Journal of Clinical Virology 37 (2006) 21–26

Molecular and serological evidence of the epidemiological association of

HPV 13 with focal epithelial hyperplasia: A case-control study
Viviana Cuberos a , Juan Perez a , Cesar Julian Lopez a , Felipe Castro a,1 ,
Leonor Victoria Gonzalez a,e , Luis Alfonso Correa b , Gloria Sanclemente a,b ,
Angela Gaviria a,c , Martin Müller d , Gloria Ines Sanchez a,∗
a Group Infection and Cancer, School of Medicine, Universidad de Antioquia, A.A. 1226, Medellı́n, Colombia
b Dermatology Section, Department of Internal Medicine, School of Medicine, Universidad de Antioquia, Medellı́n, Colombia
c School of Bacteriology, Colegio Mayor de Antioquia, Medellı́n, Colombia
d Research Program of Infection and Cancer, German Cancer Research Center, 69120 Heidelberg, Germany
e School of Dentistry, Universidad de Antioquia, Medellı́n, Colombia

Received 6 December 2005; received in revised form 4 April 2006; accepted 11 April 2006

Abstract

Background: Focal epithelial hyperplasia is a benign proliferative condition that is more frequently found in children of certain ethnic groups.
Human papillomavirus 13 and 32 DNA has been consistently detected in these lesions.
Objective: To demonstrate the epidemiological association of HPV 13 with FEH in the Emberá-Chamı́ community of Antioquia, Colombia.
Methods: A population-based, case-control study was conducted. One hundred and thirty-eight children were screened and 17 clinical and
histologically-confirmed cases were sex and age-matched with 27 controls. Biopsies from FEH lesions and mouth washes from controls were
obtained for DNA analysis. HPV 13 DNA was identified using a previously described type-specific PCR test. HPV 13 VLPs were produced
by cloning of L1 from the HPV 13 cloned genome and seroreactivity against HPV 13 VLPs of sera from cases and controls were evaluated
by ELISA.
Results: Among the whole population the prevalence of FEH was 13%. One-hundred-percent of the cases and 29.6% of the controls were
HPV 13 positive. There was a significant difference in HPV DNA status between cases and controls (one-tailed Fisher exact test: P < 0.0001).
Antibodies against HPV 13 VLPs were found in 58.8% of cases and in 33.3% of controls, this difference was not statistically significant
(P = 0.089 Fisher exact test). However, the median of the ODs of the ELISA positive sera of the cases was 0.596 (interquartile range:
0.5075–0.8245) versus 0.452 (interquartile range: 0.337–0.479) in the controls and this was significantly different (P = 0.0041 Man–Whitney
test).
Conclusions: We demonstrated a risk for association of FEH with infection with HPV 13. The higher level of antibodies against HPV 13
VLPs in cases may suggest the requirement of higher viral load or viral persistence for disease development.
© 2006 Elsevier B.V. All rights reserved.

Keywords: Focal epithelial hyperplasia; Papillomavirus; Emberá-Chamı́; Colombia; HPV 13; FEH

1. Introduction

Focal epithelial hyperplasia (FEH) is an unusual, benign

Abbreviations: FEH, focal epithelial hyperplasia
∗ Corresponding author. Tel.: +57 4 210 6066; fax: +57 4 263 3509.
E-mail address: sanchezg@medicina.udea.edu.co (G.I. Sanchez).
1 Present address: Tampere School of Public Health, University of Tam-
pere, FIN-33014, Finland.
and proliferative disease, which affects the oral mucosa of
children and young adults from distinct areas worldwide,
particularly certain Indian communities. It has been fre-
quently described in Indian communities from North, Cen-
tral and South America (Archard et al., 1965; Carlos and
Sedano, 1994; Decker and De Guzman, 1969; Estrada, 1956;

1386-6532/$ – see front matter © 2006 Elsevier B.V. All rights reserved.
doi:10.1016/j.jcv.2006.04.003
22 V. Cuberos et al. / Journal of Clinical Virology 37 (2006) 21–26
Fischman, 1969; Gomez et al., 1969; Tan et al., 1969; Witkop
and Niswander, 1965) but also in Eskimos from Greenland
(Clausen et al., 1970; Jarvis and Gorlin, 1972) and in oth-
ers ethnic groups (Buchner and Mass, 1973; Edwards and
Hamza, 1978; Hettwer and Rodgers, 1966; Perriman and
Uthman, 1971; Waldman and Shelton, 1968). The disease
is featured by single or multiple fibrous, well-defined lesions
like nodules and papules which frequently coalesce, with a
size range from 0.1 cm to 1 cm in diameter. These lesions are
usually painless and mainly found on the mucosa epithelia of
the lower lip, upper lip, tongue and hard palate (Buchner et al.,
1975; Mealey et al., 1993; Morrow et al., 1993; Pilgard, 1984;
Sawyer et al., 1983). The main histological characteristics
include epidermal acanthosis and parakeratosis, thickening
and elongation of the rete ridges, and pronounced koilocy-
tosis with characteristic mitosoid figures (van Wyk et al.,
1977a). The lesions may persist for several years but do
not become malignant and finally tend to regress sponta-
neously.
Human papillomavirus (HPV) have been consistently
identified in these lesions. Viral particles are found in tissues
studied by electron microscopy (Goodfellow and Calvert,
1979; Kuffer and Perol, 1976; Paz-Bueso et al., 1986; van
Wyk et al., 1977b) and HPV 13 (Petzoldt and Pfister, 1980)
and HPV 32 (Beaudenon et al., 1987) have been detected in
DNA extracted from the lesions. After identification of these
two genotypes in FEH, several reports have documented the
infection in confined groups of diverse ethnical backgrounds
worldwide. In addition, FEH recurrence due to HPV 13 has
been observed in an HIV-positive patient (Moerman et al.,
2001), and recently HPV 13 was identified in multiple con-
junctival papillomas similar to oral FEH lesions (Benevides
Dos Santos et al., 2005). We have previously described the
prevalence of FEH and of HPV 13, in children from the
Indian community Embera-Chami of the state of Antioquia
in Colombia (Gonzalez et al., 2005; Matute et al., 1999).
Here we report the results of a case-control study in which
we investigated whether the infection by HPV 13 is a par-
ticularly necessary factor for the development of FEH and
evaluated if serological and other risk factors are associated
with FEH and HPV 13 infection.
2. Material and methods
2.1. Study population
One hundred and thirty-eight students from the only
school of the indigenous community Emberá-Chamı́ from
Jardı́n (Antioquia, Colombia) were screened for FEH oral
lesions, and a 3% acetic acid solution was applied over all
the oral mucosa when lesions were not clinically evident.
Cases were children with histological-confirmed FEH that
fulfilled the following criteria: Presence in the oral mucosa
of any flat-topped smooth papules, plaques or nodules; and/or
whitish papules, plaques or nodules, which became evident
after the use of acetic acid. Histological criteria included:
epithelial hyperplasia with acanthosis, anastomosing rete
ridges, keratinocyte-cytopathic changes, and mitosoid fig-
ures. A dermatopathologist (Dr. Luis A. Correa) confirmed all
cases. The control subjects did not have any clinically-evident
oral lesion and each case was matched by age and sex to
controls.
2.2. Specimen and data collection
The study was previously approved by the Ethics Com-
mittee of the University of Antioquia. The objectives of the
study and the informed consent were first clearly explained to
the authorities of the Indian community and school-teachers
in order to get previous approval. Informed consent was then
read in Spanish by clinicians (Dr. Gloria Sanclemente, MD
and Leonor Vicotoria Gonzalez, DDS) and when required
translated to their native language by a teacher of the com-
munity to the children parents or their nearest adult relative
or legal representative before signing. A 4-mm punch biopsy
was taken from the most representative lesion of each case,
after administering local anesthesia. Biopsy specimens were
cut into two portions. One piece was fixed in 10% buffered
formalin, and then cut and embedded in paraffin. Sections
were stained with hematoxylin and eosin. The other portion
was initially frozen at −70 ◦ C and used later for DNA extrac-
tion. A non-invasive procedure (oral wash with 1× PBS)
was used to obtain exfoliated cells from the oral mucosa of
controls. Individual, sterile and disposable implements were
used in all the procedures to avoid contamination. To evalu-
ate some other risk factors which could be related with FEH,
we used a questionnaire to interview all children and their
parents about some habits such as spoon- and toothbrush-
sharing, breast-feeding and history of similar lesions in any
family member.
2.3. DNA extraction
DNA from biopsies and oral washes was obtained using
the Wizard DNA purification kit (Promega, Madison, WI,
USA) according to manufacturer’s instructions. DNA was
resuspended in 100 ␮L of Tris–EDTA and frozen at −20 ◦ C
until use. A fragment of 250 bp of the human ␤-globin gene
was amplified to asses the quality of DNA
2.4. HPV 13 genotyping
Viral typing was performed by the technique described by
Williamson and Dennis (1991). The sequence of the specific
primers to amplify a segment of 240 bp from the HPV 13
L1 gene were: forward primer 5 -AAATCCCAGCAGAAT-
TATAT-3 ; reverse primer 5 -AAAGAGATGATGTAGT-
GGC-3 . Optimal PCR amplification was established with an
annealing temperature of 50 ◦ C and a MgCl2 concentration
of 3 ␮M.
 V. Cuberos et al. / Journal of Clinical Virology 37 (2006) 21–26 23

2.5. Production of HPV 13 VLPs and ELISA
To produce the VLPs, we assembled the complete L1 gene
from the HPV 13 DNA cloned genome (Pfister et al., 1983).
Recombinant HPV 13 L1 baculovirus and HPV 13 VLPs
were generated as previously described (Muller et al., 1997).
HPV 13 L1 recombinant baculovirus was used to infect H5
insect cells and the lysates of the infected insect cells were
subjected to lineal gradients of sucrose and CsCl. To eval-
uate the integrity of the VLPs, 2.5 ml of each fraction was
analyzed by western blotting and a capture-ELISA using the
monoclonal antibody Ritti, a monoclonal antibody produced
against HPV 16 VLPs that shows increased reactivity to disas-
sembled VLP preparations (Muller et al., 1997). The integrity
of the VLPs was also evaluated by electron microscopy.
The presence and level of antibodies against HPV 13
VLPs was determined using the indirect ELISA technique
as previously described (Muller et al., 1997). Flat-bottomed
wells, 96-well microplates (Nunc, Life Technologies, Eragny,
France) were coated overnight at 4 ◦ C with 80 ng of VLPs in
100 ␮l of PBS 1×, pH 7.4. To determine the unspecific bind-
ing, all sera were also tested against wells coated with skim
milk only (800 ng/well in 100 ␮l of 1× PBS). After washing 3
times with washing buffer (PBS 1×, 0.1% Tween 20 and 2%
milk powder) the blocking solution (PBS 1×, 0.05% Tween
20 and 1.5% milk powder) was added and the plates were
incubated for 3 h at 37 ◦ C. Each serum sample was added to
the wells in triplicate at 1:20 dilution and incubated at 45 ◦ C
for 60 min. After three washes with washing buffer, 100 ␮l
of goat anti-human IgG 1 conjugated to horseradish peroxi-
dase (Sigma, Monoclonal Antibody to Peroxidase, clone no.
PG-38), diluted 1:5000 in blocking solution was added and
incubated at 45 ◦ C for 1 h. Finally, after three washes with
washing buffer, 100 ␮l of a OPD substrate solution was added
and incubated for 20 min at room temperature. The reaction
was stopped by the addition of 100 ␮l of 4 N H2 SO4 , and
optical densities (OD) were read at 405 nm. For each serum
sample the background reactivity found in the wells coated
with powder milk, was subtracted from the OD found in each
of the HPV 13-VLP coated wells. To determine the cut-off
value above which an OD value was a sample considered
positive, we tested sera from 61 healthy children (reference
group Fig. 2) from a different and ethnically mixed popula-
tion against HPV 13 VLP in the ELISA test. The mean OD
value in this group was 0.066 (S.D.: 0.061). The cut-off value
(mean + 3S.D.) was 0.249.
2.6. Data analysis
Firstly, a general description of demographic variables
of the population was performed. Thereafter, a bivariate
analysis between case and control groups was made to
explore the association of FEH with risk factors such as
spoon- and toothbrush-sharing, previous breast-feeding,
HPV 13 DNA and the presence and level of antibodies
against HPV 13 VLPs. The percentage of HPV positive
samples was estimated only on adequate samples. Samples
were adequate when positive for HPV 13 and/or the human
␤-globin gene PCR fragment. For all qualitative variables we
used a χ2 of independence or Fisher test and for comparison
of antibodies-levels we used the Mann–Whitney test. We
used the software Statistical Package for Social Sciences
version 10 (SPSS, Inc., Chicago, IL, USA) for the analysis of
results.
3. Results
3.1. Description of the population and clinical findings
We evaluated 63 boys and 75 girls with age ranging from
4 to 21 years (mean age 9.8 years). Clinical characteristics of
FEH were identified in 10 girls and 7 boys with an age ranging
from 5 to 14 years (mean age 9.8 years). FEH prevalence in
this population was 13%. In the case group we identified
multiple lesions in 12 subjects. The location of the lesions
was: 12 cases on the lower lip, 3 cases on the upper lip, 3
cases on on the anterior buccal mucosa and 1 case on the
right buccal mucosa. The age and sex matched control group
included 11 girls and 16 boys.

Table 1
Risk factors for focal epithelial hyperplasia in indigenous community Emberá-Chamı́ from Jardin, Antioquia, Colombia
Risk factor Cases N (%) Controls N (%) P value
Sex (male) 7 (41.1) 16 (59.2) 0.195a
Relative with FEH 3 (17.6) 5 (18.5) 0.830b
Breast feeding 14 (82.3) 27 (100) 0.133a
Sharing the spoon 7 (41.1) 13 (48.1) 0.445a
Sharing the toothbrush 2 (11.7) 0 (0) 0.144a
HPV 13 DNA 17 (100) 8 (29.6) 0.00001a
HPV 13 VLPs ELISA positive 10 (58.8) 9 (33.3) 0.089a
Median ODs of HPV 13 VLPs ELISAc (interquartile range) 0.596 (0.5075–0.8245) 0.452 (0.337–0.479) 0.0041d
a One-tailed Fisher exact test.
b χ2 -test.
c Only the ODs from the 10 ELISA positive sera from cases and the 9 from controls were included in the analysis.
d Mann–Whitney test.
24 V. Cuberos et al. / Journal of Clinical Virology 37 (2006) 21–26
Fig. 1. Electron micrograph of HPV 13 VLPs.
3.2. HPV-13 DNA identification
We identified HPV-13 DNA in all (100%) cases of
FEH, and in only 8 (29.6%) subjects of the control group.
(P = 0.00001, One-tailed Fisher exact test, cases versus con-
trols) (Table 1).
3.3. HPV 13 VLPs seroreactivity
The western blotting and ELISA with the antibody
Ritti, demonstrated that HPV 13 L1 protein was efficiently
expressed and assembled in the baculovirus system (data not
shown). Moreover, a high amount of icosahedral particles
were observed in the ME (Fig. 1). In the ELISA technique, ten
out of 17 cases (58.8%), and 9 out of 27 controls (33.3%) had
antibodies against HPV 13 VLPs. However, there was not any
significant difference between both groups. (P = 0.089 One-
tailed Fisher exact test). We also evaluated if there was any
difference in the level of antibodies and for that purpose we
compared the median of the ODs of the ELISA positive sera
from cases versus the median of the ODs of the ELISA pos-
itive sera from controls. The median of the ODs in the cases
was 0.596 (interquartile range: 0.5075–0.8245) versus 0.452
(interquartile range: 0.337–0.479) in the controls. The level
of antibodies was significantly different (Mann–Whitney test,
P = 0.041). (Table 1 and Fig. 2).
3.4. Other risk factors
Some risk factors in relation with viral infection were
evaluated among the population. 17.6% of the cases have
had relatives with FEH lesions. 11.7% subjects reported
toothbrush-sharing and 44.4% spoon-sharing. These as well
as possible familiar relationship did not show statistically
significant difference (Table 1).
Fig. 2. Comparison of HPV 13 VLPs ELISA ODs between seropositive
(Ab) and seronegative (No Ab) sera from cases, and controls. * P = 0.0041
Mann–Whitney test. As a comparison, the distribution of the ODs of the
sera of the reference group that was used to calculate the cut-off value on
the ELISA is included.
4. Discussion
In this study we found compelling evidence of the asso-
ciation of HPV 13 with FEH. To our knowledge, this is the
first case-control study conducted in the world that demon-
strates the association between HPV 13 and FEH. Several
methodological facts strongly support our observations. We
conducted a population-based study among a confined pop-
ulation and cases and controls were derived from children
belonging to the same Embera-Chami community. We used
type specific primers to detect HPV 13 (Williamson and
Dennis, 1991) and therefore this permitted us to achieve the
highest sensitivity in our assay, and improved our analysis
by including only those samples with good quality DNA,
as evaluated by the amplification of the human ␤-globin
gene fragment. In order to avoid invasive procedures in con-
trols, we previously evaluated cytobrush and mouth washes
to collect exfoliated cells from oral mucosa. Only oral wash
produced adequate amount of DNA. We cannot completely
rule out the possibility of incomparability on the type of sam-
ple collected from cases and controls. However, as with other
low-risk HPV types, HPV 13 life cycle final outcome should
be the production of infectious virions, which are lost from
the epithelial surface. Therefore, we believe that this type of
sample permits accurate detection of the virus DNA.
As we have reported before, it is striking that we find HPV
13 in 100% of the cases. In this study we used an HPV 13
genotype-specific PCR, hence we cannot exclude the pos-
sibility of infection with other genotypes. However, in an
previous population-based survey that we conducted in the
same cohort, we found only HPV 13 on the FEH lesions
(Gonzalez et al., 2005). Because in this previous study we
used the general GP5+/GP6+ primers and sequenced the
amplified fragments, we have concluded that in this popu-
lation HPV 13 is the only genotype involved in FEH. This
is in contrast with other studies that have also reported HPV
32 in FEH (Henke et al., 1989). The major difference of our
study compared to others, in which HPV 32 has been associ-
ated with FEH, is that we obtained a population-based sample
 V. Cuberos et al. / Journal of Clinical Virology 37 (2006) 21–26
from a confined Indian community instead of patients from
different clinical settings and with a variety of ethnical origins
and ages (Jimenez et al., 2001).
We found that 60% of cases and 33% of controls had
antibodies against HPV 13 VLPs, but this difference was
not statistically different. Several studies have demonstrated
that non-type specific cross-reaction observed on ELISA may
be due to the recognition of cross-reactive epitopes that are
exposed on dissembled or partially assembled VLPs. How-
ever, in our study the integrity and assembling of the VLPs
used in the direct ELISA technique were confirmed by a cap-
ture ELISA with antibody Ritti and by Electron microscopy.
Thus we are confident that the antibodies detected in this
study are HPV 13 type-specific. This result suggests that as
has been observed with other HPV-related diseases, the use
of serology for diagnosis of FEH is limited because of the
high seroprevalence in subjects without the disease. How-
ever, since we found that there is a higher level of antibodies
against HPV 13 in FEH cases, compared to the controls, this
finding could suggest either higher viral load in patients with
FEH or alternatively, this could be associated with a role
of the immune response. In fact, a recently found associa-
tion of HLA-DR4 (DRB1*0404) with HPV infection in FEH
individuals from a mestizo population from Mexico (Garcia-
Corona et al., 2004) suggests a role for the immune responses
on the susceptibility or protection against this HPV infection.
The finding of HPV 13 as the only HPV genotype infect-
ing the oral mucosa of the confined indian Emberá-Chamı́
community in this study, will permit us to evaluate the asso-
ciation of immunogenetic markers with HPV infection in the
future.
Acknowledgements
This project received financial support form the Commit-
tee of Research of the Universidad of Antioquia (Project
code: 110.355.01 of Centro de Investigaciones Agrarias). FC
received support from DAAD (German Academic Exchange
Service), Bi-lateral exchange program for a short visit to
the German Cancer Research Center, Heidelberg, Germany.
Special thanks to professor Sara Paris (Grupo Inmunologia
Cellular e Inmunogenetica, Universidad de Antioquia) for
her help on the standardization on ELISA technique and the
authorities and members of the community Emberá-Chamı́
(Jardin, Antioquia)
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