Vol. 118 No.

6 December 2014

Keratosis of unknown significance and leukoplakia:

a preliminary study
Sook-Bin Woo, DMD,a,d,e Rebecca L. Grammer, DMD, MD,b and Mark A. Lerman, DMDc

Objective. The objectives were to (1) determine the frequency of specific diagnoses in a series of white lesions, and (2)
describe the nature of keratotic lesions that are neither reactive nor dysplastic.
Study Design. White lesions were analyzed and diagnosed as reactive keratoses, dysplastic/malignant, or keratoses of
unknown significance (KUS).
Results. Of the 1251 specimens that were evaluated, 703 met criteria for inclusion, and approximately 75% were reactive,
10% dysplastic/malignant, and 14% KUS. Excluding reactive keratoses, 43% were dysplastic/malignant and 57% were KUS.
Conclusions. Reactive keratoses were the most common white lesions followed by lichen planus. Dysplastic/malignant
lesions constituted almost 50% of all true leukoplakias. KUS constituted the remaining cases and do not show typical reactive
histopathology as well as clear dysplasia. They may represent evolving or devolving reactive keratoses but may also represent
the very earliest dysplasia phenotype. Clinical findings may be helpful in differentiating the two. (Oral Surg Oral Med Oral
Pathol Oral Radiol 2014;118:713-724)

Similar to other mucosal and skin cancers, oral squa-
mous cell carcinoma (SCCa) has a readily identifiable
precursor lesion; in the mouth, it usually takes the form
of a white plaque, referred to as leukoplakia, that
may be homogeneous or nonhomogeneous (eryth-
roleukoplakia or nodular/verrucous leukoplakia).1,2
Most cases are localized, and multifocal or extensive
leukoplakias are referred to as proliferative verrucous
leukoplakias (PVLs).3 The definition of leukoplakia
from the World Health Organization (WHO) in 1996
had specifically excluded white lesions caused by fric-
tion from the category of leukoplakia.4 In 2005, leu-
koplakia was defined by the WHO at a consensus
conference as “white plaques of questionable risk,
having excluded (other) known diseases or disorders
that carry no increased risk for oral cancer.”5 Leuko-
plakia is therefore a clinical diagnosis of exclusion.
Table I presents a list of other conditions that may
mimic leukoplakia but have fairly specific clinical
This abstract was presented as a poster on May 18, 2010, at the annual
meeting of the American Academy of Oral and Maxillofacial Pa-
thology, held in Tucson, Arizona.
a
Associate Professor, Department of Oral Medicine, Infection, and
Immunity, Harvard School of Dental Medicine, Boston, MA, USA.
b
Resident in Oral and Maxillofacial Surgery, Department of Oral and
Maxillofacial Surgery, Massachusetts General Hospital, Boston, MA,
USA.
c
Associate Professor, Department of Oral Pathology, Oral Medicine,
and Craniofacial Pain, Tufts University School of Dental Medicine,
Boston, MA, USA.
d
Associate Pathologist, StrataDx, Lexington, MA, USA.
e
Attending Dentist, Division of Oral Medicine and Dentistry, Brigham
and Women’s Hospital, Boston, MA, USA.
Received for publication Mar 31, 2014; returned for revision Sep 5,
2014; accepted for publication Sep 12, 2014.
Ó 2014 Elsevier Inc. All rights reserved.
2212-4403/$ - see front matter
http://dx.doi.org/10.1016/j.oooo.2014.09.016
appearances and/or histories, and well-defined histo-
logic features.
The frequency of epithelial dysplasia (ED), carci-
noma-in-situ (CIS), verrucous carcinoma, or invasive
SCCa in leukoplakias varied from 8.6% to 60.0%.6-11
Malignant transformation of oral ED or CIS occurs in
5% to 15% of cases,10,12-16 although a figure as high as
36.4% has been reported6; rates were higher in patients
who chewed betel leaf.10 The annual transformation
rate is 1% to 5% for all leukoplakias.6,9,12,17 However,
keratotic lesions without histopathologic evidence of
dysplasia also showed malignant transformation in 1%
to 30% of cases.6,9,12,13,18,19
PVL, a clinicopathologic entity that spreads relent-
lessly, has a 50% to 100% malignant transformation
rate, depending on the length of follow-up.3,20,21 The
histopathologic changes are often architectural, that is,
verrucous epithelial hyperplasia, rather than showing
significant cytologic atypia or dysplasia.3,22 The ma-
jority of such lesions evolve into either verrucous car-
cinoma, an epithelial malignancy known to also exhibit
minimal cytologic atypia, or conventional SCCa.21,22
The primary objective of this study is to determine
the frequency of reactive keratosis, ED, verrucous
hyperplasia (VH), CIS, verrucous carcinoma, and
invasive SCCa in a large series of biopsies of white
lesions accessioned and evaluated in one surgical
Statement of Clinical Relevance
The majority of true leukoplakias are keratoses of
unknown significance (KUS). Recognition of this
entity and distinguishing between KUS and reactive
keratoses is significant because of the different pa-
tient management strategies for each.

713
ORAL AND MAXILLOFACIAL PATHOLOGY
714 Woo, Grammer and Lerman
Table I. Classification of oral keratotic lesions
Developmental
Cannon white sponge nevus
Hereditary benign intraepithelial dyskeratosis
Oral involvement by other genodermatoses (e.g., pachynychia
congenita)
Reactive/frictional/factitial
Leukoedema
Mouthwash-induced desquamation (not true keratosis, but
clinically white)
Morsicatio mucosae oris
Benign alveolar ridge keratosis
Early smokeless tobacco lesions*
Nicotinic stomatitis
Hairy tongue
Nonspecific reactive
Infectious
Candidiasis
Hairy (Epstein Barr viruseassociated) leukoplakia
Immune-mediated
Lichen planus/lichenoid mucositis
Lupus erythematosus
Chronic graft-versus-host disease
Preneoplastic and neoplastic
Leukoplakias, dysplastic or otherwise
Carcinomas
Metabolic
Uremic stomatitisy
Palifermin-associated hyperkeratosis
* These are the gray, opalescent, poorly demarcated lesions, which
resolve when the habit is discontinued, and not leukoplakias that
develop within them.
y
Although clinically recognized, this lesion has not been histopath-
ologically characterized.
pathology laboratory. The secondary objective was to
describe the nature of keratotic lesions that are neither
cytologically dysplastic nor frictional/factitial in nature
and to offer suggestions as to their etiopathogenesis.
METHODS AND MATERIALS
All specimens submitted to Pathology Services Inc., a
private surgical pathology laboratory in Cambridge,
Massachusetts, from January 2007 to June 2008, with
the terms “leukoplakia,” “hyperkeratosis,” “keratosis,”
“white lesion,” “lichen planus,” “lichenoid,” and
“papilloma” were identified. The reason lichen planus
(which is not a leukoplakia) is included is that eryth-
roleukoplakia, a lesion highly associated with ED, may
be misdiagnosed clinically as lichen planus, and some
clinicians refer to leukoplakia as “plaque-type lichen
planus.” The reason papillomas were included is that
verrucous leukoplakias may be clinically misdiagnosed
as papillomas.
Demographic and clinical data were collected from
the requisition forms, including the age and gender of
the patient and the location of the lesion. Each spec-
imen was then reviewed by two pathologists (ML and
SW) independently and a diagnosis rendered. The
OOOO
December 2014
diagnoses of morsicatio mucosae oris (MMO),
chronic chewing/frictional/factitial keratoses of the
nonkeratinized mucosa (Figure 1, A-C), and benign
alveolar ridge (frictional) keratosis (BARK) (see
Figure 2, A to C), were made on the basis of defined
histopathologic criteria (Table II).23,24 These are pri-
mary frictional keratoses; secondary frictional keratoses
that overlie areas of ED or carcinoma were diagnosed
as ED or carcinoma. Diagnoses of ED, verrucous car-
cinoma, and SCCa were made on the basis of estab-
lished criteria.25-27 VH was diagnosed if the following
were present: broad-based papillary or verruciform
epithelial proliferation with parakeratosis or hyperker-
atosis in a mostly exophytic pattern (Figure 3, A and B)
(see Table II).28,29 The term hyperkeratosis is used
throughout this report to connote hyperorthokeratosis,
and the presence of parakeratin was designated
“parakeratosis,” in keeping with the convention used by
general and skin pathologists, with the under-
standing that the tongue dorsum may show true
hyperparakeratosis.
Lesions that were keratotic and acanthotic and
showed inflammation and vascular ectasia without
dysplasia, which, in the pathologist’s opinion, were
within the realm of a reactive keratosis, were classified
as “nonspecific reactive” (Figure 4, A and B; Figure 5).
Lesions that were keratotic but did not have significant
evidence of inflammation, vascular ectasia, or fibrosis
were placed in the category of “keratosis of unknown
significance (KUS)”; lesions with equivocal mild
epithelial atypia were included (Figure 6, A-C).
For the purposes of analysis and discussion, the term
All Keratoses (AK) is defined here as reactive keratoses
(MMO, BARK, and nonspecific reactive keratoses)
plus true leukoplakias (TL), which include ED, CIS,
VH, verrucous carcinoma, invasive SCCa, and KUS.
Descriptive statistics were used to determine the
frequency of reactive keratoses (specific or nonspe-
cific), ED, CIS, VH, verrucous carcinoma, and invasive
SCCa. The frequencies of ED and carcinoma occurring
at different anatomic sites in the mouth were also
determined.
RESULTS
There were 4,869 specimens accessioned during the
period, of which 1,251 fulfilled the criteria for evalu-
ation. Five hundred and forty eight were well-recog-
nized entities that were specific histopathologic
entities and excluded from the analysis, leaving 703
cases of AK (Table III). The male-to-female ratio was
1.5:1 for AKs. Among the AK group, there were 186
current and former smokers and 38 never-smokers,
and 33 who currently drank alcohol and 8 who never
did; these figures are likely to be low and inaccurate
OOOO ORIGINAL ARTICLE
Volume 118, Number 6 Woo, Grammer and Lerman 715

Fig. 1. A, Frictional/bite keratosis with irregular surface and “fading” margins. B, Frictional keratosis from buccal mucosa: shaggy
parakeratosis with fissures and clefts rimmed by bacteria, benign epithelial hyperplasia, and keratinocyte edema
(magnification 40). C, Rete ridges confluent at the tips with no or minimal reactive atypia (magnification 200).

Fig. 2. A, Benign alveolar ridge keratosis of the retro molar pad with “fading” margins. B, Benign alveolar ridge keratosis: hy-
perkeratosis with wedge-shaped hypergranulosis, undulating surface and benign epithelial hyperplasia with tapered rete ridges
(magnification 40). C, Tapered rete ridges with confluence at the tips, with no or minimal reactive atypia (magnification 200).

because such data are not often recorded on the
requisition form.
Frequency of reactive keratoses, epithelial
dysplasia, and carcinoma
MMO and BARK together and nonspecific reactive
keratoses constituted 37.4% and 38.7%, respectively, of
AK, for a total of 76.1% (see Table III). Specific
frictional/factitial keratoses (MMO and BARK)
comprised 28% (150/535) and 21.1% (113/535) for a
total of 49.1% of all reactive keratoses, respectively,
with the rest being nonspecific reactive keratoses. As
such, frictional and reactive keratosis was the most
common white lesion that was biopsied, followed by
lichen planus. The male-to-female ratios for MMO and
BARK were 1:1 and 3.5:1, respectively, whereas the
ratio for nonspecific reactive keratosis was 1:1.
ORAL AND MAXILLOFACIAL PATHOLOGY OOOO
716 Woo, Grammer and Lerman December 2014

Table II. Histopathologic features of keratoses

Morsicatio mucosae oris
Parakeratosis mostly (often with shaggy
surface); some hyperkeratosis*; edge
of keratin usually tapering
Parakeratosis with fissures and
impetiginization
Epithelium sometimes has undulating
surface or papillomatosis
Plasma pooling and keratinocyte edema
often noted
Acanthosis with tapered rete ridges;
no cytologic
atypia unless ulcer present
Minimal to no inflammation unless
ulcerated
* Hyperkeratosis here refers to hyperorthokeratosis.
Benign alveolar ridge keratosis
Hyperkeratosis mostly; some
parakeratosis if recently
traumatized; edge of
keratin usually tapering
Parakeratosis with fissures and
impetiginization only if
recently traumatized
Epithelium often has undulating
surface or papillomatosis
Usually without plasma pooling or
keratinocyte edema unless recently
traumatized with parakeratosis
Acanthosis with tapered rete ridges;
no cytologic atypia unless ulcer
present
Minimal to no inflammation
unless ulcerated
Verrucous hyperplasia
Hyperkeratosis and/or parakeratosis; edge often sharply
demarcated from adjacent normal epithelium
Parakeratosis with fissures and impetiginization only
if secondarily traumatized
Prominent papillomatosis or verruciform architecture
Usually without plasma pooling or keratinocyte edema
unless recently traumatized
Exophytic squamous proliferation; if endophytic, likely
verrucous carcinoma; may show very mild basal cell
crowding or hyperplasia equivocal for atypia; rete
ridges may be bulbous or drop-shaped
Minimal to no inflammation unless ulcerated

Fig. 3. A, Verrucous hyperplasia: marked hyperkeratosis, marked thick hypergranulosis, “skip” areas of normal mucosa, epithelial
hyperplasia (H&E, magnification 40). B, Minimal epithelial atypia (magnification 100).

There were 168 cases of TL, and 42.9% were ED,
CIS, VH, verrucous carcinoma, or invasive SCCa
(Table IV); the prevalence of SCCa and verrucous
carcinoma was 8.3% and that of VH was 5.4% of TLs.
Fifty-seven percent of lesions (96 cases) were KUS,
keratotic lesions of unclear etiology that did not appear
to be reactive in nature but that were not obviously
dysplastic. When considering only dysplastic or
cancerous lesions (72 cases), 68.1% were ED or CIS,
12.5% were VH, 18.1% were invasive SCCa, and 1.4%
were verrucous carcinoma. The male-to-female ratio for
TL, ED/SCCa, and KUS were 2.1:1, 2.0:1 and 2.1:1,
respectively.
Of the 186 current and former smokers, 12 (6.5%)
developed VH and ED, and 10 (5.4%) developed
SCCa. However, these data are of limited use. For
example, of the 58 VH, ED, and CIS cases, only 12
subjects had indicated a smoking history, and there
were no data on 46 subjects. In other words, only 12
patients reported a positive smoking history, and all 12
had ED. Similarly, 3 patients each in the VH, ED, CIS,
and SCCa groups consumed alcohol, and these were the
only cases that reported alcohol use. No negative report
of use of tobacco or alcohol was made in any of the
dysplasia and SCCa groups. Of the 96 patients with
KUS, 23 (24.0%) were current/former smokers, and 8
were nonsmokers.
If the 535 cases of reactive keratoses were included
(inappropriately) in the category of TL, the frequency
of ED, CIS, VH, and invasive SCCa would decrease
from 42.9% (72/168) to 10.2% (72/703), a marked
underestimation of the actual frequency.
Sites of involvement
As expected, most reactive frictional keratoses
(82.8%) involved the lateral and ventral tongue, buccal
mucosa and gingiva (Table V). Most EDs and CIS
occurred on the tongue and floor of the mouth
(67.4%), and SCCAs were most common on the
tongue (38.5%) and equally on the floor of the mouth,
soft palate, and gingiva. By far, the most common site
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Volume 118, Number 6
Fig. 4. A, Parakeratosis, benign epithelial hyperplasia and mild chronic inflammation, reactive in nature (magnification 40). B,
Mild reactive basal cell hyperplasia and chronic inflammation (magnification 200).
Fig. 5. Frictional/bite keratosis of the buccal mucosa, typical
on the right and similar to Figure 1, B, reactive keratosis on
the left, similar to Figure 4, A and B (magnification 40).
for VH was the gingiva (55.6%). However, ED, CIS,
SCCa, VH, and verrucous carcinoma of the floor of
the mouth and of the soft palate constituted 40% and
26.7%, respectively, of AK biopsied from those sites
(Table VI). These figures increased to 62.5% and
42.1% for TL.
KUS lesions also were common on the lateral
tongue, with a frequency similar to frictional keratoses
(26.5% vs 27.1%, respectively). However, these same
lesions showed a much higher frequency of occurrence
on the floor of the mouth and on the soft palate, both
high risk sites for ED and carcinoma, compared with
frictional keratoses.
Keratosis of unknown significance and cases of
epithelial atrophy
There were 96 cases of keratotic lesions that did not fall
into the category of typical frictional keratosis, ED,
CIS, VH, or carcinoma and were diagnosed as KUS.
They exhibited parakeratosis or hyperkeratosis, and 78
showed epithelial hyperplasia without clear evidence of
ED; some showed very slight atypia (e.g., slight
crowding of basal cells) that may or may not represent
reactive atypia. The lesion shown in Figure 6, A, on the
alveolar ridge mucosa is sharply demarcated clinically,
and the keratosis correspondingly is sharply demarcated
ORIGINAL ARTICLE
Woo, Grammer and Lerman 717
histologically; there is very minimal, if any, cytologic
atypia (see Figure 6, A-C). This did not represent a
BARK histopathologically.
Thirty-six cases of keratotic lesions showed epithelial
atrophy and mild chronic inflammation, and of these, 29
were considered either lichenoid in nature or otherwise
related to inflammation (Table VII). The remaining seven
cases showed very mild atypia that was not commensurate
with the degree of inflammation present and could not be
classified definitively as reactive; they were placed in the
category of KUS (included in the 96 KUS cases).
There were 19 keratotic lesions with epithelial atrophy
and minimal-to-no inflammation (Figure 7, A-C). Of these,
3 were considered to be related to previous inflammation
because of the presence of fibrosis and vascular ectasia
(reactive keratoses), 5 showed obvious ED, and 11 were
considered unlikely to be reactive and were placed in the
category of KUS (included in the 96 KUS cases).
DISCUSSION
Leukoplakias are noted in 1% to 3% of patients in
Western countries and in higher numbers in countries
where there is a much higher rate of areca nut and betel
leaf use; malignant transformation occurs in 1% to 5%
of cases annually; these have been well reviewed.30-32
Leukoplakia is a clinical diagnosis only, and the clini-
cian may need to modify the initial impression of leu-
koplakia after histopathologic evaluation, that is, to
“hyperkeratosis with dysplasia or carcinoma” or “hy-
perkeratosis or parakeratosis without dysplasia (with or
without acanthosis, atrophy, or inflammation),” what
we refer to here as KUS.
The ventral/lateral tongue, floor of mouth, soft palate,
and buccal mucosa were common sites of involvement
by ED, CIS, or carcinoma in the current study as has
been well established. The gingiva was the most com-
mon site for VH in this study, and this is also the most
common site for PVL.33 VH may be misdiagnosed as
“benign papillary hyperplasia” because of minimal evi-
dence of cytologic atypia/dysplasia. However, it is the
broad-based, verrucous or papillary architecture that is
the worrisome feature in these lesions.
ORAL AND MAXILLOFACIAL PATHOLOGY OOOO
718 Woo, Grammer and Lerman December 2014

Fig. 6. A, Well-demarcated, asymptomatic, homogeneous leukoplakia on the crest of the alveolar ridge without the fading borders
of a benign alveolar ridge keratosis (magnification 40). B, Excisional biopsy from Figure 6, A. Sharply demarcated keratosis on
either end, tapered rete ridges and lack of inflammation (magnification 40). C, Minimal cytologic atypia.

Table III. All-white lesions (N ¼ 1251) Table IV. Diagnoses for true leukoplakia
Specific diagnoses (not leukoplakia) N ¼ 548 True leukoplakia N ¼ 168
LP 203 (37.0%) Keratosis of unknown significance 96 (57.1%)
Papilloma 133 (24.2%) Dysplasia or invasive squamous cell 72 (42.9%)
Fibroma* 89 (16.2%) carcinoma (SCCa)
Candidiasisy 15 (2.7%) Verrucous hyperplasia 9 (12.5%)
Verruca vulgaris 7 (1.3%) Mild dysplasia 22 (30.6%)
Mucocele 7 (1.3%) Moderate dysplasia 17 (23.6%)
Scar 7 (1.3%) Severe dysplasia 9 (12.5%)
BMG 6 (1.1%) Carcinoma-in-situ 1 (1.4%)
Papillary epithelial hyperplasia 6 (1.1%) Invasive SCCa 13 (18.1%)
Otherz 48 (8.8%) Verrucous carcinoma 1 (1.4%)
Total 72 (100.1%)
All keratoses N ¼ 703
Reactive 535 (76.1%) SCCa, squamous cell carcinoma.
MMO 150 (21.3%)
BARK 113 (16.1%)
Nonspecific 272 (38.7%)
to 53.2%.9,11,19 These figures are similar to the 42.9%
Nonreactive (TL) 168 (23.9%)
KUS 96 (13.7%) noted in the current study. The study by Lee et al. showed
Dysplasia 58 (8.3%) a prevalence of 46.8%, but almost 90% of patients in this
Cancer 14 (1.9%) study were from a Taiwanese population who smoked
BARK, benign alveolar ridge (frictional) keratosis; BMG, benign cigarettes, drank alcohol, and chewed betel quid.
migratory glossitis; KUS, keratosis of unknown significance; LP, The clinical appearance of the lesion is very helpful
lichen planus; MMO, morsicatio mucosae oris; SCCa, squamous cell when trying to determine whether a keratotic lesion is
carcinoma; TL, true leukoplakia. reactive/frictional or likely not. A clinical history is
* Includes 22 giant cell fibromas.
y
Primary candidiasis and excludes candidiasis associated with other
usually not reliable or helpful in such situations, as
conditions. many patients with typical MMO or BARK deny par-
z
Any category of lesion that had contained five cases or fewer (e.g., afunctional habits. Furthermore, ED or cancerous le-
smokeless tobacco keratosis and verruca vulgaris). sions may be secondarily traumatized. Many lesions
with ED have sharply defined margins (see Figure 6, A;
The prevalence of ED in leukoplakias in older studies Figure 8, A). This is in contrast to clinical lesions of
had been shown to range from 8.6% to 26.6%.6-8 Newer MMO and BARK that have fading, poorly defined
studies have shown the prevalence to be as high as 38.9% margins (see Figures 1, A, and 2, A).
OOOO ORIGINAL ARTICLE
Volume 118, Number 6 Woo, Grammer and Lerman 719

Table V. Diagnosis by site

Attached
Lateral or ventral Buccal gingiva/nonattached Hard Upper/Lower
tongue/dorsum/NOS FOM Soft palate mucosa gingiva palate lip
Diagnosis by site [%] [%] [%] [%] [%] (%) (%) NOS Total
Factitial þ reactive 130/9/3 (26.5) 9 (1.7) 11 (2.1) 116 (21.7) 177/8 (34.6) 27 (5.0) 4/21 (4.7) 20 (3.7) 535 (100.0)
KUS 24/1/1 (27.1) 6 (6.3) 11 (11.5) 10 (10.4) 22/3 (26.0) 4 (4.2) 2/7 (9.4) 5 (5.2) 96 (100.1)
Verrucous hyperplasia 1/0/0 (11.1) 1 (11.1) 1 (11.1) 1 (11.1) 5/0 (55.6) 0 0 0 9 (100.0)
Dysplasia þ CIS 25/0/1 (53.1) 7 (14.3) 4 (8.2) 5 (10.2) 3/1 (8.2) 0 0/3 (6.1) 0 49 (100.1)
Squamous cell 5/0/0 (38.5) 2 (15.4) 2 (15.4) 1 (7.7) 2/0 (15.4) 1 (7.7) 0 0 13 (100.1)
carcinoma
Verrucous carcinoma 0 0 1 (100.0) 0 0 0 0 0 1 (100.0)
Total number of 200 25 30 133 221 32 37 25 703
cases of AK
AK, all keratoses; CIS, carcinoma-in-situ; FOM, floor of mouth; KUS, keratosis of unknown significance; NOS, not otherwise specified.

Table VI. Frequency of diagnoses by site

Tongue, Floor of Soft Buccal Gingiva, Hard Upper/Lower
Diagnosis by site all sites mouth palate mucosa all sites palate lip
No. of VH, ED, CIS, 32/200 (16.0%) 10/25 (40.0%) 8/30 (26.7%) 7/135 (5.2%) 11/221 (5.0%) 1/32 (3.1%) 3/37 (8.1%)
SCCa, and VCa/AK
No. of VH, ED, CIS, 32/58 (55.1%) 10/16 (62.5%) 8/19 (42.1%) 7/19 (36.8%) 11/36 (30.6%) 1/5 (20.0%) 3/12 (25.0%)
SCCa, and VCa/TL
AK, all keratoses; CIS, carcinoma-in-situ; ED, epithelial dysplasia; SCCa, squamous cell carcinoma; TL, true leukoplakia; VCa, verrucous carci-
noma; VH, verrucous hyperplasia.

Table VII. Hyperkeratosis and epithelial atrophy inflammation” without further interpretation, such a
Atrophy with chronic Atrophy without
descriptive diagnosis is nonspecific and is also consis-
inflammation chronic inflammation tent with the histopathologic features of TL, a keratotic
Buccal mucosa 12 4 lesion that has a high association with dysplasia or
Ventral tongue 4 1 SCCa, which, in this case, would be misleading. To
Lateral tongue 2 5 use the same descriptive diagnosis for both conditions
Dorsal tongue 0 1 is inconsistent with the current WHO definition of
Attached/Unattached 5/0 3/0
leukoplakia, which is “white plaques of questionable
gingiva
Hard palate 4 0 risk having excluded (other) known diseases or
Lower lip 3 1 disorders that carry no increased risk for oral
Soft palate 1 3 cancer.”5 This has important and practical clinical
Upper lip 1 0 implications.
Floor of mouth 0 1
A lesion diagnosed as “frictional keratosis,” MMO,
Unknown 4 0
TOTAL 36* 19y or BARK, which specifically addresses the etiology of
the lesion and its benign nature, means that it is un-
* Of 36, 25 were considered reactive, 4 were lichenoid and 7 were
considered unlikely reactive and of uncertain etiology.
likely to require periodic biopsy. However, a diagnosis
y
Of 19, 3 were considered reactive, 11 were considered unlikely of “hyperkeratosis (or parakeratosis), acanthosis, and/
reactive and of uncertain etiology, 5 were mild dysplasia. or chronic inflammation (not otherwise specified)”
suggests that although the lesion is not cytologically
dysplastic, it also may not be reactive and may even
In this histopathologic study of 703 cases of AK, represent a very early dysplasia because of historical
frictional keratoses constituted 76.1% of lesions. evidence that such “benign hyperkeratosis” may
However, if frictional keratoses (which carry no develop into invasive SCCa. We suggest the term
increased risk for carcinoma development) are included “keratosis of unknown significance, or KUS” for these
in the category of TL, the prevalence of ED, CIS, VH, lesions. These lesions should be followed up and
or invasive SCCa was 10.2%. When these were rebiopsied periodically or, in some cases, even
excluded from the TL category, the frequency increased excised. This group of lesions constituted 57.1% of
4.2-fold to 42.9%. cases of leukoplakia in this study, and 24.3% to 61.1%
Although it is not incorrect to diagnose frictional in other studies, although this term was not
keratoses as “hyperkeratosis, acanthosis, and/or chronic applied.9,11,17,19
ORAL AND MAXILLOFACIAL PATHOLOGY
720 Woo, Grammer and Lerman
Fig. 7. A, Hyperkeratosis and epithelial atrophy with minimal inflammation of the tongue dorsum (magnification 100). B,
Minimal cytologic atypia (magnification 400). C, Proliferative leukoplakia of the tongue.
Many cases of KUS (42/91; 46.2%) occurred at sites
that are high risk for ED and SCCa, such as the tongue,
floor of mouth, and soft palate. However, the lateral
tongue is also a site frequently associated with frictional
keratosis, and this begs the question: Are KUS lesions a
spectrum of frictional keratosis or early dysplasia? It is
quite possible that a certain percentage of KUS lesions
represent frictional keratosis since 26.5% vs 27.1% of
frictional keratoses vs KUS occurred on the lateral/
ventral tongue, respectively. However, frictional kera-
tosis vs KUS occurred with a frequency of 1.7% vs
6.3% on the floor of mouth, a site not readily trauma-
tized. Similarly, the frequency of frictional keratoses vs
KUS of the soft palate was 2.1% vs 11.5%, respec-
tively. Yet these KUS lesions from these disparate sites
shared essentially the same histopathology. The point is
that there is a keratotic lesion that pathologists and re-
searchers recognize and label “hyperkeratosis,” which
is histopathologically somewhat different from fric-
tional and reactive keratoses, and to these we have
applied the term KUS; the concept is not new.
The possibility that KUS may represent an early
dysplastic lesion is also supported by reports of lesions
of “benign hyperkeratosis” developing into invasive
SCCa in 1% to 30% of cases.6,9,12,13,18,19 The term
KUS, rather than “benign hyperkeratosis,” may be more
appropriate because the significance is unknown; some
may be reactive, and some may progress to dysplasia
and SCCa. It has been suggested that cases of “benign
hyperkeratosis” developing into dysplasia and SCCa
over time may result from sampling error.34-36 The fact
that different samples within the same leukoplakia may
OOOO
December 2014
yield areas of dysplasia, SCCa, and KUS actually
supports the concept that KUS falls within the spectrum
of dysplasia and may be the very earliest manifestation
of it (Figure 8, A-E). We do not know what the biologic
significance of KUS lesions unassociated with
dysplasia or SCCa is, but the histopathologic features
are the same; as such, patients with KUS should be very
carefully monitored, and using separate terminology
may be helpful, rather than merely using the term
“hyperkeratosis,” which a clinician may automatically
equate with “benign,” since they may see the same
histopathologic sign-out diagnosis with bite keratoses.
Furthermore, hyperkeratosis with no or only minimal
atypia/dysplasia or VH may be seen in patients with
PVL, a form of leukoplakia that is often multifocal or
large, that spreads relentlessly over the mucosa, and
that is highly associated with the development of can-
cer.20,33,37 Studies have demonstrated that a large leu-
koplakia strongly correlates with development of
dysplasia and carcinoma,38 with a recent study showing
that a lesion larger than 4 cm was strongly associated
with malignant transformation, even though the ma-
jority of transformed cases showed no evidence of
dysplasia at first biopsy.19 This concept of KUS is also
supported by the fact the PVLs that usually show
minimal to no dysplasia on multiple biopsies, never-
theless have a malignant transformation rate of up to
70%.3,21,22
The presence of hyperkeratosis or parakeratosis
with epithelial atrophy that is not clearly reactive
needs further investigation. If such lesions are
consistently associated with well-demarcated plaques
OOOO ORIGINAL ARTICLE
Volume 118, Number 6 Woo, Grammer and Lerman 721

Fig. 8. A, Leukoplakia with well-demarcated margin on ventral tongue (Courtesy of Dr. Craig Meadows, Martinsburg, West
Virginia). B, One area showing hyperkeratosis (magnification 100). C, High power showing minimal cytologic atypia, namely,
keratoses of unknown significance (KUS) (magnification 400). D, Edge of lesion showing sharp demarcation of keratosis and
slight budding of rete ridges (magnification 40). E, High power showing mild dysplasia with basal cell hyperplasia and bud-
shaped rete ridges (400).

and/or seen as part of PVL (see Figure 7, A-C), this
would be further evidence that they truly belong in the
category of KUS.
The diagnosis of KUS in a white lesion allows the
pathologist to indicate to the clinician that the biologic
behavior is unclear. Although it is not likely to be
frictional or reactive, it also may not be entirely
innocuous, especially if it is at a high-risk site. KUS
should be monitored carefully or even removed
altogether, depending on the clinical presentation and
circumstances (Figure 9).
Invasive cancer occurs as a result of cumulative
genetic mutations, the first few of which lead to the
preinvasive, precursor lesion, with many dysplastic
lesions sharing the same genetic alterations as invasive
SCCa.39,40 In the evolution of dysplasia arising in
leukoplakia, it is possibledand, indeed, probabled
that the very earliest mutation may lead to a lesion that
ORAL AND MAXILLOFACIAL PATHOLOGY OOOO
722 Woo, Grammer and Lerman December 2014

Fig. 9. Management algorithm after biopsy.

shows only increased para- or orthokeratin formation recurrences over time than those whose margins show
without evidence of phenotypic dysplasia. The time truly normal mucosa with normal keratosis or no
that it takes to acquire sufficient mutations that result keratosis.
in phenotypic dysplasia and invasive carcinoma varies
greatly and may not occur within a patient’s lifetime.
CONCLUSIONS
This concept of a visible clonal “patch” with cells that
This retrospective study of oral leukoplakia showed that
share a common genotype that arises within a larger
approximately 75% of 703 AKs were frictional/reactive
“field” representing the very earliest precursor lesion
in nature, exhibiting keratosis and benign epithelial
to phenotypic dysplasia, has been well discussed.41,42
hyperplasia. Frictional keratosis was the most common
One of the drawbacks of this study is that photo-
white lesion biopsied, surpassing even lichen planus. Of
graphs of the lesions were provided in only a minority
the remaining 168 cases of TLs, 42.9% were ED, CIS,
of cases. We believe that the diagnosis of any form of
VH, or invasive SCCa, whereas the majority (57.1%)
leukoplakia is substantially aided by the pathologist’s
was KUS. However, if frictional/factitial keratoses were
familiarity with the clinical presentation. In this time of
included in the analysis, dysplastic and cancerous le-
easy access to technology, even an image taken with a
sions constituted only 10.2% of AKs because of dilu-
smartphone may help the pathologist in differentiating
tion, a gross underrepresentation. The term “keratosis of
frictional keratosis from leukoplakia, and it is essential
unknown significance” (KUS) is suggested for those
that the pathologist works closely with the clinician for
keratotic lesions that do not appear to be frictional or
accuracy of diagnosis.
reactive in nature, and it is unclear what the biologic
Research that focuses on molecular changes in le-
behavior of these lesions is. Since the follow-up for
sions of KUS and how these are similar or different
frictional keratosis is essentially reassurance of the pa-
from those of ED as well as frictional keratosis would
tient without further biopsy, whereas the follow-up for
greatly help us understand the nature of KUS and
KUS is ongoing monitoring and periodic biopsies, the
whether it is, indeed, the very earliest form of
distinction between the two directly impacts patient
dysplasia.43-45 This concept of KUS within a “canc-
care.
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