oral pathology

Editor.
JAMES J. SCIUBBA, D.M.D., Ph.D.
American Academy of Oral Pathology
Department of Dentistry
Long Island Jewish-Hillside Medical Center
New Hyde Park, New York 11042

Proliferative verrucous leukoplakia

A long-term study of thirty patients

Louis S. Hansen, D.D.S., * James A. Olson, D.D.S.. ** and Sol Silverman, Jr., D. D.S., ***
San Francisco, CalijI

DEPARTMENT OF STOMATOLOGY, UNIVERSITY OF CALIFORNIA SAN FRANCISCO

Up to 6% of oral leukoplakia. a relatively common mucosal disease, can be expected to become

malignant. This report describes a long-term study of 30 patients in whom a particular form of leukoplakia
was identified and labeled proliferativeverrucous leukoplakia (PVL), a disease of unknown origin, which
exhibits a strong tendency to develop areas of carcinoma. PVL begins as a simple hyperkeratosis but
tends to spread and become multifocal. PVL is slow-growing, persistent, and irreversible, and in time areas
become exophytic, wartlike, and apparently resistant to all forms of therapy as recurrence is the rule. The
disease was most commonly seen in elderly women and had been present for many years. Patients were
followed for 1 to 20 years. Thirteen died of or with their disease, 14 were alive with PVL, and 3 were alive
without PVL at last contact. PVL rarely regressed despite therapy. All patients who died had persistent or
recurrent disease. PVL appears to constitute a continuum of hyperkeratotic disease, ranging from a simple
hyperkeratosis at one end to invasive squamous cell carcinoma at the other. Microscopic findings are
dependent upon the stage of the disease’s development and the location and adequacy of the biopsy.
(ORAL SURG. ORAL MED. ORAL PATHOL. 60~285-298, 1985)

I n 1978 the WHO Collaborating Centre for Oral location, and cultural habits.2-‘s In most studies
Precancerous Lesions proposed that leukoplakia be prevalence seems to center around 3% to 5%.
defined as a clinical white patch of the oral mucosa Many studies have been undertaken to assess the
that cannot be characterized clinically or pathologi- fate of these lesions.4*5.‘6-3i Most were designed to
cally as any other disease.’ Even though this excludes establish the rate of malignant transformation.
such diseases as lichen planus, discoid lupus erythe- B&Gczy,32 in a study of 670 patients followed for
matosus, white sponge nevus, candidiasis, and hyper- more than 30 years, reported that the lesions disap-
keratoses due to cheek- and lip-biting, oral leukopla- peared in 31.0% of her patients, improved in 29.7%,
kia must, by this definition, be regarded as a relative- remained unchanged in 2X8%, spread in 7.5%, and
ly common mucosal disease. Its prevalence around became malignant in 6%. Others have found rates of
the world in random population groups 14 years of malignant transformation ranging from 0.13% to
age and older has been reported to range from 0.2% 17.5% and averaging around 4.5% to 6.0%.4 The
to 24.8%, depending on clinical criteria used, geo- variation in transformation rates appears to be re-
graphic location of the population group, intraoral lated to such variables as period of observation, age,
sex, location and type of leukoplakia, treatment
This study was supported in part by a grant from the Donald T. methods, geographic location (probably reflecting
Elliott Oral Cancer Research Fund and National Cancer Institute differences in oral habits and local customs), and
Grant No. CA 17914-08
*Professor and Chairman, Division of Oral Pathology.
various etiologic factors.4* 22-24, 29,33-:7 In Bgnhzy’s
**Associate Clinical Professor, Division of Oral Medicine. study there was a very significant correlation (p less
***Professor and Chairman, Division of Oral Medicine. than 0.001) between clinical type and malignant
286 Hansen, Olson, and Silverman
PROLIFERATIVE VERR~OU~
O-l-2-3-4-S--6-?-8-9-10
Normal Glinical verrucous
Leukoptakia Xyperplasia
Fig. 1. Diagram illustrating the histologic criteria used to grade proliferative verrucous leukoplakia
(PVL) on a scaleof 1 to 10. Grade 0 illustrated is from normal mucosaof hard palate.
change.29 Leukoplakia simplex (homogeneous leuko-
plakia) showed the lowest frequency of malignant
transformation, and leukoplakia erosiva (erythroleu-
koplakia) and nodular leukoplakia (speckled leuko-
plakia) the highest. 32Banoczy also found that nonho-
mogeneous verrucous leukoplakia exhibiting exo-
phytic warty surfaces had a greater tendency to
malignant transformation than homogeneous leuko-
plakia, but not as great as erythroleukoplakia.29
Hyperkeratotic (leukoplakic) oral lesions, then,
vary considerably in appearance as well as in proba-
ble causative factors. This makes long-term treat-
ment plans difficult and outcome unpredictable. In
order to aid clinicians in approaches to this manage-
ment problem, we prospectively assessed risk factors
in 257 oral leukoplakic patients followed for a mean
of 8 years.4
One prominent high-risk factor found in the study
was a fairly specific form of leukoplakia. It bega’n as
a simple hyperkeratosis but tended to extend and
become multifocal over varying periods of time. The
lesions were slow-growing, persistent, irreversible,
and frequently developed erythematous components.
Some areas later became exophytic and wartlike and
transformed into lesions that were clinically and
microscopically identical to verrucous carcinoma and
squamous cell carcinoma. In addition, they were
resistant to every kind of therapy. We have termed
this type of hyperkeratosis proliferative verrucous
leukoplakia (PVL). In the early stages of PVL,
diagnosis was difficult, because in the simple hyper-
keratoses we could not distinguish those that might
be reversible or treatable from those that were
actually the early stages of the persistent and irre-
versible PVL. Thus, we were led to believe that the
patient’s leukoplakia was relatively innocuous
because of the slow growth and the microscopically
Oral Surg.
September, 1985
LEUKOPLAKIA
Vbrrucous Papillary
Carcinoma squamous Cell
Carcinoma
benign appearance of the early lesions and some of
the later ones. It is not until multifocal, persistent,
and other clinical characteristics of PVL begin to
develop that the diagnostician suspects the true
nature of the patient’s hyperkeratosis.
Because of the dangerous potential of PVL, a
special study was undertaken to determine more
specifically the risk of malignant transformation.
The purpose of this article is to describe the clinical,
microscopic, and follow-up findings in thirty patients
with this highly precancerous form of leukoplakia.
METHODS AND MATERIALS
The patients included in this study were selected
retrospectively from those diagnosed, treated, and
followed in the Oral Medicine Clinic at the Univer-
sity of California San Francisco from 1961 to 1983.
Selection criteria included the following:
1. Patients with clinical leukoplakia diagnosed on
biopsy as a simple hyperkeratosis without dysplasia,
areas of which later developed proliferative, warty
epithelial overgrowths.
2. Patients with verrucous hyperplasia, verrucous
carcinoma, or squamous cell carcinoma, diagnosed
on biopsy, who had a history and clinical findings
consistent with proliferative verrucous leukoplakia.
Such findings included a long history (in years) of
slow-growing, persistent, diffuse, or multifocal leu-
koplakia.
These patients had been followed for periods of 1
to 20 years (average, 6.1 years), during which time
the number of biopsies per patient ranged from 3 to
89, for a total of 427 or an average of 14.2 per
patient. The sections were processed in the usual
manner and stained with hematoxylin and eosin. In
addition, 19 patients had at least one section stained
by the periodic acid-Schiff (PAS) method, and in 26
 -
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Number
60
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Proliferative verrucous lelr k@akia 287

-n
Table I. Clinical and microscopic findings in thirty patients with proliferative verrucous leukoplakia (PVL,)
/ Microscopic

Chsr 4gP Sex

I ‘7 M P, T, BM, V CT 13 + x

2 I: F LBM. LMAM CT 6 + x. s

3 90 F LT ND 3 + None I) + ii
4 62 F LBM, S, H CT 5 ND x. s I) + I)
5 78 F H, BM, AM CT 7 + x IIt I)
6 84 F F, RBM, LBM, CT IO - Y 1) t I)
RAM
7 70 F RT, RBM, LBM, 34 + x. c 11 t I)
S. H. RUAM
8 63 F T. F CT 9 IO ND s,, x *\ c I3
9 x9 t- RUAM. H None 6 + c I> + II
IO 67 F RBM. L.BM CT 5 - x. s I‘, t I)
II 73 F LT. t CT 3 ND s, L A - II
12 54 ,: RS. RF. RBM, CT 15 89 S. MB, C. R. 0 A t I)
RV, T
13 17 F L.BM. LMAM None IO I9 + x, s
14 63 F T CT 4 ND x. c. l D + I‘,
IS 65 M RBM, LT None 5 20 S. R 4 + 1)
16 14 M P, G, BM, MAM CT, PP I1 28 ND x, s
17 66 F RBM CT 8 18 + x. s, c I)+ L,
IX 68 F RBM, RV None 5 IO + 1 ‘Z t I>
19 70 F RT, LT. BM, SN 20 23 - 1. 5 2-t 1)
AM, F. S.
H, G
20 40 M RUAM, LUAM CG 9 I7 ND s. x ,\ + I>
21 80 F RMAM, RBM. None 4 + x. s I) + I)
RS. RF
22 87 F H, S CT 3 + h0ile 4 + D
23 61 F P. RUAM, BM, None 18 41 MB. (‘. 0. s A + I)
LUAM
24 53 M F. G, P, BM CT 6 1.s - MB A + D
2s 14 F G None 6 ND S. MB \ -. 1)
26 43 F T, V. P None IO ND x. s I) + I>
27 36 F BM, ‘I- None 12 5 ND M B AiLl
28 87 F RT. LT None 4 3 ND X 4 t D
29 60 F MAM. UAM CT 3 ND s. x .A t 1)
30 35 M RBM, LBM, G, CT 7 + L A + D
F’. T, AM, S

*Age a1 first biopsy. ND = No determination

tL = Left, R = right; V = lip; BM = buccal mucosa; T = tongue; F = floor of mouth: P = palate: Y = soft palate; H = hard palate; AM = itjvc,~lil~ ,~wwa;
UAM = maxtllary alveolar mucosa; MAM = mandibular alveolar mucosa; G = gingiva.
$CT = Cigarettes; CC = cigars; PP = pipe; SN = snuff.
§X = Radiation: S = surgery; MB = multiple excisional biopsies; L = laser surgery; C = chemotherapy: R = retinoids: 0 = orher
I/A + D = Alive with PVL. (any grade); A - D = alive without PVL (any grade); D + D = died wtth PVL. (any grade)

patients the oral lesions were cultured for Candida with little or no dysplasia. However, when the
albicans. leukoplakia exhibited papillary exophytic prolifera-
The 427 biopsy specimens were reviewed and, tion of squamous epithelium, it was designated grade
irrespective of the original diagnoses, each specimen 4. In grade 4 there was no evidence of invasion, and
was graded on a scale of 0 to 10 according to the the hyperkeratotic epithelium exhibited little or no
severity of the microscopic findings (Fig. 1). For dysplasia. PVL of this grade was indistinguishable
each patient, the least malignant and the most from what has been termed “verrucous hyperplasia.”
malignant grades were recorded. Grade 6 was also a papillary exophytic proliferation
Grade 0 represented normal oral mucosa. The of squamous epithelium, usually with hyperkeratosis
least malignant pathologic finding was designated as and little or no dysplasia. However, there was, in
grade 1. Grade 2 consisted of a simple hyperkeratosis addition, a downgrowth of well-differentiated squa-
288 Hansen, Olson, and Silverman
Fig. 2. Case 23. A, Photograph taken when patient was
73 years of age. Multiple biopsies revealed grade 2 PVL.
Numerous biopsies of the leukoplakia from age 67 to age
77 also revealed grade 2 PVL. B, Same patient at age 85.
At age 79 she developed an area of grade 8 PVL, which
was locally excised from the right alveolar mucosa and
alveolar process. At the age of 88 she is alive with
proliferative verrucous leukoplakia.
mous epithelium exhibiting broad, blunt rete ridges
with intact basement membranes. There was inva-
sion of the lamina propria which in some cases
extended to the minor salivary glands and skeletal
muscle. An area of PVL graded 6 could not be
differentiated histologically from verrucous carcino-
ma. Grade 8 PVL was characterized by an exophytic
and invasive growth of well-differentiated squamous
epithelium with keratin formation and minimal dys-
plasia. However, the invasive fingers of epithelium
were narrower and had a less distinct basement
membrane than in grade 6. Histologically, the
growth resembled papillary squamous cell carcino-
ma. Grade 10 was characterized by loss of cohesion
of moderately differentiated or poorly differentiated
tumor cells. There was moderate or severe dysplasia,
and keratin formation was minimal or absent. The
tumor cells were infiltrative and indistinguishable
from a moderately differentiated to poorly differen-
tiated squamous cell carcinoma.
Oral Surg.
September. 19x5
Fig. 3. Case 30. Photograph of patient at age 41. When
the first biopsy was performed 6 years earlier, the right and
left buccal mucosae, tongue, and floor of the mouth
exhibited grade 2 PVL. At the last biopsy the patient’s
condition had progressed in some areas to grade 5 PVL.
Fig. 4. Case 16. At age 74 the patient had this diffuse
keratosis which, upon multiple biopsies, exhibited grades 2
to 6 PVL. The lesion was excised; then it recurred, spread,
and was later diagnosed as grade 7 PVL.
Biopsy specimens that could not be definitively
graded with even numbers according to the above
criteria were assigned an intermediate grade, desig-
nated by an odd number from 1 to 9 (Fig. 1).
The sections stained with PAS were recorded as
either positive or negative for Candida albicans. Also
recorded were the patient’s clinical data, including
sex, age at time of first biopsy, tobacco usage,
location of the oral lesions, type of treatment or
treatments, and the patient’s status at last contact.
RESULTS
The clinical and microscopic findings for the 30
patients are compiled in Table I. Six of our 30
patients were men whose ages at first biopsy ranged
Volume 60 Proliferative verrucous Ieukoplakia 289
Number 3

Fig. 5. Case 12. The patient was 54 years old at the time of the first biopsy. A, Photograph taken 9 years
later. Multiple biopsies over the first 6 years revealed grade 2 PVL. The patient then developed grade 6
disease and later grade 8. She was treated with multiple local excisions, cryosurgery, electrosurgery,
methotrexate, and retinoids. The lesion always recurred, but she is alive with her disease 1S years sifter the
first biopsy. B, Photograph taken 13 years after the first biopsy. Disease has spread to involve the lips,

from 27 to 74 years (mean, 49 years). Twenty-four
were women, ranging in age from 36 to 90 years
(mean, 70.2 years, median, 70). Twenty-one of the
24 women (87.5%) were 60 years of age or older.
We were unable to determine the duration of the
patients’ PVL. However, follow-up extended beyond
the years from first to last biopsy (Table I). Further-
more, at first biopsy, the patients or their referring
doctors almost always indicated that their leukopla-
kias had been present for a long time, sometimes for
more than 20 years. Therefore, “years from first to
last biopsy” represents only the minimal duration.
Eighteen of 29 patients (62%) used some form of
tobacco, usually cigarettes, during their lifetime.
One woman used snuff, but ten of the women
(43.5%) never used tobacco in any form. Thus, the
typical patient as seen by us was an elderly woman
who was likely to have had her disease for many
years and may or may not have used tobacco.
In 12 of 19 patients (63%) at least one section was
positive for Candida albicans by PAS staining. In
addition, 17 of 26 patients (65%) had positive
candidal cultures, but it must be pointed out that 10
of the 17 were treated by radiation.
The buccal mucosa was the most common site of
PVL (23 lesions), followed by the mucosa of the hard
and soft palate (18), alveolar mucosa (16), tongue
(15), floor of the mouth (8), gingiva (5), and lip
(4).
In early PVL, especially in isolated lesions, the
clinical finding was simply a white keratotic patch,
sometimes associated with adjacent erythematous
mucosa, which could not be differentiated from the
more common varieties of clinical leukoplakia. As
the disease progressed, however, the solitary lesions
spread and similar lesions appeared elsewhere on the
mucosa, often accompanied by erythematous
changes. The early keratoses were thickened but
essentially flat (Figs. 2 to 4).
Some patients with PVL later developed areas of
severe erosions, but the keratoses became exophytic
and wartlike, with further extension and develop-
ment of multifocal lesions (Fig. 5, A and B).
In late PVL some areas were clinically indistin-
guishable from verrucous carcinoma or papillary
squamous cell carcinoma (Figs. 6 and 7).
For each of the 30 patients the biopsy specimens
with the least malignant and the most malignant
grades of PVL were selected and tabulated (Table
II). For 28 patients areas of grade 2 PVL, were found
(Fig. 8), irrespective of higher grades that were
present, but in two patients higher grades of PVL
were the least malignant disease found in the sections
examined.
290 Hansen, Olson, and Silverman Oral Surg.
September. I985

Fig. 6. Case 6. Photograph of patient at age 87. This
woman, who was 84 years of age at the time of the first
biopsy, originally had grade 2 PVL, which spreadto the
right and left buccalmucosaeand floor of the mouth. She
developedgrade 7 PVL, was treated with radiation, and
died with her disease.
Table II. Microscopic grading of pathologic findings
in thirty patients with PVL
Fig. 7. Case7. When first seen,this 70-year-oldwoman
had extensiveleukoplakiaon her tongue, palate, alveolar
mucosa,and right and left buccal mucosae,which had
beenpresent for at least 8 years. By the age of 73 this
exophytic masshad developed.Microscopic examination
revealed grade 6 PVL. The patient did not respondto
radiation and chemotherapyand developedgrade 9 PVL.
She died of local extensionof the carcinomaand of other
causesat age 77.

Least Most
malignant malignant Table Ill. Treatment modalities in thirty patients with
Grade Histologic resemblance grade grade PvL*

0 Normal oral mucosa No. of

Treatment patients
2 Homogeneous leukoplakia 28
3 I I Radiation I8
4 Verrucous hyperplasia 2 Surgery 17
5 1 Chemotherapy 6
6 Verrucous carcinoma I 3 Multiple excisional biopsies 5
7 6 Laser surgery 4
8 Papillary squamous carcinoma 12 Retinoids (vitamin A) 2
9
^
L Other 2
IO Less differentiated carcinoma 1 None 2
Totals 30 30
*Nineteen patients were treated by mire than one modality.

The most malignant grades for each of the 30
patients ranged from 3 to 10 (Table II). Two cases
were evaluated as grade 4, which resembled verru-
cous hyperplasia (Fig. ’ 9). Three cases resembled
verrucous carcinoma and were graded as grade 6
PVL (Fig. 10). One specimen appeared to be more
than grade 4 and less than grade 6. Twelve cases
were indistinguishable from well-differentiated pap-
illary squamouscell carcinoma and were graded as
grade 8 PVL (Fig. 11). In six patients the most
malignant areas appeared more severe than grade 6
and lessmalignant than grade 8 and were therefore
evaluated as grade 7 PVL. The remaining five cases
were obvious carcinomas and were graded as PVL,
grades 9 or 10 (Fig. 12).
The patients were treated by a variety of methods.
External radiation, including radium implants, and
surgery were by far the most used modalities. Nine-
teen patients received treatment by more than one
method (Table III). After consideration of the gen-
eral health and desires of the patient, multiple
excisional biopsies of the more malignant-appearing
areas were performed when the disease was so
widespread as to discourage radiation or ablative
surgery. Areas of PVL that were eliminated by
surgery, laser, and multiple biopsies recurred, usual-
ly in a matter of months. Radiation and chemother-
apy would also temporarily eliminate the PVL.
Irrespective of the type of treatment, the PVL could
not be permanently eliminated, except possibly in
three of the 30 patients.
The patients were followed for 1 to more than 20
years. Thirteen died with their PVL; 12 of these had
oral squamous carcinoma at the time of their death,
Volume (10 Proliferative verrucous leuknplakia 291
Number 3

Fig. 8. Case 12. Photomicrograph of grade 2 PVL. The lesion is a simple hyperkeratosis with little or no
dysplasia. Seven years after the first biopsy, the patient developed grade 4 PVL, followed by grade 6 at 9
years and grade 8 at 12 years. (Hematoxylin and eosin stain. Magnification, x45.)

whereas 1 died of other causes at age 93. Once a Table IV. Status of thirty patients with PVL (any
recurrence of persistent squamous carcinoma devel- grade) at last contact
oped and no longer responded to therapy, the patient .Yo. -r-
Sta1li.7 76
tended to be lost to follow-up because of transfer to
another hospital, a nursing home, a hospice, etc. .4live with PVL 13 43
Details, therefore, as to direct cause of death, num- Died with PVL 14 41
Alive without PVL 3 3
ber and type of metastases, etc. were generally
Died without PVL 0 0
unavailable. Fourteen patients were alive with PVL - .._____
(any grade) and three patients were alive without
evidence of disease when last seen. Patient 1 has been tic criteria.49-5’ This may lead the pathologist to
free of PVL 6% years following radiation and radium return a descriptive histopathologic diagnosis, mak-
implants. Patient 11 was treated surgically, but the ing patient management difficult for the clinician. A
PVL recurred. She was then treated by laser surgery review of the literature revealed that the laryngolo-
and has been free of PVL for 2 years 8 months. gist has been faced with the same problem.52-56 This
Patient 25 has had two recurrences but has been suggests that on the larynx there may be a disease
without evidence of PVL for 13 months following the similar, if not identical, to PVL.
last treatment. No patient has yet died without At the outset we found that attempts to diagnose
evidence of PVL (Table IV). our patients in the usual way (by clinical findings,
history, and incisional biopsy) led to confusion, with
DISCUSSION
subsequent overtreatment or undertreatment. A pre-
For years clinicians and pathologists have been cise diagnosis was often impossible because of clini-
faced with the problem of diagnosing and treating cal variations, stage of the disease, and inadequate
patients who have verrucous leukoplakic epithelial microscopic material, particularly with regard to
overgrowths of oral mucosa.38-40More or less specific quality and site of biopsy. Indeed, Shear and Pind-
diagnoses, such as verrucous leukoplakia,‘6* 4’, 42ver- borg43 specifically point out that the diagnosis of
rucous hyperplasia,38.43 verrucous carcinoma,38’44 oral verrucous hyperplasia must be made histologically
florid papillomatosis,45, 46or papillary squamous cell and that adequate biopsy specimens are necessary.
carcinoma,38s47 have often been impossible because of Eventually we concluded that we were dealing
vaguely defined diagnostic terminology,48-50 lack of with a spectrum of disease expression and that a
clinical information,50 inadequate biopsy materi- definitive diagnosis at the first evaluation of clinical
al 140,43,4yor overlap of clinical and histologic diagnos- and histopathologic findings was unlikely. We there-
292 Hansen, Olson, and Silverman Oral Surg.
September, 1985

Fig. 9. Case 26. Photomicrographof grade 4 PVL. There is severehyperkeratosiswith little or no

dysplasia.The lesionis exophytic, with no evidenceof invasion.At first biopsythe patient had grade7 PVL
of the labial mucosa,which wascontrolledsurgically. Shealsohad grade2 diseaseon the tongueand palate.
One year later the grade4 diseaseseenin the photomicrographdevelopedon the tongue.Twelve yearslater
grade8 diseasedevelopedon the tongue;this respondedpoorly to surgeryand radiation, and the patient died
with her cancer. (Hematoxylin and eosinstain. Magnification, X45.)

fore began to make tentative diagnoses using the
term proliferative verrucous leukoplakia (PVL)-
leukoplakia because our cases seemed to originate in
flat, white keratotic patches, histologically simple
hyperkeratoses without dysplasia; verrucous because
in all cases, over a period of time, warty, verrucal,
exophytic, keratotic lesions developed within areas of
the leukoplakia; proliferative because in all of our
patients the disease, although slow-growing, was
persistent and progressive and in most cases became
diffuse or multifocal. We visualized PVL as a contin-
uum of disease ranging from a simple hyperkeratosis
at one end to an invasive squamous cell carcinoma
fully capable of local and distant metastases at the
other. The continuum, diagrammatically illustrated
in Fig. 1, provides for relatively innocuous lesions on
the left, with progressively more severe lesions on the
right, ending in poorly differentiated, invasive squa-
mous cell carcinoma. The concept provides that a
patient’s lesion may initially be graded at any point
on the continuum, remain there for an indefinite
period, or progress slowly or rapidly to a more serious
lesion on the right. It has been our experience that
lesions of PVL rarely, if ever, regress (revert from a
more serious lesion on the right to a less grave lesion
on the left).
It was then clear to us that although some patients
might be accorded a definitive diagnosis early on,
many could not, and the diagnosis could change
along the continuum according to clinical behavior,
additional histopathologic findings, and response to
therapy.
The concept of a continuum of PVL enables
clinicians and pathologists to understand why there
has been controversy as to the diagnosis and treat-
ment of verrucous hyperplasia, verrucous carcinoma,
squamous cell carcinoma, etc. Many of us failed to
recognize that in some cases we are not dealing with
separate and distinct clinicopathologic entities but,
rather, one pathologic disease process with a contin-
uous spectrum of clinical and histopathologic expres-
sion. The concept has the distinct advantage, if
mutually understood by both the clinician and the
pathologist, of allowing diagnosis (place on the
continuum) of a disease process that cannot be
precisely diagnosed in the conventional manner. It
also permits placement of the diagnosis between the
recognized clinicopathologic entities when neces-
sary.
Differential diagnosis
In the following paragraphs we emphasize our
differential diagnostic criteria, because of the serious
prognosis of PVL and the similarity to other kera-
toses, both benign and malignant.
Leukoplakia. Leukoplakia (leukoplakia simplex,
homogeneous leukoplakia) is a uniformly whitish
hyperkeratosis with a smooth or corrugated surface.
Volume 60 Proliferative verrucous leukopiakia 293
Number !

Fig. 10. Case 15.Photomicrographof grade 6 PVL. Histologically, in addition to the exophytic growth,
there is invasionof the lamina propria and deepstructureswith broad, blunt fingersof well-differentiated
squamousepitheliumthat hasan intact basementmembrane.Dysplasia,if present,is minimal. The disease
was controlled temporarily with surgery, but grade 8 diseasedeveloped.The patient was again treated
surgically, and 5 yearsafter the first biopsyhe isalive with persistentdisease.(Hematoxylin and eosinstain.
Magnification, ~37.)

In a solitary lesion without dysplasia, differentia-
tion of PVL is not possible until the characteristic
history and clinical findings of PVL develop in the
patient.
We have noted that in disease at the left end of the
PVL continuum, epithelial dysplasia was character-
istically either absent or mild. Should a lesion on first
appearance be classified as leukoplakia with severe
dysplasia, it would be expected that the patient has a
carcinoma in situ rather than PVL, and the lesion
would be expected to progress rapidly to a well- or
less well-differentiated squamous cell carcinoma that
may or may not be papillary in nature.
Erythroleukoplakia and nodular leukoplakia.
Also called erosive or speckled leukoplakia, these are
varieties of leukoplakia that include red areas. These
lesions are likely to exhibit dysplasia and may lack
the long history and white keratoses without signifi-
cant dysplasia seen in PVL.
Verrucous leukoplakia. Verrucous leukoplakia
has been described as an exophytic lesion with
irregular sharp or blunt projections.42~57 It may be
identical to a stage of what we are calling prolifera-
tive verrucous leukoplakia, except that the lesion
may not be preceded by the slow-growing diffuse or
multifocal keratoses and other characteristics of
PVL.
Verrucous hyperplasia. Verrucous hyperplasia,
first described by Shear and Pindborg43 in 1980, may
resemble verrucous carcinoma both clinically and
histologically and, indeed, over a period of time
becomes verrucous carcinoma or even invasive squa-
mous cell carcinoma. Shear and Pindborg regard
verrucous hyperplasia as a distinct clinicopathologic
entity, whereas Batsakis and associatess2 regard it as
merely an early stage of verrucous carcinoma. We
agree with the idea of using the term verrucous
hyperplasia as a descriptive diagnosis but not as a
separate clinicopathologic entity, as we have seen
what has been described as verrucous hyperplasia in
patients with verrucous carcinoma as well as in oral
florid papillomatosis. Moreover, often faced with
sparse biopsy material, we usually have been unable
to distinguish between the two according to the
criteria advanced by Shear and Pindborg. In addi-
tion, they point out that verrucous hyperplasia and
verrucous carcinoma may be clinically indistinguish-
able and may even occur concurrently. The term
verrucous hyperplasia may well be useful for
describing certain epithelial proliferations micro-
scopically, but as a clinical diagnosis it may be
misleading to the clinician. We cannot microscopi-
cally distinguish grade 4 PVL from what has been
described as verrucous hyperplasia.
Verrucous carcinoma. Many authors44~4Y,58-62 con-
sider verrucous carcinoma as an entity distinct from
the more common squamous cell carcinoma of the
oral cavity. We agree that some patient.s have a
294 Hansen, Olson, and Silverman Oral Surg.
September, 1985

Fig. 11. Case 29. Photomicrographof grade 8 PVL. Here the fingers of invasive epithelium become
narrower and lesswell differentiated, and the basementmembranebecomeslessdistinct. Adjacent mucosa
exhibited diseaseof grades2 to 6. The patient wastreated surgically, but grade 8 PVL recurred. She was
then treated by ablative surgery,followed by radiation. There is nowno evidenceof carcinoma,but the PVL
hasrecurred. (Hematoxylin and eosinstain. Magnification, X25.)

limited disease that behaves in the classically
described manner of verrucous carcinoma, but some
cases may be clinically indistinguishable from some
verrucal epidermoid carcinomas (papillary squa-
mous carcinomas) and may even occur concurrent-
ly*
49.50
Medina and associates,63 in a review of 104 cases
of verrucous carcinoma, found foci of conventional
squamous cell carcinoma in 20 patients. They con-
cluded that any verrucous carcinoma should be
extensively sampled for microscopic evaluation of
conventional squamous cell carcinoma. Arendorf and
Aldred3* came to the same conclusion. In some cases
we, too, encountered difficulty in histologically dif-
ferentiating between grade 6 PVL (verrucous carci-
noma) and grade 8 PVL (well-differentiated squa-
mous cell carcinoma) and therefore assigned the
intermediate grade of 7 (Table II).
We reserve the diagnosis of verrucous carcinoma
for solitary lesions, especially when they can be
associated with the use of tobacco. We use grade 6
PVL when the lesion has been accompanied by a
history and the diffuse and/or multifocal lesions of
PVL. We think this is an important distinction to
therapists, because verrucous carcinomas have some-
what definitive margins and have been treated suc-
cessfully by surgery and/or radiation, whereas we
have yet to find satisfactory treatment for PVL.
Squamous cell carcinoma. Histologically grades 8
to 10 of PVL were identical to well-differentiated
and less-differentiated squamous cell carcinomas
and behaved as such in regard to local invasion and
metastasis. As in the lesser grades of PVL, they
exhibited the history and clinical findings of PVL.
Oral florid papillomatosis. The term oral florid
papillomatosis has caused considerable confusion
since its introduction. Our review of the first six cases
to be reported, 56,64-68
all in the dermatology literature,
revealed many differences from patient to patient.
One lesion was solitary whereas the others were
multiple; some exhibited dysplasia; and some showed
various degrees of orthokeratosis and parakeratosis.
Some in time “transformed” from verrucous hyper-
plasia to squamous cell carcinoma. Retrospectively,
at least some of these cases could well have been
PVL, while others might well have been verrucous
carcinomas or well-differentiated squamous cell car-
cinomas. We agree with Takagi and Ishikawa69 that
some of the reported cases of oral florid papillomato
sis should be separated from verrucous carcinoma.
On the other hand, Grinspan and Abulafia70 con-
cluded that oral florid papillomatosis is a form of
verrucous carcinoma and therefore offered no sug-
gestion as to differentiation. Gaillard and co-work-
ers46recently reported their clinical and microscopic
findings in 10 cases of oral florid papillomatosis,
most of which appeared to be what we are describing
as PVL. Use of the term persists,4S-47and there may
Volume 60 Proliferative verrucous leukoplakia 295
Number ;

Fig. 12. Case 28. Photomicrograph of grade 9 PVL. Note the moderately differentiated squamous
carcinoma cells invading muscle of the tongue. When first seen, this 87-year-old woman had a diffuse
leukoplakia of the right and left sides of the tongue. Biopsy revealed grade 2 PVL. Three years Iater she
developed grade 9 PVL. She was treated by radiation and the tumor disappeared. However, 4 months after
treatment the leukoplakia recurred. (Hematoxylin and eosin stain. Magnification, ~25.)

indeed be an entity that deserves such a designation,
such as Eversole’s and Sorenson’s” original case of
florid papillomatosis. Their case, involving all muco-
sal surfaces in a 13-year-old boy, is unique but does
not fit our criteria for PVL. Even the young age of
their patient suggests to us a different pathologic
process, an observation also made by others.‘O
We have on rare occasions seen cases for which we
think the diagnosis of oral florid papillomatosis
would be appropriate. These patients have wide-
spread papillomatous lesions that are essentially
nonkeratinizing, without significant dysplasia and
the antecedent leukoplakia characteristic of PVL.
Takagi and Ishikawa69 describe one case that might
fit this category. They preferred to designate it as
recurring oral papillomatosis. We would agree with
those who think verrucous hyperplasia, verrucous
carcinoma, and oral florid papillomatosis may be
different expressions of the same disease. PVL is
certainly closely related to this group and can be
distinguished only by the history, clinical findings,
and multiple biopsies.
Keratoacanthoma. The keratoacanthoma is a rela-
tively common, benign, infiltrating, self-limiting,
localized growth of squamous epithelium, usually
arising on skin exposed to actinic radiation. Rook
and Champion,‘* in their detailed study of kerato-
acanthoma, concluded that it is not found on
mucous membranes but may occur on mucocutane-
ous sites, such as the lip, and arises most probably
from the pilosebaceous apparatus. Nonetheless, nine
cases have been reported to occur on oral mucous
membranes.73-7’ Since the origin of keratoacanthoma
has not been unequivocally established, the possibili-
ty of surface epithelial origin remains. Our review of
published cases suggests that at least some of the
nine oral mucosal cases might well have been kera-
toacanthomas.” Some of these would have to be
differentiated from PVL since mucosal keratoacan-
thoma and PVL could be confused because of very
similar clinical and histopathologic findings, espe-
cially in the early stages.
Other papillary lesions. Just as only a few simple
hyperkeratoses (grade 2 on the spectrum) progress as
proliferative verrucous leukoplakia, only a few papil-
lary lesions of oral mucous membrane can be
regarded as PVL. The common squamous papilloma
and the clinically similar virus-induced lesions, such
as verruca vulgaris, molluscum contagiosum, and
condyloma acuminatum,47, b9,76 plus other localized
papillary or verrucoid, pedunculated or sessile epi-
thelial proliferations, do not follow the clinical course
of PVL. The diagnostic problem arises when the
pathologist receives inadequate tissue or clinical
information on papillary lesions3’ When one is
dealing with very early and superficial lesions, it may
not be possible to differentiate histologically between
PVL and these other papillary lesions.
296 Hansen, Olson, and Silverman
In addition to the focal or solitary papillary
lesions, diffuse and multifocal papillary lesions that
occur on the oral mucosa may also be confused with
PVL. One common benign condition is papillary
inflammatory hyperplasia. This condition, usually
seen on the hard palate under ill-fitting dentures,
should rarely, if ever, be confused with PVL if
adequate tissue and a history are available to the
pathologist.
Treatment
In view of the reported approximately 6% rate of
malignant transformation,5x 20-26it would seem advis-
able to eliminate all leukoplakias surgically. Since
some patients have diffuse or multifocal keratoses,
however, surgical removal is not a practical means to
prevent development of more serious disease. These
patients may be followed for years without signifi-
cant alterations in their hyperkeratoses. However, in
those patients in whom PVL develops aggressive
therapy should be undertaken quickly.
Since in many of our patients lesions indistinguish-
able from carcinoma developed in the course of PVL
(Table II), we believe that it is the natural history of
PVL for areas to become malignant unless adequate
treatment is somehow instituted early and the pa-
tient followed carefully and treated for expected re-
currence or development of additional lesions. Man-
agement of patients with widespread and multifocal
lesions requires frequent multiple biopsies to detect
areas where higher grades of PVL are developing.
Although our patients underwent a variety of
therapeutic measures (Table III), no treatment was
able to control the disease for long. Twenty-eight of
our patients received some type of treatment, and all
but Patient 1 had at least one recurrence. Three of
our 30 patients are currently without evidence of
disease, but they are not regarded as cured over the
long term. Patient 1 may be an exception. Since this
young man does not fit the PVL profile, it is possible
that his disease, although indistinguishable from
PVL, may actually be something different. Gaillard
and co-workers,46 in treating a series of 10 patients,
some of whom exhibited disease similar if not identi-
cal to PVL, concluded that radiation therapy should
be formally excluded and that the treatment of
choice is wide surgical excision followed by recon-
structive surgery whenever possible. We agree that in
a widespread disease such as PVL radiation therapy
has not been entirely satisfactory.
Prognosis
Perhaps PVL can be controlled in some patients,
but the prognosis is nonetheless poor because recru-
Oral Surg.
September, 1985
descence is likely. The prognosis is especially poor in
widespread disease because of the inability to treat
all of the involved and potentially affected mucosa
satisfactorily.
The slow growth, innocuous microscopic findings,
and lack of painful symptoms in the early lesions
may lead to insufficiently aggressive treatment.
Complications due to the advanced age of these
patients can also contribute to difficulty in control.
Etiology
Although numerous etiologic factors have been
implicated in the development of oral keratoses, such
as tobacco, candidiasis, and chronic irritation associ-
ated with dental restorations and cheek-biting, the
cause remains obscure in many cases.
More than half of our patients used tobacco
and/or developed candidiasis. The latter, when asso-
ciated with leukoplakia, is thought by some to be an
etiologic factor. K ‘l, ” The use of tobacco may be a
contributing factor in some patients with PVL.
Nonetheless, many of our patients had never used
tobacco or were free of candidiasis. Therefore, the
origin of PVL remains obscure or idiopathic.
Since sideropenic dysphagia has on occasion been
associated with widespread leukoplakia, as seen in
our cases,~3’~ we reviewed our records of 13 women
and 5 men without finding any association.
It has been suggested that a human papillomavirus
may be involved in PVL. We agree that this may be a
productive approach in future etiologic investiga-
tions.79,80Therefore, we are initiating research on our
material with the use of immunohistochemical tech-
niques.
CONCLUSIONS
In 28 of the 30 patients in this study, the least
malignant diagnosis was grade 2 PVL, a simple
hyperkeratosis, sometimes found concurrently with
an exophytic papillary lesion. In these patients it was
assumed that papillary lesions had arisen or would
eventually arise from simple hyperkeratoses.
When first seen 2 of the 30 patients had already
developed verrucous lesions, but we were unable to
demonstrate by biopsy a previous leukoplakia. How-
ever, because of the subsequent clinical progression
of the disease, it was assumed that their lesions had
arisen from a pre-existing grade 2 keratosis,
although we could not determine the length of time
over which such development took place. We con-
cluded, therefore, that in all 30 cases eventually
diagnosed as PVL, it was likely that the initial lesion
was a simple hyperkeratosis.
Although we believe that all PVL originates in
Volume 6(, Proliferative verrucous leukodakia 297
Number 3

homogeneous leukoplakia, we know that all clinical tissues. Parts I and II. ORAL SLRG OK,\B. bIti> :)IC,I P~TIIOI 5:
762-78 I, 884-994, 1952.
leukoplakias do not result in PVL. Also, we believe IO .4tkinson L, Chester IC, Smyth FG. ten S&lam REJ: Oral
that PVL will very likely develop areas of verrucous cancer in New Guinea: a studs in demogray’;! :!nd c:tiologv.
hyperplasia and carcinoma if the patient is untreated Cancer 17: 1289-1298, 1964. ’
1I Pindborp JJ, Chawla TN. Misra RK, hagl“~ul Rk. C;upta
and lives long enough, but by no means do we believe VK: Frequency of oral carcinoma, Icukoplakla. lcukokerato-
that all verrucous hyperplasia, verrucous carcinoma, sis. leukoedema. submucous fibrosis. and l:hen planuh in
and squamous cell carcinomas are a part of the PVL 10.000 Indians in Lucknow, Uttar Pr,rdckh India: prelim-
nary report. J Dent Res 44: 615, 1965
spectrum. I2 Pindborg JJ, Barmes D, Roed-Petersen H: I<pldcmiology and
For example, a snuff dipper who holds tobacco in a histoloev of oral leukoolakia among l’ap:ia;~\ and \e~
specific area may eventually develop verrucous Guine&s. Cancer 22: 37$-384. 196X.
I3 Mehta FS, Pindborg JJ, Gupta PC. Daftar\ Dh. E.pidcmlo-
hyperplasia, verrucous carcinoma, or even an inva- logic and histologic study of oral cancer .ind leukoplakia
sive squamous cell carcinoma. We do not think it among 50,915 villagers in India. Cancer 21: %3?-84Y. lYh9
likely that this patient has the same lesion as a 14. Gangadharan P. Paymaster JC: Leukaplaki:! tin epidemio-
logic study of 1,504 cases observed a~ the r3~;i Memorial
nonsmoker with PVL, even though there may be Hospital, Bombay, India. Br J Cancer 25: (1’~?-6hl(, I97 I.
areas that are histologically identical. It is possible 15. Axtll T: A preliminary report on prevalence\ 01 oral mucosal
that the snuff dipper might be cured of the disease by lesions in a Swedish population. Cnmmo~ II\ Dent Or:ti
Epidemiol 3: 143-145. 1975
early and ablative therapy and abstinence from BBn6czy J, Sugiir L: Longitudinal studic, II? c.r:!I lcuhoplaki;~.
16.
tobacco, but the prognosis is still poor for the patient J Oral Path01 1: 265-272, 1972.
with PVL. 17. Pogrel MA: Sublingual keratosis and malipn:!nr transform-
tion. J Oral Pathol 8: 176-I 78, 1970.
Since simple hyperkeratoses can eventuate into 18. Waldron CA. Shafer WG: Leukoplakia rc\ xircd: ;I climco-
lesions other than PVL, our material was reviewed pathologic stud) of 326 oral Icukoplal,! \ (‘anccr 36:
for some histologic finding that might lead the l386- 13Y2. 1975.
19. L(ining T, Burkhardt A: Dyskeratosih in hu:rlan and cxperr-
observer to predict eventual transformation to PVL mental oral precancer and cancer: an ImmuiiohIstochcmic;rl
or to some other oral disease, or even no change at and ultrastructural study in men. mice :Ind r;~ii. i\rch Oral
all. We concluded that we could not predict, on Biol 27: 361-366, 19X2.
20. Pindborg JJ, Renstrup G, JQlst 0. Roe&Pclcrsen B: Studies
histologic grounds, those relatively few clinical kera- in oral leukoplakia: a preliminar) report an the period
toses that would develop into PVL. prevalence of malignant transformation in icukoplakia based
on a follow-up stud) of 248 patient\. J ,2m Dent Assoc 76:
The authors thank Mr. Ron Walters for the diagram, 767-771. 1968.
Ms. Evangeline Leash for editorial assistance, and Ms. 21 Silverman S Jr, Rozen RD: Observatlunh on the clinical
Teresita Arenas for processing the manuscript. characteristics and natural history of oral is*~koplnkl;l. J <\\I,,
Dent Assoc 76: 772-777, 196X.
22. Roed-Petersen B: Cancer development in OIU/ ieukoplaki,l:
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