A Potpourri of Head and Neck Pathology
Moderators: Dr. Leon Barnes and Dr. Antonio Cardesa
Section 4 -
White Lesions of the Oral Mucosa with Emphasis on Dysplasia
King's College London
White lesions in the mouth grouped by aetiology
White sponge naevus and Cannon's syndrome
Hereditary benign intraepithelial dyskeratosis
Cheek and tongue biting
Smokeless tobacco lesions
Chronic hyperplastic type
Chronic mucocutaneous types
Lichen planus, reticular and plaque types
Idiopathic keratosis ("leukoplakia") with or without dysplasia
homogeneous and speckled leukoplakia
proliferative verrucous leukoplakia
White lesions of renal failure
Diagnosis requires good clinical information, as an absolute minimum the patient's age, sex, ethnic
origin and the appearance, extent and exact site of the lesion(s), particularly whether any red or
ulcerated areas are associated with it, and any risk factors for oral malignancy including tobacco
habits, alcohol intake or betel quid use. Knowledge of presence or absence of a rash is also helpful.
Could this be a developmental condition?
The developmental conditions are relatively rare. Commonest is white sponge naevus caused by
mutations in the genes for keratin 4 or 13. Diagnosis requires both clinical and histological
information. A family history may aid diagnosis and the pattern of inheritance is usually autosomal
dominant. However, sporadic cases appear relatively frequently and it is not uncommon for clinicians to
request exclusion of white sponge naevus on biopsy specimens. The most diagnostic histological
appearances are seen after puberty and oral lesions maybe minimal or absent during the first decade. Not
all cases show the classical condensation of the cytoplasm around the nucleus.
Is a lesion normal, tongue biting or hairy leukoplakia?
Tongue biting, hairy leukoplakia and white sponge naevus share several features. The key diagnostic
feature of hairy leukoplakia in routine preparations is the presence of large koilocyte-like cells and
cytological evidence of viral infection in prickle cells. These cells are identified on the basis of
their enlarged pale staining finely granular eosinophilic cytoplasm, smooth cell borders and perinuclear
haloes. Nuclei usually show pyknotic changes but these are little different from the features of cells
in the normal upper prickle cell layer. Unfortunately clusters of similar cells are a normal feature of
the oral mucosa of the lateral tongue, the commonest site for hairy leukoplakia. HAART has caused florid
presentations of hairy leukoplakia to become rare and the histological features are markedly suppressed
by treatment. This has made confident diagnosis of hairy leukoplakia considerably more difficult and
Immunocytochemistry or in situ hybridization are required to differentiate trivial lesions including
tongue biting on occasion.
Can a lichenoid lesion be more fully characterised?
The lichenoid histological features of interface stomatitis with keratinocyte destruction maybe the
end point of several different pathological processes. The individual features are relatively
non-specific and it is often not possible to differentiate the underlying cause with any degree of
Eosinophils are rare in classical oral lichenoid reactions and when present are usually relatively
sparse. Many lichenoid reactions are indistinguishable from lichen planus and it is our practice to
report lichen planus and lichenoid reactions as a single entity. However, a number of histological
pointers may favour a lichenoid drug reaction. These include a mismatch between the density of the
infiltrate and the amount of epithelial destruction, lymphocytic infiltration focused at the suprabasal
or prickle cell levels, a plasma cell component to the deeper infiltrate (in the absence of fungal
infection) and deep perivascular inflammatory infiltrates separated from the subepithelial band.
Topical lichenoid reactions triggered by dental restorations are almost always strongly suggested by
the clinical presentation, particularly ulceration or atrophy close to the restoration. Typically these
reactions show marked atrophy, superficial germinal centres (in the absence of fungal infection),
prominent apoptoses in a localized band and very dense sharply demarcated perivascular infiltrates
Is dysplasia present in a lichenoid lesion?
It is usual for dysplasia of the oral epithelium to elicit a lymphocytic host response. The processes
of lymphocytic infiltration and killing of epithelial cells are essentially lichenoid and
indistinguishable from the features of lichen planus, lichenoid reactions and lupus erythematosus.
Clinical information may be a helpful pointer but it is important to maintain a high index of suspicion.
There have been no detailed histopathological studies comparing the features of the host response in
dysplasia and lichen planus and the following diagnostic tips have only an anecdotal evidence base.
Destruction of the basal cells in lichen planus can give rise to a range of atypical features. When
basal cell destruction is limited, there is usually reactive basal cell hyperplasia. This may account
for a degree of basal cell crowding and the presence of scattered hyperchromatic cells along the basement
membrane but almost never causes significant generalized expansion of the basaloid compartment. The rete
process pattern of lichen planus will vary from site to site in the mouth. On the dorsum and lateral
tongue the rete processes are often large and irregularly shaped and retain the residue of the pattern
normally associated with the filiform papillae, which are lost early in disease. Thus, regularly spaced
acanthotic rete processes are not worrying, particularly when the lichenoid infiltrate is associated with
only the tips of the rete processes, a common feature of lichenoid lesions on the dorsal/lateral tongue.
More rounded short rete processes are worrying and indicate dysplasia if accompanied by a generalized
enlargement of the basaloid cell compartment.
Dysplasia and Malignant Transformation
Dysplasia remains the best indicator of a risk of malignant change but the data are old and this may
be about to change. Several classical studies have demonstrated the relationship between dysplasia and
* included lip lesions
| ||total lesions ||no. with dysplasia ||no. excised ||transformation rate %|
|Silverman et al. 1984 ||257 || || ||17|
|Mincer et al 1972 || ||45 ||31 ||11|
|Banoczy and Csiba 1976 * ||500 ||120/68** ||66 ||13.2|
|Pindborg et al. 1977 || ||61 || ||6.6|
|Gupta et al. 1980 || ||90 ||0 ||7|
|Lumerman et al. 1995 || ||44 || ||14|
** 68 followed up.
Interestingly, the value of grading is unproven and importance should be
attached to even slight dysplasia. It is known that grade alone is not directly proportional to the risk
(Lind 1987) and also that many dysplastic lesions can regress. The distribution of dysplasia grades in
idiopathic white patches in various studies is shown in the following table.
| ||% mild ||% moderate ||% severe|
|Waldon and Shafer 1975 ||12 ||5|
|Platkajs 1979 ||7 ||5 ||3|
|Seifert and Burkhardt 1979 ||45 ||9|
|Grossel and Hornstein 1982 ||10 ||5 ||3|
|Banoczy 1982 ||5 ||14 ||5|
How should dysplasia be graded?
I know of no peer-reviewed published data explaining the detail of how dysplasia should be scored and
there appears to be almost no published data on which valid scoring systems could be based. Almost all
papers on dysplasia grading identify the same list of features of dysplasia without definitions and no
explanation as to how their severity should be recorded and no indication of the weighting which should
be applied to each.
The WHO 'blue book' published in 2004 made significant changes. It now recommends using a "thirds
affected" step in grading dysplasia, but allows the pathologist to up or downgrade lesions based on
mitotic activity and atypia. However, there is still no defined scheme and many of the criteria used
mean very different things to different people. Size of cells, nuclei and total epithelial thickness are
routinely ignored but probably significant.
Given the difficulty in grading reproducibly, it is perhaps unfortunate that the new WHO system
continues to validate the concept of carcinoma in situ. This is intended to imply that malignant
transformation has occurred but that invasion is not present. This is more of a concept than a definable
histological grade but it is suggested that full thickness cytological atypia with atypical mitoses would
Many pathologists perceive that the problems with dysplasia grading systems lie at the level of
hyperplasia and mild dysplasia. Lesions arise relatively frequently in which microinvasive carcinoma is
covered by an intact layer of well-stratified epithelium showing relatively good maturation. In many
well- and moderately-well differentiated carcinomas there may not be significant expansion of the
basaloid compartment and only a mild degree of uniform cytological atypia. Grading systems that
recognise this type of risk lesion would be a great advantage.
Other risk assessment methods
To date, no immunocytochemical or molecular analytical method has proved a better independent
predictor of malignant transformation than dysplasia grading. Immunocytochemistry for a proliferation
marker (we prefer mib1) and simple keratin (8 or 18) and increased levels of p53 form a panel that has
some value but in general the staining patterns reflect changes visible histologically.
Ploidy analysis (large scale genomic status) is measurement of individual cell variation from diploid
state and reflects chromosomal instability, a fundamental and consistently early step in malignant
transformation. Image-based systems have advantages for routine laboratories. No fresh tissue is
required and paraffin-embedded samples can almost always be processed to provide a result, making it a
more reproducible technique than flow cytometry. In a major retrospective series performed at the Radium
Hospital, Oslo, Norway (Sudbo et al 2001), of 105 diploid leukoplakias only 3 carcinomas developed (at
35, 46 and 76 months), a 97% disease free survival. Conversely, in 20 tetraploid lesions 12 carcinomas
developed and in 27 aneuploid lesions 21 carcinomas developed with a mean delay of 35 months. In this
referral population the positive predictive value of ploidy analysis (84% for an aneuploid result) far
exceeds the published figure for dysplasia grading.
Unfortunately, there is no good data to indicate the positive predictive value of dysplasia grading
for comparison. We started a ploidy analysis service early in 2004 and coupled this to a major
retrospective analysis of malignant transformation rates in the UK. The database includes 2800 biopsy
specimens of white and other suspicious lesions from 2000 patients, each of which was graded by agreement
of two pathologists. 926 specimens showed dysplasia and follow up (5-15 years) was available from
National Cancer Registries for 657 lesions in 273 patients.
When our data is analysed by patient, assuming a "field change" risk, the positive predictive value of
dysplasia grade for malignant transformation was: mild dysplasia 4.9%, moderate dysplasia 10.4%
and severe dysplasia 16.4%. When ploidy analysis was performed on dysplastic lesions, the positive
predictive values were aneuploid 46.2%, (95%ci 0.34-0.56), tetraploid 5.5%. Thus ploidy analysis
outperforms dysplasia grading alone. However, as with all tests, the predictive value falls when applied
to a population with a low prevalence. Ploidy analysis performed indiscriminately on all white lesions
has a predictive value about the same as conventional dysplasia grading. When the relatively few lesions
in which it could be confidently said that biopsy was performed at, or adjacent to, the site of malignant
transformation, were analysed, an abnormal ploidy result predicted transformation in 14 of 21 lesions
regardless of dysplasia grade, a strikingly successful result. These results will change as further
patients are analysed.
- Banoczy J, Monograph, Oral Leukoplakia,1982 , M Nijhof, The Hague.
- Banoczy J, Csiba A Oral Surg 1976, 42:766-74.
- Grossel, Hornstein Mund Kiefer Gesichts Chir 1982 6:343.
- Gupta PC et al., Commun Dent Oral Epidemiol 1980, 8:287-333.
- Lind P, J Dent Res 1987, 95:449-55.
- Lumerman H, Freedman P and Kerpel S, Oral Surg 1995, 79:321-9.
- Mincer HH, Coleman SA, Hopkins KP, Oral Surg 1972, 33:389-99.
- Pindborg JJ, Daftary JK, Mehta FS, Oral Surg 1977, 43:383-90.
- Platkajs MA, J Can Dent Assoc 1979, 45:107-13.
- Seifert G, Burkhardt A, Verh Dtsch Ges Pathol 1979 63:74-82.
- Silverman S, Gorsky M, Lozada F, Cancer 1984, 53:563-8.
- Sudbo J, Kildal W, Risberg B et al.,N Engl J Med 2001, 344:1270-8.
- Waldon CA , Shafer WG, Cancer 1975, 36:1386-92.