Open Access
Review
Grading systems in head and neck dysplasia: their prognostic value, weaknesses and utility
Stijn Fleskens*
1and Piet Slootweg
2Address: 1Department of Otolaryngology/Head and Neck Surgery, University Medical Center St Radboud, PO Box 9101, 6500 HB Nijmegen, the Netherlands and 2Department of Pathology, Radboud University Nijmegen Medical Centre, PO Box 9101, 6500 HB Nijmegen, the Netherlands Email: Stijn Fleskens* - [email protected]; Piet Slootweg - [email protected]
* Corresponding author
Abstract
Background: 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.
Objectives: 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.
Conclusion: 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.
Introduction
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 diag- nosis 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 epithe- lium shows a variety of cytological and architectural
changes that have traditionally brought under the com- mon denominator dysplasia.[3]
The presence of dysplastic areas in the epithelium of the upper aerodigestive tract (UADT) is believed to be associ- ated 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
Published: 11 May 2009
Head & Neck Oncology 2009, 1:11 doi:10.1186/1758-3284-1-11
Received: 29 March 2009 Accepted: 11 May 2009
This article is available from: http://www.headandneckoncology.org/content/1/1/11
© 2009 Fleskens and Slootweg; licensee 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.
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 pro- gression to malignancy makes dysplasia grading neces- sary.
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.[11]
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.[4] 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 clas- sification 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 inva- sive disease, limiting the need for radical surgery and improving survival while avoiding unnecessary follow-up in cases which lack significant premalignant poten- tial.[10]
Grading systems: overview
During the last decades many classifications of intraepi- thelial head and neck lesions have been proposed as illus- trated 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 differ- ent histopathological classifications and initial interven- tions 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 cer- vix.[21,22] Whether this is justified, is debatable. In cervi- cal 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 conse- quently the definition of the degree of dysplasia is much more susceptible for discussion, this resulting in substan- tial intra- and inter-observer variability.[8,10,23]
When looking at the current classification systems as men- tioned in the WHO-IARC blue book series the following ones are proposed. The WHO classification is similar to the classification for the uterine cervix, and is widely used in spite of the shortcomings as mentioned. It recognizes low, moderate and severe dysplasia and carcinoma in situ (CIS), defined in the same way as for cervical lesions. The SIN classification (squamous intraepithelial neoplasia) can be considered synonymously, excepted that severe dysplasia and CIS are combined as SIN 3 (Table 1).
Besides the WHO and SIN classification system, the Ljubljana classification is mentioned (Table 1).[3,11]
The Ljubljana classification, developed by laryngeal pathologists and used since 1971, focuses on the clinical
Table 1: Classification systems that categorize intraepithelial head and neck lesions.[3,11]
2005 WHO Classification Squamous Intraepithelial Neoplasia (SIN) Ljubljana Classification Squamous Intraepithelial Lesions (SIL)
squamous cell hyperplasia squamous cell (simple) hyperplasia
mild dysplasia SIN 1 basal/parabasal cell hyperplasia*
moderate dysplasia SIN 2 atypical hyperplasia**
severe dysplasia SIN 3*** atypical hyperplasia**
carcinoma in-situ SIN 3*** carcinoma in-situ
* basal/parabasal cell hyperplasia may histologically resemble mild dyplasia, but the former is conceptually benign lesion and the latter the lower grade of precursor lesions.
** 'risky epithelium'. The analogy to moderate and severe dysplasia is approximate.
*** the advocates of SIN combine severe dysplasia and carcinoma in-situ.
decision points which involve the identification of: 1) purely hyperplastic lesions that do not require close fol- low-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' hyper- plasia), 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 differ- entiate between severe dysplasia and carcinoma in situ is debatable. Several authors have commented on the diffi- culty in separating these categories in conventional classi- fication systems.[4,5,13] To reduce categories still further, occasionally a binary classifying system has been pro- posed.[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 sta- tistical methods of analysis. Since most grading and scor- ing 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
Reproducibility refers to the degree to which observer measurement or diagnosis remains the same on repeated independent observations of an unchanged characteris- tic.[29] 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 appropri- ate gold standard is not available.[30]
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.[27] In histopathology, results of the diagnostic evaluation are discrete diagnostic catego- ries (for example, moderate dysplasia in a laryngeal lesion) rather than variable parameters and for this reason kappa statistics are often used as indicators of perform- ance .[31-33] Kappa statistics measure levels of agreement between observers and make allowance for the degree of agreement that would occur by chance alone.[34] Since most grading systems in squamous lesions produce an ordinal categorical result then kappa statistics are a rele- vant means of assessing reproducibility.[8,27,32,34,35] A kappa statistic of 1 represents perfect agreement and 0 rep- resents the level of agreement expected by chance alone.[27] Landis et al. described guidelines to interpret the quantitative significance of kappa.[31]
Concerning the head and neck region, data of oral lesions outnumber laryngeal lesions. Pindborg et al. for the first time indicated the need for an internationally accepted set of criteria for oral epithelial dysplasia in 1975.[36] Since then, several studies have shown large intra- and interob- server variability in the assessment of intraepithelial head and neck lesions (Table 2).[10,26,30,36-41]
There are also additional features that negatively influence reproducibility. Fischer et al. suggested that inflamma- tion, lesion site, and biopsy technique (punch and wedge) modifies the reliability of oral histological lesions.[38]
Clinical information submitted with biopsy specimens did not increase accuracy and consistency.[41]
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.[10] Data con- cerning 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), eval- uated 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.[26] Fischer et al. also reduced the number of pathologic diagnoses to three categories ('no abnormality/hyperkeratosis', 'mild, moderate, or severe dysplasia', 'carcinoma in situ/carci- noma') which resulted in a kappa value of 0.70 (com- pared with 0.59 using the various pathologic diagnoses separately).[38] 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 over- view 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; carci- noma in situ and keratosis, respectively.[42,43] Since then several follow-up studies concerning the natural evolu- tion and long-term risk of malignant progression in intraepithelial lesions have been reported. In these stud- ies, usually no distinction between natural evolution without treatment (prognostic value) and predictive value
(response to treatment) is made. Therefore, data on malig- nant 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], moder- ate 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 fol- lows: SIN I 5%, SIN II 25%, and SIN III 11–25%.[5,53]
Table 2: Observer variability in head and neck lesions.
Studies/
References
Localisation Number of slides
Histopathologic al classification
Number of examinators
Agreement Kappa value
Abbey et al. 1995 oral cavity/
oropharynx
120 WHO° 6 35.8–57.5% 0.15–0.41
Fischer et al. 20041 oral cavity/
oropharynx
87 WHO° 24 0.59
(95% CI: 0.45–
0.72) 0.70 (95% CI:
0.56–0.84)2
Karabulut et al.
1995
oral cavity/
oropharynx
100 WHO° 4 49–69% 27–45%3
Tabor et al. 2003 oral cavity/
oropharynx
43 WHO 3 53% 0.58
Abbey et al. 1998 oral cavity/
oropharynx
120 WHO° 6 38.5% 0.174
Brothwell et al.
2003
oral cavity/
oropharynx
64 WHO° 3 51% 0.37
Kujan et al. 20061 oral cavity/
oropharynx
68 WHO and binary
system ("low-risk" or
"high-risk")
4 WHO:
37.7%
(unweighted) 92.8% (weighted) Binary system:
74.3%
WHO:
0.22 (95% CI:
0.11–0.35 unweighted) 0.63 (95% CI:
0.42–0.78 weighted) Binary system:
0.50
Mclaren et al. 2000 larynx 100 WHO and two-
grade (low and high grade)
13 WHO: 0.32
Two-grade: 0.52
° = WHO is not explicitely stated, but terms are in agreement with this system.
1 = The unweighted kappa considers all disagreements to be equally important, while the weighted kappa (Kw) yields a higher reliability when disagreements between raters are small compared with when they are large.
2 = the pathologic diagnoses are restricted to three categories ('no abnormality/hyperkeratosis', 'mild, moderate, or severe dysplasia', 'carcinoma in situ/carcinoma').
3 = when comparing the kappa values between the two pairs of pathologists with the same education, these values did not diverge from the general level of kappa values, indicating that the interobserver variability was due to individual differences rather than to educational background.
4 = Clinical information submitted with biopsy. Same population as [37].
Photomicrograph showing area of increased epithelial thick- ness together with hyperkeratosis: mild dysplasia (WHO) or parabasal hyperplasia (Ljubljana)
Figure 1
Photomicrograph showing area of increased epithe- lial thickness together with hyperkeratosis: mild dys- plasia (WHO) or parabasal hyperplasia (Ljubljana).
Photomicrograph showing blunt and elongated epithelial ridges and cytonuclear atypia confined to the lower epithelial half: moderate dysplasia (WHO) or atypical hyperplasia (Ljubljana)
Figure 2
Photomicrograph showing blunt and elongated epi- thelial ridges and cytonuclear atypia confined to the lower epithelial half: moderate dysplasia (WHO) or atypical hyperplasia (Ljubljana).
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%).[25] 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).[20]
Few studies have examined the cancer risk related to dif- ferent 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 speci- fied.[56] Schepman et al. reported 12% malignant trans- formation in oral lesions histopathological classified with the WHO classification. Leukoplakias consisting of mod- erate or severe epithelial dysplasia, had a significantly higher risk of developing a carcinoma than leukoplakias of a lower stage (p < 0.01).[55] In another study 26% of cases with hyperplasia/mild dysplasia and 67% of cases with moderate/severe dysplasia developed into carci- noma.[54] Lumerman et al. studied malignant transfor- mation in hyperplasia with dysplasia, mild dysplasia, moderate dysplasia, severe dysplasia, and CIS; respec- tively 29%, 8%, 17%, 17%, 0%.[57] 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 intraepithe- lial 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 hyper- plasia progressed to invasive cancer.[58]
Interpretation of these reported data of oral intraepithelial lesions are hampered by small sample sizes, surgical inter- vention carried out for high-risk dysplasias and variability in reporting dysplasia grades. The greater part of pub- lished 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.[8]
Size, and not histology seems to be the most important in predicting malignant transformation.[61]
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 devel- opment of premalignancies to carcinoma are still unknown, and we are still forced to conclude that over (or
under)-expression of biomarkers itself adds little predic- tive value over standard histology .[62-66] Therefore, until now they are not applicable in clinical practice.[67]
Finally, some remarks have to be made on the relation- ship between clinical aspects and risk of malignant pro- gression. In general, homogeneous leukoplakic lesions are thought to have a low risk of malignant transforma- tion, mixed white and red lesions (or speckled leukopla- kia) 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 histolog- ical 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 macro- scopic features is still a subject of discussion.[69]
Evaluation
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.[10] Its prognostic significance is as follows: hyper-
plasia 0–3%.[13,44,45], mild dysplasia 0–30% [13,45- 47], moderate dysplasia 0–44% [5,13,45-49], severe dys- plasia 20–57% [13,45,47,49,50], CIS 0–80%
[13,44,45,48-52]. For oral lesions, inter- and intraob- server figures of the WHO classification vary between kappa scores of 0.15 and 0.59.[26,30,37-41] Its prognos- tic 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 rela- tion to predictive value of oral lesions are not available in current literature.
Regarding the Ljubljana classification, its use for the lar- ynx has been documented extensively. Its relevance for prognosis has been amply demonstrated by the patholo- gists and clinicians who developed the system. However, its usefulness has not yet resulted in widespread accept- ance. For the oral cavity, there is only one study that reports its use in this anatomic location.[58] 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 dys- plasia system.
Although the histological assessment of the WHO dyspla- sia system and the Ljubljana system are based on the same architectural and cytological changes, there is no simple relationship or overlapping between the classification sys- tems.[3,11,19,20] Figure 1, figure 2, and figure 3 illustrate the areas of similarity in the classification systems but also the problems arising when matching the WHO categories moderate and severe dysplasia with the Ljubljana category atypical hyperplasia. According to Gale et al., comparing the three discussed classification systems, it is unlikely that they will come together in the very near future. On the other hand, future discoveries mainly in molecular biology could be the basis for a single, universal classifica- tion system for intraepithelial lesions of the UADT.[20]
Competing interests
The authors declare that they have no competing interests.
Authors' contributions
All authors read and approved the final manuscript.
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