- Open Access
Grading systems in head and neck dysplasia: their prognostic value, weaknesses and utility
© Fleskens and Slootweg; licensee BioMed Central Ltd. 2009
Received: 29 March 2009
Accepted: 11 May 2009
Published: 11 May 2009
Grading of dysplasia, including head and neck lesions, continues to be a hotly debated subject. It is subjective and lacks intra- and inter-observer reproducibility due to the insufficiency of validated morphological criteria and the biological nature of dysplasia. Moreover, due to the absence of a consensus, several systems are currently employed.
The aims of this review are to:
1) Highlight the significance of dysplasia and the importance of a valid method for assessing precursor lesions of the head and neck.
2) Review the different histopathological classification systems for grading intraepithelial lesions of the head and neck.
3) Discuss and review quality requirements for these grading systems.
Regarding the different classification systems, data concerning the WHO classification system are the most available in current literature. There is no simple relationship or overlapping between the classification systems. Further studies should be done to see whether other systems have advantages above the current WHO system and to discover indications that could lead to an universal classification system for intraepithelial lesions of the head and neck.
Head and neck squamous cell carcinoma (HNSCC) is one of the most often encountered malignancies; it carries a bad prognosis.[1, 2] To improve survival, adequate diagnosis and treatment of precursor lesions is urgently needed. These precursor lesions are defined as an altered epithelium with an increased likelihood for progression to squamous cell carcinoma (SCC). The altered epithelium shows a variety of cytological and architectural changes that have traditionally brought under the common denominator dysplasia.
The presence of dysplastic areas in the epithelium of the upper aerodigestive tract (UADT) is believed to be associated with a likely progression to cancer. There is evidence that in an individual lesion, the more severe the dysplasia the greater the likelihood is of progression to malignancy. Rarely however, non-dysplastic lesions may also show malignant development .[3–8] Therefore, presence and severity of dysplasia cannot be used as a reliable guide for the treatment of individual cases. Nevertheless, the crude relationship between grading dysplasia and risk of progression to malignancy makes dysplasia grading necessary.
Grading of dysplasia, including head and neck lesions, continues to be a hotly debated subject. It is subjective and lacks intra- and inter-observer reproducibility due to the insufficiency of validated morphological criteria and the biological nature of dysplasia .[8–10] Moreover, due to the absence of a consensus, several systems are currently employed.
Nevertheless conventional histopathological evaluation based on light microscopic examination of hematoxylin & eosin-stained slides is, in spite of the above mentioned shortcomings, still the most valid method for assessing the malignant potential of preneoplastic head and neck lesions. Moreover, it is important to notice that making a diagnosis is a prerequisite for selecting the treatment which ensures the best prognosis, making the disease classification system a predictive system.[8, 12] The aim should be to tailor forms of therapy to the likelihood of disease progression thus reducing the incidence of invasive disease, limiting the need for radical surgery and improving survival while avoiding unnecessary follow-up in cases which lack significant premalignant potential.
Grading systems: overview
During the last decades many classifications of intraepithelial head and neck lesions have been proposed as illustrated by the fact that for intraepithelial laryngeal lesions, more than 20 classification systems have been described .[13–18] This seriously hampers the assessment of the long-term risk of subsequent malignancy, because different histopathological classifications and initial interventions make comparison of reported data difficult or even impossible because of inconsistencies in the criteria used for evaluation of the histological features.[8, 19, 20] The need for uniformity in reporting these lesions is obvious.
The majority of the classifications in the current literature have followed criteria similar to those in common use for the grading of epithelial lesions of the uterine cervix.[21, 22] Whether this is justified, is debatable. In cervical epithelium, there is clear distinction between normal and abnormal layers of the epithelium and consequently the degree of dysplasia can be assessed by determining the horizontal level of this border in the epithelium, resulting in substantial intra- and inter-observer consistency. Such a sharp distinction between normal and abnormal layers in the epithelium of the UADT is less obvious and consequently the definition of the degree of dysplasia is much more susceptible for discussion, this resulting in substantial intra- and inter-observer variability.[8, 10, 23]
2005 WHO Classification
Squamous Intraepithelial Neoplasia (SIN)
Ljubljana Classification Squamous Intraepithelial Lesions (SIL)
squamous cell hyperplasia
squamous cell (simple) hyperplasia
basal/parabasal cell hyperplasia*
The Ljubljana classification, developed by laryngeal pathologists and used since 1971, focuses on the clinical decision points which involve the identification of: 1) purely hyperplastic lesions that do not require close follow-up (simple or abnormal hyperplasia), 2) mild degrees of atypia who require close follow-up to recognize any progression to severe atypia (atypical or 'risky' hyperplasia), 3) severe atypia (carcinoma in situ) who require treatment (surgery or radiotherapy).[4, 16, 19, 24, 25]
Apart from these taxonomic problems, the need to differentiate between severe dysplasia and carcinoma in situ is debatable. Several authors have commented on the difficulty in separating these categories in conventional classification systems.[4, 5, 13] To reduce categories still further, occasionally a binary classifying system has been proposed.[10, 26]
Quality requirements for grading systems
A grading system can be devised in two ways: an arbitrary system can be composed with no detailed knowledge of the domain, or data about the domain can be used in statistical methods of analysis. Since most grading and scoring systems in histopathology are imposed on domains without prior data analysis, the psychological factors that affect the creation of these systems becomes important. There is often an interaction between histopathological grading systems and clinical therapies especially if trials of treatment for a particular condition are widespread. Some authors suggest that the pathologist is required only to divide cases into the number of different treatment options available. Others, including Morris, argue that the pathologist should transmit the maximum amount of information possible from their interpretations without the addition of extraneous 'noise'.[27, 28] Furthermore, reproducibility and prognostic value (use of results) are important conditions.
Reproducibility refers to the degree to which observer measurement or diagnosis remains the same on repeated independent observations of an unchanged characteristic. This consistency can be assessed between different observers (interobserver) or within a single observer (intraobserver). When studying the accuracy in grading dysplasia of the UADT there is no test available, which is thought to be better than the pathologist's observation; an accepted gold standard is not available for assessing the validity obtained when grading these lesions. Therefore, reproducibility, normally used to assess precision, is used to provide an indication of validity. When combined for this goal, inter- and intraobserver agreement levels give an estimate of the degree of bias and validity in situations (like grading dysplasia of the UADT), where an appropriate gold standard is not available.
If a scoring system is to be clinically useful then it should be reproducible both between pathologists and for the same pathologist at different times: inter- and intra-observer reproducibility. In histopathology, results of the diagnostic evaluation are discrete diagnostic categories (for example, moderate dysplasia in a laryngeal lesion) rather than variable parameters and for this reason kappa statistics are often used as indicators of performance .[31–33] Kappa statistics measure levels of agreement between observers and make allowance for the degree of agreement that would occur by chance alone. Since most grading systems in squamous lesions produce an ordinal categorical result then kappa statistics are a relevant means of assessing reproducibility.[8, 27, 32, 34, 35] A kappa statistic of 1 represents perfect agreement and 0 represents the level of agreement expected by chance alone. Landis et al. described guidelines to interpret the quantitative significance of kappa.
Observer variability in head and neck lesions.
Number of slides
Number of examinators
Abbey et al. 1995
Fischer et al. 20041
0.59 (95% CI: 0.45–0.72)
0.70 (95% CI: 0.56–0.84)2
Karabulut et al. 1995
Tabor et al. 2003
Abbey et al. 1998
Brothwell et al. 2003
Kujan et al. 20061
WHO and binary system ("low-risk" or "high-risk")
0.22 (95% CI: 0.11–0.35 unweighted)
0.63 (95% CI: 0.42–0.78 weighted)
Mclaren et al. 2000
WHO and two-grade (low and high grade)
There are also additional features that negatively influence reproducibility. Fischer et al. suggested that inflammation, lesion site, and biopsy technique (punch and wedge) modifies the reliability of oral histological lesions. Clinical information submitted with biopsy specimens did not increase accuracy and consistency.
With these considerations in mind, reproducibility for the larynx gave an overall kappa value of 0.32 for the WHO classification, whereas the use of a two grade system (low and high grade) gave a kappa figure of 0.52. Data concerning the SIN classification and Ljubljana classification in relation to reproducibility of laryngeal lesions are not available in current literature. Agreement for lesions of the oral cavity and oropharynx varies from 35.8 to 92.8% for the WHO classification, kappa values varying from 0.15 to 0.59.[26, 30, 37–41] A binary system (high/low risk), evaluated by Kujan et al., resulted in 74.3% agreement and a kappa value of 0.50. Particularly for the cases of moderate dysplasia the binary grading system may have merit in helping clinicians to make critical decisions. Fischer et al. also reduced the number of pathologic diagnoses to three categories ('no abnormality/hyperkeratosis', 'mild, moderate, or severe dysplasia', 'carcinoma in situ/carcinoma') which resulted in a kappa value of 0.70 (compared with 0.59 using the various pathologic diagnoses separately). Data concerning the SIN classification and Ljubljana classification in relation to reproducibility of oropharyngeal lesions and lesions of the oral cavity are not available in current literature. Table 2 shows an overview of observer variability in head and neck lesions.
Prognostic and predictive value
Altmann et al. and Putney et al. reported the first follow-up studies of precancerous conditions of the larynx; carcinoma in situ and keratosis, respectively.[42, 43] Since then several follow-up studies concerning the natural evolution and long-term risk of malignant progression in intraepithelial lesions have been reported. In these studies, usually no distinction between natural evolution without treatment (prognostic value) and predictive value (response to treatment) is made. Therefore, data on malignant progression as summarized below concern both treated and untreated cases.
Malignant progression of intraepithelial laryngeal lesions diagnosed with the WHO classification is, according to current literature, as follows: hyperplasia 0–3%.[13, 44, 45], mild dysplasia 0–30% [13, 45–47], moderate dysplasia 0–44% [5, 13, 45–49], severe dysplasia 20–57% [13, 45, 47, 49, 50], CIS 0–80% [13, 44, 45, 48–52].
Regarding the SIN classification, relevant figures are as follows: SIN I 5%, SIN II 25%, and SIN III 11–25%.[5, 53] Clinical data concerning follow-up on laryngeal lesions graded with the Ljubljana classification showed a marked increase in the incidence of malignant progression from simple, abnormal, and atypical hyperplasia (resp. 0.7%, 1.0%, and 9.5%). Recently, a study by Gale et al. showed 1.1% (12/1089) progression to carcinoma of squamous hyperplasia/basal-parabasal hyperplasia and 9.5% (17/179) of atypical hyperplasia (CIS is not included).
Few studies have examined the cancer risk related to different grades of oral dysplasias .[54–57] Silverman et al. reported malignant transformation in 36% of cases with oral dysplasia. The degree of dysplasia is not specified. Schepman et al. reported 12% malignant transformation in oral lesions histopathological classified with the WHO classification. Leukoplakias consisting of moderate or severe epithelial dysplasia, had a significantly higher risk of developing a carcinoma than leukoplakias of a lower stage (p < 0.01). In another study 26% of cases with hyperplasia/mild dysplasia and 67% of cases with moderate/severe dysplasia developed into carcinoma. Lumerman et al. studied malignant transformation in hyperplasia with dysplasia, mild dysplasia, moderate dysplasia, severe dysplasia, and CIS; respectively 29%, 8%, 17%, 17%, 0%. Data concerning the SIN classification in relation to predictive value of oral lesions are not available in current literature. The only study in current literature which studied the application of the Ljubljana classification to grading oral intraepithelial lesions has been published by Zerdoner et al. No cases of simple (0/79) or abnormal (0/42) hyperplasia showed progression to carcinoma, 18.2% (2/11) of atypical hyperplasia progressed to invasive cancer.
Interpretation of these reported data of oral intraepithelial lesions are hampered by small sample sizes, surgical intervention carried out for high-risk dysplasias and variability in reporting dysplasia grades. The greater part of published data only considered macroscopical features (i.e. leukoplakia) and no histology.[59, 60] It should also be noted that the predictive value of dysplasia is dependent on the prevalence of leukoplakia in a given population. Size, and not histology seems to be the most important in predicting malignant transformation.
So, it appears that regarding reproducibility as well as in terms of prognosis, still a lot of progress has to be made.
Molecular markers are subject of investigation: in spite of many studies, the molecular events that induce the development of premalignancies to carcinoma are still unknown, and we are still forced to conclude that over (or under)-expression of biomarkers itself adds little predictive value over standard histology .[62–66] Therefore, until now they are not applicable in clinical practice.
Finally, some remarks have to be made on the relationship between clinical aspects and risk of malignant progression. In general, homogeneous leukoplakic lesions are thought to have a low risk of malignant transformation, mixed white and red lesions (or speckled leukoplakia) an intermediate risk, and pure erythroplakia (red lesions) the highest risk of cancer development. However, none of these macroscopic features is reliably diagnostic of any histological grade of precursor lesion, and histological analysis of these lesions is mandatory to determine their biological potential. Occasionally precursor lesions may appear clinically normal.[3, 11, 20, 68] Furthermore, nomenclature or terminology concerning the macroscopic features is still a subject of discussion.
As outlined before, a histological dysplasia system ideally should meet two basic requirements. At first, it should be easily applicable in daily routine practice with low inter- and intra-observer variability. Secondly, it should allow a clear separation between patients who need treatment to prevent progression towards malignancy and those for whom no treatment is needed.
Regarding inter- and intraobserver variability, evaluation of the WHO classification shows for laryngeal lesions an overall kappa value of 0.32, whereas the use of a two grade system (low and high grade) gave a kappa figure of 0.52. Its prognostic significance is as follows: hyperplasia 0–3%.[13, 44, 45], mild dysplasia 0–30% [13, 45–47], moderate dysplasia 0–44% [5, 13, 45–49], severe dysplasia 20–57% [13, 45, 47, 49, 50], CIS 0–80% [13, 44, 45, 48–52]. For oral lesions, inter- and intraobserver figures of the WHO classification vary between kappa scores of 0.15 and 0.59.[26, 30, 37–41] Its prognostic significance is 12–67%, as can be inferred from the data mentioned before.
When looking at the SIN classification it has to be noted, that with respect to reproducibility, no data of head and neck lesions are available in current literature. Concerning prognostic significance of laryngeal lesions the following data are available: SIN I 5%, SIN II 25%, SIN III 11–25%.[5, 53] Data concerning the SIN classification in relation to predictive value of oral lesions are not available in current literature.
Regarding the Ljubljana classification, its use for the larynx has been documented extensively. Its relevance for prognosis has been amply demonstrated by the pathologists and clinicians who developed the system. However, its usefulness has not yet resulted in widespread acceptance. For the oral cavity, there is only one study that reports its use in this anatomic location. In that study a prognostic significance, similar to the larynx was noted. However, data on reproducibility are also lacking for this anatomic area. Further studies should be done to see whether it has an advantage above the current WHO dysplasia system.
- Jemal A, Siegel R, Ward E, Hao Y, Xu J, Murray T, Thun MJ: Cancer statistics, 2008. CA Cancer J Clin. 2008, 58: 71-96. 10.3322/CA.2007.0010.View ArticlePubMedGoogle Scholar
- Forastiere A, Koch W, Trotti A, Sidransky D: Head and neck cancer. N Engl J Med. 2001, 345: 1890-1900. 10.1056/NEJMra001375.View ArticlePubMedGoogle Scholar
- Gale N, Pilch BZ, Sidransky D, Westra W, Califano J: Tumours of the hypopharynx, larynx and trachea (Epithelial precursor lesions). World Health Organization Classification of Tumours. Pathology & genetics. Head and neck tumours. International Agency for Research on Cancer (IARC). Edited by: Barnes L, Eveson JW, Reichart P, Sidransky D. 2005, Lyon: IARC Press, 140-143.Google Scholar
- Helliwell TR: 'Risky' epithelium in the larynx – a practical diagnosis?. Histopathology. 1999, 34: 262-265. 10.1046/j.1365-2559.1999.00631.x.View ArticlePubMedGoogle Scholar
- Hellquist H, Lundgren J, Olofsson J: Hyperplasia, keratosis, dysplasia and carcinoma in situ of the vocal cords – a follow-up study. Clin Otolaryngol Allied Sci. 1982, 7: 11-27. 10.1111/j.1365-2273.1982.tb01557.x.View ArticlePubMedGoogle Scholar
- Pindborg JJ, Reichart P, Smith CJ, Waal van der I: World Health Organization: histological typing of cancer and precancer of the oral mucosa. 1997, Berlin: Springer-VerlagView ArticleGoogle Scholar
- Stenersen TC, Hoel PS, Boysen M: Carcinoma in situ of the larynx: an evaluation of its natural clinical course. Clin Otolaryngol Allied Sci. 1991, 16: 358-363. 10.1111/j.1365-2273.1991.tb00948.x.View ArticlePubMedGoogle Scholar
- Warnakulasuriya S, Reibel J, Bouquot J, Dabelsteen E: Oral epithelial dysplasia classification systems: predictive value, utility, weaknesses and scope for improvement. J Oral Pathol Med. 2008, 37: 127-133.View ArticlePubMedGoogle Scholar
- Bosman FT: Dysplasia classification: pathology in disgrace?. J Pathol. 2001, 194: 143-144. 10.1002/1096-9896(200106)194:2<143::AID-PATH883>3.0.CO;2-Z.View ArticlePubMedGoogle Scholar
- McLaren KM, Burnett RA, Goodlad JR, Howatson SR, Lang S, Lee FD, Lessells AM, Ogston S, Robertson AJ, Simpson JG, Smith GD, Tavadia HB, Walker F, Scottish Pathology Consistency Group: Consistency of histopathological reporting of laryngeal dysplasia. The Scottish Pathology Consistency Group. Histopathology. 2000, 37: 460-463. 10.1046/j.1365-2559.2000.00998.x.View ArticlePubMedGoogle Scholar
- Gale N, Pilch BZ, Sidransky D, El-Naggar AK, Westra W, Califano J, et al: Tumours of the oral cavity and oropharynx (Epithelial precursor lesions). World Health Organization Classification of Tumours. Pathology & genetics. Head and neck tumours. International Agency for Research on Cancer (IARC). Edited by: Barnes L, Eveson JW, Reichart P, Sidransky D. 2005, Lyon: IARC Press, 177-179.Google Scholar
- Wulff HR, Gotzsche PC: Rational Diagnosis and Treatment. Evidence-Based Clinical Decision-Making. 1981, Oxford: Blackwell Scientific Publications, 68-Google Scholar
- Blackwell KE, Fu YS, Calcaterra TC: Laryngeal dysplasia. A clinicopathologic study. Cancer. 1995, 75: 457-463. 10.1002/1097-0142(19950115)75:2<457::AID-CNCR2820750208>3.0.CO;2-9.View ArticlePubMedGoogle Scholar
- Gale N, Kambic V, Michaels L, Cardesa A, Hellquist H, Zidar N, Poljak M: The Ljubljana classification: a practical strategy for the diagnosis of laryngeal precancerous lesions. Adv Anat Pathol. 2000, 7: 240-251. 10.1097/00125480-200007040-00006.View ArticlePubMedGoogle Scholar
- Kambic V, Gale N: Significance of keratosis and dyskeratosis for classifying hyperplastic aberrations of laryngeal mucosa. Am J Otolaryngol. 1986, 7: 323-333. 10.1016/S0196-0709(86)80020-5.View ArticlePubMedGoogle Scholar
- Kambic V: Epithelial hyperplastic lesions – a challenging topic in laryngology. Acta Otolaryngol Suppl. 1997, 527: 7-11. 10.3109/00016489709124025.View ArticlePubMedGoogle Scholar
- Sengiz S, Pabuccuoglu U, Sarioglu S: Immunohistological comparison of the World Health Organization (WHO) and Ljubljana classifications on the grading of preneoplastic lesions of the larynx. Pathol Res Pract. 2004, 200: 181-188. 10.1016/j.prp.2003.11.002.View ArticlePubMedGoogle Scholar
- Vodovnik A, Gale N, Kambic V, Luzar B: Correlation of histomorphological criteria used in different classifications of epithelial hyperplastic lesions of the larynx. Acta Otolaryngol Suppl. 1997, 527: 116-119. 10.3109/00016489709124051.View ArticlePubMedGoogle Scholar
- Hellquist H, Cardesa A, Gale N, Kambic V, Michaels L: Criteria for grading in the Ljubljana classification of epithelial hyperplastic laryngeal lesions. A study by members of the Working Group on Epithelial Hyperplastic Laryngeal Lesions of the European Society of Pathology. Histopathology. 1999, 34: 226-233. 10.1046/j.1365-2559.1999.00581.x.View ArticlePubMedGoogle Scholar
- Gale N, Michaels L, Luzar B, Poljak M, Zidar N, Fischinger J, Cardesa A: Current review on squamous intraepithelial lesions of the larynx. Histopathology. 2009, 54 (6): 639-656. 10.1111/j.1365-2559.2008.03111.x.View ArticlePubMedGoogle Scholar
- Richart RM: Natural history of cervical intraepithelial neoplasia. Clin Obstet Gynecol. 1967, 10: 748-784. 10.1097/00003081-196712000-00002.View ArticleGoogle Scholar
- Scully RE, Bonfiglio TA, Kurman RJ, Silverberg SG, Wilkinson : Histological typing of female genital tract tumours (International histological classification of tumours). 1994, Berlin: SpringerView ArticleGoogle Scholar
- Bouquot JE, Speight PM, Farthing PM: Epithelial dysplasia of the oral mucosa-Diagnostic problems and prognostic features. Current Diagnostic Pathology. 2006, 12: 11-21. 10.1016/j.cdip.2005.10.008.View ArticleGoogle Scholar
- Kambic V, Lenart I: [Our classification of hyperplasia of the laryngeal epithelium from the prognostic point of view]. J Fr Otorhinolaryngol Audiophonol Chir Maxillofac. 1971, 20: 1145-1150.PubMedGoogle Scholar
- Kambic V, Gale N: Epithelial hyperplastic lesions of the larynx. 1995, Amsterdam: ElsevierGoogle Scholar
- 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: 987-993. 10.1016/j.oraloncology.2005.12.014.View ArticlePubMedGoogle Scholar
- Cross SS: Grading and scoring in histopathology. Histopathology. 1998, 33: 99-106. 10.1046/j.1365-2559.1998.00495.x.View ArticlePubMedGoogle Scholar
- Morris JA: Information and observer disagreement in histopathology. Histopathology. 1994, 25: 123-128. 10.1111/j.1365-2559.1994.tb01567.x.View ArticlePubMedGoogle Scholar
- Houston WJ: The analysis of errors in orthodontic measurements. Am J Orthod. 1983, 83: 382-390. 10.1016/0002-9416(83)90322-6.View ArticlePubMedGoogle Scholar
- Brothwell DJ, Lewis DW, Bradley G, Leong I, Jordan RC, Mock D, Leake JL: Observer agreement in the grading of oral epithelial dysplasia. Community Dent Oral Epidemiol. 2003, 31: 300-305. 10.1034/j.1600-0528.2003.00013.x.View ArticlePubMedGoogle Scholar
- Landis JR, Koch GG: The measurement of observer agreement for categorical data. Biometrics. 1977, 33: 159-174. 10.2307/2529310.View ArticlePubMedGoogle Scholar
- Silcocks P: Some issues in observer error studies in pathology. J Pathol. 1992, 168: 255-256. 10.1002/path.1711680302.View ArticlePubMedGoogle Scholar
- Svanholm H, Starklint H, Gundersen HJ, Fabricius J, Barlebo H, Olsen S: Reproducibility of histomorphologic diagnoses with special reference to the kappa statistic. APMIS. 1989, 97: 689-698.View ArticlePubMedGoogle Scholar
- Cross SS: Kappa statistics as indicators of quality assurance in histopathology and cytopathology. J Clin Pathol. 1996, 49: 597-599. 10.1136/jcp.49.7.597.PubMed CentralView ArticlePubMedGoogle Scholar
- Silcocks PB: Measuring repeatability and validity of histological diagnosis – a brief review with some practical examples. J Clin Pathol. 1983, 36: 1269-1275. 10.1136/jcp.36.11.1269.PubMed CentralView ArticlePubMedGoogle Scholar
- Pindborg JJ, Reibel J, Holmstrup P: Subjectivity in evaluating oral epithelial dysplasia, carcinoma in situ and initial carcinoma. J Oral Pathol. 1985, 14: 698-708. 10.1111/j.1600-0714.1985.tb00549.x.View ArticlePubMedGoogle Scholar
- Abbey LM, Kaugars GE, Gunsolley JC, Burns JC, Page DG, Svirsky JA, Eisenberg E, Krutchkoff DJ, Cushing M: Intraexaminer and interexaminer reliability in the diagnosis of oral epithelial dysplasia. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1995, 80: 188-191. 10.1016/S1079-2104(05)80201-X.View ArticlePubMedGoogle Scholar
- Fischer DJ, Epstein JB, Morton TH, Schwartz SM: Interobserver reliability in the histopathologic diagnosis of oral pre-malignant and malignant lesions. J Oral Pathol Med. 2004, 33: 65-70. 10.1111/j.1600-0714.2004.0037n.x.View ArticlePubMedGoogle Scholar
- Karabulut A, Reibel J, Therkildsen MH, Praetorius F, Nielsen HW, Dabelsteen E: Observer variability in the histologic assessment of oral premalignant lesions. J Oral Pathol Med. 1995, 24: 198-200. 10.1111/j.1600-0714.1995.tb01166.x.View ArticlePubMedGoogle Scholar
- Tabor MP, Braakhuis BJ, Wal van der JE, van Diest PJ, Leemans CR, Brakenhoff RH, Kummer JA: Comparative molecular and histological grading of epithelial dysplasia of the oral cavity and the oropharynx. J Pathol. 2003, 199: 354-360. 10.1002/path.1285.View ArticlePubMedGoogle Scholar
- Abbey LM, Kaugars GE, Gunsolley JC, Burns JC, Page DG, Svirsky JA, Eisenberg E, Krutchkoff DJ: The effect of clinical information on the histopathologic diagnosis of oral epithelial dysplasia. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1998, 85: 74-77. 10.1016/S1079-2104(98)90401-2.View ArticlePubMedGoogle Scholar
- Altmann F, Ginsberg I, Stout AP: Intraepithelial carcinoma (cancer in situ) of the larynx. AMA Arch Otolaryngol. 1952, 56: 121-133.View ArticlePubMedGoogle Scholar
- Putney FJ, O'keefe JJ: The clinical significance of keratosis of the larynx as a premalignant lesion. Ann Otol Rhinol Laryngol. 1953, 62: 348-357.View ArticlePubMedGoogle Scholar
- Hirade Y, Aso M, Kurita S, Hirano M, Shin T: Epithelial hyperplasia of the larynx. A 10-year review of 88 patients. Auris Nasus Larynx. 1983, 10 (Suppl): S73-S81.View ArticlePubMedGoogle Scholar
- Plch J, Par I, Navratilova I, Blahova M, Zavadil M: Long term follow-up study of laryngeal precancer. Auris Nasus Larynx. 1998, 25: 407-412. 10.1016/S0385-8146(98)00041-8.View ArticlePubMedGoogle Scholar
- Moesgaard NV, Hojslet PE, Palvio D: Reinke's oedema: a premalignant condition?. J Laryngol Otol. 1986, 100: 1159-1162.View ArticleGoogle Scholar
- Uno Y, Saito R, Hamaya K, Nose S: Epithelial hyperplasia of the larynx a clinical follow-up study. Auris Nasus Larynx. 1997, 24: 309-314. 10.1016/S0385-8146(96)00038-7.View ArticlePubMedGoogle Scholar
- Hojslet PE, Nielsen VM, Palvio D: Premalignant lesions of the larynx. A follow-up study. Acta Otolaryngol. 1989, 107: 150-155. 10.3109/00016488909127492.View ArticlePubMedGoogle Scholar
- Riera V, Suarez NC, Pedrero de BC, Alvarez MC: Premalignant lesions of the larynx: pathological prognostic factors. J Otolaryngol. 1987, 16: 367-370.Google Scholar
- Hellquist H, Olofsson J, Grontoft O: Carcinoma in situ and severe dysplasia of the vocal cords. A clinicopathological and photometric investigation. Acta Otolaryngol. 1981, 92: 543-555. 10.3109/00016488109133294.View ArticlePubMedGoogle Scholar
- Stenersen TC, Hoel PS, Boysen M: Carcinoma in situ of the larynx. Results with different methods of treatment. Acta Otolaryngol Suppl. 1988, 449: 131-133. 10.3109/00016488809106395.View ArticlePubMedGoogle Scholar
- Hintz BL, Kagan AR, Nussbaum H, Rao AR, Chan PY, Miles J: A 'watchful waiting' policy for in situ carcinoma of the vocal cords. Arch Otolaryngol. 1981, 107: 746-751.View ArticlePubMedGoogle Scholar
- Crissman JD, Zarbo RJ: Dysplasia, in situ carcinoma, and progression to invasive squamous cell carcinoma of the upper aerodigestive tract. Am J Surg Pathol. 1989, 13 (Suppl 1): 5-16.PubMedGoogle Scholar
- Lee JJ, Hong WK, Hittelman WN, Mao L, Lotan R, Shin DM, Benner SE, Xu XC, Lee JS, Papadimitrakopoulou VM, Geyer C, Perez C, Martin JW, El-Naggar AK, Lippman SM: Predicting cancer development in oral leukoplakia: ten years of translational research. Clin Cancer Res. 2000, 6: 1702-1710.PubMedGoogle Scholar
- Schepman KP, Meij van der EH, Smeele LE, van dWI: Malignant transformation of oral leukoplakia: a follow-up study of a hospital-based population of 166 patients with oral leukoplakia from The Netherlands. Oral Oncol. 1998, 34: 270-275.View ArticlePubMedGoogle Scholar
- Silverman S, Gorsky M, Lozada F: Oral leukoplakia and malignant transformation. A follow-up study of 257 patients. Cancer. 1984, 53: 563-568. 10.1002/1097-0142(19840201)53:3<563::AID-CNCR2820530332>3.0.CO;2-F.View ArticlePubMedGoogle Scholar
- Lumerman H, Freedman P, Kerpel S: Oral epithelial dysplasia and the development of invasive squamous cell carcinoma. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1995, 79: 321-329. 10.1016/S1079-2104(05)80226-4.View ArticlePubMedGoogle Scholar
- Zerdoner D: The Ljubljana classification – its application to grading oral epithelial hyperplasia. J Craniomaxillofac Surg. 2003, 31: 75-79.View ArticlePubMedGoogle Scholar
- 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.View ArticlePubMedGoogle Scholar
- Reibel J: Prognosis of oral pre-malignant lesions: significance of clinical, histopathological, and molecular biological characteristics. Crit Rev Oral Biol Med. 2003, 14: 47-62. 10.1177/154411130301400105.View ArticlePubMedGoogle Scholar
- Holmstrup P, Vedtofte P, Reibel J, Stoltze K: Long-term treatment outcome of oral premalignant lesions. Oral Oncol. 2006, 42: 461-474. 10.1016/j.oraloncology.2005.08.011.View ArticlePubMedGoogle Scholar
- Cowan JM, Beckett MA, hmed-Swan S, Weichselbaum RR: Cytogenetic evidence of the multistep origin of head and neck squamous cell carcinomas. J Natl Cancer Inst. 1992, 84: 793-797. 10.1093/jnci/84.10.793.View ArticlePubMedGoogle Scholar
- Perez-Ordonez B, Beauchemin M, Jordan RC: Molecular biology of squamous cell carcinoma of the head and neck. J Clin Pathol. 2006, 59: 445-453. 10.1136/jcp.2003.007641.PubMed CentralView ArticlePubMedGoogle Scholar
- Staibano S, Merolla F, Testa D, Iovine R, Mascolo M, Guarino V, Castellone MD, Di Benedetto M, Galli V, Motta S, Melillo RM, De Rosa G, Santoro M, Celetti A: OPN/CD44v6 overexpression in laryngeal dysplasia and correlation with clinical outcome. Br J Cancer. 2007, 97: 1545-1551. 10.1038/sj.bjc.6604070.PubMed CentralView ArticlePubMedGoogle Scholar
- Zukerberg L: The molecular basis of dysplasia. Semin Diagn Pathol. 2002, 19: 48-53.PubMedGoogle Scholar
- Koren R, Kristt D, Shvero J, Yaniv E, Dekel Y, Gal R: The spectrum of laryngeal neoplasia: the pathologist's view. Pathol Res Pract. 2002, 198: 709-715. 10.1078/0344-0338-00325.View ArticlePubMedGoogle Scholar
- Kim MM, Califano JA: Molecular pathology of head-and-neck cancer. Int J Cancer. 2004, 112: 545-553. 10.1002/ijc.20379.View ArticlePubMedGoogle Scholar
- Wenig BM: Squamous cell carcinoma of the upper aerodigestive tract: precursors and problematic variants. Mod Pathol. 2002, 15: 229-254. 10.1038/modpathol.3880520.View ArticlePubMedGoogle Scholar
- Warnakulasuriya S, Johnson NW, van dWI: Nomenclature and classification of potentially malignant disorders of the oral mucosa. J Oral Pathol Med. 2007, 36: 575-580.View ArticlePubMedGoogle Scholar
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.