CHAPTER

Oral premalignancy
16
Various oral mucosal lesions, particularly red lesions
(erythroplasias) and some white lesions (leukoplakias), have a Table 16.2 Risk factors for malignant change in white lesions
potential for malignant change (Table 16.1). In some of them,
such as chronic hyperplastic candidosis, the risk may be very History Betel quid usage
Tobacco smoking or snuff dippinga
low. By contrast, the risk with erythroplasia is exceedingly High alcohol intake
high. Genetic disorders (see Ch. 17)
In general, the most common white lesions have the lowest Clinical aspects Advanced age
Female genderb
risk of malignant transformation. Practitioners will see many Areas of reddening in the lesion
oral white lesions, but few carcinomas. However, they must be Areas of speckling in the lesion
able to recognise lesions at particular risk and several features Nodular areas or ulceration
High risk site:
help to assess the likelihood of malignant transformation. The posterolateral tongue
accuracy of such predictions is low, but the process of identifying floor of mouth
‘at risk’ lesions is fundamental to diagnosis and treatment retromolar region
anterior pillar of fauces
planning. Important factors are listed in Table 16.2 and infor- Large lesions
mation on each of these should be sought. Lesions present for long periods
The best predictor of the potential for malignant transformation Enlargement or change in character of
pre-existing lesion
is the degree of dysplasia seen histologically. For this reason, Special investigations Degree of dysplasia on biopsy
and because a few lesions will already be malignant, biopsy of
a
red and white patches is mandatory. The term dysplasia (literally, Nevertheless surveys indicate that the risk of malignant change in
white lesions is higher in non-smokers
abnormal growth) is given to the cytological abnormalities seen b
Surveys indicate that malignant change in white lesions is more
in both malignant and premalignant cells (Table 16.3). frequent in women
Premalignancy is distinguished from malignancy only by the
latter’s invasiveness and release of metastases.

Table 16.1 Lesions with potential for malignant change

Lesion/condition Aetiology Risk of malignant changea Prevalence in the UK

Dysplastic leukoplakia Unknown High, but can regress Uncommon

Erythroplasia Idiopathic/smoking Very high Rare
Speckled leukoplakia Idiopathic/smoking High Rare
Tertiary syphilis Treponema pallidum Very high No longer seen
Oral submucous fibrosis ‘Betel’ chewing High Uncommon
Dyskeratosis congenita Genetic High Rare
Pipe smokers’ keratosis Pipe smoking Low and not in the keratotic area Becoming uncommon
Snuff-dippers’ keratosis Smokeless tobacco Low Uncommon
Chronic candidosis Candida albicans Low Uncommon
Lichen planus Idiopathic Low Common
Discoid lupus erythematosus Autoimmune Unclear (mainly lip) Uncommon
a
Risks of malignant change are difficult to determine accurately and vary with many factors discussed below. If more than 25% of lesions become
malignant in 5 years this is considered an exceptionally high risk. Malignant change in 2–3% of lesions in 5 years is considered a relatively low risk.
Note that the highest risk lesions are uncommon. Common lesions appear in between 1% and 5% of the population.
230
 ORAL PREMALIGNANCY

CHAPTER
Table 16.3 Epithelial dysplasia: histological features
16
● Drop-shaped rete ridges
● Nuclear hyperchromatism
● Nuclear pleomorphism and altered nuclear/cytoplasmic ratio
● Excess mitotic activity
● Loss of polarity of cells
● Deep cell keratinisation
● Disordered or loss of differentiation
● Loss of intercellular adherence

It must be emphasised that the implications of epithelial

dysplasia are quite different from fibrous dysplasia, in which
there is no risk of carcinomatous change.
Nuclei stain more densely due to heavier nucleic acid content.
They are variable in size, out of proportion to that of the cell, so
that there may be little surrounding cytoplasm. Mitoses may be
frequent and at superficial levels. Loss of polarity refers to the
fact that basal cells in particular may lie higgledy-piggledy at
angles to one another. Deep cell keratinisation (dyskeratosis)
refers to individual cells which start to keratinise before the Fig. 16.1 Mild dysplasia. In this lesion there is a thin layer of
parakeratin and the structure, maturation and orderly differentiation of the
surface is reached and show eosinophilic change deeply within epithelial cells is largely unaffected. However, there is a degree of
the epithelium. As differentiation is lost, organisation of the irregularity of basal cells with variation in size and hyperchromatism.
individual cell layers deteriorates and clearly-defined basal and
spinous cell layers cannot be identified. Drop-shaped rete
ridges are regarded as a particularly adverse feature. With loss
of intercellular adherence, the cells become separated.
A lymphoplasmacytic infiltrate of highly variable intensity is
usually present in the corium.
Dysplasia is usually graded as mild, moderate and severe as
a guide to patient management (Figs 16.1–16.4). Carcinoma-
in-situ is a controversial term sometimes used for the most
severe dysplasia where the abnormalities extend throughout the
thickness of the epithelium; a state sometimes graphically
called ‘top-to-bottom change’. In such a lesion all the cellular
abnormalities characteristic of malignancy may be present;
only invasion is absent. The significance of this grading is dis-
cussed below, but the histological assessment of oral epithelial
dysplasia is notoriously unreliable because it is subjective and
changes are not reliably correlated with behaviour.

PREMALIGNANT LESIONS AND CONDITIONS

Premalignant lesions are those lesions in which carcinoma may
develop. Premalignant conditions are associated with a risk of
carcinoma at some site within the mouth, not necessarily marked
by a pre-existing lesion.
Fig. 16.2 Mild dysplasia. In this lesion there is prominent orthokeratosis
and a keratohyaline layer immediately below it. Dysplasia is more
prominent than in the previous figure, with enlarged hyperchromatic and
bizarre cells in the basal and lower prickle cell layers.

‘erythroplakia’ is misleading) but, instead, they are flat or

Erythroplasia (‘erythroplakia’)
Erythroplasia are red patches. The surface is frequently velvety
in texture and the margin may be sharply defined. Lesions of
this type typically do not from plaques (hence the term
depressed below the level of the surrounding mucosa (Fig.
16.5). Erythroplasia is uncommon in the mouth but carries the
highest risk of malignant transformation and lesions are often
231
already malignant on first biopsy.
 SOFT-TISSUE DISEASE

CHAPTER

16

Fig. 16.3 Moderate dysplasia. The dermal papillae extend close to the
surface and there are elongated rete processes, some of which are broader
deeply. Enlarged and hyperchromatic cells are visible at this low power in Fig. 16.5 Erythroplasia. This slightly depressed, well-defined red patch
rete processes and in most of the prickle cell layer. on the dorsolateral tongue showed squamous carcinoma on biopsy.

Fig. 16.6 Speckled leukoplakia. A poorly-defined speckled leukoplakia

on the cheek of an elderly female. Carcinoma was present at the first
biopsy.

Fig. 16.4 Severe dysplasia. This rete process is composed almost

entirely of cells with dark and irregularly shaped nuclei. Only the most
superficial layers of cells show maturation to squamous cells and the
orderly maturation and differentiation of epithelial cells has been lost.

Pathology
Erythroplastic lesions usually show epithelial dysplasia which
may be severe. In other cases, there may be micro- or frankly
invasive carcinoma. The epithelium is atrophic and this, together
with inflammation, accounts for the red colour seen clinically.

Speckled leukoplakia
This term applies to lesions consisting of white flecks or fine
nodules on an atrophic erythematous base (Figs 16.6 and 16.7).
232
They can be regarded as a combination of or transition between
Fig. 16.7 Premalignant lesion in a betel quid chewer. The classical
appearance of a speckled leukoplakia such as this is almost always
associated with either severe dysplasia or invasive carcinoma. Note also
the brown betel quid staining on the teeth.
 ORAL PREMALIGNANCY

leukoplakia and erythroplasia. Speckled leukoplakia also more CHAPTER

frequently shows dysplasia than lesions with a homogeneous
white surface. The histological characteristics are usually, 16
therefore, intermediate between leukoplakia and erythroplasia.
Many cases of chronic candidosis have this appearance.

IDIOPATHIC LEUKOPLAKIA

Leukoplakia is defined as a white patch which cannot be wiped

off the mucosa or ascribed to any specific disease process.
Although the term is often used loosely for any white patch it
should be reserved for idiopathic lesions. If investigations fail
to reveal any cause, the term may be appropriate.
The most extensive follow-up studies on white patches
suggest that idiopathic leukoplakia now has the highest risk of Fig. 16.9 An innocent-looking, poorly-defined inconspicuous white
developing cancer, especially now that late stage syphilis forms patch which showed dysplasia on biopsy. Despite excision, malignant
transformation followed several months later.
a negligibly small group. Nevertheless, the malignant trans-
formation rate of leukoplakia is relatively low, around 1–2% in
5 years, and even in smokers the vast majority of leukoplakias
show no dysplasia histologically and carry no risk of malignant
transformation.

Clinical features
Idiopathic leukoplakias and dysplastic lesions do not have any
specific clinical appearance, but are tough and adherent and
typically form plaques whose surface is slightly raised above
the surrounding mucosa. The surface is usually irregular. Small
and innocent-looking white patches are as likely to show
epithelial dysplasia as large and irregular ones (Figs 16.8 and
16.9). However, lesions with red, nodular or verrucous areas
(Fig. 16.10) should be regarded with particular suspicion. The
most common sites are the posterior buccal mucosa, retromolar
region, floor of mouth and tongue.

Fig. 16.10 White patch with dysplasia. This postcommissural lesion is

poorly defined and comprises both red and white areas. Lesions at this
site are frequently due to candidosis.

Fig. 16.8 Homogeneous leukoplakia. There is a bright, white, sharply-
defined patch extending from the gingiva on to the labial mucosa. The
surface has a slightly rippled appearance and no red areas are associated.
Pathology
The histopathology is highly variable but there is always
parakeratosis or orthokeratosis, or both in different areas, and
the two may alternate along the length of the specimen. The
keratin gives the lesion its white appearance. The epithelium
ranges from thinner than normal (atrophic) to much thicker
(acanthotic) (see Figs 16.1 and 16.2).
Most leukoplakias show no dysplasia histologically. A
minority display a range of dysplasia from mild to severe and
treatment is planned partly on this basis. An inflammatory
233
reaction of lymphocytes and plasma cells induced by the
 SOFT-TISSUE DISEASE

CHAPTER
abnormal dysplastic cells is often present in the underlying
connective tissue.
16
SUBLINGUAL KERATOSIS

The term sublingual keratosis is applied to white lesions on the

floor of mouth and ventral tongue. Whether this lesion is a
different entity from other leukoplakias is unclear. Malignant
change was reported in an unusually high proportion of cases
(30%) in one series but this has not been widely confirmed.
Probably the risk of malignant transformation is less than 10%
and possibly much lower.

Clinical features
Sublingual keratosis is a white, soft plaque, usually with a finely Fig. 16.11 Sublingual keratosis. This white patch involving the entire
ventral tongue and floor of mouth has a uniformly wrinkled appearance.
wrinkled surface, an irregular but well-defined outline and No red areas are associated but the site alone may indicate a high risk of
sometimes bilateral with a butterfly shape. The plaque typically malignant transformation.
extends from the anterior floor of the mouth to the undersurface
of the tongue (Figs 16.11 and 16.12). There is usually no
associated inflammation.

Pathology
Sublingual keratosis is not distinctive histologically and the
appearances are those described above for leukoplakia.

PIPE SMOKERS’ KERATOSIS

As noted earlier (Ch. 15), palatal keratosis due to pipe smoking

is benign. Any carcinomas related to pipe-smoking appear in
another site in the mouth and may not be preceded by keratosis.

SMOKELESS TOBACCO-RELATED KERATOSES

Hyperkeratotic mucosal lesions can result from smoking or use
of smokeless tobacco (‘topical tobacco’ — snuff-dipping and
tobacco chewing). By contrast, there is no characteristic
hyperkeratotic lesion associated with the far more common
habit of cigarette smoking.
Tobacco chewing and snuff-dipping (holding flavoured
tobacco powder in an oral sulcus) are popular habits in the USA
and some parts of Europe. Loose oral snuff appears to cause
more severe changes than tobacco-chewing but not all topical
tobacco habits are associated with a risk of malignant change.
The use of Scandinavian-type snuff sachets appears to carry no
risk and it is important to ascertain exactly what type of tobacco
is used and how it is prepared. Many smokeless tobacco users
also smoke and, regardless of this, all lesions is the mouths of
234
tobacco users should be regarded with suspicion.
Fig. 16.12 Sublingual keratosis. This more irregular white patch is
associated with some reddening in the floor of the mouth.
Clinical features
The habit of snuff-dipping or tobacco-chewing may be
maintained for decades and gives rise to keratoses in the buccal
or labial sulcus, where the tobacco is held. Early changes are
erythema and mild, whitish thickening. Long-term use gives
rise to extensive white thickening and wrinkling of the buccal
mucosa. Malignant change can follow, but only after several
decades of use. A high proportion of carcinomas in snuff users
are verrucous in type (Ch. 17) but if they remain untreated
invasive squamous carcinoma may develop.
 ORAL PREMALIGNANCY

Pathology CHAPTER

The main changes are thickening of the epithelium with plump 16

or squared-off rete ridges. There are varying degrees of hyper-
orthokeratosis or parakeratosis and there may be subepithelial
fibrosis in the area where the tobacco is held. Dysplasia may
eventually be seen.

Management
Diagnosis is based on the history of snuff use and the white
lesion in the area where the tobacco is held. Biopsy is required
to exclude dysplasia or early malignant change. Paradoxically,
however, it appears that in snuff-dippers carcinomas appear at a
later age and are better differentiated than in non-users. Fig. 16.13 Chronic hyperplastic candidosis. This white localised patch
and its associated erythema are the result of candidal infection alone and
Snuff-dippers’ lesions will resolve on stopping the habit even no dysplasia was present despite the speckled clinical appearance.
after 25 years of use. This therefore is the main measure. If this
fails, regular follow-up and biopsies are required.

CHRONIC HYPERPLASTIC CANDIDOSIS (CANDIDAL

LEUKOPLAKIA)

Chronic oral candidosis produces a tough adherent plaque,

distinguishable only by biopsy from other leukoplakias.

Clinical features
Adults, typically males of middle age or over, are affected. The
usual sites are the dorsum of the tongue and the post-commissural
buccal mucosa. The plaque is variable in thickness and often Fig. 16.14 Chronic hyperplastic candidosis. The typical site is the
rough or irregular in texture, or nodular with an erythematous postcommissural buccal mucosa. This florid example is white and slightly
nodular.
background (speckled). Angular stomatitis may be associated,
is sometimes continuous with intra-oral plaques and suggests
the candidal nature of the lesion (Figs 16.13 and 16.14).

Pathology
Unlike thrush, the plaque cannot be wiped off, but fragments
can be detached by firm scraping. Gram or periodic acid–Schiff
(PAS) staining then shows candidal hyphae embedded in clumps
of detached epithelial cells.
Like thrush, the plaque of chronic candidosis is parakeratotic,
but more coherent because it is not widely infiltrated by
inflammatory exudate. In haematoxylin and eosin stained sections,
hyphae form only faint tracks through the epithelium and are
difficult to see. PAS stain clearly shows the hyphae growing (as
in thrush) through the full thickness of the keratin to the prickle
Fig. 16.15 Chronic hyperplastic candidosis. Many hyphae are growing
cell layer where the inflammatory cells tend to be more down through the epithelial plaque. (PAS stain).
concentrated (Fig. 16.15).
Electron microscopy shows Candida albicans to be an Induction of epithelial proliferation by Candida albicans
intracellular parasite growing within the epithelial cytoplasm infection has been demonstrated experimentally and in candidal
(Fig. 16.16). The hyphae, therefore, grow in relatively straight plaques there is often rete hyperplasia with rounded down-
lines and do not follow a tortuous path along the intercellular growths and acanthosis. Dysplasia may be present, especially
235
spaces. in speckled lesions.
 SOFT-TISSUE DISEASE
CHAPTER
16
Fig. 16.16 Two candidal hyphae growing through superficial
keratinocytes of the oral mucosa.
The chronic inflammatory infiltrate in the corium is variable
and a fibrinous inflammatory exudate may be seen at the basement
membrane.
Management
After confirmation of the diagnosis by histology, treatment
should be with a systemic antifungal drug such as fluconazole,
but this may have to be continued for several months. Other
factors likely to perpetuate candidal infection should be
controlled. Stopping the patient from smoking and elimination
of candidal infection from under an upper denture are
important. Any iron deficiency should also be treated.
Excision of candidal plaque alone is of little value, as the
infection can recur in the same site even after skin grafting.
Vigorous antifungal therapy is therefore essential, but sometimes
some residual (uninfected) plaque may persist after treatment
and lesions often recur and require long term intermittent
antifungal therapy.
The potential for malignant change exists. The level of risk is
controversial but low.
ORAL SUBMUCOUS FIBROSIS
In oral submucous fibrosis (Ch. 11) affected areas of the oral
mucosa such as the palate or buccal mucosa appear almost
white. The pallor is due to the underlying fibrosis and ischaemia
rather than a superficial plaque, and the mucosa is typically
smooth, thin and atrophic (see Figs 11.4 ad 11.5). However,
erythroplasia and leukoplakia may be associated (see Fig. 16.7)
and the epithelium may show dysplasia on biopsy.
Surveys suggest that oral submucous fibrosis undergoes
malignant transformation in 4.5–7.6% of cases and may
contribute to the high incidence of oral cancer in the Indian
236
subcontinent and in Asian immigrant populations in other
countries. Submucous fibrosis is probably premalignant because
of its association with betel quid chewing.
LICHEN PLANUS
As noted in Chapter 13, it was estimated that 1–4% of patients
develop carcinomas after 10 years.
However, as noted earlier, the potential of lichen planus to
undergo malignant change is controversial. Rates quoted in
earlier reports have been questioned, particularly because of
doubts about the original diagnosis.
LUPUS ERYTHEMATOSUS
Lupus erythematosus is an uncommon connective tissue disease
(Chs 12 and 23). There is a small risk of malignant change in
cutaneous lupus, especially in lesions of the lower lip.
DYSKERATOSIS CONGENITA
Dyskeratosis congenita is a rare heritable recessive or dominant
trait. The main features are dysplastic white or red lesions of
the oral mucosa, cutaneous pigmentation, dystrophies of the
nails and haematological abnormalities. Many patients may
also be immunodeficient or have other abnormalities.
Causes of death include cancers of the mouth or other sites,
bleeding (gastrointestinal or cerebral) but in 50% from infections,
which are frequently opportunistic.
SYPHILITIC LEUKOPLAKIA
Leukoplakia of the dorsum of the tongue is a characteristic
complication of tertiary syphilis but is of little more than
historical interest.
Clinical features
Syphilitic leukoplakia has no distinctive features, but typically
affects the dorsum of the tongue and spares the margins. The
lesion has an irregular outline and surface. Cracks, small erosions
or nodules may prove on histology to be foci of invasive
carcinoma (Fig. 16.17). Carcinoma developing near the centre
of the dorsum of the tongue is typically a sequel to syphilitic
leukoplakia and, as a consequence of the great decline in late-
stage syphilis, is exceedingly rare in this site now.
Pathology
In addition to hyperkeratosis and acanthosis, often with dysplasia,
the characteristic late syphilitic chronic inflammatory changes,

Fig. 16.17 Syphilitic leukoplakia. Carcinoma has developed in a patch
of leukoplakia on the tongue of a patient who had had tertiary syphilis for
many years. (Taken before the advent of colour photography.)
with plasma cells predominating, may be seen. Giant cells and,
rarely, granulomas may be present. Endarteritis of small arteries
is particularly characteristic. However, distinctive features of a
syphilitic tissue reaction may be lacking.
Behaviour and management
The diagnosis is confirmed mainly by the serological findings.
However, even if positive, biopsy is still essential, as minute
areas of malignant change may be found, and the management
is affected accordingly. In particular, the presence of syphilitic
endarteritis, may be a contraindication to radiotherapy.
Antibiotic treatment of syphilis does not cure the leukoplakia,
which persists and can undergo malignant change even after
serology has become negative.
EARLY CARCINOMA
Occasionally an early carcinoma produces surface keratin and
appears as a white patch (see Fig. 17.4). It should not be
interpreted as malignant change in a leukoplakia.
MANAGEMENT OF DYSPLASTIC LESIONS
As noted in Chapter 17, the prognosis in oral carcinoma is good
only when the diagnosis is made early and the tumour is small.
Accurate assessment of the risk of malignant change in red and
white patches is therefore desirable, but assessment is highly
subjective. The level of risk cannot be reliably assessed from
the histopathology alone and the clinical features listed in Table
16.2 should be used to help gauge the risk for an individual
lesion.
ORAL PREMALIGNANCY
The best predictor of malignant potential is the presence of CHAPTER
dysplasia on biopsy. However, even this is rather poorly
correlated with behaviour for such reasons such as inadequate 16
sampling at biopsy and the subjective nature of assessment.
In the most extensive study based on no fewer than 782 cases
of histologically unspecified oral white lesions followed for an
average of 12 years, 2.4% underwent malignant change in 10
years and fewer than 5% after 20 years. However, even this low
rate represents a risk of malignant change 50–100 times that in
the normal mouth. It was also conspicuous, that in this and in
other studies the rate of malignant change in oral leukoplakias
has been up to 10 times higher in non-smokers than in smokers
and more frequent in women. Other, smaller, series have
suggested rates of malignant change of 30% or more in
unspecified types of white lesions, though in many cases no
time scale has been indicated. The wide variation in the rate of
malignant change in these different series suggests that the
findings have been significantly affected by selection of cases.
It must be emphasised that these large follow-up studies have
been on oral keratoses which had not been histologically assessed.
Because of the rarity of dysplastic oral lesions there are very
few studies, and none on a large scale, that have followed their
progress for adequate periods. In a study of 45 patients with
oral dysplastic lesions, followed for up to 8 years, 11% underwent
malignant change in this period and up to 30% of them
regressed or even ultimately disappeared spontaneously.
The principles of the management of dysplastic lesions are
summarised in Table 16.4.
Table 16.4 Principles of management of dysplastic lesions
● Stop any associated habits, e.g. betel quid or smoking
● Treat candidal infection and/or iron deficiency if present
● Biopsy to assess dysplasia
● Assess risk of premalignant change on clinical and histological
findings
● Consider ablation of individual lesions (see Table 16.5)
● Maintain observation for signs of malignant change
The management of dysplastic oral lesions remains
controversial as their relative rarity has made it impossible as
yet to accumulate enough data to make reliable predictions or
evaluate treatment. It has to be assumed that dyplasia represents
an early stage in the development of carcinoma and provides an
opportunity to treat carcinoma at an exceptionally early, and
potentially curative preinvasive stage.
Unfortunately, these assumptions are not well supported by
clinical evidence. Lesions which are excised appear more likely
to become frankly malignant, though this may reflect selection
of the highest risk cases for surgery.
If lesions are of manageable size, it is tempting to excise
them — this should presumably do no harm, but it is essentially
a treatment of hope rather than certainty. An alternative approach
is to observe the lesions for signs of deterioration, in the hope
of detecting carcinoma as early as possible. Once carcinoma
237
develops the treatment options are much more clear-cut.
 SOFT-TISSUE DISEASE
CHAPTER
Table 16.5 Options for management of premalignant lesions
16
● Observation for early detection of carcinoma
● Surgical excision with grafting, if required
● Cryotherapy
● Laser excision or vaporisation
● Topical chemotherapy
● Retinoids
A dysplastic lesion is associated with a higher risk of
developing lesions elsewhere in the mouth and of developing
more than one oral carcinoma. This process is sometimes
described as ‘field change’ to convey the idea that large areas of
the oral epithelium may be premalignant. Regular examination
of the whole mouth is therefore essential.
Some dysplastic lesions regress spontaneously and surveys
suggest that dysplastic lesions may regress as frequently as they
undergo malignant change. However, disappearance of a white
lesion does not necessarily indicate resolution of dysplasia and
continued observation may still be indicated. Photographs or
video records of lesions are an invaluable aid to long-term
observation of lesions and should be used for high-risk lesions.
In practice, an attempt is usually made to remove lesions
with moderate or severe dysplasia or high-risk clinical features
(Table 16.5).
Surgical excision is the most common approach. It provides
an excision biopsy specimen which can be examined for the
extent of the dysplasia and for possible carcinoma. Unfortunately,
lesions in the highest risk areas in the posterior floor of mouth
are technically difficult to excise and large lesions may require
grafting.
The effectiveness of other treatments has not yet been assessed
on any adequate scale.
After cryotherapy ablation, the area heals rapidly to leave an
apparently normal mucosa. However, there is some uncertainty
about the risk of invasive carcinomas subsequently arising in
these sites. Carbon dioxide laser ablation has also been advocated,
but the same objections may apply. Topical chemotherapeutic
agents such as bleomycin have also been used experimentally.
Treatment with systemic or topical retinoids has also been tried.
Topical retinoids are largely ineffective and though a proportion
of white lesions resolve with systemic treatment, toxic effects
are usually unacceptable. Further, lesions which resolve with
treatment recur on withdrawal of the drugs.
With all such treatments the lesion is not available for
histological examination and multiple biopsy before treatment
is required to ensure that malignant change is not already present.
They may be of value in those for whom surgery is not practical
because of, for instance, unfitness for anesthesia.
In summary, frequent clinical observation, preferably with
photographic records, and immediate biopsy of any areas that
are suspicious or change in appearance, is generally the best
option. Selected lesions with clinical features of high-risk or
238
severe dysplasia on biopsy are probably best excised.
SUGGESTED FURTHER READING
Abbey L M, Kaugars G E, Gunsolley J C et al 1995 Interexaminer and
intraexaminer reliability in the diagnosis of oral epithelial dysplasia.
Oral Surg Oral Med Oral Pathol Oral Radiol Endod 80:188–191
Axell T, Pindborg J J, Smith C J et al 1996 Oral white lesions with
special reference to precancerous and tobacco-related lesions:
conclusions of an international symposium held in Uppsala,
Sweden, May 18–21 1994. J Oral Pathol Med 25:49–54
Barnard N A, Scully C, Eveson J W, Cunningham S, Porter S R 1993
Oral cancer development in patients with oral lichen planus. Oral
Pathol Med 22:421–424
Barrett A W, Kingsmill V J, Speight P M 1998 Frequency of fungal
infection in biopsies of oral mucosal lesions. Oral Diseases 4:26–31
Baudet-Pommel M, Janin-Mercier A, Souteyrand P 1991 Sequential
immunopathologic study of oral lichen planus treated with tretinoin
and etretinate. Oral Surg Oral Med Oral Pathol 71:197–202
Borle R M, Borle S R 1991 Management of oral submucous fibrosis: a
conservative approach. J Oral Maxillofacial Surg 49:788–791
Cawson R A 1966 Chronic oral candidiasis and leukoplakia. Oral
Surg Oral Med Oral Pathol 22:582–591
Cawson R A 1973 Induction of epithelial hyperplasia by Candida
albicans. Br J Dermatol 89:497–503
Cawson R A, Rajasingham K C 1972 Ultrastructural features of the
invasive phase of Candida albicans. Br J Dermatol 87:435–443
Cawson R A, Binnie W H 1980 Candida leukoplakia and carcinoma: a
possible relationship. In Mackenzie I C, Debelsteen E, Squier C A
eds. Oral premalignancy. Proceedings of the first Dow Symposium.
University of Iowa, Iowa, 59–66
Cooke B E D 1956 Leukoplakia buccalis and oral epithelial naevi.
Br J Dermatol 68:151–174
Cribier B, Garnier C, Lausriat D, Heid E 1994 Lichen planus and
hepatitis C virus infection: an epidemiologic study. J Am Acad
Dermatol 31:1070–1072
Daniels T E, Hansen L S, Greenspan J S et al 1992 Histopathology of
smokeless tobacco lesions in professional baseball players.
Associations with different types of tobacco. Oral Surg Oral Med
Oral Pathol 73:720–725
Davidson H R, Connor J M 1988 Dykeratosis congenita. J Med Genet
25:843–846
Einhorn J, Wersall J 1967 Incidence of oral carcinoma in patients with
leukoplakia of the oral mucosa. Cancer 20:2184–2193
Eisen D, Ellis C N, Duell E A, Griffiths C E M, Voorhees J J 1990
Effect of topical cyclosporine rinses on oral lichen planus. A double
blind analysis. N Engl J Med 323:290–294
Eisenberg E, Krutchkoff D, Yamase H 1992 Incidental oral hairy
leukoplakia in immunocompetent persons. A report of two cases.
Oral Surg Oral Med Oral Pathol 74:332–333
Epstein J B, Fatahzadeh M, Matisic J, Anderson G 1995 Exfoliative
cytology and electron microscopy in the diagnosis of hairy
leukoplakia. Oral Surg Oral Med Oral Pathol 79:564–569
Epstein J B, Sherlock C H, Wolber R A 1993 Hairy leukoplakia after
bone marrow transplantation. Oral Surg Oral Med Oral Pathol
75:690–696
Eveson J W 1983 Oral premalignancy. Cancer Surveys 2:403–424
Field E A, Field J K, Martin M V 1989 Does candida have a role in
epithelial neoplasia. J Med Vet Mycol 27:277–294
Garewal H S, Katz R V, Meyskens F et al 1999 웁-carotene produces
sustained remissions in patients with oral leukoplakia. Results of a
multicenter prospective trial. Arch Otolaryngol Head Neck Surg
125:1305–1310
Greenspan D, Greenspan J S, Hearst N G, Li-Zhen P, Conant M A,
Abrams D I, Hollander H, Levy J A 1987 Relation of oral hairy
leukoplakia to infection with the human immunodeficiency virus
and the risk of developing AIDS. J Infect Dis 155:475–481
Greenspan D, Greenspan J S, Conant M, Peterson V, Silverman S,
DeSouza Y 1984 Oral ‘hairy’ leukoplakia in male homosexuals:
evidence of an association with both papillomavirus and a herpes
group virus. Lancet ii:831–834
Hietanen J, Pihlman K, Linder E, Reunala T 1987 No evidence of
hypersensitivity to dental restorative materials in oral lichen planus.
Scand J Dent Res 95:320–327

SUGGESTED FURTHER READING (cont’d)
Higgs J M, Wells R S 1974 Classification of chronic muco-cutaneous
candidosis. Clinical data and therapy. Hautartz 25:159–165
Ho V C, Gupta A K, Ellis C N, Nickoloff B J, Vorrhees J J 1990
Treatment of severe lichen planus with cyclosporine. J Am Acad
Dermatol 22:64–68
Holmstrup P, Thorn J J, Rindum J, Pindborg J J 1988 Malignant
development of lichen planus-affected oral mucosa. J Oral Pathol
Med 17:219–225
Holmstrup P 1992 The controversy of a premalignant potential of oral
lichen planus is over. Oral Surg Oral Med Oral Pathol 73:704–706
Janthi V, Probert C S J, Sher K S, Mayberry J F 1992 Oral submucosal
fibrosis — a preventable disease. Gut 33:4–6
Karjalainen T K, Tomich C E 1989 A histopathologic study of oral
mucosal lupus erythematosus. Oral Surg Oral Med Oral Pathol
67:547–554
Kaugars G E 1992 The prevalence of oral lesions in smokeless tobacco
users and an evaluation of risk factors. Cancer 70:2579–2585
Kaugars G E, Silverman S, Lovas J G L et al 1996 Use of antioxidant
supplements in the treatment of human oral leukoplakia. Review of
the literature and current studies. Oral Surg Oral Med Oral Pathol
Oral Radiol Endod 81:5–14
Kramer I R H, El-Labban N, Lee K W 1978 The clinical features and
risk of malignant transformation in sublingual keratosis. Br Dent J
144:171–176
Laine J, Kalimo K, Forssell H, Happonen R-P 1992 Resolution of oral
lichenoid lesions in patients allergic to mercury compounds. Br J
Dermatol 126:10–15
Larrson A, Axéll T, Andersson G 1991 Reversibility of snuff dippers’
lesion in Swedish moist snuff users: a clinical and histologic study.
J Oral Pathol Med 20:258–264
Laskaris G, Laskaris M, Theodoridou M 1995 Oral leukoplakia in a
child with AIDS. Oral Surg Oral Med Oral Pathol 79:570–571
Lin R Y, Goodhart P 1993 The role of oral candidiasis in survival and
hospitalization patterns: analysis of an inner city hospital human
immunodeficiency virus/acquired immune deficiency registry. Am
J Med Sci 305:345–353
Lippman S M, Batsakis J G, Toth B T, Weber R S, Lee J J, Martin J W
et al 1993 Comparison of low-dose isotretinoin with beta carotene to
prevent oral carcinogenesis. N Engl J Med 328:15–20
Maher R, Lee A J, Warnakulasuriya K A A S 1994 Role of areca nut in
the causation of oral submucous fibrosis: a case-control study in
Pakistan. J Oral Pathol Med 23:65–69
McCreary C E, Flint S R, McCartan et al 1992 Uremic stomatitis
mimicking oral hairy leukoplakia. Report of a case. Oral Surg Oral
Med Oral Pathol Oral Radiol Endod 83:350–353
McGrath J A 1999 Dyskeratosis congenita: new clinical and molecular
insights into ribosome function. Lancet 353:1204–1205
Mincer H H, Coleman S S, Hopkins K P 1972 Observations on the
clinical characteristics of oral lesions showing histologic epithelial
dysplasia. Oral Surg 33:389–399
ORAL PREMALIGNANCY
CHAPTER
Morris L F, Phillips C M, Binnie W H, Sander H M, Silverman H K, 16
Menter M A 1992 Oral lesions in patients with psoriasis: a controlled
study. Cutis 49:339–344
Murti P R, Daftary D K, Bhonsle R B et al 1986 Malignant potential of
oral lichen planus: observations in 722 patients from India. J Oral
Pathol 15:71–77
Murti P R, Bhonsle R B, Pindborg J J et al 1985 Malignant
transformation rate in oral submucous fibrosis over a 17-year period.
Community Dent Oral Epidemiol 13:340–341
Nicholas G E et al 1990 White sponge nevus. Obstet Gynecol
76:545–548
Nowparast B, Howell F V, Rick G M 1981 Verruciform zanthoma: a
clinicopathologic review and report of fity-four cases. Oral Surg Oral
Med Oral Pathol 51:619–625
O’Grady J F, Reade P C 1992 Candida albicans as a promotor of oral
neoplasia. Carcinogenesis 13:783–786
Pillai R, Balaram P, Reddiar K S 1992 Pathogenesis of oral submucous
fibrosis. Relationship to risk factors associated with oral cancer.
Cancer 69:2011–2020
Pindborg J J, Roed-Petersen B, Renstrup G 1972 Role of smoking in
floor of the mouth leukoplakias. J Oral Pathol 1:22–27
Resnick L, Herbst J S, Ablashi D V et al 1988 Regression of oral hairy
leukoplakia after orally administered acyclovir therapy. JAMA
259:384–388
Rhodus N L, Johnson D K 1990 The prevalence of oral manifestations
of lupus erythematosus. Quintessence Int 21:461–465
Shibuya H, Amagasa T, Seto K-I, Ishibashi K, Horiuchi J-I 1986
Leukoplakia-associated multiple carcinomas in patients with tongue
carcinoma. Cancer 57:843–846
Sigurgeirsson B, Lindelöf B 1991 Lichen planus and malignancy. An
epidemiologic study of 2017 patients and a review of the literature.
Arch Dermatol 127:1684–1688
Silverman S, Gorsky M, Lozada F 1984 Oral leukoplakia and
malignant transformation. A follow-up study of 257 patients. Cancer
53:563–568
Silverman S, Bhargava R, Mani N J, Smith L W, Malaowalla A M 1976
Malignant transformation and natural history of oral leukoplakia in
57,518 industrial workers in Gujerat, India. Cancer 38:1790–1795
Sklavounou A, Laskaris G 1990 Oral psoriasis: report of a case and
review of the literature. Dermatologica 180:157–159
Voute A B E, de Jong W F B, Schulten E A J M, Snow G B, van der
Waal I 1992 Possible premalignant character of oral lichen planus;
the Amsterdam experience. J Oral Pathol Med 21:326–329
Yavalzyilmaz E 1992 Oral-dental findings in dyskeratosis congenita.
J Oral Pathol Med 21:280–284
Zain R B, Ikeda N, Gupta P C et al 1999 Oral mucosal lesions
associated with betel quid, areca nut and tobacco chewing habits:
consensus from a workshop held in Kuala Lumpur, Malaysia,
November 25–27, 1996. J Oral Pathol Med 28:1–4
239
 SOFT-TISSUE DISEASE

CHAPTER

16

Summary 16.1 Differential diagnosis and management of the common

causes of red and white patches of the oral mucosa.

240
 ORAL PREMALIGNANCY
Summary 16.2 Summary of the key features of the common and important oral white patches.

16
CHAPTER
241
 SOFT-TISSUE DISEASE

CHAPTER

16

Summary 16.3 Differential diagnosis of common and important red

patches affecting the oral mucosa.

242