Proliferative verrucous leukoplakia: Recognition and differentiation from conventional leukoplakia and mimics

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1 CLINICAL REVIEW David W. Eisele, MD, Section Editor Proliferative verrucous leukoplakia: Recognition and differentiation from conventional leukoplakia and mimics Ann M. Gillenwater, MD, 1 Nadarajah Vigneswaran, DMD, 2 Hanadi Fatani, MD, 3 Pierre Saintigny, MD, 4 Adel K. El-Naggar, MD, 3* 1 Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas, 2 Department of Diagnostic Sciences, The University of Texas School of Dentistry at Houston, Houston, Texas, 3 Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, 4 Department of Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. Accepted 10 September 2013 Published online 28 August 2014 in Wiley Online Library (wileyonlinelibrary.com). DOI /hed ABSTRACT: The majority of conventional leukoplakia remains constant and only a subset progress to high-grade dysplasia or invasive carcinoma. A less recognized form known as proliferative verrucous leukoplakia (PVL) represents a unique progressive and elusive variant. Identifying patients with this form can only be achieved through the keen clinical observation of the temporal gross and histologic progression in individual patients with squamous cell carcinoma. The difficulty in the early diagnosis of PVL stems from the overlapping clinical and pathologic features with conventional multifocal leukoplakia with dysplasia. We present the current view on the clinicopathologic and biological characteristics of PVL and discuss their diagnosis, differential diagnosis, and management. VC 2014 Wiley Periodicals, Inc. Head Neck 36: , 2014 KEY WORDS: oral leukoplakia, verrucous hyperplasia, squamous dysplasia, squamous tumorigenesis, lichen planus INTRODUCTION The World Health Organization Collaborating Center for Oral Cancer and Precancer defines oral leukoplakia as a white plaque of questionable risk having excluded (other) known mimicking diseases or disorders that carry no known risk for cancer. 1,2 Implicitly, therefore, leukoplakia represents a provisional clinical diagnosis that requires timely observation and histological confirmation to monitor the potential dysplastic development and progression. Histopathologically, leukoplakia displays as squamous epithelial hyperplasia and hyperkeratosis and/or parakeratosis (Figure 1). 3,4 Most leukoplakias are of limited size and pursue a benign clinical course. However, a subset of this entity presents at multiple sites, expands (granular leukoplakia), manifests a patchy red appearance (erythroplakia) (Figures 2 and 3), and may progress to cancer. Histologically, these lesions typically manifest early and/or with advanced dysplastic changes. Proliferative verrucous leukoplakia (PVL), on the other hand, is a rare aggressive subset of oral premalignancy. Because of the shared features with conventional leukoplakia, PVL early recognition is generally delayed and is currently based on observing the progressive clinical course of the disease Accordingly, the early recognition and differentiation of PVL from sporadic leukoplakia rests on the *Corresponding author: A. K. El-Naggar, Department of Pathology, Unit 85, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX anaggar@mdanderson.org Ehab Y. Hanna, MD, Editor, was recused from consideration of this manuscript. keen observation of the temporal clinical progression by practitioners. 4,9,15,16 Four broad phases were found to characterize this entity: (1) focal early presentation; (2) geographic expansion with time; (3) development of a verrucoid/warty appearance; and (4) development of cancer. Etiology To date, no risk factors have been associated with PVL. Attempts to link traditional risk factors associated with the conventional form of oral leukoplakia, including the use of smokeless and smoked tobacco, alcohol, and areca nuts, have been unsuccessful Similarly, no evidence for an association between human papillomavirus and Epstein Barr virus and PVL has been established Clinicopathologic characteristics of proliferative verrucous leukoplakia Because of the lack of early clinical or pathologic diagnostic features, PVL is most often recognized late in the course of the disease by the temporal observation of its clinical progression In practical terms, a definitive PVL diagnosis is retrospectively made and aided by a high degree of suspicion and close communication between clinicians and pathologists. 14,16,17 Certain features, however, have been identified in patients with PVL lesions; including its preponderance in women than men (4:1), older patients (>60 years), lack of risk factors, and frequent occurrence at the buccal mucosa and oral tongue sites. 18,22,24,25 However, recent studies and our own experience indicate that the gingiva, alveolar ridge, and palate are not uncommonly affected and are the sites of squamous cell carcinoma development in these patients (Figure 2). 25, HEAD & NECK DOI /HED NOVEMBER 2014

2 PROLIFERATIVE AND CONVENTIONAL ORAL LEUKOPLAKIA AND ITS MIMICS FIGURE 1. Localized leukoplakia with well-circumscribed white lesion. (A) With simple hyperplasia and hyperkeratosis. (B) This lesion may occur early in proliferative verrucous leukoplakia. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.] Pathologic characteristics PVL cannot definitely recognized based on the histopathologic findings alone, and definitive diagnosis can only be based on high suspicion and temporal, clinical, and pathologic observations. Nevertheless, certain subtle pathologic features, such as the presence of dense lichenoid chronic inflammation, wavy hyperorthokeratosis, and exophytic warty configuration, can provide early pathologic clues for PVL16 (Figures 2,3). In addition, the finding of flat, localized, or multifocal leukoplakia, especially at the gingiva and the alveolar ridge in an elderly female with no risk factors should raise the suspicion for PVL Currently, 4 histopathologic manifestations of PVL have been characterized (Figure 4 & 5): (1) localized flat hyperplasia and hyperkeratosis (Figure 5); (2) multifocal/geographic expansion with and without dysplasia; (3) development of verrucous hyperplasia; and (4) progression to verrucous or conventional squamous cell carcinoma. 16 Concurrent or sequential detection of these phenotypic developments in a given subject are important in early diagnosis and treatment of this condition. 16,24 26 Differential diagnosis The conditions listed below should be considered in the differential diagnosis, especially in early stages of PVL (Table 2). FIGURE 2. Geographic spread of leukoplakia lesion (A) with histologic features of squamous hyperplasia and hyperkeratosis. Early proliferative verrucous leukoplakia may manifest identical manifestations. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.] HEAD & NECK DOI /HED NOVEMBER

3 GILLENWATER ET AL. FIGURE 3. Leukoplakia lesion (A) with corresponding histologic features of mild hyperkeratotic dysplasia. Similar lesions may also occur in conventional and proliferative verrucous leukoplakia. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.] Conventional localized and multifocal leukoplakia. Typically, patients with conventional leukoplakia present with either single flat or variable multifocal slightly raised white lesions on the lateral and ventral surfaces of the tongue and floor of the mouth 23 (Figures 1 and 2). In Southeast Asian countries, patients practicing chewing betel quid (betel leaf, areca nut and slacked lime, and tobacco) present with leukoplakia involving the buccal mucosa, mandibular sulcus, and gingiva. 3,13 The majority of sporadic, localized leukoplakias are stable and run a benign clinical course. Multifocal presentations (unstable field affect) have been associated with increased risk of malignant progression. 3,4 The incidence for the acquisition of dysplastic and the progression to invasive carcinoma varies from 5% to 15% (Figure 1). 3 The development of dysplasia is an early predictor for progression and requires close clinical followup (Figure 2). 4 However, other studies have challenged these findings. 23 Patients with this form are typically older men with long histories of tobacco or alcohol consumption, and they experience a more aggressive course. Multifocal geographic leukoplakia is more likely to progress than is the flat, homogenous leukoplakia (Table 1). FIGURE 4. Verrucoid gross development (A) and corresponding histologic warty keratosis, especially in the appropriate setting, is suggestive of proliferative verrucous leukoplakia. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.] 1664 HEAD & NECK DOI /HED NOVEMBER 2014

4 PROLIFERATIVE AND CONVENTIONAL ORAL LEUKOPLAKIA AND ITS MIMICS FIGURE 5. Verrucoid and erythroblastic lesion (A) and verrucous carcinoma stage of proliferative verrucous leukoplakia. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.] Verrucous hyperplasia and carcinoma. Gross verrucoid development in PVL can occasionally be confused with sporadic verrucous hyperplasia or carcinoma occurring at different head and neck regions (Table 2). Sporadic verrucoid lesions represent isolated conditions in the oral cavity and other sites, including the larynx and sinonasal tract. 17 Only in the context of the natural history of PVL should the verrucoid terminology manifestations be considered. As in PVL, both lesions have a slight female predominance; they are most common in old age and present in the oral cavity, the alveolar, and the gingival mucosa. In practical terms, the management of both is the same and constitutes the need for a surgical excision. 16,17 Oral lichen planus. Oral lichen planus, an autoimmune condition, is a persistent, bilateral, and symmetrical white mucosal lesion with reticular, plaque-like erythematous, or ulcerative appearance (Figure 6) Iatrogenic oral lichen planus (lichenoid) lesions can be precipitated by a variety of medications (lichenoid drug reactions) or by a contact hypersensitivity reaction to dental restorative materials (ie, amalgam) and flavoring additives (ie, cinnamon). 1 Less than 50% of patients with TABLE 1. Comparison of clinicopathologic characteristics of proliferative verrucous leukoplakia and multifocal oral hairy leukoplakia. Parameter PVL OHL Age Elderly Middle age M:F 4:1 1:2 Risk factors * Yes Sites Oral cavity, tongue, gingiva Oral cavity Cancer progression High Low Dysplasia Rare 5% to 15% Lichenoid infiltration Low Low Abbreviations: PVL, proliferative verrucous leukoplakia; OHL, oral hairy leukoplakia. * Unknown. cutaneous lichen planus present with oral mucosal lesions. In rare instances, reticular and plaque variants of lichen planus can be mistaken for conventional leukoplakia and early PVL lesions. 15,16,27 29 Histologically, oral lichen planus is characterized by hyperkeratosis, interface mucositis, with dense subepithelial, band-like chronic inflammation, spongiosis, and lymphocytic migration in the squamous epithelium (Table 2). 30,31 Although published studies indicate a malignant transformation rate of <2%, 32,33 a confirmation of such occurrence is a subject of debate because these lesions may represent dysplastic leukoplakias with lichen planus-like features lichenoid dysplasias. 34,35 Oral hairy leukoplakia. Human immunodeficiency virusrelated oral hairy leukoplakia (OHL) is a white verrucoid lesion of the oral mucosa in patients with acquired immunodeficiency syndrome. OHL presents at the lateral border of the tongue; however, it may spread to involve the entire dorsal and lateral surfaces (Figure 7). This condition is etiologically linked to Epstein Barr virus and present histologically as thickened hyperkeratosis and parakeratosis, with cytopathic features ballooning degeneration and nuclear clearing of the upper spinous layer. 36,37 These features, however, are distinctively different from those of conventional leukoplakia and early stages of PVL (Table 2). Other conditions Grossly and microscopically, other sporadic conditions, including oral wart and condylomas, may also resemble PVL lesions. These lesions are limited in nature and do not progress with time. 16 Biological characteristics One of the unique characteristics of PVL is its development in patients with no known risk factors, especially in elderly women. This raises the possibility of either an inherent susceptibility to the disease or to an infectious etiology. Studies to identify infectious agents and HEAD & NECK DOI /HED NOVEMBER

5 GILLENWATER ET AL. TABLE 2. Comparison of clinicopathologic features of lichen planus, verrucous hyperplasia, and verrucous carcinoma, and oral hairy leukoplakia. Feature LP VH/VC OHL Age Middle age Elderly Young Sex Mostly female Male Male Risk factor Stress Smoking HIV Viral association No * EBV Site Buccal mucosa, tongue Buccal mucosa, larynx Lateral tongue, oral cavity Cancer development Yes Yes No Dysplasia presence No Yes No Lichenoid infiltration High Minimal None Abbreviations: LP, lichen planus; VH, verrucous hyperplasia; VC, verrucous carcinoma; OHL, oral hairy leukoplakia; HIV, human immunodeficiency virus; EBV, Epstein Barr virus. * Unknown. surrogate markers that may aid in the early detection and treatment of this condition have been unsuccessful Although relatively under-investigated, several molecular studies of these lesions have been conducted. In earlier studies, loss of heterozygosity at chromosome 9p loci were frequently reported using a combination of limited microsatellite markers. 43 Interestingly, these findings are similar to those reported for dysplastic premalignant lesions of the oral cavity. 44,45 Other specific gene targets have also been investigated in PVL; the most commonly reported being the p16, p14, and p53 tumor-suppressor genes. 38,42,43 Surprisingly, no p53 gene mutations have been identified in PVL; variable p53 expression has been reported, but the significance of these findings in PVL development is currently unknown Interestingly, homozygous deletion of exon 1b of the p14 gene, a rare genetic occurrence, has been reported in PVL lesions. 39 Similar findings in studies of squamous cell carcinoma provide additional evidence for the aggressive nature of PVL. 43 The small size of these studies, along with the lack of prospective, sequentially acquired lesions for analysis, preclude a definitive conclusion on the involvement of these molecular and phenotypic findings in PVL. Future efforts to identify the submicroscopic molecular, genetic, and epigenetic alterations must avoid the shortcomings of their predecessors. To achieve this goal, consecutive biopsies of PVL s temporal progression and comparative analyses with conventional leukoplakia must be performed to validate these markers. It is also important to determine whether predictive molecular markers, including polymorphisms in repair-related genes can be identified. These tests should be performed in a prospective, collaborative, multicenter setting Treatment Currently, no curative treatment exists for PVL or multifocal conventional leukoplakia with dysplasia. Preinvasive disease is best managed with less aggressive modalities, such as CO 2 laser ablation or photodynamic therapy. Conservative surgical treatments have all been FIGURE 6. Lichen planus. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.] 1666 HEAD & NECK DOI /HED NOVEMBER 2014

6 PROLIFERATIVE AND CONVENTIONAL ORAL LEUKOPLAKIA AND ITS MIMICS FIGURE 7. Hairy leukoplakia. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.] unsuccessful, likely because of PVL s inherent geographic spread and progressive nature Recently, photodynamic therapy has been suggested, but the effectiveness of this modality requires further studies. 58,59 Nonsurgical treatment of PVL, including radiation therapy, topical agents, cryotherapy, and phototherapy, as single or combined modalities, have also been unsuccessful The most effective approach is to shift the therapeutic goal from cure to control, maintaining close surveillance to detect invasive cancer early and performing wide local excision of invasive disease when possible. Radiation therapy, which does not halt or delay the progression of preneoplastic disease to invasive carcinoma, should be reserved for invasive carcinomas with aggressive features. Perspectives Because early diagnosis and effective detection and treatment remain challenging, investigating the molecular genetics of conventional leukoplakia and PVL is critical to understanding their clinicopathologic characteristics. 61,62 Definitive progress can only be made through concerted, prospective, multi-institutional collaborations that incorporate common clinical and pathologic inclusion criteria and follow-up schedules and establish biorepositories for periodic biopsy specimens and ancillary patient materials. The availability of these resources will allow us to identify the molecular and biological events that underlie PVL development and progression and develop early diagnostic and therapeutic strategies for early intervention and prevention ,63,64 Acknowledgments The authors thank Ms. Ann Sutton for editing the manuscript and Jason Martinez for typing and administrative assistance. REFERENCES 1. van der Waal I. 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