system which categorized the dysplasias as mild, moderate, or severe depending on the involvement of lower 1/3rd, middle 1/3rd, or upper 1/3rd of the epithelial compartment. Some of these classifications considered hyperplasia as the earliest and carcinoma in situ, the term used to denote a borderline malignancy characterized by top to bottom cytological and architectural changes of the epithelium, as the most advanced phase in the progression of dysplasias. One of the main issues with the three-tier system of grading was the faint line of distinction between mild and moderate, and moderate and severe dysplasias. In an attempt to overcome this problem, Kujan et al. proposed the binary system which segregated dysplasias into two groups, high risk and low risk based on the WHO 2005 criteria. Lesions presenting with at least 4 architectural changes and 5 cytological changes were regarded as high-risk group and those presenting with < 4 architectural changes or < 5 cytological changes as low-risk group. This grading system improved the interobserver agreement and made the decision-making regarding the choice of treatment easier for the clinician. Later, Nankivell et al. demonstrated that the binary system had a better reproducibility as compared to the WHO classification in the grading of OED and prognostication can be improved by refining diagnostic threshold of the binary system to 4 cytologic and 4 architectural features. The WHO classification 2017 brought in some modifications in the existing WHO criteria and at present is the most acceptable and widely used system. This classification adopted the three-tier system omitting the terms squamous hyperplasia and carcinoma in situ, from the previous WHO 2005 classification. Hyperplasia is no more considered separately, as there is no specific combination of histological features which are reliable to distinguish hyperplasia from mild dysplasia whereas carcinoma in situ is now considered synonymous with severe dysplasia. The term carcinoma in situ was also removed as there are always flattened matured cells at the superficial layer and “full-thickness dysplasias” are never found in oral lesions. Also, no evidences suggesting the prognostic relevance of segregating severe dysplasia from carcinoma in situ had been documented. Increase in nuclear size, mentioned as cytological feature indicative of dysplasia in the previous classification, had been dropped and “loss of epithelial cohesion” had been added under architectural changes as one of the parameters for assessing oral epithelial dysplasia. The WHO classification for the first time advocated the use of the binary system in risk assessment of oral dysplasia and also made a mention on the criteria which had been suggested to decide the cut-off point between the high-risk and low-risk groups.
| Challenges in Prediction of Malignant Transformation Based on Oral Epithelial Dysplasias|| |
Validity of the application of the existing criteria
The grading of dysplasia based on the thirds of epithelial thickness affected is adopted from the cervical intraepithelial neoplasia which has proven value in grading of cervical dysplasia., Most of the features of dysplasia described in cervical mucosa where transformation is very high are absolutely dependent on the type and pattern of HPV infection of a relative thin mucosa without rete ridges which cannot keratinize. But whether the similar criteria can be applied to entirely different epithelia from different sites remain unclear.
The reliability of using dysplasia as a predictor of malignant transformation
Although the presence and the degree of dysplasia correlate to the development of squamous cell carcinoma, the transformation rate is found to be relatively very low in OEDs. It has been observed that dysplastic lesions may regress/may remain stable and OSCC may arise de novo from normal epithelium without any precursor lesion. Given that most of the cases of epithelial dysplasias do not progress to carcinoma, the reliability of using epithelial dysplasia as a predictor of malignant transformation needs to be addressed and substantiated.
Sampling inaccuracies during biopsy
The accurate assessment of dysplasia in OPMDs depends largely on the clinical judgment regarding the site from where the biopsy is made. In smaller lesions undergoing excisional biopsy, the whole lesion will be available for microscopic study. When the lesion is large, proper clinical assessment should be carried out and biopsy should be made from areas representing the most advanced phase of transformation and multiple biopsies should be considered in extensive lesions with heterogeneous clinical presentation to avoid underassessment of the grade.
Errors in the assessment of dysplasia
Interpretation of the findings should not be based on algorithmic assessment of features and should be seen as a reflexion of structural and functional disturbances of the epithelium. It is important to identify the features individually and to understand how these features collectively, in the correct clinical context indicate dysplasia. Cellular changes associated with reactive proliferation, need to identified, and mentioned as cellular atypia and not as dysplasia.
Interobserver variability and reduced reproducibility
One of the major criticisms regarding the efficacy of epithelial dysplasia in predicting malignant transformation is the interobserver variability and reduced reproducibility in assessing the parameters. The modification made in the criteria to be considered and the introduction of binary system for the assessment of the risk involved are expected to improve upon these flaws to some extent and bring in more consistency in reporting of OED. Experience and expertise are key to accurate assessment of OED and double reporting and consensus grading by more than one pathologist may be beneficial.
| Conclusion|| |
Early diagnosis is the mainstay for the successful management of OSCC. In spite of all the shortcomings, recognition and grading of dysplasia in the tissue sections still remains the main predictor of malignant transformation in OPMDS. Identifying the early changes which precede the development of cancer in the mucosa and assessing the dysplastic features in the tissue sections hence play a major role in the prevention of oral cancer development. Careful histopathological assessment carried out considering the functional disturbances involved during the transformation in the correct clinical context may help in improving the accuracy in interpretation of OED.
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| References|| |
Sankaranarayanan R, Ramadas K, Amarasinghe H, Subramanian S, Johnson N. Oral Cancer: Prevention, Early Detection, and Treatment. In: Gelband H, Jha P, Sankaranarayanan R, Horton S, editors. Cancer: Disease Control Priorities, 3rd
Edition. Washington (DC): The International Bank for Reconstruction and Development / The World Bank; 2015;3. Chapter 5. PMID: 26913350.
Smith CJ, Pindborg JJ. Histological Grading of Oral Epithelial Atypia by Using Photographic Standards. Copenhagen: WHO Reference Centre for Oral PrecancerousConditions; 1969.
Bancoczy J, Csiba A. Occurrence of epithelial dysplasia in oral leukoplakia – Analysis and follow-up study of 120 cases. Oral Surg Oral Med Oral Pathol 1976;42:766-74.
Pindborg JJ, Reichart PA, Smith CJ, van der Waal I. World Health Organization: Histological Typing of Cancer and Precancer of the Oral Mucosa. Berlin: Springer-Verlag; 1997.
Kramer IR, Sobin LH. Leukoplakia and related lesions: An aid to studies on oral precancers”. WHO collaborating centre for oral precancerous lesions. Oral Surg Oral Med Oral Pathol 1978;46:518-39.
Speight PM, Farthing PM, Bouquot JE. The pathology of oral cancer and precancer. Curr Diag Pathol 1996;3:165-76.
Soames JV, Southem JC. Oral Pathology. New York: Oxford Medical Publications; 1998. p. 138-66.
Kuffer J, Lombardi S. Reconsideration oral risk lesions. Oral Dis 2002;38:302-7.
Zerdoner D. The Ljubljana classification – Its application to grading oral epithelial hyperplasia. J Craniomaxillofac Surg 2003;31:75-9.
Brothwell DJ, Lewis DW, Bradley G, Leong I, Jordan RC, Mock D, et al.
Observer agreement in the grading of oral epithelial dysplasia. Community Dent Oral Epidemiol 2003;31:300-5.
The Working Committee on New Histopathological Criteria for Borderline Malignancies of the Oral Mucosa, the Japanese Society for Oral Pathology. Guidelines for Histopathological Diagnosis of Borderline Malignancies of the Oral Mucosa. A Preliminary Proposal 2005. Niigata: Yamazaki Publishing; 2005.
Barnes L, Eveson JW, Reichart P, Sidransky S. World Health Organisation Classification of Tumours. Pathology and Genetics. Head and Neck Tumours. Lyon, France: International Agency for Research on Cancer Press; 2005.
Gale N, Blagus R, El-Mofty SK, Helliwell T, Prasad ML, Sandison A, et al.
Evaluation of a new grading system for laryngeal squamous intraepithelial lesions – A proposed unified classification. Histopathology 2014;65:456-64.
Kujan O, Oliver RJ, Khattab A, Roberts SA, Thakker N, Sloan P. Evaluation of a new binary system of grading oral epithelial dysplasia for prediction of malignant transformation. Oral Oncol 2006;42:987-93.
Bouquot J, Speight PM, Farthing PM. Epithelial dysplasia of the oral mucosa – Diagnostic problems and prognostic features. Curr Diagn Pathol 2006;12:11-22.
Japan Society for Oral Tumors. General Rules for Clinical and Pathological Studies on Oral Cancer. 1st
ed. Tokyo: Kanehara; 2010.
El Naggar AK, Chan JK, Grandis JR, Takata T, Slootweg PJ(Eds): WHO classification of head and neck tumours (4th
ed): IARC: Lyon 2017.
Neville BW, Damm DD, Allen CM, Bouquot JE. Oral and Maxillofacial Pathology. 3rd
ed. Philadelphia, Pennsylvania, USA: Saunders; 2008.
Sivapaadasundaram B, Rajendran R. Epithelial tumours of oral cavity. In: Sivapathasundharam B, editor. Shafer's Textbook of Oral Pathology. 8th
ed. Noida: Elsevier; 2009. p. 133-80.
Reichart PA, Philipsen HP. Oral erythroplakia – A review. Oral Oncol 2005;41:551-61.
Petti S. Pooled estimate of world leukoplakia prevalence: A systematic review. Oral Oncol 2003;39:770-80.
Reibel J. Prognosis of oral premalignant lesions: Significance of clinical, histopathological, and molecular biological characteristics. Crit Rev Oral Biol Med 2003;14:47-62.
Mehanna HM, Rattay T, Smith J, McConkey CC. Treatment and follow-up of oral dysplasia – A systematic review and meta-analysis. Head Neck 2009;31:1600-9.
Warnakulasuriya S, Kovacevic T, Madden P, Coupland VH, Sperandio M, Odell E, et al.
Factors predicting malignant transformation in oral potentially malignant disorders among patients accrued over a 10-year period in South East England. J Oral Pathol Med 2011;40:677-83.
Iocca O, Sollecito TP, Alawi F, Weinstein GS, Newman JG, De Virgilio A, et al.
Potentially malignant disorders of the oral cavity and oral dysplasia: A systematic review and meta-analysis of malignant transformation rate by subtype. Head Neck 2020;42:539-55.
Gilvetti C, Soneji C, Bisase B, Barrett AW. Recurrence and malignant transformation rates of high grade oral epithelial dysplasia over a 10 year follow up period and the influence of surgical intervention, size of excision biopsy and marginal clearance in a UK regional maxillofacial surgery unit. Oral Oncol 2021;121:105462.
Nanci A, Cate AR. Ten Cate's Oral Histology: Development, Structure, and Function. St. Louis, Mo: Mosby; 2003.
Odell E, Thavaraj S, Gale N, Nadal A, Zidar N, Gnepp D. Precursor lesions for squamous carcinoma of the upper aerodigestive tract. In: Gnepp D, Bishop J, editors. Gnepp's Diagnostic Surgical Pathology of the Head and Neck. 3rd ed: Elsevier; Amsterdam, The Netherlands 2020. p. 1-62.
Ranganathan K, Kavitha L. Oral epithelial dysplasia: Classifications and clinical relevance in risk assessment of oral potentially malignant disorders. J Oral Maxillofac Pathol 2019;23:19-27.
] [Full text]
Gupta S, Jawanda MK, Madhushankari GS. Current challenges and the diagnostic pitfalls in the grading of epithelial dysplasia in oral potentially malignant disorders: A review. J Oral Biol Craniofac Res 2020;10:788-99.
Nankivell P, Williams H, Matthews P, Suortamo S, Snead D, McConkey C, et al.
The binary oral dysplasia grading system: Validity testing and suggested improvement. Oral Surg Oral Med Oral Pathol Oral Radiol 2013;115:87-94.
The Working Committee for New Histopathological Criteria for Borderline Malignancies of the Oral Mucosa, the Japanese Society of Oral Pathology. Carcinoma in situ
of the oral mucosa: Its pathological diagnostic concept based on the recognition of histological varieties proposed in the JSOP Oral CIS catalog. J Oral Maxillofac Surg Med Pathol 2014;26:397-40.
Richart RM. Natural history of cervical intraepithelial neoplasia. Clin Obstet Gynecol 1967;10:748-84.
Richart RM. Cervical intraepithelial neoplasia. Pathol Annu 1973;8:301-28.
Woo SB. Oral epithelial dysplasia and premalignancy. Head Neck Pathol 2019;13:423-39.
[Table 1], [Table 2]