Insights Into Proliferative Verrucous Leukoplakia

Oral leukoplakia describes white lesions affecting the oral mucosa that cannot be removed by scraping or diagnosed clinically as any other disease.¹ The prevalence of oral leukoplakia is estimated to be between 2% and 5% worldwide and most lesions pursue a benign course.^2–4 A multifocal variant of leukoplakia, known as proliferative verrucous leukoplakia (PVL), was first described in 1985 by Hansen et al.⁴ They identified this specific variant in 30 patients and stated that it was of unknown origin. It was also observed that these white plaques were slow growing, persistent, and eventually manifested as exophytic and wart-like lesions that had a high tendency to undergo malignant transformation to oral squamous cell carcinoma.⁴ The World Health Organization has further described PVL as a rare yet distinctive, high-risk leukoplakia without a single diagnostic sign or symptom, but with specific features and behaviors.5

Describing a white lesion that gradually manifests clinical and histo­patho­logical changes, PVL often presents initially as a single lesion, but almost always evolves into a multisite disorder.¹ Prior to 1985, PVL was referred to as oral florid papillomatosis,⁶ but it is now classified as a potentially malignant disorder of the oral cavity. By a 4-to-1 ratio, this condition predominantly affects women (as compared to men).⁷ In a systematic review of 26 articles on PVL, 66.9% of patients were women.8 Most individuals affected with PVL are in their 60s, with an average age at diagnosis of 63.9.⁸

The etiology of PVL is not fully understood. Tobacco does not appear to be an etiologic factor, as the majority of patients with PVL are nonsmokers.⁸ Silverman et al stated that only 31% of the studied subjects with PVL used tobacco products.⁹ Among a group of PVL patients evaluated by Fettig et al, one half used tobacco.¹⁰ A meta-analysis by Cabay et al identified that 37% of PVL patients studied were tobacco users.¹ Habits involving alcohol consumption have not been widely investigated in patients affected by PVL.⁷ While no correlation between immunodeficiency and PVL is known,¹ the role of human papillomavirus (HPV) in the origin of PVL remains debatable. Earlier studies suggested that HPV was of significance; more recently, however, the relationship between PVL and HPV has been challenged. A study by Palefsky et al found that 89% of subjects with PVL tested positive for HPV.¹¹ Another study found that up to 24.1% of PVL samples contained HPV DNA.¹² Specifically, a high-risk subtype of the virus, HPV-16, is thought to be involved in these lesions. In contrast, Fettig et al and Bagan et al found no association between PVL and HPV.^10,13

Epstein-Barr virus may be involved in some PVL cases.⁶ Marx et al identified Candida organisms in the majority of the PVL cases they investigated.¹⁴ It remains unclear, however, whether the identification of these Candida species is a coincidental finding in such cases because the rough and corrugated surface morphology of PVL can encourage entrapment of Candida organisms. Specific gene aberrations and telomerase alterations have also been identified in PVL cases.^7,14

CLINICAL FINDINGS

This condition can affect any oral mucosal surface, and is most commonly associated with the buccal mucosa and tongue.^1,4,15 Other oral sites include the palatal mucosa, floor of the mouth, and lips. The gingiva and periodontal sites are also frequently involved.^7,10 In a study of 47 patients with PVL, 87.2% presented with involvement of the alveolar crest mucosa, with gingival involvement noted in 46.8% of subjects.⁷ Cutaneous involvement is exceedingly rare, with only one case reported.¹⁶

Initially presenting as a single, distinct white lesion or scattered, multiple irregular white patches or plaques (Figure 1 through Figure 4), with time, additional identical lesions appear surrounding the initial lesion.^1,6 The presentation is often flat and white, with a rough, grainy or verrucous surface.¹ These lesions represent the concept of field cancerization, which suggests the entire epithelial surface is at increased risk of developing premalignant and malignant lesions due to multiple genetic abnormalities in the whole tissue region. Therefore, the normal mucosa undergoes gradual transformation, both clinically and histologically.¹⁴

Clinically, PVL follows a pattern of transformation, starting with one or more innocuous white lesions that progress to verrucous hyperplasia, and can then evolve into malignancies, such as verrucous carcinoma and squamous cell carcinoma.¹⁴ Diagnosis of these lesions is often delayed, as multifocal involvement is progressive.⁶ Although most initial lesions are asymptomatic, redness and pain are sometimes present.¹⁴ Evidence of ulceration and induration in longstanding PVL may be an indication of malignant transformation.¹⁴

MICROSCOPIC FINDINGS

Histologically, PVL has four stages of development: hyperkeratosis without any cellular atypia, verrucous hyperplasia, verrucous carcinoma, and squamous cell carcinoma.¹⁷ Verrucous hyperplasia refers to a lesion that is either an irreversible precursor to verrucous carcinoma, or a morphological variant of verrucous carcinoma.¹⁸

Previously, Hansen et al proposed a microscopic grading system for PVL using a scale of one to 10 to define the severity of cellular changes.⁴ Although histopathology is helpful in arriving at a diagnosis, the histologic diagnosis depends on the area biopsied. Thus, PVL may have multiple histologic presentations, ranging from benign hyperkeratosis to carcinoma.^4,6 The histopathologic features are progressive, suggesting that the diagnosis may change over time.¹ Sometimes, the initial lesion may display a histologic pattern with a collagenous lymphocytic infiltrate, often seen in lichen planus. This can cause confusion in reaching a diagnosis.¹ In advanced cases, the underlying bone may be eroded.¹

DIAGNOSIS AND TREATMENT

A PVL diagnosis is made based on a combination of clinical and histologic findings, including clinical appearance and extension. In one study, a set of major and minor criteria, as well as specific combinations among them, was proposed for diagnosing PVL (Table 1).¹⁹ This proposal still awaits unanimous acceptance, however, and modifications have been recommended.

The ideal goal of treatment is to delay the malignant transformation of proliferative verrucous leukoplakia lesions

The ideal goal of treatment is to delay the malignant transformation of PVL lesions. There is a lack of consensus, however, regarding which management protocol is most effective.⁶ A complete head and neck exam should always be performed.¹⁴ Based on size and location, excision of suspicious lesions is recommended (as long as it is feasible). Treatment of PVL lesions largely depends on the histopathologic diagnosis, and multiple biopsies are usually required to accurately confirm progression.⁸

Chemoprevention that includes two months of treatment with fluconazole and nystatin oral suspension has been recommended because of the proposed etiologic role of Candida. The use of antifungals may be contraindicated in select patients, however, due to side effects or interactions with current medications. Moreover, Marx et al acknowledge that this form of chemoprevention protocol is empirical.¹⁴ Although laser ablation is not recommended due to its association with rapid recurrence, some investigators have experimented using lasers (CO₂ and Nd:YAG) and suggested that the recurrence potential is similar to that of scalpel biopsy.⁶ Radiotherapy does not alter the progression of PVL lesions.¹⁴ Femiano et al reported that patients treated with surgery and the antiviral methisoprinol experienced significant improvement, but these data need further confirmation.²⁰ Photodynamic therapy has also been tried, but with varying results.

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key takeaways

• Oral leukoplakia describes white lesions affecting the oral mucosa that cannot be removed by scraping or diagnosed clinically as any other disease.¹
• Proliferative verrucous leukoplakia (PVL) are typically slow growing, persistent, and eventually manifest as exophytic and wart-like lesions that have a high tendency to undergo malignant transformation to oral squamous cell carcinoma.⁴
• A PVL diagnosis is made based on a combination of clinical and histologic findings, including clinical appearance and extension.
• The ideal goal of treatment is to delay the malignant transformation of PVL lesions.
• Treatment largely depends on the histopathologic diagnosis, and multiple biopsies are usually required to accurately confirm progression.⁸

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CLINICAL BEHAVIOR

Lesions typically undergo multiple recurrences, with a high risk of malignant transformation over five years to 15 years. Of the 30 patients who were originally described by Hansen et al, 13 died from the disease.⁴ In another study that analyzed the clinical progression and outcomes in 54 cases of PVL, 38 patients showed progression to carcinoma during an average follow-up of 11.5 years, and 21 of those succumbed to oral cancer.⁹ A higher incidence of recurrence and malignancy was noted with lesions affecting the gingiva.⁶

Malignant transformation occurs in almost 71.2% of cases, although the transformation may range between 40% and 100%.^1,6,8 A study investigating 30 patients with PVL noted that recurrence after treatment was found in 86.7% of cases, and newer lesions arose in 83.3%.⁶ Lymph node metastasis, both regional and distant, is very rare.¹⁴

DIFFERENTIAL DIAGNOSIS

The initial appearance of PVL may mimic benign processes, such as hyper­keratosis, lichen planus or candidiasis.¹⁴ Clinically, gradual, widespread involvement and failure to effectively manage these lesions are indicators of PVL.

Lichen planus is most frequently confused with PVL. It is a chronic disorder of the skin that affects mostly middle-age women. Oral lichen planus usually presents as bilateral and sometimes multifocal pinpoint white papules that gradually enlarge and coalesce to form a broad white plaque. It may be asymptomatic, although discomfort may be noted in lesions that present with redness and surface ulceration.²¹ In a majority of cases, histopathologic diagnosis of the biopsied tissue specimen can help distinguish between the two processes.

CONCLUSION

Limited knowledge, an increased risk of malignant transformation, and high recurrence make the overall management of PVL challenging. Since PVL frequently appears as an innocuous white lesion, it may be overlooked or considered insignificant.¹ Because PVL has a high rate of malignant transformation (in contrast to the conventional leukoplakias’ very low malignant potential of 5%), early diagnosis is imperative.¹ Close patient follow-up, possibly every two months, may be necessary to assess for progressive changes.¹⁴ Referral to a specialist well versed in oral mucosal diseases is appropriate for follow-up and management. Patients need to understand that the lesions are not contagious, and that PVL is an aggressive lesion with a relentless growth pattern and often has poor outcomes.

In order to achieve better outcomes in patients with PVL, the oral health care community needs to develop a better understanding of PVL’s etiopathogenesis. In addition, new diagnostic and therapeutic approaches will be necessary. Dental providers play an important role by identifying changes affecting the oral mucosa, and may notice subtle changes by performing a thorough head and neck examination.

References

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From Decisions in Dentistry. July 2016;1(09):24–27.