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 patient’s 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 patient’s 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

Postoperative photograph showing extensive carbon dioxide laser ablation of recurrent lesions.FIGURE 1. Third attempt to surgically treat the recurrent lesions. FIGURE 2. FIGURE 3. A skin graft was performed in the right buccal mucosa to help alleviate scarring contracture from previous operations. Recurrence of the lesions at the periphery of the skin graft sparing the skin graft itself. Initial presentation of extensive verrucous leukoplakia covering the right anterior and posterior maxillary gingiva and right buccal mucosa extending posteriorly behind last molar tooth. Mild verruciform epithelial dysplasia with marked hyperorthokeratosis (hematoxylin and eosin stain. original magnification !100). FIGURE 4. FIGURE 5. .

A biopsy revealed mild epithelial dysplasia with marked hyperkeratosis. Fiberoptic examination of the nasopharynx. 11. This therapeutic regimen was discontinued in August 1991.628 PROLIFERATIVE VERRUCOUS LEUKOPLAKIA FIGURE 7. cells with viral-like alterations were observed. There was no regional lymphadenopathy. Due to technical difficulty at the time. From 1990 through 1991. from hyperplasia with hyperkeratosis to mild epithelial dysplasia with hyperparakeratosis. In situ hybridization for human papilloma virus (HPV) subtypes 6. the patient received 4 cycles of 5-fluorouracil with leucovorin rescue. Fourth recurrence in the right maxillary gingiva with resulting right partial maxillectomy. A and B. right upper lip. At this time. In the superficial epithelium. C. HPV subtypes 16 and 18 were not assessed. Multisite recurrent lesions in the right posterior buccal ridge with transformation to squamous cell carcinoma. and larynx revealed no apparent disease involvement. Physical examination at this time showed leukoplakic changes surrounding the margins of the skin graft involving the right anterior buccal mucosa. and 35 was negative. FIGURE 8. the leukoplakic lesion recurred. 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). Eighteen months later showing recurrence in the region of the previous partial maxillectomy with erythroplakia and leukoplakia. and mitoses (hematoxylin and eosin stain. In 1990. prominent nucleoli. 31. An otorhinolaryngologist also carried out a panendoscopic examination that showed only normal mucosa. The patient presented with a mass in the right anterior maxillary gingiva in January 1992 (Fig 6A). The patient had a significant amount of trismus at this time. A biopsy from the anterior maxilla revealed epithelial dysplasia with marked hyperkeratosis. original magnification !400). Well-differentiated island of squamous cell carcinoma. The oral surgical specimen revealed a superficial infiltrating well-differ- . FIGURE 6. One percent topical bleomycin was applied every day for 15 days without success. and the disease returned within 1 month. Epithelial cells show nuclear pleomorphism. 33. hypopharynx. which resulted in 80% regression of the mucosal lesions. Topical chemotherapy was initiated. extraction of multiple nonrestorable teeth and a partial right maxillectomy (Fig 6B) with a skin graft was performed. and right upper gingival mucosa in the area of the incisors. the remainder of the oral cavity and oropharynx appeared to be uninvolved. By November 1989.

A computed tomography scan showed a 1. she underwent a right anterior partial maxillectomy. VH with or without dysplasia. Therefore.6 Because the microscopic interpretation of PVL lesions is complex and challenging.3 The diagnosis of VH can only be established through microscopic analysis. verrucous carcinoma. As seen in this case.! 1. over a protracted period of time. relentless. but persistent. They omitted papillary SCC. A gastric tube was placed to allow for adequate nutrition during the course of subsequent radiation and chemotherapy. At the recommendation of the medical oncologists. In November 1994. and irreversible. In the original report in which PVL was introduced as a clinical entity. the patient noticed a mass in the right mandible (Fig 7).4 Both the initial clinical presentation and the early biopsy findings of PVL can lull the clinician into a false sense of comfort. The typical PVL patient is a woman in her 60s who has had repeated biopsies for leukoplakia over a long span of time. The lesions from the marginal mandibular gingiva were consistent with well-differentiated microinvasive SCC arising in verrucous carcinoma. under the microscope. the patient was weaned off Tegison in January 1994. Discussion Proliferative verrucous leukoplakia is a very highrisk precancerous lesion with a high mortality rate. After receiving hospice care. and extraction of multiple nonrestorable teeth.! 2. The patient’s physical examination at this time was significant for trismus (20-mm opening) with no palpable lymphadenopathy. The patient was brought to the operating room for a partial mandibulectomy with preservation of the inferior cortex and placement of a reconstruction plate. No further treatment was performed at this time.3 Batsakis et al3 reduced the number of histologic stages to 4 with intermediates: hyperkeratosis without dysplasia. SCC are shown.5 cm were also seen. The disease was designated as a stage IV (T4 Nx Mx) SCC of the right mandible. varying degrees of epithelial dysplasia. surgical stripping of leukoplakic tissues in the right mandible. with a female-to-male ratio of approximately 4:1. and conventional SCC.VIGLIANTE. She had received a total of 7. Due to intolerance of the drug’s side effects. . stating that the oropharynx. During the course of disease. there is frequently widespread disease and progression to carcinoma.5 Although VH can be a histologic component in the evolutionary spectrum of PVL. often over a protracted period of time. Nutley. Unlike other forms of leukoplakia. 4 months later. Each has shown to have a considerable propensity to progress to malignancy— either verrucous carcinoma or conventional SCC with varying degrees of differentiation. Although approximately 5% of all dysplastic leukoplakias transform to cancer over an average period of 5 years.7. PVL has an almost 100% rate of malignant transformation. A biopsy 1 month after completion of chemotherapy revealed superficially infiltrating. The microscopic appearance of the lesions parallels the clinical appearance. the initial oral finding is a solitary homogeneous leukoplakic lesion that. 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. verrucous carcinoma. The patient was seen again in June 1995 after 6 weeks of chemotherapy and radiation.200 Gy and concomitant chemotherapy with cisplatin. In the specimen from the maxilla. A medical oncologic treatment plan was instituted primarily for palliation. to result in a diffuse. the diagnosis was VH with superficial infiltrating SCC arising from verrucous carcinoma. and.0. Given the extensive nature of the disease and poor prognosis.9 cm in the greatest dimension (Fig 8). the patient was followed closely. Our patient’s clinical course mirrored the progression of the disease in most of the 30 629 patients studied by Hansen et al in 1985. Submandibular lymph nodes measuring 1. An incisional biopsy revealed verrucous carcinoma. However. PVL lesions can exhibit any combination of these histologic stages during their progressive clinical course. PVL exhibits a strong female predilection. the lesions are slow growing. and the leukoplakia returned at the margins of the skin graft. Microscopic evaluation revealed invasive well-differentiated SCC measuring 2.3 but this can occur over an extended follow-up period of 5 to 20 years. with or without an erythematous component.1 In many PVL patients. nor indeed is VH confined to the oral cavity. There was invasion into the mandibular bone to within 1 mm of the deep surgical margin. In July 1994. can exhibit hyperkeratosis and epithelial hyperplasia with or without evidence of epithelial dysplasia. Hansen et al1 suggested histologic stages in the continuum of PVL (normal hyperkeratosis without dysplasia3 VH3verrucous carcinoma3papillary SCC3less-differentiated squamous carcinoma with intermediate subtypes).4 This case study is a typical example of the clinical behavior of PVL. She subsequently developed erythroplakia with leukoplakia in the right anterior maxillary gingiva (Fig 6C) and leukoplakia of the right mandibular gingiva in June 1994. VH. AND ALAWI entiated squamous cell carcinoma (SCC) with regions of verrucous hyperplasia (VH) with mild epithelial dysplasia. the patient was lost to further follow-up. By March 1993. ultimately. progressive. Combined radiation and chemotherapy had apparently failed to control the disease. The review of systems was notable for an 11-lb weight loss.3 They discuss how PVL and VH are 2 interrelated oral mucosal lesions. PVL should be used only as a clinical description and not as a definitive diagnosis.5-cm soft tissue mass along the superior aspect of the body of the right mandible with bony erosion involving the superior mandibular cortex. the patient began treatment with etretinate (Tegison. a retinoid. the patient refused any further radical surgery at this time. is the usual site of that disease.3 PVL has no single defining histopathologic feature. the oral lesions were markedly improved. QUINN. not the oral cavity. NJ). it is not exclusive to PVL. The clinical lesion tends to recur and proliferate. in November 1992. During the next year. Roche Labs. diagnostic accuracy is best achieved through consultation by an oral and maxillofacial pathologist. moderately differentiated SCC. widespread exophytic lesion.

10 Topical applications of bleomycin 0. Radiotherapy for oral leukoplakias has been widely studied with mixed results. With this modality. and the patient closely followed accordingly. Palefsky et al2 published the first study characterizing HPV infection in PVL. if any. with benign microscopic features. In their 1997 study.2 Using polymerase chain reaction. These investigators’ findings essentially confirmed the findings of Hansen et al. Kannan et al8 studied the role of transforming growth factor-! (TGF-!) overexpression. Silverman and Gorsky also evaluated the presence of Candida colonization on the biopsy specimens. In contrast to Palefsky et al. most often the gingiva and tongue. chemotherapy.630 Twelve years after the initial description of PVL. if any.9 local block resections were required to prevent recurrences. There are apparently no clinical distinguishing features that can be used to separate PVLG from other gingival leukoplakias. 70. therefore. as her lesions recurred. Multiple intraoral sites were involved. especially in the anterior regions. aggressive surgical resection is the current treatment of choice. Unfortunately. The initial lesions in these patients were white keratotic plaques or papillary/verruciform lesions. radiation. This was the only documented curative procedure. multiple mucosal sites can be treated simultaneously with relatively low morbidity and no residual scarring. These data suggested that HPV 16 infection might play a role in the pathogenesis of PVL-associated oral dysplasia and cancer.1 The average age at diagnosis was 62 years.2 Gopalakrishnan et al7 looked at p53 expression and HPV integration in PVL and oral SCC. PVL-associated carcinoma resulted in the death of 21 patients (39%).11 However. They found that increased TGF-! immunoreactivity occurs relatively early in PVL and persists as the disease progresses.7 Carbon dioxide laser ablation was used on our patient with only marginal results.9 Attempts at conservative treatments for management of PVL have met with limited success. patients must be forewarned of the strong likelihood of recurrence. The only treatments that resulted in any type of regression of our patient’s leukoplakia involved 5-fluorouracil and Tegison. The block resections were done with removal of teeth adjacent to the gingival disease process.0% solution have shown promise in the treatment of oral leukoplakias. When bland microscopic findings are correlated with what appears to be aggressive clinical behavior.7 Further studies will be necessary to clarify the role. of TGF-! in the transformation of PVL to SCC are necessary. In an attempt to aid in the early diagnosis of PVL versus other forms of leukoplakia.14 Zakrzewska et al15 addressed the possible role of photodynamic therapy.4 The etiology of PVL still remains elusive. Our patient was not a smoker. with frequencies of HPV presence ranging from 0% to 78%. and women outnumbered men 4:1. Because PVL . In the PVLG study.13 success was only temporary in our patient’s case. Controversy surrounds this treatment method because of early reports that suggest proclivity for anaplastic transformation after irradiation. The anatomic distribution was limited to the gingiva. of HPV and genetic mutations in the etiology of PVL. They concluded that prospective studies to define the role. PVL has a high recurrence rate and is typically resistant to all treatment modalities. and laser excision. PVLG should be strongly considered. including surgery. Smoking and the presence of Candida are no longer thought to have any influence on the occurrence and progression of PVL. but the most common were buccal mucosa in women and tongue in men.4 there was no apparent association with smoking. Silverman and Gorsky4 reported a prospective follow-up study on 54 patients with PVL. as 69% of their patients had never used tobacco in any form. cancer transformation rates in PVL were identical (70%).6 years after initial biopsy. Due to its multifocal presentation. it is incumbent on the clinician to obtain a biopsy and to follow the lesion indefinitely.4 In contrast to the consistent association between cervical cancer and HPV. In other reports. However. They found HPV DNA in 8 of the 9 lesions studied.3% of the patients developed SCC at a site of PVL.12.4 The role of human papillomavirus (HPV) remains speculative regarding the significance of its presence and possible regulatory influence on PVL occurrence and progression. our patient did not show any improvement with this therapy. these modalities produced similarly disappointing results: PVL appears to resist all forms of therapy. her improvement was only temporary because the side effects of the regimens were intolerable. The mean follow-up time was 11. According to Silverman and Gorsky. In patients in whom PVL is suspected. findings from studies of HPV and oral SCC have varied widely. Although clinical trials have shown the efficacy of retinoids and beta-carotene in reversing oral leukoplakia. In comparing smokers and nonsmokers. Evaluation of this approach to treatment needs to be further explored. 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 years. There was no clear association between the presence or absence of Candida and the potential to develop carcinoma. there is no way to predict which gingival white lesions will follow the relentless clinical path described for PVLGs.5% or 1. several biopsies are required to rule out the presence of a SCC.9 Currently. After a mean time of 7. and 7 were positive for HPV subtype 16. PROLIFERATIVE VERRUCOUS LEUKOPLAKIA Fettig et al9 recently described a subset of PVL called proliferative verrucous leukoplakia of the gingiva (PVLG).

et al: Anaplastic transformation in verrucous carcinoma of the oral cavity after radiation therapy. Malmstrom M. et al: Transforming growth factor-alpha overexpression in proliferative verrucous leukoplakia and oral squamous cell carcinoma. Ann Otol Rhinol Laryngol 103:660.631 lesions have a high rate of malignant transformation. Perez CA. Kahn MA. Strong EW. et al: Proliferative verrucous leukoplakia. et al: Mutated and wild-type p53 expression and HPV integration in proliferative leukoplakia and oral squamous cell carcinoma. El-Naggar AK: Proliferative verrucous leukoplakia and its related lesions. et al: Topical treatment of oral leukoplakia with bleomycin. Kannan R. Lopes V. Gorsky M: Proliferative verrucous leukoplakia: A follow-up of 54 cases. 1997 5. Batsakis JG: Proliferative verrucous leukoplakia and verrucous hyperplasia. Because prognosis cannot be based solely on histology. et al: Association between proliferative verrucous leukoplakia with human papilloma virus type 16. Shear M. Silverman S Jr. Radiology 26:108. the entire mouth must be carefully evaluated for new lesions at each follow-up visit. 1985 2. An immunohistochemical study. 1983 13. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 82:69. Silverman S Jr. Cancer 46:1855. J Oral Pathol Med 24:193. et al: Proliferative verrucous leukoplakia of the gingiva. 1997 8. Although the most frequently affected sites are the gingiva and alveolar mucosa. Lehman TA. Mallery SR. 1996 . Oral Surg Oral Med Oral Pathol Oral Radiol Endod 83:471. Hermann-Petrin JM: Proliferative verrucous leukoplakia. correlating the microscopic diagnosis with the clinical progression of the patient’s lesions is the only rational means to evaluate the status of PVL. Pogrel MA. 1990 14. Br J Oral Maxillofac Surg 26:491. Hansen LS. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 84:154. Dockter ME. Oral Surg Oral Med Oral Pathol 60:285. Four cases with flow cytometric analysis. J Clin Oncol 8:1715. 1996 9. Garewal HS. 2000 10. Killen D. Silverman S Jr. Silverman S Jr: Proliferative verrucous leukoplakia: A long-term study of thirty patients. Olson JA. Pindborg JJ: Verrucous hyperplasia of the oral mucosa. Weghorst CM. A report of ten cases. 1988 12. et al: Effect of retinoids on oral leukoplakia. Abdel-Salaam M. References 1. Meyskens FL. Fettig A. Oral Surg Oral Med Oral Pathol 78:469. Murrah VA. Batsakis JG. 1994 7. Kraus FT. Am J Surg 146:466. Gopalakrishnan R. Zakrzewska JM. 1994 15. 1995 3.15 Long-term follow-up at regular intervals is mandatory. 1980 6. Shah JP. Sane J. Oral Oncol 35:354. Hietanen J. 1966 11. Palefsky JM. Decosse JJ. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 90:723. Evans JC. et al: Response of oral leukoplakia to beta-carotene. Speight P. 1999 4. Suarez P. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 82:396. it is extremely important to examine the oral mucosal surface thoroughly in an attempt to disclose other clinically verruciform changes. Bijur GN.