Proliferative verrucous leukoplakia: diagnosis, management and current advances☆

Capella, Diogo Lenzi; Gonçalves, Jussara Maria; Abrantes, Adelino António Artur; Grando, Liliane Janete; Daniel, Filipe Ivan

doi:10.1016/j.bjorl.2016.12.005

Diogo Lenzi Capella

Universidade Federal de Santa Catarina (UFSC), Programa de Pós-graduação em Odontologia, Florianopolis, SC, Brazil

Jussara Maria Gonçalves

Universidade Federal de Santa Catarina (UFSC), Programa de Pós-graduação em Odontologia, Florianopolis, SC, Brazil

Adelino António Artur Abrantes

Universidade Federal de Santa Catarina (UFSC), Programa de Pós-graduação em Odontologia, Florianopolis, SC, Brazil

Liliane Janete Grando

Universidade Federal de Santa Catarina (UFSC), Departamento de Patologia, Florianopolis, SC, Brazil

Filipe Ivan Daniel ^** Corresponding author. E-mails:filipe.daniel@ufsc.brE-mail:filipedaniel06@gmail.com (F.I. Daniel).

Universidade Federal de Santa Catarina (UFSC), Departamento de Patologia, Florianopolis, SC, Brazil

* Corresponding author. E-mails:filipe.daniel@ufsc.brE-mail:filipedaniel06@gmail.com (F.I. Daniel).

Conflicts of interest

The authors declare no conflicts of interest.

Figures (2)
Tables (5)

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Figure 1
(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×).

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Figure 2
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.

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Table 1
Studies of PVL cases series.

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Table 2
Studies about HPV presence in PVL.

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Table 3
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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Table 4
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.

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Table 5
Treatments applied in cases series from literature.

Authors	No. of cases	Age Mean (range)	Sex (M/F)	Tobacco use	Alcohol use	Follow-up (years, mean)	Malignant transf.		Recurrence
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.	30	65.9 (27-90)	6/24	18	Non-reported	6.1^a a Follow up until the cure. ,^b b Follow up during proliferative verrucous leukoplakia progress. ,^d d Follow up until death.	VC	9	90%
	30	65.9 (27-90)	6/24	18	Non-reported		OSCC	17	90%
Kahn et al. (1994)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.	4	72.25 (75-79)	2/2	2	0	4^a a Follow up until the cure. ,^c c Follow up until malignant transformation.	VC	1	75%
	4	72.25 (75-79)	2/2	2	0		OSSC	2	75%
Zakrzewska et al. (1996)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.	10	63.6 (42-81)	5/5	7	Non-reported	7.5^a a Follow up until the cure. ,^b b Follow up during proliferative verrucous leukoplakia progress. ,^d d Follow up until death.	VC	4	90%
	10	63.6 (42-81)	5/5	7	Non-reported		OSCC	6	90%
Silverman and Gorsky (1997)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.	54	62 (22-89)	11/43	17	Non-reported	11.6^a a Follow up until the cure. ,^b b Follow up during proliferative verrucous leukoplakia progress. ,^d d Follow up until death.	OSCC	38	85%
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.	10	65.2 (51-82)	6/4	3	Non-reported	5^b b Follow up during proliferative verrucous leukoplakia progress. ,^c c Follow up until malignant transformation.	VC	3	100%
	10	65.2 (51-82)	6/4	3	Non-reported		OSCC	5	100%
Bagan et al. (2003)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.	30	70.97 (84-58)	6/24	7	Non-reported	4.7^b b Follow up during proliferative verrucous leukoplakia progress. ,^c c Follow up until malignant transformation.	VC	8	86.7%
	30	70.97 (84-58)	6/24	7	Non-reported		OSCC	19	86.7%
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.	9	61.6 (24-76)	2/7	4	1	4.7^b b Follow up during proliferative verrucous leukoplakia progress. ,^c c Follow up until malignant transformation.	VC	-	55.5%
	9	61.6 (24-76)	2/7	4	1		OSCC	-	55.5%
Campisi et al. (2004)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.	58	66.5 (54-79)	22/36	17	10	Non-reported	VC	3	Non-reported
	58	66.5 (54-79)	22/36	17	10	Non-reported	OSCC	22	Non-reported
Bagan et al. (2007)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.	13	68.3 (45-86)	0/13	3	Non-reported	Non-reported	OSCC	6	Non-reported
	13	68.3 (45-86)	0/13	3	Non-reported	Non-reported	VC	0	Non-reported
Klanrit et al. (2007)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.	6	65.8 (56-81)	1/5	1	1	6^c c Follow up until malignant transformation.	-	3	Non-reported
Morton et al. (2007)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.	3	80 (73-89)	1/2	1	Non-reported	3.7^c c Follow up until malignant transformation.	VC	1	66.6%
	3	80 (73-89)	1/2	1	Non-reported	3.7^c c Follow up until malignant transformation.	OSCC	2	66.6%
Gandolfo et al. (2009)¹³13 Gandolfo S, Castellani R, Pentenero M. Proliferative verrucous leukoplakia: a potentially malignant disorder involving periodontal sites. J Periodontol. 2009;80:274-81.	47	65.9 (40-86)	10/37	17	12	6.89^b b Follow up during proliferative verrucous leukoplakia progress. ,^c c Follow up until malignant transformation.	VC	9	Non-reported
	47	65.9 (40-86)	10/37	17	12		OSCC	32	Non-reported
Bagan et al. (2011)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.	55	61.69 (73-50)	19/36	20	Non-reported	7.53^b b Follow up during proliferative verrucous leukoplakia progress. ,^c c Follow up until malignant transformation.	OSCC	27	85%
Gouvêa et al. (2013)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.	21	65.5 (79-52)	3/18	Non-reported	Non-reported	7.38^b b Follow up during proliferative verrucous leukoplakia progress. ,^c c Follow up until malignant transformation.	OSCC	7	Non-reported
	21	65.5 (79-52)	3/18	Non-reported	Non-reported		VC	2

Author	No. of cases	HPV positive	HPV types
Palefsky et al. (1995)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.	9	8 (88.8%)	HPV 16 (n = 7; 77.7%)
	9	8 (88.8%)	HPV 18 (n = 1; 11.1%)
Gopalakrishnan et al. (1997)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.	10	2 (20%)	HPV 16 (n = 1; 10%)
	10	2 (20%)	HPV 18 (n = 1; 10%)
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.	10	0	-
Campisi et al. (2004)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.	58	14 (24.1%)	HPV18 (n = 10; 17.24%)
	58	14 (24.1%)	HPV 16 (n = 4; 6.8%)
Bagan et al. (2007)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.	13	0	-

Major criteria			Minor criteria
A	Leukoplakia lesion with more than two different oral sites. It is frequently found in the gingiva, alveolar processes and palate.	A	Oral leukoplakia lesion that occupies at least 3 cm when adding all the affected areas.
B	The existence of a verrucous area.	B	Female patient
C	Lesions that spread or engross during the disease development	C	Non-smoker patient (male or female).
D	There has been a recurrence in a previously treated area.	D	More than 5 years of evolution.
E	Can vary from simple epithelial hyperkeratosis to OSCC, whether in situ or infiltrating.	-	-

Treatment	Author	Number of cases	Total
Radiation	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.	18	18
Chemotherapy	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.	6	6
Surgery	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.	22	136
	Kann et al. (1994)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.	2
	Zakrzewska et al. (1996)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.	1
	Silverman and Gorsky (1997)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.	42
	Bagan et al. (2003)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.	24
	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.	8
	Klanrit et al. (2007)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.	6
	Morton et al. (2007)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.	2
	Bagan et al. (2011)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.	21
	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.	8
Surgery and radiation	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.	11	23
	Zakrzewska et al. (1996)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.	1
	Silverman and Gorsky (1997)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.	11
Surgery and ablation laser (CO₂)	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.	1	2
Surgery and ablation laser (CO₂)	Zakrzewska et al. (1996)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.	1	2
Ablation laser (CO₂)	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.	2	64
	Kahn et al. (1994)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.	2
	Zakrzewska et al. (1996)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.	2
	Bagan et al. (2003)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.	5
	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.	18
	Klanrit et al. (2007)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.	1
	Bagan et al. (2011)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.	34
Photodynamic therapy and laser ablation	Zakrzewska et al. (1996)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.	4	4
Block resection	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.	1	1
Retinoid	Poveda-Roda et al. (2010)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.	16	18
Retinoid	Hansen²2 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. (1985)	2	18

[1] * Corresponding author. E-mails:filipe.daniel@ufsc.brE-mail:filipedaniel06@gmail.com (F.I. Daniel).

Brasil

Brasil

Proliferative verrucous leukoplakia: diagnosis, management and current advances^☆ ☆ 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.

Abstract

Introduction:

Objective:

Methods:

Results:

Conclusion:

Brasil

Brasil

Proliferative verrucous leukoplakia: diagnosis, management and current advances☆ ☆ 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.

Abstract

Introduction:

Objective:

Methods:

Results:

Conclusion: