- Email: [email protected]
Great diversity of oncogenic human papillomaviruses is revealed in an outbreak of multifocal epithelial hyperplasia
Journal Pre-proof Great diversity of oncogenic human papillomaviruses is revealed in an outbreak of multifocal epithelial hyperplasia Sandra Margarita Jiménez Aguilar, DDS, Daniel Lizárraga Rodríguez, DDS, Víctor Fernando Muñoz Estrada, DDS, Silvestre Guadalupe Cázarez Salazar, MSc, Jesús Salvador Velarde Félix, PhD, Rocío Susana Méndez Martínez, PhD PII:
S0190-9622(19)33318-3
DOI:
https://doi.org/10.1016/j.jaad.2019.12.041
Reference:
YMJD 14094
To appear in:
Journal of the American Academy of Dermatology
Received Date: 25 October 2018 Revised Date:
16 December 2019
Accepted Date: 19 December 2019
Please cite this article as: Jiménez Aguilar SM, Rodríguez DL, Muñoz Estrada VF, Cázarez Salazar SG, Velarde Félix JS, Méndez Martínez RS, Great diversity of oncogenic human papillomaviruses is revealed in an outbreak of multifocal epithelial hyperplasia, Journal of the American Academy of Dermatology (2020), doi: https://doi.org/10.1016/j.jaad.2019.12.041. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier on behalf of the American Academy of Dermatology, Inc.
1
Article type: Research Letter
2 3
Title: Great diversity of oncogenic human papillomaviruses is revealed in an outbreak of multifocal epithelial hyperplasia.
4 5 6
Sandra Margarita Jiménez Aguilar,DDS1,Daniel Lizárraga Rodríguez,DDS1, Víctor Fernando Muñoz Estrada,DDS2, Silvestre Guadalupe Cázarez Salazar, MSc3, Jesús Salvador Velarde Félix, PhD4, Rocío Susana Méndez Martínez, PhD5.
7 8 9 10 11 12 13 14 15 16 17
1
18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39
Sandra Margarita Jiménez Aguilar, DDS. Facultad de Odontología Universidad Autónoma de Sinaloa. Calle Lic. Benito Juárez 426pte. Entre Donato Guerra y Vicente Riva Palacio. Colonia Centro. C.P.80000 Culiacán, Sinaloa, México. E-mail: [email protected]
Facultad de Odontología de la Universidad Autónoma de Sinaloa. Departamento de Dermatología y Micología del Centro de Investigación y Docencia en Ciencias de la Salud del Hospital Civil de Culiacán. Facultad de Medicina de la Universidad Autónoma de Sinaloa. 3 Departamento de Medicina Genómica del Hospital General de Culiacán (Servicios de Salud de Sinaloa) y Departamento de Ciencias de la Salud. Universidad Autónoma de Occidente. 4 Departamento de Medicina Genómica del Hospital General de Culiacán (Servicios de Salud de Sinaloa) y Escuela de Biomedicina (Universidad Autónoma de Sinaloa), Culiacán, Sinaloa, México. 5 Unidad de Investigación Biomédica en Cáncer, Subdirección de Investigación Básica, Instituto Nacional de Cancerología, SS, Ciudad de México, México. 2
Corresponding author:
Funding sources: None. Conflicts of Interest: None declared. Reprint requests: None. Manuscript word count: 370 words [excluding title, references and tables]. Abstract wordcount:0 Capsule summary word count:0 References:4 Figures: 1 Tables:1 Keywords: human papilloma virus; oral lesions; Heck's disease; multifocal epithelial hyperplasia; pediatric; oncogenic.
40
Great diversity of oncogenic human papillomaviruses is revealed in an outbreak of multifocal
41
epithelial hyperplasia
42
Multifocal epithelial hyperplasia (MEH; Heck disease) presents with multiple soft papules and plaques
43
on the oral mucosa due to infection with human papillomavirus (HPV), primarily types 13 and 32.1 To
44
date, only HPV type 13 has been identified in Mexican patients with MEH. The exact route of
45
transmission is unknown, although it may be associated with the common use of contaminated objects.2
46
In the Mexican indigenous population, genetic predisposition related to HLA alleles has been found.3
47 48
From 2011-2015, 336 children (159 girls, 177 boys) attending elementary school in Navolato, Sinaloa,
49
Mexico underwent oral examination. Oral lesions suggestive of MEH were identified in 33 individuals,
50
representing a prevalence of 9.8%; their parents denied a history of MEH or maternal genital warts.
51
Parents of 22 children with MEH provided consent for study participation including a 5 mm punch biopsy
52
and molecular HPV analysis at Hospital General de Culiacan, Sinaloa and Instituto Nacional de
53
Cancerologia, Mexico City.
54 55
To identify viral types present in the samples, we used PCR for HPV-13 detection, and the INNO-LiPA®
56
HPV Genotyping Extra kit (INNOGENETICS), which can detect 28 HPV genotypes. All PCR reactions
57
incorporated a negative control.
58 59
Molecular analysis was possible in 21 children, 11 boys and 10 girls of ages 6 -13 years (mean, 9.9 years).
60
Multiple HPV types were identified, including high-risk as HPV-16, 18, 31, 39, 51, 52, 58, and 68 (52% of
61
patients); medium-risk HPV-66 (33% of patients); low-risk HPV-11, 13, and 40 (86% of patients); and
62
HPV-69/71 (33% of patients). HPV-13 was found in 71% of cases. The most common anatomic location
63
was lower lip, alone or in combination with the buccal mucosa or tongue (Figure 1). Table I shows the
64
demographic, clinical and molecular findings of the study participants.
65 66
The prevalence of MEH in this population is higher than that prior Mexican studies.4 This may be
67
explained by closer, more constant exposure to contamination sources in the setting of overcrowding,
68
poor hygiene and inadequate nutrition. Genetic susceptibility in this small, closed community is another
69
likely factor.2,3
70
Our study shows that diverse HPV types can promote the development of MEH. Infection with
71
oncogenic HPV types may increase cancer risk, underscoring the importance of disease control through
72
improved sanitary conditions, education, and epidemiologic surveillance.
73 74
References
75
1. De la Teja AE, Martínez SB, Téllez RJ, Ramírez PLF, Durán GA, Cadena GA. Hiperplasia epitelial
76
multifocal. Manifestaciones bucales en niños. Revisión de la literatura. Acta Pediatr Mex 2008;29(1):31-
77
35.
78
2. Mendez A, Ledesma C. Multifocal epitelial hyperplasia. N Am J MedSci. 2012; 4: 510-51.
79
3. García-Corona C, Vega-Memije E, Mosqueda-Taylor A. Association of HLA-DR4 (DRB1*0404) with
80
human Papillomavirus infection in patients with focal epithelial hyperplasia. ArchDermatol 2004; 140:
81
1227-1231.
82
4. Cerón García IA, Cerón Espinosa J, González Losa MR. Hiperplasia epitelial multifocal: revisión de 71
83
casos. Dermatología CMQ 2011; 9: 176–180.
84 85 86 87 88 89 90 91
92
Tables
93
Table1. “Clinical and demographic data results”.
N°
Age
Gender
Relatives
Lesions
Location
affected 1
12
F
No
15-20
2
8
M
Brother
10-14
3
9
M
Brother
5-9
4
11
F
No
5-9
5
6
M
Cousin
15-20
6
9
F
No
15-20
7
8
M
No
5-9
8
9
F
Cousin
10-14
9
10
M
No
15-20
10
12
F
No
10-14
11
6
M
No
15-20
12
6
F
Cousin
15-20
13
10
F
Cousin
10-14
14
11
M
No
15-20
15
12
M
No
10-14
16
12
F
Sister
15-20
17
13
F
Sister
5-9
18
13
F
No
5-9
Left lower lip mucosa and tongue Left lower lip mucosa and tongue Left lower lip mucosa Upper and lower left lip mucosa Upper and lower left lip mucosa
Size (mm)
HPV Type
3-8
13, 66
2-5
13, 51, 69/71
4-10
11, 51, 52, 58, 66, 68, 69/71
1-5
16, 51, 52, 66, 69/71
1-6
13
1-8
13
2-4
13, 31
2-10
13, 52
2-15
13
2-10
13, 52
3-4
13
3-10
13
Lower lip mucosa and tongue Left lower lip mucosa Upper and lower lip mucosa, and buccal mucosa bilateral All the oral cavity including tongue Left lower lip mucosa and tongue Right lower lip mucosa Left lower lip mucosa and left buccal mucosa Lower lip mucosa Tongue and mucosa of the left retromolar triangle Left lower lip mucosa, buccal mucosa bilateral and gums Right lower lip mucosa, tongue and gums Left lower lip mucosa and gums Left lower lip mucosa
1-10
13, 16, 18, 39, 40, 51, 66, 68, 69/71, 74
4-13
13
2-14
13, 51, 52, 66
1-6
13
1-3
39, 40, 51, 66, 68, 69/71, 74
2-4
51, 69/71
19
9
M
Brother
15-20
20
9
M
No
10-14
21
12
M
Brother
10-14
94
All the oral cavity including tongue Lower lip mucosa, buccal mucosa bilateral Lower lip mucosa and left buccal mucosa
1-2
13
2-6
51, 52, 66
1-7
13, 69/71
95
S0190-9622(19)33318-3
DOI:
https://doi.org/10.1016/j.jaad.2019.12.041
Reference:
YMJD 14094
To appear in:
Journal of the American Academy of Dermatology
Received Date: 25 October 2018 Revised Date:
16 December 2019
Accepted Date: 19 December 2019
Please cite this article as: Jiménez Aguilar SM, Rodríguez DL, Muñoz Estrada VF, Cázarez Salazar SG, Velarde Félix JS, Méndez Martínez RS, Great diversity of oncogenic human papillomaviruses is revealed in an outbreak of multifocal epithelial hyperplasia, Journal of the American Academy of Dermatology (2020), doi: https://doi.org/10.1016/j.jaad.2019.12.041. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier on behalf of the American Academy of Dermatology, Inc.
1
Article type: Research Letter
2 3
Title: Great diversity of oncogenic human papillomaviruses is revealed in an outbreak of multifocal epithelial hyperplasia.
4 5 6
Sandra Margarita Jiménez Aguilar,DDS1,Daniel Lizárraga Rodríguez,DDS1, Víctor Fernando Muñoz Estrada,DDS2, Silvestre Guadalupe Cázarez Salazar, MSc3, Jesús Salvador Velarde Félix, PhD4, Rocío Susana Méndez Martínez, PhD5.
7 8 9 10 11 12 13 14 15 16 17
1
18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39
Sandra Margarita Jiménez Aguilar, DDS. Facultad de Odontología Universidad Autónoma de Sinaloa. Calle Lic. Benito Juárez 426pte. Entre Donato Guerra y Vicente Riva Palacio. Colonia Centro. C.P.80000 Culiacán, Sinaloa, México. E-mail: [email protected]
Facultad de Odontología de la Universidad Autónoma de Sinaloa. Departamento de Dermatología y Micología del Centro de Investigación y Docencia en Ciencias de la Salud del Hospital Civil de Culiacán. Facultad de Medicina de la Universidad Autónoma de Sinaloa. 3 Departamento de Medicina Genómica del Hospital General de Culiacán (Servicios de Salud de Sinaloa) y Departamento de Ciencias de la Salud. Universidad Autónoma de Occidente. 4 Departamento de Medicina Genómica del Hospital General de Culiacán (Servicios de Salud de Sinaloa) y Escuela de Biomedicina (Universidad Autónoma de Sinaloa), Culiacán, Sinaloa, México. 5 Unidad de Investigación Biomédica en Cáncer, Subdirección de Investigación Básica, Instituto Nacional de Cancerología, SS, Ciudad de México, México. 2
Corresponding author:
Funding sources: None. Conflicts of Interest: None declared. Reprint requests: None. Manuscript word count: 370 words [excluding title, references and tables]. Abstract wordcount:0 Capsule summary word count:0 References:4 Figures: 1 Tables:1 Keywords: human papilloma virus; oral lesions; Heck's disease; multifocal epithelial hyperplasia; pediatric; oncogenic.
40
Great diversity of oncogenic human papillomaviruses is revealed in an outbreak of multifocal
41
epithelial hyperplasia
42
Multifocal epithelial hyperplasia (MEH; Heck disease) presents with multiple soft papules and plaques
43
on the oral mucosa due to infection with human papillomavirus (HPV), primarily types 13 and 32.1 To
44
date, only HPV type 13 has been identified in Mexican patients with MEH. The exact route of
45
transmission is unknown, although it may be associated with the common use of contaminated objects.2
46
In the Mexican indigenous population, genetic predisposition related to HLA alleles has been found.3
47 48
From 2011-2015, 336 children (159 girls, 177 boys) attending elementary school in Navolato, Sinaloa,
49
Mexico underwent oral examination. Oral lesions suggestive of MEH were identified in 33 individuals,
50
representing a prevalence of 9.8%; their parents denied a history of MEH or maternal genital warts.
51
Parents of 22 children with MEH provided consent for study participation including a 5 mm punch biopsy
52
and molecular HPV analysis at Hospital General de Culiacan, Sinaloa and Instituto Nacional de
53
Cancerologia, Mexico City.
54 55
To identify viral types present in the samples, we used PCR for HPV-13 detection, and the INNO-LiPA®
56
HPV Genotyping Extra kit (INNOGENETICS), which can detect 28 HPV genotypes. All PCR reactions
57
incorporated a negative control.
58 59
Molecular analysis was possible in 21 children, 11 boys and 10 girls of ages 6 -13 years (mean, 9.9 years).
60
Multiple HPV types were identified, including high-risk as HPV-16, 18, 31, 39, 51, 52, 58, and 68 (52% of
61
patients); medium-risk HPV-66 (33% of patients); low-risk HPV-11, 13, and 40 (86% of patients); and
62
HPV-69/71 (33% of patients). HPV-13 was found in 71% of cases. The most common anatomic location
63
was lower lip, alone or in combination with the buccal mucosa or tongue (Figure 1). Table I shows the
64
demographic, clinical and molecular findings of the study participants.
65 66
The prevalence of MEH in this population is higher than that prior Mexican studies.4 This may be
67
explained by closer, more constant exposure to contamination sources in the setting of overcrowding,
68
poor hygiene and inadequate nutrition. Genetic susceptibility in this small, closed community is another
69
likely factor.2,3
70
Our study shows that diverse HPV types can promote the development of MEH. Infection with
71
oncogenic HPV types may increase cancer risk, underscoring the importance of disease control through
72
improved sanitary conditions, education, and epidemiologic surveillance.
73 74
References
75
1. De la Teja AE, Martínez SB, Téllez RJ, Ramírez PLF, Durán GA, Cadena GA. Hiperplasia epitelial
76
multifocal. Manifestaciones bucales en niños. Revisión de la literatura. Acta Pediatr Mex 2008;29(1):31-
77
35.
78
2. Mendez A, Ledesma C. Multifocal epitelial hyperplasia. N Am J MedSci. 2012; 4: 510-51.
79
3. García-Corona C, Vega-Memije E, Mosqueda-Taylor A. Association of HLA-DR4 (DRB1*0404) with
80
human Papillomavirus infection in patients with focal epithelial hyperplasia. ArchDermatol 2004; 140:
81
1227-1231.
82
4. Cerón García IA, Cerón Espinosa J, González Losa MR. Hiperplasia epitelial multifocal: revisión de 71
83
casos. Dermatología CMQ 2011; 9: 176–180.
84 85 86 87 88 89 90 91
92
Tables
93
Table1. “Clinical and demographic data results”.
N°
Age
Gender
Relatives
Lesions
Location
affected 1
12
F
No
15-20
2
8
M
Brother
10-14
3
9
M
Brother
5-9
4
11
F
No
5-9
5
6
M
Cousin
15-20
6
9
F
No
15-20
7
8
M
No
5-9
8
9
F
Cousin
10-14
9
10
M
No
15-20
10
12
F
No
10-14
11
6
M
No
15-20
12
6
F
Cousin
15-20
13
10
F
Cousin
10-14
14
11
M
No
15-20
15
12
M
No
10-14
16
12
F
Sister
15-20
17
13
F
Sister
5-9
18
13
F
No
5-9
Left lower lip mucosa and tongue Left lower lip mucosa and tongue Left lower lip mucosa Upper and lower left lip mucosa Upper and lower left lip mucosa
Size (mm)
HPV Type
3-8
13, 66
2-5
13, 51, 69/71
4-10
11, 51, 52, 58, 66, 68, 69/71
1-5
16, 51, 52, 66, 69/71
1-6
13
1-8
13
2-4
13, 31
2-10
13, 52
2-15
13
2-10
13, 52
3-4
13
3-10
13
Lower lip mucosa and tongue Left lower lip mucosa Upper and lower lip mucosa, and buccal mucosa bilateral All the oral cavity including tongue Left lower lip mucosa and tongue Right lower lip mucosa Left lower lip mucosa and left buccal mucosa Lower lip mucosa Tongue and mucosa of the left retromolar triangle Left lower lip mucosa, buccal mucosa bilateral and gums Right lower lip mucosa, tongue and gums Left lower lip mucosa and gums Left lower lip mucosa
1-10
13, 16, 18, 39, 40, 51, 66, 68, 69/71, 74
4-13
13
2-14
13, 51, 52, 66
1-6
13
1-3
39, 40, 51, 66, 68, 69/71, 74
2-4
51, 69/71
19
9
M
Brother
15-20
20
9
M
No
10-14
21
12
M
Brother
10-14
94
All the oral cavity including tongue Lower lip mucosa, buccal mucosa bilateral Lower lip mucosa and left buccal mucosa
1-2
13
2-6
51, 52, 66
1-7
13, 69/71
95