CASE REPORTS

J Oral Maxillofac Surg

61:626-631, 2003

Proliferative Verrucous Leukoplakia:

Report of a Case With Characteristic
Long-Term Progression
Craig E. Vigliante, DMD, MD,* Peter D. Quinn, DMD, MD,
and Faizan Alawi, DDS
There have been documented case series and reports
over the past 2 decades of a distinctive form of oral
leukoplakia. In 1985, Hansen et al1 coined the term
proliferative verrucous leukoplakia (PVL) after a
long-term study of 30 patients with this disease. The
condition arises as clinical foci of hyperkeratosis that
progressively spread and become multifocal. The lesions
eventually assume an exophytic, verrucous appearance
and are extremely resistant to treatment. Ultimately,
many progress to invasive cancer, and 30% or more of
patients with PVL die of this disease.2 Many potential
etiologies have been hypothesized, but little has been
proved about the origins of this disease process.
PVL is a very aggressive form of oral leukoplakia
with high morbidity and mortality rates due to its
strong potential for malignant transformation. Oral
leukoplakia is not uncommon. In dysplastic oral leukoplakias, the malignant transformation rate is approximately 5% over an average period of 5 years.3
The PVL form of oral leukoplakia specifically is characterized by a malignant transformation rate as high as
86.7% in some studies.1 The approach to treatment
and follow-up for multifocal oral leukoplakias pose a
challenge, because the aggressive and benign forms
can appear histopathologically indistinguishable depending on when the biopsy samples are taken during
the course of the disease. Among the complications
encountered during follow-up of PVL is the potential

for late progression to malignancy (ie, after a decade

or longer).
The following report describes the diagnosis,
course, and management of a case of PVL with multiple recurrences that were unresponsive to surgical
and medical therapy over a 15-year period and eventually led to the patients death.

Report of a Case
A 65-year-old woman with a long history of oral leukoplakia dating back to 1981 presented to the Department of
Oral and Maxillofacial Surgery in August 1988 with a
roughening of the white lesions in her mouth. At initial
presentation in 1981, she had had biopsies of the right
maxillary gingiva that revealed hyperkeratosis without dysplasia. There was no further treatment at that time.
The patients past medical history was significant for congenital hearing loss, hypertension controlled with clonidine,
and 2 natural childbirths. Her past surgical history consisted of
a dilatation and curettage in 1980. She had a documented allergy to penicillin. The patient denied any family history of oral
lesions. Notably, she had no history of tobacco or alcohol use.
On physical examination, there were asymptomatic, thick,
white spongy keratoses of the right maxillary gingiva and
contiguous buccal mucosa (Fig 1). The examination was negative for erythroplakia and ulceration. She denied dysphagia
and dysphonia. There was trismus with maximal incisal opening of 20 mm. There was no palpable cervical lymphadenopathy. A panoramic jaw radiograph failed to reveal any osseous
abnormalities. The clinical diagnosis was PVL.
In August 1988, the patient underwent surgical stripping
of the extensive leukoplakic lesion followed by placement
of a split-thickness skin graft in an attempt to avoid postsurgical trismus. On microscopic examination of the surgical specimen, a diagnosis of mild epithelial dysplasia with
marked hyperorthokeratosis was reported (Fig 2). Three
months later, the hyperkeratotic lesions returned at all surgical sites, including the periphery of the skin graft along
the hard palate (Fig 3). There was no clinical evidence of
recurrence noted within the skin graft itself. The lesions
failed to resolve after attempts at treatment with retinoic
acid and beta-carotene.
Carbon dioxide laser ablation was performed in March
1989. This procedure involved removal of the lesions from
the right maxillary labiobuccal and palatal gingiva down to
the periosteum (Fig 4). Multiple punch biopsy specimens
before laser treatment revealed histologic changes ranging

*Chief Resident, Department of Oral and Maxillofacial Surgery,

University of Pennsylvania, Philadelphia, PA.
Professor and Chairman, Department of Oral and Maxillofacial
Surgery, University of Pennsylvania, Philadelphia, PA.
Assistant Professor, Department of Oral and Maxillofacial Pathology, University of Pennsylvania, Philadelphia, PA.
Address correspondence and reprint requests to Dr Quinn: Department of Oral and Maxillofacial Surgery, The University of Pennsylvania, 5th Floor, White Building, 3400 Spruce St, Philadelphia,
PA 19104; e-mail: peter.quinn@uphs.upenn.edu
2003 American Association of Oral and Maxillofacial Surgeons

0278-2391/03/6105-0015$30.00/0
doi:10.1053/joms.2003.50119

626

FIGURE 1. Initial presentation of extensive verrucous leukoplakia

covering the right anterior and posterior maxillary gingiva and right
buccal mucosa extending posteriorly behind last molar tooth.

FIGURE 3. Recurrence of the lesions at the periphery of the skin graft

sparing the skin graft itself.

FIGURE 4. Postoperative photograph showing extensive carbon dioxide laser ablation of recurrent lesions.

FIGURE 2. Mild verruciform epithelial dysplasia with marked hyperorthokeratosis (hematoxylin and eosin stain, original magnification
!100).

FIGURE 5. Third attempt to surgically treat the recurrent lesions. A skin

graft was performed in the right buccal mucosa to help alleviate
scarring contracture from previous operations.

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PROLIFERATIVE VERRUCOUS LEUKOPLAKIA

FIGURE 7. Multisite recurrent lesions in the right posterior buccal

ridge with transformation to squamous cell carcinoma.

FIGURE 8. Well-differentiated island of squamous cell carcinoma.

Epithelial cells show nuclear pleomorphism, prominent nucleoli, and
mitoses (hematoxylin and eosin stain, original magnification !400).

FIGURE 6. A and B, Fourth recurrence in the right maxillary gingiva

with resulting right partial maxillectomy. C, Eighteen months later
showing recurrence in the region of the previous partial maxillectomy
with erythroplakia and leukoplakia.

from hyperplasia with hyperkeratosis to mild epithelial dysplasia with hyperparakeratosis. In situ hybridization for human papilloma virus (HPV) subtypes 6, 11, 31, 33, and 35
was negative. Due to technical difficulty at the time, HPV
subtypes 16 and 18 were not assessed. By November 1989,
recurrence of the lesions and concomitant scarring with
contracture in the region of the skin graft prompted a
second attempt to surgically excise and skin graft the region
on the right buccal mucosa (Fig 5). A biopsy revealed mild
epithelial dysplasia with marked hyperkeratosis.
In 1990, the leukoplakic lesion recurred. A biopsy from
the anterior maxilla revealed epithelial dysplasia with

marked hyperkeratosis. In the superficial epithelium, cells

with viral-like alterations were observed. Physical examination at this time showed leukoplakic changes surrounding
the margins of the skin graft involving the right anterior
buccal mucosa, right upper lip, and right upper gingival
mucosa in the area of the incisors. The patient had a significant amount of trismus at this time; the remainder of the
oral cavity and oropharynx appeared to be uninvolved.
Fiberoptic examination of the nasopharynx, hypopharynx,
and larynx revealed no apparent disease involvement. There
was no regional lymphadenopathy. Topical chemotherapy
was initiated. One percent topical bleomycin was applied
every day for 15 days without success. From 1990 through
1991, the patient received 4 cycles of 5-fluorouracil with
leucovorin rescue, which resulted in 80% regression of the
mucosal lesions. This therapeutic regimen was discontinued in
August 1991, and the disease returned within 1 month.
The patient presented with a mass in the right anterior
maxillary gingiva in January 1992 (Fig 6A). At this time,
extraction of multiple nonrestorable teeth and a partial right
maxillectomy (Fig 6B) with a skin graft was performed. An
otorhinolaryngologist also carried out a panendoscopic examination that showed only normal mucosa. The oral surgical specimen revealed a superficial infiltrating well-differ-

VIGLIANTE, QUINN, AND ALAWI

entiated squamous cell carcinoma (SCC) with regions of
verrucous hyperplasia (VH) with mild epithelial dysplasia.
During the next year, the patient was followed closely,
and the leukoplakia returned at the margins of the skin
graft. At the recommendation of the medical oncologists,
the patient began treatment with etretinate (Tegison; Roche
Labs, Nutley, NJ), a retinoid, in November 1992. By March
1993, the oral lesions were markedly improved. Due to
intolerance of the drugs side effects, the patient was
weaned off Tegison in January 1994. She subsequently developed erythroplakia with leukoplakia in the right anterior
maxillary gingiva (Fig 6C) and leukoplakia of the right mandibular gingiva in June 1994. An incisional biopsy revealed
verrucous carcinoma.
In July 1994, she underwent a right anterior partial maxillectomy, surgical stripping of leukoplakic tissues in the
right mandible, and extraction of multiple nonrestorable
teeth. In the specimen from the maxilla, the diagnosis was
VH with superficial infiltrating SCC arising from verrucous
carcinoma. The lesions from the marginal mandibular gingiva were consistent with well-differentiated microinvasive
SCC arising in verrucous carcinoma.
In November 1994, 4 months later, the patient noticed a
mass in the right mandible (Fig 7). The patients physical
examination at this time was significant for trismus (20-mm
opening) with no palpable lymphadenopathy. The review
of systems was notable for an 11-lb weight loss. A computed
tomography scan showed a 1.7- ! 2.0- ! 1.5-cm soft tissue
mass along the superior aspect of the body of the right
mandible with bony erosion involving the superior mandibular cortex. Submandibular lymph nodes measuring 1.5 cm
were also seen. The patient was brought to the operating
room for a partial mandibulectomy with preservation of the
inferior cortex and placement of a reconstruction plate.
Microscopic evaluation revealed invasive well-differentiated
SCC measuring 2.9 cm in the greatest dimension (Fig 8).
There was invasion into the mandibular bone to within 1
mm of the deep surgical margin. The disease was designated as a stage IV (T4 Nx Mx) SCC of the right mandible.
Given the extensive nature of the disease and poor prognosis, the patient refused any further radical surgery at this
time. A medical oncologic treatment plan was instituted
primarily for palliation. A gastric tube was placed to allow
for adequate nutrition during the course of subsequent
radiation and chemotherapy.
The patient was seen again in June 1995 after 6 weeks of
chemotherapy and radiation. She had received a total of
7,200 Gy and concomitant chemotherapy with cisplatin.
Physical examination revealed radiation changes and recurrence of the lesion on the palate and anterior mandibular
alveolar ridge and right buccal mucosa in the region of the
split thickness skin graft. A biopsy 1 month after completion
of chemotherapy revealed superficially infiltrating, moderately differentiated SCC. Combined radiation and chemotherapy had apparently failed to control the disease. No
further treatment was performed at this time. After receiving hospice care, the patient was lost to further follow-up.

Discussion
Proliferative verrucous leukoplakia is a very highrisk precancerous lesion with a high mortality rate.4
This case study is a typical example of the clinical
behavior of PVL. Our patients clinical course mirrored the progression of the disease in most of the 30

629
patients studied by Hansen et al in 1985.1 In many PVL
patients, the initial oral finding is a solitary homogeneous leukoplakic lesion that, under the microscope,
can exhibit hyperkeratosis and epithelial hyperplasia
with or without evidence of epithelial dysplasia. The
clinical lesion tends to recur and proliferate, often
over a protracted period of time, to result in a diffuse,
widespread exophytic lesion, with or without an erythematous component. As seen in this case, the
lesions are slow growing, but persistent, progressive,
relentless, and irreversible. The microscopic appearance of the lesions parallels the clinical appearance.
During the course of disease, varying degrees of epithelial dysplasia, VH with or without dysplasia, verrucous carcinoma, and, ultimately, SCC are shown. Unlike other forms of leukoplakia, PVL exhibits a strong
female predilection, with a female-to-male ratio of
approximately 4:1. Although approximately 5% of all
dysplastic leukoplakias transform to cancer over an
average period of 5 years, PVL has an almost 100%
rate of malignant transformation,3 but this can occur
over an extended follow-up period of 5 to 20 years.4
Both the initial clinical presentation and the early
biopsy findings of PVL can lull the clinician into a false
sense of comfort. However, over a protracted period of
time, there is frequently widespread disease and progression to carcinoma. The typical PVL patient is a
woman in her 60s who has had repeated biopsies for
leukoplakia over a long span of time. In the original
report in which PVL was introduced as a clinical entity,
Hansen et al1 suggested histologic stages in the continuum of PVL (normal hyperkeratosis without dysplasia3
VH3verrucous carcinoma3papillary SCC3less-differentiated squamous carcinoma with intermediate subtypes). PVL lesions can exhibit any combination of these
histologic stages during their progressive clinical
course.3 Batsakis et al3 reduced the number of histologic
stages to 4 with intermediates: hyperkeratosis without
dysplasia, VH, verrucous carcinoma, and conventional
SCC. They omitted papillary SCC, stating that the oropharynx, not the oral cavity, is the usual site of that
disease.3 They discuss how PVL and VH are 2 interrelated oral mucosal lesions. Each has shown to have a
considerable propensity to progress to malignancy
either verrucous carcinoma or conventional SCC with
varying degrees of differentiation.3 PVL has no single
defining histopathologic feature. Therefore, PVL should
be used only as a clinical description and not as a
definitive diagnosis.3 The diagnosis of VH can only be
established through microscopic analysis.5 Although VH
can be a histologic component in the evolutionary spectrum of PVL, it is not exclusive to PVL, nor indeed is VH
confined to the oral cavity.6 Because the microscopic
interpretation of PVL lesions is complex and challenging, diagnostic accuracy is best achieved through consultation by an oral and maxillofacial pathologist.

630
Twelve years after the initial description of PVL,
Silverman and Gorsky4 reported a prospective follow-up study on 54 patients with PVL. The mean
follow-up time was 11.6 years after initial biopsy.
These investigators findings essentially confirmed the
findings of Hansen et al.1 The average age at diagnosis
was 62 years, and women outnumbered men 4:1.
Multiple intraoral sites were involved, but the most
common were buccal mucosa in women and tongue
in men. After a mean time of 7.7 years, 70.3% of the
patients developed SCC at a site of PVL, most often
the gingiva and tongue. PVL-associated carcinoma resulted in the death of 21 patients (39%).4
The etiology of PVL still remains elusive. Smoking and
the presence of Candida are no longer thought to have
any influence on the occurrence and progression of
PVL. Our patient was not a smoker. According to Silverman and Gorsky,4 there was no apparent association
with smoking, as 69% of their patients had never used
tobacco in any form. In comparing smokers and nonsmokers, cancer transformation rates in PVL were identical (70%). In their 1997 study, Silverman and Gorsky
also evaluated the presence of Candida colonization on
the biopsy specimens. There was no clear association
between the presence or absence of Candida and the
potential to develop carcinoma.4
The role of human papillomavirus (HPV) remains
speculative regarding the significance of its presence
and possible regulatory influence on PVL occurrence
and progression.4 In contrast to the consistent association between cervical cancer and HPV, findings
from studies of HPV and oral SCC have varied widely,
with frequencies of HPV presence ranging from 0% to
78%.2 Using polymerase chain reaction, Palefsky et al2
published the first study characterizing HPV infection
in PVL. They found HPV DNA in 8 of the 9 lesions
studied, and 7 were positive for HPV subtype 16.
These data suggested that HPV 16 infection might
play a role in the pathogenesis of PVL-associated oral
dysplasia and cancer.2 Gopalakrishnan et al7 looked at
p53 expression and HPV integration in PVL and oral
SCC. In contrast to Palefsky et al, they concluded that
p53 gene mutations and HPV infections do not provide a means to differentiate between leukoplakia and
carcinoma and do not provide a predictive test for
progression of leukoplakia to carcinoma.7 Further
studies will be necessary to clarify the role, if any, of
HPV and genetic mutations in the etiology of PVL.
In an attempt to aid in the early diagnosis of PVL
versus other forms of leukoplakia, Kannan et al8 studied the role of transforming growth factor-! (TGF-!)
overexpression. They found that increased TGF-! immunoreactivity occurs relatively early in PVL and persists as the disease progresses. They concluded that
prospective studies to define the role, if any, of TGF-!
in the transformation of PVL to SCC are necessary.

PROLIFERATIVE VERRUCOUS LEUKOPLAKIA

Fettig et al9 recently described a subset of PVL

called proliferative verrucous leukoplakia of the gingiva (PVLG). The initial lesions in these patients were
white keratotic plaques or papillary/verruciform lesions, with benign microscopic features. The anatomic distribution was limited to the gingiva, especially in the anterior regions. There are apparently no
clinical distinguishing features that can be used to
separate PVLG from other gingival leukoplakias;
therefore, it is incumbent on the clinician to obtain a
biopsy and to follow the lesion indefinitely.9 Currently, there is no way to predict which gingival white
lesions will follow the relentless clinical path described for PVLGs. When bland microscopic findings
are correlated with what appears to be aggressive
clinical behavior, PVLG should be strongly considered, and the patient closely followed accordingly.9
Attempts at conservative treatments for management
of PVL have met with limited success. PVL has a high
recurrence rate and is typically resistant to all treatment
modalities, including surgery, radiation, chemotherapy,
and laser excision.7 Carbon dioxide laser ablation was
used on our patient with only marginal results, as her
lesions recurred. Radiotherapy for oral leukoplakias has
been widely studied with mixed results. Controversy
surrounds this treatment method because of early reports that suggest proclivity for anaplastic transformation after irradiation.10 Topical applications of bleomycin 0.5% or 1.0% solution have shown promise in the
treatment of oral leukoplakias.11 However, our patient
did not show any improvement with this therapy. Although clinical trials have shown the efficacy of retinoids
and beta-carotene in reversing oral leukoplakia,12,13 success was only temporary in our patients case. In other
reports, these modalities produced similarly disappointing results: PVL appears to resist all forms of therapy.14
Zakrzewska et al15 addressed the possible role of
photodynamic therapy. With this modality, multiple
mucosal sites can be treated simultaneously with relatively low morbidity and no residual scarring. Evaluation of this approach to treatment needs to be further explored. The only treatments that resulted in
any type of regression of our patients leukoplakia
involved 5-fluorouracil and Tegison. Unfortunately,
her improvement was only temporary because the
side effects of the regimens were intolerable.
In patients in whom PVL is suspected, aggressive
surgical resection is the current treatment of choice.
However, patients must be forewarned of the strong
likelihood of recurrence. Due to its multifocal presentation, several biopsies are required to rule out the
presence of a SCC. In the PVLG study,9 local block
resections were required to prevent recurrences. The
block resections were done with removal of teeth
adjacent to the gingival disease process. This was the
only documented curative procedure. Because PVL

631
lesions have a high rate of malignant transformation, it
is extremely important to examine the oral mucosal
surface thoroughly in an attempt to disclose other
clinically verruciform changes.15 Long-term follow-up
at regular intervals is mandatory. Although the most
frequently affected sites are the gingiva and alveolar
mucosa, the entire mouth must be carefully evaluated
for new lesions at each follow-up visit. Because prognosis cannot be based solely on histology, correlating
the microscopic diagnosis with the clinical progression of the patients lesions is the only rational means
to evaluate the status of PVL.

References
1. Hansen LS, Olson JA, Silverman S Jr: Proliferative verrucous
leukoplakia: A long-term study of thirty patients. Oral Surg Oral
Med Oral Pathol 60:285, 1985
2. Palefsky JM, Silverman S Jr, Abdel-Salaam M, et al: Association
between proliferative verrucous leukoplakia with human papilloma virus type 16. J Oral Pathol Med 24:193, 1995
3. Batsakis JG, Suarez P, El-Naggar AK: Proliferative verrucous
leukoplakia and its related lesions. Oral Oncol 35:354, 1999
4. Silverman S Jr, Gorsky M: Proliferative verrucous leukoplakia: A
follow-up of 54 cases. Oral Surg Oral Med Oral Pathol Oral
Radiol Endod 84:154, 1997
5. Shear M, Pindborg JJ: Verrucous hyperplasia of the oral mucosa. Cancer 46:1855, 1980

6. Murrah VA, Batsakis JG: Proliferative verrucous leukoplakia and

verrucous hyperplasia. Ann Otol Rhinol Laryngol 103:660, 1994
7. Gopalakrishnan R, Weghorst CM, Lehman TA, et al: Mutated
and wild-type p53 expression and HPV integration in proliferative leukoplakia and oral squamous cell carcinoma. Oral Surg
Oral Med Oral Pathol Oral Radiol Endod 83:471, 1997
8. Kannan R, Bijur GN, Mallery SR, et al: Transforming growth
factor-alpha overexpression in proliferative verrucous leukoplakia and oral squamous cell carcinoma. An immunohistochemical study. Oral Surg Oral Med Oral Pathol Oral Radiol
Endod 82:69, 1996
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leukoplakia of the gingiva. Oral Surg Oral Med Oral Pathol Oral
Radiol Endod 90:723, 2000
10. Perez CA, Kraus FT, Evans JC, et al: Anaplastic transformation
in verrucous carcinoma of the oral cavity after radiation therapy. Radiology 26:108, 1966
11. Malmstrom M, Hietanen J, Sane J, et al: Topical treatment of
oral leukoplakia with bleomycin. Br J Oral Maxillofac Surg
26:491, 1988
12. Shah JP, Strong EW, Decosse JJ, et al: Effect of retinoids on oral
leukoplakia. Am J Surg 146:466, 1983
13. Garewal HS, Meyskens FL, Killen D, et al: Response of oral
leukoplakia to beta-carotene. J Clin Oncol 8:1715, 1990
14. Kahn MA, Dockter ME, Hermann-Petrin JM: Proliferative verrucous leukoplakia. Four cases with flow cytometric analysis.
Oral Surg Oral Med Oral Pathol 78:469, 1994
15. Zakrzewska JM, Lopes V, Speight P, et al: Proliferative verrucous leukoplakia. A report of ten cases. Oral Surg Oral Med
Oral Pathol Oral Radiol Endod 82:396, 1996