Abstract
Introduction:
Proliferative verrucous leukoplakia is a multifocal and progressive lesion of the oral mucosa, with unknown etiology, and commonly resistant to all therapy attempts with frequent recurrences. It is characterized by a high rate of oral squamous cell carcinoma and verrucou carcinoma transformations.
Objective:
To analyze the studies about Proliferative verrucous leukoplakia and develop a concise update.
Methods:
A Pubmed search identifying studies (laboratory research, case series and reviews of literature) that examined patients with Proliferative verrucous leukoplakia was realized.
Results:
There are not enough studies about Proliferative verrucous leukoplakia in the literature. The few found studies not present a consensus about its etiology and diagnosis criteria. Although several treatment strategies have been proposed, most of them still show a high recurrence rate.
Conclusion:
More research about Proliferative verrucous leukoplakia is necessary to understand and treat this disease.
KEYWORDS
Leukoplakia oral; Leukoplakia; Proliferative verrucous leukoplakia; Oral cancer; Squamous cell carcinoma; Head and neck cancer
Resumo
Introdução:
Leucoplasia verrucosa proliferativa (LVP) é uma lesão multifocal e progressiva da mucosa oral, com etiologia desconhecida e comumente resistente a todas as tentativas terapêuticas, com recorrências frequentes. É caracterizada por uma alta taxa de transformação em carcinoma de células escamosas e carcinoma verrucoso da cavidade oral.
Objetivo:
Analisar os estudos sobre LVP e elaborar uma atualização resumida.
Método:
Foi realizada uma pesquisa na base de dados Pubmed que identificou estudos (pesquisas laboratoriais, séries de casos e revisões de literatura) que avaliaram pacientes com LVP.
Resultados e discussão:
Não há estudos suficientes sobre LVP na literatura. Os poucos estudos encontrados não apresentam consenso quanto aos critérios de etiologia e diagnóstico. Embora várias estratégias de tratamento tenham sido propostas, a maioria ainda apresenta alta taxa de recorrência.
Conclusão:
Mais pesquisas sobre LVP são necessárias para entender e tratar essa doença.
PALAVRAS-CHAVE
Leucoplasia oral; Leucoplasia; Leucoplasia verrucosa proliferativa; Câncer oral; Carcinoma, Célula escamosa; Câncer de cabeça e pescoço
Introduction
Proliferative verrucous leukoplakia (PVL) is a very aggressive and rare form of oral leukoplakia (OL) with high morbidity.11 Campisi G, Giovannelli L, Ammatuna P, Capra G, Colella G, Di Liberto C, et al. Proliferative verrucous vs conventional leukoplakia: no significantly increased risk of HPV infection. Oral Oncol. 2004;40:835-40. The first description has been made by Hansen et al. (1985) as a distinct form of OL which develops initially as a white plaque that eventually becomes multifocal slow-growing lesions resistant to all therapeutic procedures, including surgery, with a high recurrence rate and an oral cancer transformation trend.22 Hansen LS, Olson JA, Silverman S. Proliferative verrucous leukoplakia. A long-term study of thirty patients. Oral Surg Oral Med Oral Pathol. 1985;60:285-98. With the introduction of the term PVL, the previously used term "oral florid papillomatosis" has disappeared from the literature.33 Grinspan D, Abulafia J. Oral florid papillomatosis (verrucous carcinoma). Int J Dermatol. 1979;18:608-22. Actually, the World Health Organization (WHO) (2005) described PVL as "a rare but distinctive high-risk clinical form of oral precursor lesions".44 Barnes L, Eveson JW, Reichart P, Sidransky D. Pathology & genetics head and neck tumours. World Health Organ Classif Tumours. 2005. Several studies have examined PVL characteristics and its propensity to develop into oral carcinoma.44 Barnes L, Eveson JW, Reichart P, Sidransky D. Pathology & genetics head and neck tumours. World Health Organ Classif Tumours. 2005. Thirty years after its discovery, it is still a challenging disease with no confirmed etiology and efficient treatment. Although there are published papers about PVL diagnosis criteria, they may be imprecise in detecting early disease presentations, either for clinical or histopathological view. The objective of this paper is to analyze the PVL literature and to develop a concise update.
Review methods
A PubMed search using the term "Proliferative Verrucous Leukoplakia" was made from 1985 to 2015 (30 years). Additional papers were included based upon the original literature search and references in the selected papers. Papers concerning laboratory research, case series, as well as reviews of literature were also included.
Results and discussion
Etiology
Hansen et al. (1985) described PVL as a disease with unclear etiology, but typically associated with tobacco use.22 Hansen LS, Olson JA, Silverman S. Proliferative verrucous leukoplakia. A long-term study of thirty patients. Oral Surg Oral Med Oral Pathol. 1985;60:285-98. However, the role of tobacco in PVL lesions is unknown since these lesions are seen in smokers and nonsmokers (Table 1).11 Campisi G, Giovannelli L, Ammatuna P, Capra G, Colella G, Di Liberto C, et al. Proliferative verrucous vs conventional leukoplakia: no significantly increased risk of HPV infection. Oral Oncol. 2004;40:835-40.,22 Hansen LS, Olson JA, Silverman S. Proliferative verrucous leukoplakia. A long-term study of thirty patients. Oral Surg Oral Med Oral Pathol. 1985;60:285-98.,55 Zakrzewska JM, Lopes V, Speight P, Hopper C. Proliferative verrucous leukoplakia: a report of ten cases. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1996;82:396-401.
6 Silverman S, Gorsky M. Proliferative verrucous leukoplakia: a follow-up study of 54 cases. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1997;84:154-7.
7 Fettig A, Pogrel MA, Silverman S, Bramanti TE, Costa MD, Regezi JA. Proliferative verrucous leukoplakia of the gingiva. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2000;90:723-30.
8 Bagan JV, Jimenez Y, Sanchis JM, Poveda R, Milian MA, Murillo J, et al. Proliferative verrucous leukoplakia: high incidence of gingival squamous cell carcinoma. J Oral Pathol Med. 2003;32:379-82.
9 Ghazali N, Bakri MM, Zain RB. Aggressive, multifocal oral verrucous leukoplakia: proliferative verrucous leukoplakia or not?. J Oral Pathol Med. 2003;32:383-92.
10 Bagan JV, Jimenez Y, Murillo J, Gavaldá C, Poveda R, Scully C, et al. Lack of association between proliferative verrucous leukoplakia and human papillomavirus infection. J Oral Maxillofac Surg. 2007;65:46-9.
11 Klanrit P, Sperandio M, Brown AL, Shirlaw PJ, Challacombe SJ, Morgan PR, et al. DNA ploidy in proliferative verrucous leukoplakia. Oral Oncol. 2007;43:310-6.
12 Morton TH, Cabay RJ, Epstein JB. Proliferative verrucous leukoplakia and its progression to oral carcinoma: report of three cases. J Oral Pathol Med. 2007;36:315-8.
13 Gandolfo S, Castellani R, Pentenero M. Proliferative verrucous leukoplakia: a potentially malignant disorder involving periodontal sites. J Periodontol. 2009;80:274-81.
14 Bagan JV, Jiménez-Soriano Y, Diaz-Fernandez JM, Murillo-Cortés J, Sanchis-Bielsa JM, Poveda-Roda R, et al. Malignant transformation of proliferative verrucous leukoplakia to oral squamous cell carcinoma: a series of 55 cases. Oral Oncol. 2011;47:732-5.-1515 Kahn MA, Dockter ME, Hermann-Petrin JM. Proliferative verrucous leukoplakia. Four cases with flow cytometric analysis. Oral Surg Oral Med Oral Pathol. 1994;78:469-75. Several studies evaluated alcohol use by PVL patients, but the relation between them was not stablished (Table 1).11 Campisi G, Giovannelli L, Ammatuna P, Capra G, Colella G, Di Liberto C, et al. Proliferative verrucous vs conventional leukoplakia: no significantly increased risk of HPV infection. Oral Oncol. 2004;40:835-40.,99 Ghazali N, Bakri MM, Zain RB. Aggressive, multifocal oral verrucous leukoplakia: proliferative verrucous leukoplakia or not?. J Oral Pathol Med. 2003;32:383-92.,1111 Klanrit P, Sperandio M, Brown AL, Shirlaw PJ, Challacombe SJ, Morgan PR, et al. DNA ploidy in proliferative verrucous leukoplakia. Oral Oncol. 2007;43:310-6.,1313 Gandolfo S, Castellani R, Pentenero M. Proliferative verrucous leukoplakia: a potentially malignant disorder involving periodontal sites. J Periodontol. 2009;80:274-81.
In recent years, it has been hypothesized that human papillomavirus (HPV) may influence both potentially and already stablished oral malignant lesions.1616 Bouda M, Gorgoulis VG, Kastrinakis NG, Giannoudis A, Efthymia T, Danassi-Afentaki D, et al. High risk' HPV types are frequently detected in potentially malignant and malignant oral lesions, but not in normal oral mucosa. Mod Pathol. 2000;13:644-53. Although the association between oral squamous cell carcinoma (OSCC) and HPV is already mentioned, its influence on PVL cases is not confirmed yet.1717 Ostwald C, Rutsatz K, Schweder J, Schmidt W, Gundlach K, Barten M. Human papillomavirus 6/11, 16 and 18 in oral carcinomas and benign oral lesions. Med Microbiol Immunol. 2003;192:145-8. Over the last decades, some studies reported different and contradictory frequencies of HPV DNA detection in PVL (Table 2).11 Campisi G, Giovannelli L, Ammatuna P, Capra G, Colella G, Di Liberto C, et al. Proliferative verrucous vs conventional leukoplakia: no significantly increased risk of HPV infection. Oral Oncol. 2004;40:835-40.,77 Fettig A, Pogrel MA, Silverman S, Bramanti TE, Costa MD, Regezi JA. Proliferative verrucous leukoplakia of the gingiva. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2000;90:723-30.,1010 Bagan JV, Jimenez Y, Murillo J, Gavaldá C, Poveda R, Scully C, et al. Lack of association between proliferative verrucous leukoplakia and human papillomavirus infection. J Oral Maxillofac Surg. 2007;65:46-9.,1818 Palefsky JM, Silverman S, Abdel-Salaam M, Daniels TE, Greenspan JS. Association between proliferative verrucous leukoplakia and infection with human papillomavirus type 16. J Oral Pathol Med. 1995;24:193-7.,1919 Gopalakrishnan R, Weghorst CM, Lehman TA, Calvert RJ, Bijur G, Sabourin CLK, et al. Mutated and wild-type p53 expression and HPV integration in proliferative verrucous leukoplakia and oral squamous cell carcinoma. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1997;83:471-7.
About other possible etiologies, there are few studies with PVL that tried to identify the presence of Candida albicans. Silverman et al. (1997) reported 19 of 38 specimens with C. albicans positivity, but without correlation between the fungal infection and PVL occurrence or progression to carcinoma, characterizing it as a probable secondary infection.66 Silverman S, Gorsky M. Proliferative verrucous leukoplakia: a follow-up study of 54 cases. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1997;84:154-7. Similarly, Hansen et al. (1985) observed that 12 of 30 patients were positive for C. albicans.22 Hansen LS, Olson JA, Silverman S. Proliferative verrucous leukoplakia. A long-term study of thirty patients. Oral Surg Oral Med Oral Pathol. 1985;60:285-98. Concerning to Epstein Barr Virus (EBV), Bagan et al. (2008) was the only one to detect EBV in a PVL group (60% of 6 patients).2020 Bagan J, Jiménez Y, Murillo J, Poveda R, Díaz JM, Gavaldá C, et al. Epstein-Barr virus in oral proliferative verrucous leukoplakia and squamous cell carcinoma: a preliminary study. Med Oral Patol Oral Cir Bucal. 2008;13:110-3. Therefore, none of these studies have yet established the exact role of microbiological agents in PVL pathogenesis.
Epidemiological and clinical characteristics
In the studies evaluated in this paper, PVL occurred predominantly in women, with a 2.72:1 (female/male) rate, and a mean age of 66.8 years (Table 1). 11 Campisi G, Giovannelli L, Ammatuna P, Capra G, Colella G, Di Liberto C, et al. Proliferative verrucous vs conventional leukoplakia: no significantly increased risk of HPV infection. Oral Oncol. 2004;40:835-40.,22 Hansen LS, Olson JA, Silverman S. Proliferative verrucous leukoplakia. A long-term study of thirty patients. Oral Surg Oral Med Oral Pathol. 1985;60:285-98.,55 Zakrzewska JM, Lopes V, Speight P, Hopper C. Proliferative verrucous leukoplakia: a report of ten cases. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1996;82:396-401.
6 Silverman S, Gorsky M. Proliferative verrucous leukoplakia: a follow-up study of 54 cases. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1997;84:154-7.
7 Fettig A, Pogrel MA, Silverman S, Bramanti TE, Costa MD, Regezi JA. Proliferative verrucous leukoplakia of the gingiva. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2000;90:723-30.
8 Bagan JV, Jimenez Y, Sanchis JM, Poveda R, Milian MA, Murillo J, et al. Proliferative verrucous leukoplakia: high incidence of gingival squamous cell carcinoma. J Oral Pathol Med. 2003;32:379-82.
9 Ghazali N, Bakri MM, Zain RB. Aggressive, multifocal oral verrucous leukoplakia: proliferative verrucous leukoplakia or not?. J Oral Pathol Med. 2003;32:383-92.
10 Bagan JV, Jimenez Y, Murillo J, Gavaldá C, Poveda R, Scully C, et al. Lack of association between proliferative verrucous leukoplakia and human papillomavirus infection. J Oral Maxillofac Surg. 2007;65:46-9.
11 Klanrit P, Sperandio M, Brown AL, Shirlaw PJ, Challacombe SJ, Morgan PR, et al. DNA ploidy in proliferative verrucous leukoplakia. Oral Oncol. 2007;43:310-6.
12 Morton TH, Cabay RJ, Epstein JB. Proliferative verrucous leukoplakia and its progression to oral carcinoma: report of three cases. J Oral Pathol Med. 2007;36:315-8.
13 Gandolfo S, Castellani R, Pentenero M. Proliferative verrucous leukoplakia: a potentially malignant disorder involving periodontal sites. J Periodontol. 2009;80:274-81.
14 Bagan JV, Jiménez-Soriano Y, Diaz-Fernandez JM, Murillo-Cortés J, Sanchis-Bielsa JM, Poveda-Roda R, et al. Malignant transformation of proliferative verrucous leukoplakia to oral squamous cell carcinoma: a series of 55 cases. Oral Oncol. 2011;47:732-5.-1515 Kahn MA, Dockter ME, Hermann-Petrin JM. Proliferative verrucous leukoplakia. Four cases with flow cytometric analysis. Oral Surg Oral Med Oral Pathol. 1994;78:469-75.,2121 Gouvêa AF, Santos Silva AR, Speight PM, Hunter K, Carlos R, Vargas PA, et al. High incidence of DNA ploidy abnormalities and increased Mcm2 expression may predict malignant change in oral proliferative verrucous leukoplakia. Histopathology. 2013;62:551-62. The most affected sites were gingiva, 88 Bagan JV, Jimenez Y, Sanchis JM, Poveda R, Milian MA, Murillo J, et al. Proliferative verrucous leukoplakia: high incidence of gingival squamous cell carcinoma. J Oral Pathol Med. 2003;32:379-82.
9 Ghazali N, Bakri MM, Zain RB. Aggressive, multifocal oral verrucous leukoplakia: proliferative verrucous leukoplakia or not?. J Oral Pathol Med. 2003;32:383-92.-1010 Bagan JV, Jimenez Y, Murillo J, Gavaldá C, Poveda R, Scully C, et al. Lack of association between proliferative verrucous leukoplakia and human papillomavirus infection. J Oral Maxillofac Surg. 2007;65:46-9.,1212 Morton TH, Cabay RJ, Epstein JB. Proliferative verrucous leukoplakia and its progression to oral carcinoma: report of three cases. J Oral Pathol Med. 2007;36:315-8.,1414 Bagan JV, Jiménez-Soriano Y, Diaz-Fernandez JM, Murillo-Cortés J, Sanchis-Bielsa JM, Poveda-Roda R, et al. Malignant transformation of proliferative verrucous leukoplakia to oral squamous cell carcinoma: a series of 55 cases. Oral Oncol. 2011;47:732-5.,1515 Kahn MA, Dockter ME, Hermann-Petrin JM. Proliferative verrucous leukoplakia. Four cases with flow cytometric analysis. Oral Surg Oral Med Oral Pathol. 1994;78:469-75. buccal mucosa,22 Hansen LS, Olson JA, Silverman S. Proliferative verrucous leukoplakia. A long-term study of thirty patients. Oral Surg Oral Med Oral Pathol. 1985;60:285-98.,55 Zakrzewska JM, Lopes V, Speight P, Hopper C. Proliferative verrucous leukoplakia: a report of ten cases. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1996;82:396-401.,66 Silverman S, Gorsky M. Proliferative verrucous leukoplakia: a follow-up study of 54 cases. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1997;84:154-7. and alveolar ridge, 1111 Klanrit P, Sperandio M, Brown AL, Shirlaw PJ, Challacombe SJ, Morgan PR, et al. DNA ploidy in proliferative verrucous leukoplakia. Oral Oncol. 2007;43:310-6.,1313 Gandolfo S, Castellani R, Pentenero M. Proliferative verrucous leukoplakia: a potentially malignant disorder involving periodontal sites. J Periodontol. 2009;80:274-81. while the tongue was less involved.2121 Gouvêa AF, Santos Silva AR, Speight PM, Hunter K, Carlos R, Vargas PA, et al. High incidence of DNA ploidy abnormalities and increased Mcm2 expression may predict malignant change in oral proliferative verrucous leukoplakia. Histopathology. 2013;62:551-62.
Zakrzewska et al. (1996) observed that initial PVL clinical features included small whitish and well-defined signs of non-homogeneous leukoplakic lesions with speckled pattern.55 Zakrzewska JM, Lopes V, Speight P, Hopper C. Proliferative verrucous leukoplakia: a report of ten cases. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1996;82:396-401. According to Ghazali et al. (2003), PVL initially presents as unifocal, homogeneous, slow and persistent growth lesion.99 Ghazali N, Bakri MM, Zain RB. Aggressive, multifocal oral verrucous leukoplakia: proliferative verrucous leukoplakia or not?. J Oral Pathol Med. 2003;32:383-92. At this stage, it is extremely difficult, if not impossible, to distinguish it from oral leukoplakia. PVL has one or more areas of homogeneous leukoplakia, which grows slowly and persistently, and tends to become multifocal with exophytic, verrucous, or erythematous areas.2222 Bagan J, Scully C, Jimenez Y, Martorell M. Proliferative verrucous leukoplakia: a concise update. Oral Dis. 2010;16:328-32. After a long period, commonly six years, the evolution to carcinoma occurs.2323 Cerero-Lapiedra R, Balade-Martinez D, Moreno-Lopez L, Esparza-Gomez G, Bagan J. Proliferative verrucous leukoplakia: a proposal for diagnostic criteria. Med Oral Patol Oral Cir Bucal. 2010;15:839-45. Areas that are erythematous, verrucous or have papillary surface are characteristic of malignant transformation, and so these areas should have a histopathological confirmation (Fig. 1).2323 Cerero-Lapiedra R, Balade-Martinez D, Moreno-Lopez L, Esparza-Gomez G, Bagan J. Proliferative verrucous leukoplakia: a proposal for diagnostic criteria. Med Oral Patol Oral Cir Bucal. 2010;15:839-45.
(A) Proliferative verrucous leukoplakia (PVL) in the lower attached gingival, vestibular sulcus and gradually extended along left alveolar ridge. (B) PVL in the buccal mucosa with different clinical patterns: larger areas of homogeneous leukoplakias and spot areas of thickening of the keratinization and/verrucous surface. (C and D) PVL in ventral tongue and floor of mouth with exophytic appearance and focal area of granular pattern in both alveolar ridges. (E) Histopathological view showing acanthosis and hyperkeratosis with mild dyplasia. (F) Exophytic, hyperkeratotic lesion with prominent verruciform or papillary surface and acanthosis forming blunt projections into the lamina propria. (G) Hyperkeratosis, acanthosis, irregularity of the basal layer and some areas of epithelial atrophy. (H) Hyperkeratosis with droplet-shaped epithelial projections and intact lamina propria (HE, original magnification 40×).
Recently, a PVL subtype designated proliferative verrucous leukoplakia of the gingiva (PVLG) has been reported as involving exclusively free and attached gingiva. PVLG is characterized as a whitish plaque, unifocal, recurrent and progressive lesion. The course is also unpredictable and may undergo OSCC or verrucous carcinoma (VC) transformation.77 Fettig A, Pogrel MA, Silverman S, Bramanti TE, Costa MD, Regezi JA. Proliferative verrucous leukoplakia of the gingiva. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2000;90:723-30.
As the evolution stages of different sites in multifocal lesions are not necessarily the same, patients should be monitored closely, with frequent and repetitive biopsies when there are changes in color, appearance or size, and when new lesions appear. 99 Ghazali N, Bakri MM, Zain RB. Aggressive, multifocal oral verrucous leukoplakia: proliferative verrucous leukoplakia or not?. J Oral Pathol Med. 2003;32:383-92.,2424 Bagán J, Murillo JM, Poveda R, Gavaldá C, Jiménez Y, Scully C. Proliferative verrucous leukoplakia: unusual locations of oral squamous cell carcinomas, and field cancerization as shown by the appearance of multiple OSCCs. Oral Oncol. 2004;40:440-3.,2525 Bishen K, Sethi A. Proliferative verrucous leukoplakia - diagnostic pitfalls and suggestions. Med Oral Patol Oral Cir Bucal. 2009;14:263-4. Patients with whitish harmless appearance and recurrence episodes should also be followed up every six months.2525 Bishen K, Sethi A. Proliferative verrucous leukoplakia - diagnostic pitfalls and suggestions. Med Oral Patol Oral Cir Bucal. 2009;14:263-4. PVL may progress to VC or OSCC over time in spite of numerous treatment interventions, suggesting that PVL is associated with diffuse submicroscopic changes of the oral mucosa, sometimes described as "field cancerization".2424 Bagán J, Murillo JM, Poveda R, Gavaldá C, Jiménez Y, Scully C. Proliferative verrucous leukoplakia: unusual locations of oral squamous cell carcinomas, and field cancerization as shown by the appearance of multiple OSCCs. Oral Oncol. 2004;40:440-3. Therefore, PVL presents a high malignant transformation rate (Table 1).2626 Liu W, Wang YF, Zhou HW, Shi P, Zhou ZT, Tang GY. Malignant transformation of oral leukoplakia: a retrospective cohort study of 218 Chinese patients. BMC Cancer. 2010;10:685-91.
Histopathology
Histopathological findings may show acanthosis and hyperkeratosis with an interface lymphocytic infiltrate within the superficial lamina propria. If the lesions continue to grow horizontally and vertically, there are histopathological changes that increase roughness of surface with verrucous aspect, and hyperplasia with or without dysplasia.1212 Morton TH, Cabay RJ, Epstein JB. Proliferative verrucous leukoplakia and its progression to oral carcinoma: report of three cases. J Oral Pathol Med. 2007;36:315-8. Therefore, over time and without treatment, there is an inexorable progression to VC or OSCC (Fig. 1).55 Zakrzewska JM, Lopes V, Speight P, Hopper C. Proliferative verrucous leukoplakia: a report of ten cases. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1996;82:396-401.,1212 Morton TH, Cabay RJ, Epstein JB. Proliferative verrucous leukoplakia and its progression to oral carcinoma: report of three cases. J Oral Pathol Med. 2007;36:315-8.,2222 Bagan J, Scully C, Jimenez Y, Martorell M. Proliferative verrucous leukoplakia: a concise update. Oral Dis. 2010;16:328-32.,2727 Cabay RJ, Morton TH, Epstein JB. Proliferative verrucous leukoplakia and its progression to oral carcinoma: a review of the literature. J Oral Pathol Med. 2007;36:255-61.
Hansen et al. (1985) described the histopathological progression of PVL in 10 stages during its clinical course.22 Hansen LS, Olson JA, Silverman S. Proliferative verrucous leukoplakia. A long-term study of thirty patients. Oral Surg Oral Med Oral Pathol. 1985;60:285-98. This classification divided PVL in five groups: hyperkeratosis, verrucous hyperplasia (VH), VC, papillary squamous cell carcinoma and OSCC poorly differentiated, with intermediate stages. Frequently the lesions move slowly up in grade, with very few reverting cases. However, Murrah and Batsakis (1999) reduced the number of histologic stages to four, removing the intermediate stages, and proposed a review that omitted papillary squamous cell carcinoma considering it a PVL independent entity more frequent in the oropharynx.2828 Murrah VA, Batsakis JG. Proliferative verrucous leukoplakia and verrucous hyperplasia. Ann Otol Rhinol Laryngol. 1994;103:660-3. Batsakis et al. (1999) also considered the possible removal of VH since it has much in common with VC, but with an exophytic growth pattern in VH in opposition to an endophytic growth pattern in VC (Fig. 2).2929 Batsakis JG, Suarez P, El-naggar AK. Proliferative verrucous leukoplakia and its related lesions. Oral Oncol. 1999;35:354-9.
Histologic stages of progression to carcinoma. Adapted from Ghazali et al. (2003).99 Ghazali N, Bakri MM, Zain RB. Aggressive, multifocal oral verrucous leukoplakia: proliferative verrucous leukoplakia or not?. J Oral Pathol Med. 2003;32:383-92.
Biomarkers
Recent findings have indicated that carcinogenesis is a result of accumulated genetic and epigenetic alterations that may lead to chromosomal instability, in the form of numerical or structural aberrations, which might be detected as abnormal DNA content or aneuploidy.3030 Torres-Rendon A, Roy S, Craig GT, Speight PM. Expression of Mcm2, geminin and Ki67 in normal oral mucosa, oral epithelial dysplasias and their corresponding squamous-cell carcinomas. Br J Cancer. 2009;100:1128-34. Ploidy analysis in PVL was performed in three different studies with a high prevalence. Khan et al. (1994) analyzed 4 PVL by flow cytometry and found DNA aneuploid in all cases.1515 Kahn MA, Dockter ME, Hermann-Petrin JM. Proliferative verrucous leukoplakia. Four cases with flow cytometric analysis. Oral Surg Oral Med Oral Pathol. 1994;78:469-75. Klanrit et al. (2007) analyzed 6 paraffin-embedded PVL samples and detected 4 (66.6%) cases with abnormal ploidy status prior to malignant transformation.1111 Klanrit P, Sperandio M, Brown AL, Shirlaw PJ, Challacombe SJ, Morgan PR, et al. DNA ploidy in proliferative verrucous leukoplakia. Oral Oncol. 2007;43:310-6. Gouvea et al. (2013) analyzed DNA of 20 patients with PVL and 19 (95%) cases showed aneuploidy, with abnormal DNA observed even in the more indolent lesions.2121 Gouvêa AF, Santos Silva AR, Speight PM, Hunter K, Carlos R, Vargas PA, et al. High incidence of DNA ploidy abnormalities and increased Mcm2 expression may predict malignant change in oral proliferative verrucous leukoplakia. Histopathology. 2013;62:551-62.
Therefore, several studies have been conducted to determine whether improved expression levels of some molecular markers involved in different cellular pathways can be valuable indicators of clinical behavior.3131 Pitiyage G, Tilakaratne WM, Tavassoli M, Warnakulasuriya S. Molecular markers in oral epithelial dysplasia: review. J Oral Pathol Med. 2009;38:737-52. Gopalakrishnan et al. (1997) studied p53 expression in 10 samples and found minimal markup in normal oral mucosa, but positivity in 8 (80%) of the cases of PVL, and in 7 (70%) of the cases of OSCC.1919 Gopalakrishnan R, Weghorst CM, Lehman TA, Calvert RJ, Bijur G, Sabourin CLK, et al. Mutated and wild-type p53 expression and HPV integration in proliferative verrucous leukoplakia and oral squamous cell carcinoma. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1997;83:471-7. Fettig et al. (2000) identified p53 expression in 4 (40%) of the 10 analyzed cases.77 Fettig A, Pogrel MA, Silverman S, Bramanti TE, Costa MD, Regezi JA. Proliferative verrucous leukoplakia of the gingiva. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2000;90:723-30. Gouvea et al. (2013) showed p53 immunoreactivity in 14 (77.7%) of the 18 cases.3232 Gouvêa AF, Vargas PA, Coletta RD, Jorge J, Lopes MA. Clinicopathological features and immunohistochemical expression of p53, Ki-67, Mcm-2 and Mcm-5 in proliferative verrucous leukoplakia. J Oral Pathol Med. 2010;39:447-52. In the same study Ki-67 expression was similar to the one observed with p53 protein progression of epithelial dysplasia in PVL. Ki-67 is a nuclear protein associated with cellular proliferation with potential predictive biomarker in early stages of OSCC and can be used in addition to conventional tumor staging for optimal therapeutic management.3333 Yu YH, Morales J, Feng L, Lee JJ, El-Naggar AK, Vigneswaran N. CD147 and Ki-67 overexpression confers poor prognosis in squamous cell carcinoma of oral tongue: a tissue microarray study. Oral Surg Oral Med Oral Pathol Oral Radiol. 2015;119:553-65. Akrish et al. (2015) realized a retrospective review of 11 patients with PVL, 38 with carcinoma arising in patients with PVL (P-SCC) and 49 with conventional squamous cell carcinoma (C-SCC).3434 Akrish S, Ben-Izhak O, Sabo E, Rachmiel A. Oral squamous cell carcinoma associated with proliferative verrucous leukoplakia compared with conventional squamous cell carcinoma-a clinical, histologic and immunohistochemical study. Oral Surg Oral Med Oral Pathol Oral Radiol. 2015;119:318-25. Overexpression of p53 was more common in P-SCC, but without ki-67 or p16 overexpression. Krest et al. (2014) evaluated cell cycle regulatory genes in 20 PVL cases and detected deletion or mutation event involving both p16INK4a and p14ARF genes in 45% of the cases.3535 Kresty L, Mallery SR, Knobloch TJ, Li J, Lloyd M, Casto BC, et al. Frequent alterations of p16INK4a and p14ARF in oral proliferative verrucous leukoplakia. Cancer Epidemiol Biomarkers Prev. 2008;17:3179-87.
Diagnostic criteria
Hansen et al. (1985) determined that lesions diagnosed as PVL could have initially a homogeneous aspect, without dysplasia, followed by warty appearance of surface areas and multiple discrete or confluent lesions in single or multiple intra-oral sites.22 Hansen LS, Olson JA, Silverman S. Proliferative verrucous leukoplakia. A long-term study of thirty patients. Oral Surg Oral Med Oral Pathol. 1985;60:285-98.
According to Cerero-Lapiedra et al. (2010), studies published on PVL followed the diagnostic criterion postulated by Hansen et al. (1985).22 Hansen LS, Olson JA, Silverman S. Proliferative verrucous leukoplakia. A long-term study of thirty patients. Oral Surg Oral Med Oral Pathol. 1985;60:285-98.,2323 Cerero-Lapiedra R, Balade-Martinez D, Moreno-Lopez L, Esparza-Gomez G, Bagan J. Proliferative verrucous leukoplakia: a proposal for diagnostic criteria. Med Oral Patol Oral Cir Bucal. 2010;15:839-45. It is a pioneering and comprehensive description, but still needs updates. Therefore, the same authors proposed the reformulation of the criteria by dividing them into major (five criteria) and minor (four criteria) (Table 3). To PVL diagnosis, patient should have one of the following combinations:
Proposal of major and minor diagnostic criteria for PVL recommended by Cerero-Lapiedra et al. (2010).2323 Cerero-Lapiedra R, Balade-Martinez D, Moreno-Lopez L, Esparza-Gomez G, Bagan J. Proliferative verrucous leukoplakia: a proposal for diagnostic criteria. Med Oral Patol Oral Cir Bucal. 2010;15:839-45. Adapted from Carrard et al.3636 Carrard V, Brouns E, Van der Waal I. Proliferative verrucous leukoplakia; a critical appraisal of the diagnostic criteria. Med Oral Patol Oral Cir Bucal. 2013;18:411-3.
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Three major criteria (one of which must include the evolution of the histopathological lesions).
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Two major criteria (one of which must include the evolution of the histopathological lesions) + two minor criteria.
Bagan et al. (2011) believed that these criteria are useful only for those with clinical experience with PVL, but can be confusing for beginners.1414 Bagan JV, Jiménez-Soriano Y, Diaz-Fernandez JM, Murillo-Cortés J, Sanchis-Bielsa JM, Poveda-Roda R, et al. Malignant transformation of proliferative verrucous leukoplakia to oral squamous cell carcinoma: a series of 55 cases. Oral Oncol. 2011;47:732-5. Corroborating with this observation, Carrard et al. (2013) suggested simplifying the diagnostic criteria by omitting the distinction between major and minor criteria. However, all four criteria should be met (Table 4).3636 Carrard V, Brouns E, Van der Waal I. Proliferative verrucous leukoplakia; a critical appraisal of the diagnostic criteria. Med Oral Patol Oral Cir Bucal. 2013;18:411-3.
Modified diagnostic criteria for PVL recommended by Carrard et al. (2013).3636 Carrard V, Brouns E, Van der Waal I. Proliferative verrucous leukoplakia; a critical appraisal of the diagnostic criteria. Med Oral Patol Oral Cir Bucal. 2013;18:411-3. Adapted from Carrard et al.3636 Carrard V, Brouns E, Van der Waal I. Proliferative verrucous leukoplakia; a critical appraisal of the diagnostic criteria. Med Oral Patol Oral Cir Bucal. 2013;18:411-3.
Treatment and recurrence
This literature review (Table 5) showed different treatments modalities. Surgery and laser ablation were the most used. Ten papers utilized surgery in 136 cases22 Hansen LS, Olson JA, Silverman S. Proliferative verrucous leukoplakia. A long-term study of thirty patients. Oral Surg Oral Med Oral Pathol. 1985;60:285-98.,55 Zakrzewska JM, Lopes V, Speight P, Hopper C. Proliferative verrucous leukoplakia: a report of ten cases. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1996;82:396-401.,66 Silverman S, Gorsky M. Proliferative verrucous leukoplakia: a follow-up study of 54 cases. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1997;84:154-7.
7 Fettig A, Pogrel MA, Silverman S, Bramanti TE, Costa MD, Regezi JA. Proliferative verrucous leukoplakia of the gingiva. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2000;90:723-30.
8 Bagan JV, Jimenez Y, Sanchis JM, Poveda R, Milian MA, Murillo J, et al. Proliferative verrucous leukoplakia: high incidence of gingival squamous cell carcinoma. J Oral Pathol Med. 2003;32:379-82.-99 Ghazali N, Bakri MM, Zain RB. Aggressive, multifocal oral verrucous leukoplakia: proliferative verrucous leukoplakia or not?. J Oral Pathol Med. 2003;32:383-92.,1111 Klanrit P, Sperandio M, Brown AL, Shirlaw PJ, Challacombe SJ, Morgan PR, et al. DNA ploidy in proliferative verrucous leukoplakia. Oral Oncol. 2007;43:310-6.,1212 Morton TH, Cabay RJ, Epstein JB. Proliferative verrucous leukoplakia and its progression to oral carcinoma: report of three cases. J Oral Pathol Med. 2007;36:315-8.,1414 Bagan JV, Jiménez-Soriano Y, Diaz-Fernandez JM, Murillo-Cortés J, Sanchis-Bielsa JM, Poveda-Roda R, et al. Malignant transformation of proliferative verrucous leukoplakia to oral squamous cell carcinoma: a series of 55 cases. Oral Oncol. 2011;47:732-5.,1515 Kahn MA, Dockter ME, Hermann-Petrin JM. Proliferative verrucous leukoplakia. Four cases with flow cytometric analysis. Oral Surg Oral Med Oral Pathol. 1994;78:469-75. and seven papers used laser ablation in 64 cases.22 Hansen LS, Olson JA, Silverman S. Proliferative verrucous leukoplakia. A long-term study of thirty patients. Oral Surg Oral Med Oral Pathol. 1985;60:285-98.,55 Zakrzewska JM, Lopes V, Speight P, Hopper C. Proliferative verrucous leukoplakia: a report of ten cases. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1996;82:396-401.,77 Fettig A, Pogrel MA, Silverman S, Bramanti TE, Costa MD, Regezi JA. Proliferative verrucous leukoplakia of the gingiva. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2000;90:723-30.,88 Bagan JV, Jimenez Y, Sanchis JM, Poveda R, Milian MA, Murillo J, et al. Proliferative verrucous leukoplakia: high incidence of gingival squamous cell carcinoma. J Oral Pathol Med. 2003;32:379-82.,1111 Klanrit P, Sperandio M, Brown AL, Shirlaw PJ, Challacombe SJ, Morgan PR, et al. DNA ploidy in proliferative verrucous leukoplakia. Oral Oncol. 2007;43:310-6.,1414 Bagan JV, Jiménez-Soriano Y, Diaz-Fernandez JM, Murillo-Cortés J, Sanchis-Bielsa JM, Poveda-Roda R, et al. Malignant transformation of proliferative verrucous leukoplakia to oral squamous cell carcinoma: a series of 55 cases. Oral Oncol. 2011;47:732-5.,1515 Kahn MA, Dockter ME, Hermann-Petrin JM. Proliferative verrucous leukoplakia. Four cases with flow cytometric analysis. Oral Surg Oral Med Oral Pathol. 1994;78:469-75. According to evaluated studies, with at least 30 patients, we found a recurrence mean rate of 85% for all treatment modalities isolated or associated.11 Campisi G, Giovannelli L, Ammatuna P, Capra G, Colella G, Di Liberto C, et al. Proliferative verrucous vs conventional leukoplakia: no significantly increased risk of HPV infection. Oral Oncol. 2004;40:835-40.,22 Hansen LS, Olson JA, Silverman S. Proliferative verrucous leukoplakia. A long-term study of thirty patients. Oral Surg Oral Med Oral Pathol. 1985;60:285-98.,66 Silverman S, Gorsky M. Proliferative verrucous leukoplakia: a follow-up study of 54 cases. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1997;84:154-7.,88 Bagan JV, Jimenez Y, Sanchis JM, Poveda R, Milian MA, Murillo J, et al. Proliferative verrucous leukoplakia: high incidence of gingival squamous cell carcinoma. J Oral Pathol Med. 2003;32:379-82.,1313 Gandolfo S, Castellani R, Pentenero M. Proliferative verrucous leukoplakia: a potentially malignant disorder involving periodontal sites. J Periodontol. 2009;80:274-81.,1414 Bagan JV, Jiménez-Soriano Y, Diaz-Fernandez JM, Murillo-Cortés J, Sanchis-Bielsa JM, Poveda-Roda R, et al. Malignant transformation of proliferative verrucous leukoplakia to oral squamous cell carcinoma: a series of 55 cases. Oral Oncol. 2011;47:732-5.
There are 2 descriptions about the association between surgery and laser ablation with no improvement.22 Hansen LS, Olson JA, Silverman S. Proliferative verrucous leukoplakia. A long-term study of thirty patients. Oral Surg Oral Med Oral Pathol. 1985;60:285-98.,55 Zakrzewska JM, Lopes V, Speight P, Hopper C. Proliferative verrucous leukoplakia: a report of ten cases. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1996;82:396-401. Zakrzewska et al. (1996) showed one patient with no recurrence at the laser-treated sites, but new lesions developed elsewhere.55 Zakrzewska JM, Lopes V, Speight P, Hopper C. Proliferative verrucous leukoplakia: a report of ten cases. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1996;82:396-401. Bagan et al. (2003), after treating 24 patients (80%) with surgery and 18 (60%) with laser ablation, detected recurrence rate of 86.7% and recognized new lesions in 83.3%.88 Bagan JV, Jimenez Y, Sanchis JM, Poveda R, Milian MA, Murillo J, et al. Proliferative verrucous leukoplakia: high incidence of gingival squamous cell carcinoma. J Oral Pathol Med. 2003;32:379-82. Fettig et al. (2000) identified that both simple excision and laser excision were ineffective in eradicating lesions.77 Fettig A, Pogrel MA, Silverman S, Bramanti TE, Costa MD, Regezi JA. Proliferative verrucous leukoplakia of the gingiva. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2000;90:723-30. Surgery, despite high recurrence rates, gives the possibility of dysplasia histologic grading and early detection of malignant transformation. Laser ablation should be indicated for lesions where the surgery would be contraindicated by lesion size or access difficulty. Development of new lesions in these patients is constant; thus, multiple interventions are always necessary.
Hansen et al. (1985) utilized radiation in 16 patients and chemotherapy in 6, with only one patient free of PVL at 6 years after treatment; therefore, they concluded that radiation therapy is not entirely satisfactory in a widespread disease such as PVL.22 Hansen LS, Olson JA, Silverman S. Proliferative verrucous leukoplakia. A long-term study of thirty patients. Oral Surg Oral Med Oral Pathol. 1985;60:285-98. In spite of these results, others papers reported the association between radiation and surgery to treat PVL, totaling 24 cases described in the literature.22 Hansen LS, Olson JA, Silverman S. Proliferative verrucous leukoplakia. A long-term study of thirty patients. Oral Surg Oral Med Oral Pathol. 1985;60:285-98.,55 Zakrzewska JM, Lopes V, Speight P, Hopper C. Proliferative verrucous leukoplakia: a report of ten cases. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1996;82:396-401.,66 Silverman S, Gorsky M. Proliferative verrucous leukoplakia: a follow-up study of 54 cases. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1997;84:154-7. Silverman et al. (1997) reported that radiation was not effective in controlling PVL based on the lack of response of the cases treated with radiotherapy.66 Silverman S, Gorsky M. Proliferative verrucous leukoplakia: a follow-up study of 54 cases. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1997;84:154-7. Zakrzewska et al. (1996) treated one patient with radiotherapy, but lesions continued to appear throughout the mouth.55 Zakrzewska JM, Lopes V, Speight P, Hopper C. Proliferative verrucous leukoplakia: a report of ten cases. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1996;82:396-401. One patient also received a limited course of chemotherapy, but new lesions appeared, demonstrating the ineffectiveness of these treatment. Radiotherapy or chemotherapy did not show improvement in lesion recurrence, and showed severe side effects such as mucositis, infection, and salivary gland problems.
Extensive surgery such as resection was performed in only one case by Fettig et al. (2000).77 Fettig A, Pogrel MA, Silverman S, Bramanti TE, Costa MD, Regezi JA. Proliferative verrucous leukoplakia of the gingiva. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2000;90:723-30. According to the authors, local block resection was required to prevent recurrences. In spite of this report, one case is not sufficient to confirm the potential of this therapy modality. In addition to its radical and debilitating characteristic, extensive resection is only acceptable when OSCC transformation with bone invasion is present.
Photodynamic therapy (PDT) associated to laser ablation would appear to offer slight improvement prognosis, because it makes treatment of multifocal areas possible with acceptable morbidity, but it did not prevent new lesions and until the moment there is only one study demonstrating its efficacy.55 Zakrzewska JM, Lopes V, Speight P, Hopper C. Proliferative verrucous leukoplakia: a report of ten cases. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1996;82:396-401.
A preliminary study of Poveda-Roda et al. (2010) revealed that topical or systemic retinoic acid produces improvement in about one-third of all patients with PVL, but clinical worsening was recorded in another third of cases.3737 Poveda-Roda R, Bagan J, Jimenez-Soriano Y, Diaz-Fernandez J, Gavalda-Esteve C. Retinoids and proliferative verrucous leukoplakia (PVL). A preliminary study. Med Oral Patol Oral Cir Bucal. 2010;15:3-9. Besides, further studies are needed to assess the safety of these products, because frequent adverse effects can occur. The most frequent adverse effects were cheilitis, desquamation, pruritus, alopecia and rhinitis, which coincided with the well-known retinoid side effects. However, two of the patients suffered serious problems not described in the Summary of Product Characteristics of the medication used; they developed intense rectal bleeding and cramps of the extremities that made standing and walking difficult. Suppression of the drug led to resolution of these manifestations.
Conclusion
Although there are not enough studies to determine PVL etiology and no simplified diagnosis criteria, the most difficult point is PVL treatment. According to the literature reviewed, PVL seems to be resistant to many therapy attempts and often has high propensity for dysplasia and/or malignancy progression. Modalities such as surgery, laser ablation, photodynamic therapy, retinoid, radiation and chemotherapy are not effective in reducing relapses and malignant transformation.
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Peer Review under the responsibility of Associação Brasileira de Otorrinolaringologia e Cirurgia Cérvico-Facial.
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☆
Please cite this article as: Capella DL, Gonçalves JM, Abrantes AA, Grando LJ, Daniel FI. Proliferative verrucous leukoplakia: diagnosis, management and current advances. Braz J Otorhinolaryngol. 2017;83:585-93.
Acknowledgment
We thank Professor Filipe Modolo Siqueira for technical assistance in reviewing histopathological findings and images.
References
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32Gouvêa AF, Vargas PA, Coletta RD, Jorge J, Lopes MA. Clinicopathological features and immunohistochemical expression of p53, Ki-67, Mcm-2 and Mcm-5 in proliferative verrucous leukoplakia. J Oral Pathol Med. 2010;39:447-52.
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33Yu YH, Morales J, Feng L, Lee JJ, El-Naggar AK, Vigneswaran N. CD147 and Ki-67 overexpression confers poor prognosis in squamous cell carcinoma of oral tongue: a tissue microarray study. Oral Surg Oral Med Oral Pathol Oral Radiol. 2015;119:553-65.
-
34Akrish S, Ben-Izhak O, Sabo E, Rachmiel A. Oral squamous cell carcinoma associated with proliferative verrucous leukoplakia compared with conventional squamous cell carcinoma-a clinical, histologic and immunohistochemical study. Oral Surg Oral Med Oral Pathol Oral Radiol. 2015;119:318-25.
-
35Kresty L, Mallery SR, Knobloch TJ, Li J, Lloyd M, Casto BC, et al. Frequent alterations of p16INK4a and p14ARF in oral proliferative verrucous leukoplakia. Cancer Epidemiol Biomarkers Prev. 2008;17:3179-87.
-
36Carrard V, Brouns E, Van der Waal I. Proliferative verrucous leukoplakia; a critical appraisal of the diagnostic criteria. Med Oral Patol Oral Cir Bucal. 2013;18:411-3.
-
37Poveda-Roda R, Bagan J, Jimenez-Soriano Y, Diaz-Fernandez J, Gavalda-Esteve C. Retinoids and proliferative verrucous leukoplakia (PVL). A preliminary study. Med Oral Patol Oral Cir Bucal. 2010;15:3-9.
Publication Dates
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Publication in this collection
Sep-Oct 2017
History
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Received
24 Feb 2016 -
Accepted
8 Dec 2016