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Lorenzo-Pouso AI, Lafuente-Ibáñez de Mendoza I, Pérez-Sayáns M Critical update, systematic review, and metaanalysis of oral erythroplakia as an oral potentially malignant disorder. J Oral Pathol Med. 2022; 51:585-593 https://doi.org/10.1111/jop.13304
Iocca O, Sollecito TP, Alawi F Potentially malignant disorders of the oral cavity and oral dysplasia: a systematic review and meta-analysis of malignant transformation rate by subtype. Head Neck. 2020; 42:539-555 https://doi.org/10.1002/hed.26006
Kristofelc N, Zidar N, Strojan P Oral verrucous carcinoma: a diagnostic and therapeutic challenge. Radiol Oncol. 2023; 57:1-11 https://doi.org/10.2478/raon-2023--0015
Capella DL, Gonçalves JM, Abrantes AAA Proliferative verrucous leukoplakia: diagnosis, management and current advances. Braz J Otorhinolaryngol. 2017; 83:585-593 https://doi.org/10.1016/j.bjorl.2016.12.005
Abadie WM, Partington EJ, Fowler CB, Schmalbach CE Optimal management of proliferative verrucous leukoplakia: a systematic review of the literature. Otolaryngol Head Neck Surg. 2015; 153:504-511 https://doi.org/10.1177/0194599815586779
Suarez P, Batsakis JG, el-Naggar AK Leukoplakia: still a gallimaufry or is progress being made? A review. Adv Anat Pathol. 1998; 5:137-155
Hazarey VK, Ganvir SM, Bodhade AS Verrucous hyperplasia: a clinico-pathological study. J Oral Maxillofac Pathol. 2011; 15:187-191 https://doi.org/10.4103/0973-029X.84492
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BDS (Hons), MFDS RCS (Ed), MFDS RCS (Eng), FRCPath, PhD, SFHEA, Senior Clinical Teacher and Honorary Consultant in Oral and Maxillofacial Pathology; School of Clinical Dentistry, University of Sheffield
Proliferative verrucous leukoplakia (PVL) is a rare, but relentless, form of leukoplakia, with a high recurrence rate and a tendency to become malignant, either as an oral squamous cell carcinoma (OSCC) or verrucous carcinoma (VC). Its aetiology is mainly unknown, and there is uncertainty around its management owing to its resistance to most treatments with a high rate of recurrence.
CPD/Clinical Relevance:
Understanding PVL is key to making prompt diagnosis and referral for improved outcome of treatment due to its high malignancy transformation rate.
Article
The World Health Organization defines oral leukoplakia (OL) as a white patch that cannot be rubbed off, cannot be characterized clinically or histologically as any other disease, and that is not associated with any physical or chemical causative agent except the use of tobacco.1 Leukoplakia is split into two main groups dependent on its colour and texture: homogeneous and non-homogeneous. Homogeneous OLs are uniform in colour and texture, whereas non-homogeneous OLs show varying colours or textures within the mucosal abnormality.
The estimated worldwide prevalence of OL is 2.6%.2 Although it is difficult to obtain accurate data on its risk of malignant progression, a systematic review by Villa et al found OL to have a malignant potential of 0.6–5% within 5 years from diagnosis if homogeneous, and 20–25% within 5 years from diagnosis if non-homogeneous.3 Oral erythroplakia (OE) is similar to OL except that it is red in colour and associated with a much higher malignancy transformation rate of up to 19.9%.4 These comparisons, along with others from this article, are summarized in Table 1.5
Comparative features
Homogeneous leukoplakia
Non-homogeneous leukoplakia
Proliferative verrucous leukoplakia
Erythroplakia
Colour
Uniform white
Non-uniform, white and red
Begins as a homogeneous white plaque and becomes non-uniform in colour and texture over time
Old age, female gender, not associated with smoking
Smoking, alcohol, male gender
PVL is a clinical diagnosis describing a specific clinical presentation of OL, which has a high risk of transforming to malignancy and characteristically progresses through different stages and presentations. PVL is not widely known about, and only 38% of dentists recognize that this type of leukoplakia is more likely to transform to malignancy,6 so it is very important to raise awareness of this condition in general practice.
Proliferative verrucous leukoplakia
PVL represents a longitudinal clinical diagnosis, in other words, the mucosal abnormality has a history of progressing over time. It may begin with a simple keratosis presenting as a homogeneous white patch (Figure 1a), which gradually becomes more verrucous over time (Figure 1b and c), with some eventually turning dysplastic or transforming into a conventional oral squamous cell carcinoma (OSCC) (Figure 1d) or sometimes a verrucous carcinoma (VC). VC is a variant of OSCC that has verrucous projections on its surface and has a much lower ability to metastasize than conventional OSCC.7 PVL will typically spread across the oral mucosa and affect multiple sites making it difficult to treat. As such, the clinician can only make a diagnosis of PVL when this pattern of progression is recognized (Figure 1). PVL predominantly affects non-smoking women (it is approximately 2.5 times more common in females compared to males), and has a mean age of 66.8 years, rarely affecting younger age groups.8 This differs to OL and OSCC, which are more commonly found in men who smoke.2
Aetiology of PVL
The cause of OL in general is widely unknown and this also applies to PVL. There are definite risk factors that are strongly correlated with OL, such as smoking and chewing tobacco, but people who have never used tobacco products can still have these mucosal changes, in which case the name ‘idiopathic leukoplakia’ is given. For PVL however, tobacco-containing products have not been identified as risk factors, and many of the patients presenting with this disease are non-smokers (65%).9
Figure 1. Clinical presentations of (a) early PVL; (b,c) verrucous hyperplasia; and (d) OSCC.
Microbiological causes have been considered, paying particular attention to human papilloma virus (HPV) and Candida albicans; however, no statistically significant evidence has yet been found to implicate these organisms.8 Immunological and vitamin deficiencies have been investigated and appear to have no link to the disease.10
When considering that there are very few known risk factors for PVL, identifying high-risk patients can be very difficult. Thorough oral examination of the soft tissues at regular intervals will increase the chance of identifying it, with onward referral for biopsy. There should be a low threshold for referral, especially if no obvious clinical cause can be ascribed to a white patch.
Features, progression and diagnosis of PVL
Diagnosis of PVL is predominantly by exclusion of other clinically or histologically defined conditions. This is carried out clinically, with accompanying histology, and is usually a retrograde diagnosis owing to the main differentiating feature of the disease being its progression through time. The histology alone is not diagnostic because many of the features of OL and PVL are non-specific. This being said, histology is still very important in understanding the progression of the disease, excluding other common causes of white patches and monitoring for dysplasia development or transformation to malignancy. Given that PVL can involve large areas of the oral mucosa, sometimes several ‘mapping’ biopsies are required to build a full picture of how it is developing.
The most common PVL clinical presentation has been reported as a diffuse, homogeneous, intra-oral white plaque (Figures 1 and 2), which would become erythematous, multifocal, verrucous and exophytic over time.9 Its multifocal nature means that the condition can begin in one area of mucosa and then spread to multiple other locations around the oral cavity, and this feature is very important for diagnosis. Suarez et al found that the most common site for PVL was the gingiva (62.7%), followed closely by the buccal mucosa (59.8%) and the tongue (49.1%).10
Figure 2. Early presentation of PVL on buccal gingivae.
Batsakis et al suggested four main stages of disease progression in PVL.11 These classifications require clinical and histological correlation
Flat homogeneous leukoplakia without dysplasia
This can give a false sense of security to the clinician who may think it is a conventional leukoplakia, but at this point there is no reliable way to differentiate PVL from OL. Histologically, it would show hyperkeratosis with no epithelial dysplasia (Figure 3). Over time, the mucosal abnormality will grow and become multifocal and diffuse.
Figure 3. Histology of (a) early PVL; (b) verrucous hyperplasia; (c) verrucous carcinoma; and (d) OSCC islands in muscle tissue.
Verrucous hyperplasia (VH)
This is diagnosed histologically and is where the epithelium becomes thickened with exophytic projections above the level of the adjacent epithelial rete ridges (Figure 3b).12 The projections are described in two forms by Shear et al. First, as sharp, narrow and heavily ortho-keratinized, but sometimes blunted, with a thin layer of para keratin on the surface.13 The blunt variety is approximately four times more common. It is also worth noting that in this stage of disease, 100% of cases will show sub-epithelial inflammation, and 68% of cases show some degree of dysplasia.12 It is important to know that VH can occur by itself, so a diagnosis of VH does not necessarily mean the mucosal change is part of a PVL.11 This reinforces the need for a thorough history of the disease and monitoring of its progression, both prospectively and retrospectively, to confirm the diagnosis.
Verrucous carcinoma (VC)
This is diagnosed histologically, and at this stage it is very important to differentiate VC from VH. The main difference between the two is that with VH, the verrucous epithelium does not extend below the level of the adjacent epithelium. In verrucous carcinoma, the epithelium is particularly proliferative with long, broad-based epithelial down growths extending below the level of the adjacent normal epithelium (Figure 3c).13
VC is a variant of squamous cell carcinoma. Even though it can invade sub-epithelial tissue, it does not typically metastasize to distant sites, therefore it has a better prognosis.7 Clinically, it appears as a broad-based lesion with a warty surface.14
Oral squamous cell carcinoma (OSCC)
OSCC is diagnosed histologically, and at this point there is clear invasion of the epithelium into the underlying connective tissue (Figure 3d).15 Clinically, it may present as ulcerated mucosa with raised, rolled indurated margins; however, sometimes early invasion is masked by the verrucous nature of these lesions. Diagnosis requires careful sampling of the mucosa and subsequent histological examination.
The full progression from a nondysplastic OL to a frank OSCC is not always evident and sometimes these mucosal abnormalities remain largely unchanged for many years. Others grow rapidly and progress through the above stages quickly.
Malignant potential
In the meta-analysis of PVL studies by Iocca et al, an annual malignant transformation rate of 9.3% was estimated using averages from all of the studies with recall periods ranging from 1 to 20 years. This can then be used to estimate a 5-year malignancy transformation rate of 46.5%.5 In a different meta-analysis by Palaia et al, which looked at a total of 699 PVL patients, a malignant transformation rate of 45.8% was estimated.16 When comparing this to the average malignant transformation rate of other potentially malignant mucosal disorders (PMMD) of 7.9%,5 it can be appreciated how much higher the chance of malignant transformation is with PVL compared with other PMMDs, again highlighting the importance of identifying and managing this disease.
When assessing potential malignancy at each biopsy, Van der Waal found that there was a higher risk if any of the following factors were present:17
Female gender;
Increased age;
Site: lateral tongue, floor of mouth;
Size: especially when greater than 200 mm;
Colour: mixed colour, presence of erythema, speckled appearance;
Texture: nodular, cauliflowerlike texture;
Presence of Candida;
Increased degree of dysplasia.
Management
As with all PMMDs, diagnosis is underpinned by a thorough clinical history and examination, with referral to secondary care when a mucosal change of concern is identified. In hospital, patients with PVL are often under long-term review. Taking clinical photographs is very important for monitoring the disease.
Management then depends on which stage of the PVL spectrum the patient is in. If the disease is in its early stages, then monitoring at regular intervals is likely to be required. Although smoking and alcohol are not as strongly associated with PVL, it is always worth reducing such habits to reduce the risk of OL and OSCC. If subsequent biopsies reveal worsening dysplasia, or there is concern that the mucosal abnormality is transforming into OSCC, treatment is likely to involve excision. However, it is important to remember that PVL is difficult to treat because it tends to grow back quickly, or develops in another area of the mouth, such is its persistent and insidious nature. There is a general lack of evidence regarding the management of PVL owing to its low prevalence and tendency not to respond to conventional treatments. A systematic review by Abadie et al showed that surgical excision was the most common intervention, used in 80.2% of cases.9 However, in PVL cases where development of malignancy occurred, radiation was used in 23.8% of cases, laser therapy in 23.0%, chemotherapy in 5.6% and photodynamic therapy in 4.8%. None of the treatments were statistically different in outcome, and the recurrence remained high (71.2%) after all treatments; 39.6% died from their disease.8
So, what is the dentist's role?
Thorough examination of patients, paying close attention to the oral soft tissues, while being aware that PVL can occur in patients without traditional risk factors for OSCC;
Photograph any suspicious lesions and refer promptly when needed;
Where necessary, manage the side effects caused by treatment of the disease, for example xerostomia.
Conclusion
PVL is a rare but relentless form of OL characterized by its progression through stages over time. It has an increased risk of malignancy compared to conventional OL and can be very resistant to treatment. There is a lack of evidence to support a specific management regimen, but prompt diagnosis, referral and monitoring is key.
