Cancer Detection and Prevention 31 (2007) 276281

www.elsevier.com/locate/cdp

Human papilloma virus (HPV)-associated gynecological alteration

in mothers of children with recurrent respiratory papillomatosis
during long-term observation
Valentin Gerein PhD, MDa,b,*, Susanne Schmandt MDc, Natalia Babkina MDa,
Nadzeya Barysik MSca, Wiltrud Coerdt PhD, MDa, Herbert Pfister PhDd
a

Department of Pediatric Pathology, Institute of Pathology, University of Mainz, Germany

b
Pediatric Clinic of Johann Wolfgang Goethe University, Frankfurt, Germany
c
Social Pediatric Center, Frankfurt, Germany
d
Institute of Virology, University of Cologne, Germany
Accepted 20 July 2007

Abstract
Background: Human papilloma virus (HPV) is one of the most frequently observed sexually transmitted infections. The study purpose
was to investigate the relation between a mothers gynecological history and the local status of her child with recurrent respiratory
papillomatosis (RRP). Methods: Forty-two patients enrolled in a prospective multicenter study between 1983 and 1990. The study included
patients with juvenile-onset and adult-onset RRP. All patients underwent surgery and treatment with a-interferon. Thirty-eight patients were
followed up until 31.01.2006. Twenty-five mothers of these patients participated in a parallel prospective study of genital HPV infection. In
19891990, all received a routine gynecological examination, an expanded colposcopy, a Pap smear, and a cervical biopsy. The mothers were
followed up until February 2006. Results: 74% of patients with RRP were the first-born children. Five (20%) mothers had condylomata
acuminata, newly diagnosed during pregnancy. Indicators of HPV infection such as koilocytes, koilocytotic dysplasia and condyloma
acuminatum were revealed cytologically in 17% of cases and histologically in 71.4% of cases. Six (24%) of mothers had had a hysterectomy.
HPV type 11 was prevalent in the children of mothers who had had a hysterectomy. Among the patients with juvenile-onset RRP, the death rate
from squamous cell carcinoma of the lung was significantly higher in those patients whose mothers had a hysterectomy ( p = 0.028).
Conclusions: Mothers of patients with RRP demonstrated cytological and histological indicators of HPV infection in the genital tract. An
adverse outcome of the disease in the child was associated with adverse gynecological history in the mother.
# 2007 International Society for Preventive Oncology. Published by Elsevier Ltd. All rights reserved.
Keywords: Respiratory tract diseases; Papillomatosis; Laryngeal neoplasms; Lung cancer; Papillomavirus infections; Human papillomavirus 6; Human
papillomavirus 11; Mothers; Gynecology; Female genital diseases; Risk factors

1. Introduction
Human papilloma virus (HPV) is the cause of one of the
most frequently observed sexually transmitted diseases.
HPV infections may cause both benign and malignant
clinical manifestations. Condyloma, genital warts in the
* Corresponding author at: Department of Pediatric Pathology, Johannes
Gutenberg University of Mainz, Langenbeckstrasse 1, 55101 Mainz,
Germany. Tel.: +49 6131174551; fax: +49 6131173546.
E-mail address: v.gerein@web.de (V. Gerein).

genital tract, and papilloma in the oral and laryngeal

epithelium are related to HPV. Strong epidemiological
evidence links HPV to the development of cervical
intraepithelial neoplasia (CIN), which can progress to
invasive cancers of the uterine cervix [1,2]. HPV also plays a
role in the development of squamous cell carcinoma of the
lung in patients with recurrent respiratory papillomatosis
(RRP) [3].
HPV perinatal vertical transmission is related to
subsequent development of RRP [4]. Incidence data on
human papillomavirus (HPV) infection is variable (560%).

0361-090X/$30.00 # 2007 International Society for Preventive Oncology. Published by Elsevier Ltd. All rights reserved.
doi:10.1016/j.cdp.2007.07.004

V. Gerein et al. / Cancer Detection and Prevention 31 (2007) 276281

Risk factors that promote RRP development include being

the firstborn and young maternal age [5]. Caesarean section
does not prevent RRP [6,7], but the risk of HPV is higher
after vaginal delivery than after cesarean section (RR: 1.8;
95%CI: 1.32.4) [8]. Because HPV is vertically transmitted,
clinical manifestations in the mother, such as the occurrence
of genital warts indicate that the child has a higher risk of
developing RRP [9]. RRP shares an identical viral etiology
with genital condyloma and RRP development in the child is
probably related to genital HPV infection in the mother. It is
therefore reasonable to conduct a parallel study that involves
patients with RRP and their mothers. The purpose of our
study was to investigate the gynaecological history and to
evaluate the genital status of mothers of children with RRP
in relation to the findings and local status of patients with
RRP.

277

revealed by acetic acid staining or from the 12 Oclock

position if the acetic acid test was negative. The mean age of
mothers at the time of the gynecological examination was
38.9  11.7 years. All mothers were followed up until
February 2006 (the mean follow-up duration was 16.7  1.3
years). The medical, sexual, gynecological, and obstetric
histories, including information on sexual partners and
genital tract infections, were updated in February 2006.
The basic characteristics of the mothers are presented in
Table 1.
The results are shown as means  standard deviation
(S.D.) or as percentages. Statistical analysis was conducted
using Students t-test and Fishers exact Test. The results
were considered significant when p < 0.05.

3. Results
2. Methods
Forty-two patients with histologically confirmed RRP
were accepted for a prospective multicenter study from
21.06.1983 to 12.08.1990. The mean age of patients in the
study was 16.6  16.6 years (range from 1 to 60 years). All
patients underwent several surgical procedures and were
subsequently treated with a-interferon. Of 42 patients, 38
were followed up until 31.01.2006; (the mean follow-up
duration was 15.3  1.8 years after the end of interferon
therapy). Four patients were excluded because they moved
away during the first 36 months of the therapy. The HPV
type was analyzed by restriction enzyme digestion and
Southern blot hybridization.
Twenty-five mothers of patients with RRP, and five
female patients with RRP gave informed consent to take part
in a parallel longitudinal study of genital HPV infection. A
routine gynecological examination was performed in 1989
1990 and was supplemented by colposcopy, Pap smear, and
cervical biopsy. A history was taken from the women. The
original obstetric records were reviewed for those women
who recalled having had condylomata during pregnancy.
Cervical biopsies were taken from abnormal foci that were

Of the 25 patients with RRP born to the mothers in our

study, 21 had juvenile-onset RRP with a mean age of onset at
3.4  2.6 years, and four had adult-onset RRP with a mean
age of onset at 21.1  4.4 years. The patients with RRP were
born from the first pregnancy in 74% of cases. Most of the
children were delivered vaginally; cesarean section was
performed in two cases (8%).
The mean age of the mothers at childbirth was 25.6  6.2
years. The characteristics of mothers are presented in
Table 1. Thirteen women (62%) had had only one sexual
partner before childbirth. The gynecologic history was
unremarkable in most cases. Genital infections were
observed in two cases, but 5 of 25 mothers (20%) reported
having had condylomata acuminata newly diagnosed at the
end of the first trimester of pregnancy. Three patients born to
mothers with condyloma acuminata during pregnancy were
affected by HPV type 6, and two of them developed RRP
within the first 6 years of life. Two were affected by HPV
type 11 and both developed RRP before 6 years of age.
A gynecological examination of 23 women was
performed after 14.2  10.6 years after birth of the child
with subsequent RRP. In most cases, Pap smears revealed
benign cellular changes or atypical squamous cell changes

Table 1
Characteristics of mothers of patients with RRP
Mean  S.D. (years)
Total
Age at examination
Follow-up period
Age at childbirth
Time between childbirth and gynecological examination
Age at hysterectomy
Condyloma acuminata newly diagnosed during pregnancy
Cytological indicators of HPV infectiona
Histological indicators of HPV infection b
Hysterectomy
a
b

Pap smear was taken from 23 mothers.

Biopsy was performed on 21 mothers.

38.9  11.7
16.7  1.8
25.6  6.1
14.2  10.6
49.3  12.8

Min (years)
25.7
16.0
15.5
1.5
40

Max (years)
66.4
17.0
41.0
47.4
77

25
23
25
25
23
6
5
4
15
6

24.0
20.0
17.4
71.4
24.0

278

V. Gerein et al. / Cancer Detection and Prevention 31 (2007) 276281

Table 2
Characteristics of patients with juvenile-onset RRP and their mothers according to HPV type
Cases associated with HPV 6
in children

Cases associated with

HPV 11 in children

Total
Age at RRP onset in children, years (mean  S.D.)
Children with squamous cell carcinoma of the lung
Children who died during follow-up

8
3.9  2.8
0
0

11
2.7  1.9
5 (45%)
5 (45%)

Mothers with indicators of HPV infection

Cytological
Histological

2 (25%)
5 (71.4%)b

2 (20%)a
6 (66.7%) c

Mothers who had had condyloma acuminata during pregnancy

Mothers who had had a hysterectomy
Mothers with CIN/malignancy

3 (37.5%)
1 (12.5%)
1 (12.5%)

2 (18%)
4 (36.4%)
3 (27%)

a
b
c

The Pap smear was taken from 10 mothers.

The biopsy was performed on 7 mothers.
The biopsy was performed on 9 mothers.

histological indicators of HPV infection, there were two

mothers of patients with adult-onset RRP associated with
HPV type 6. The characteristics of mothers and patients with
juvenile-onset RRP according to the type of HPV are
summarized in Table 2. There was no difference in cytological
and histological findings in mothers of patients with HPV type
6 and type 11.
The five female patients with RRP underwent gynecologic evaluation at a mean age of 29.5  10.0 years. Four of
them had juvenile-onset RRP (the mean age of first
symptoms was 4.7  2.2 years), and one developed disease
at the age of 28 years. The results of cytological or
histological examination did not reveal any features
characteristic of HPV infection in patients with juvenileonset RRP. The patient with adult-onset RRP had had a
hysterectomy because of cervical carcinoma.
Of 21 patients with juvenile-onset RRP, 14 had an
aggressive course of RRP and seven had a mild course

of undetermined significance. The Pap smears had characteristics of HPV infection in 4 of 23 cases (17.4%). A biopsy
containing three layers of epithelium was obtained in 21
cases. A histological examination revealed indicators of HPV
infection in 15 of 21 cases (71.4%). Absolute indicators of
genital HPV infection, such as koilocytes, koilocytotic
dysplasia, and condyloma acuminata, were found cytologically in 3 of 23 (13%) cases and histologically in 7 of 21
(33.3%) cases. Uncertain criteria, such as mild koilocytosis,
parakeratosis, multinucleation and hyperchromasia, were
found in 1 of 23 (4.3%) and 8 of 21 (38.1%) cases respectively.
In 3 of 21 (14.3%) mothers histological examination revealed
CIN 1, and one mother had endometrial adenocarcinoma. The
child of one mother had HPV type 6. HPV type 11 was found
in the children of two mothers with CIN and the child of a
mother with endometrial adenocarcinoma. Cytological
indicators of HPV infection were found only in the mothers
of patients with juvenile-onset RRP. Among the mothers with
Table 3
Findings in mothers of patients with aggressive and mild juvenile-onset RRP

Mothers of patients with

Aggressive RRP
No. of mothers with
Certain histological indicators of HPV infection
Uncertain histological indicators of HPV infection
Total histological indicators of HPV infection
Certain cytological indicators of HPV infection
Uncertain cytological indicators of HPV infection
Total cytological HPV indicators
Condyloma acuminata during pregnancy
Hysterectomy

5
4
9
2
1
3
3
5

(41.7%)a
(33.3%)a
(75%)a
(15.4%)b
(7.7%)
(23.1%)b
(21.4%)
(35.7%)

p
Mild RRP
1
3
4
1
0
1
2
0

(16.7%)c
(50%)c
(66.7%)c
(14.3%)
(14.3%)
(28.6%)

No. of mothers of patients with

HPV 6
HPV 11
HPV 6 and 11

2 (14.3%)
11 (78.6%)
1 (7.1%)

6 (85.7%)
0
1 (14.3%)

Total

14

a
b
c

The biopsy was performed on 12 mothers.

Pap smear was taken from 13 mothers.
The biopsy was performed on 6 mothers.

0.098
0.001
0.001

V. Gerein et al. / Cancer Detection and Prevention 31 (2007) 276281

(Table 3). Patients were considered to have an aggressive

course if the severity score was >4 [10], the number of
surgeries was >10/year, or a malignant transformation was
diagnosed. An aggressive course of juvenile-onset RRP was
observed more often in patients with HPV type 11
( p = 0.001). Mortality was significantly higher in patients
with HPV type 11 ( p = 0.04). There was no statistically
confirmed difference for cytological and histological findings
in the mothers of patients with either an aggressive or a mild
course of juvenile-onset RRP. Five of 14 (35.7%) mothers of
patients with an aggressive course had a hysterectomy, but no
mothers of patients with a mild course of juvenile-onset RRP
were found to have had a hysterectomy.
Of 25 mothers of patients with juvenile and adult-onset
RRP, 6 (24%) had a hysterectomy by the end of the study:
three before the gynecological examination and three within
11.4  1.6 years afterwards. Hysterectomy was indicated
for five patients with submucosal leiomyoma and one with
endometrial adenocarcinoma. The mean age at the time of
hysterectomy was 49.3  12.8 years. All women who
underwent a hysterectomy after our gynecologic examination had histological indicators of HPV infection at the time
of our gynecologic examination. There were four patients
with juvenile-onset RRP whose mothers had HPV type 11,
one patient with juvenile-onset RRP whose mother had HPV
type 6, and one patient who had adult-onset RRP whose
mother had HPV types 6 and 11. There was no statistical
confirmation that the mothers of children with HPV type 11
were more likely to have had a hysterectomy.
Six children affected by HPV type 11 had pulmonary
spread 27.2  8.0 years after the onset of RRP, and five of
them developed squamous cell carcinoma of the lung
29.7  6.9 years after the onset of RRP. Four children with

279

HPV type 11 died of squamous cell carcinoma of the lung;

one patient with HPV type 11 and one patient with HPV type
6 and 11 died of complications of the disease. The mortality
was significantly higher in patients with RRP whose mothers
had had a hysterectomy ( p = 0.032, Table 4). In patients
with juvenile-onset RRP, death from squamous cell
carcinoma of the lung was significantly more frequent if
the mother had had a hysterectomy in her gynecologic
history ( p = 0.028, Table 5). All mothers of patients who
died had indicators of HPV infection.

4. Discussion
The estimated prevalence rate of HPV genital infection in
the US adult population is 1020%. The prevalence of
clinical manifestations of HPV genital infection such as
condyloma acuminata is much lower than the rate of
infection and is estimated to be 1% in the sexually active
population [11]. In our study, 20% of the mothers had
condyloma acuminata newly diagnosed at the end of the first
trimester of pregnancy.
The gynecological history of the mother is indicative of
potential RRP in the child if it includes such factors as first
vaginal delivery and young maternal age [5]. Our study
consisted primarily of mothers who vaginally delivered firstpregnancy children at a mean age of 26. Condyloma
acuminata in the mother remains a strong predictive factor of
RRP in the child [12]. The occurrence of condyloma during
pregnancy in the mother might indicate either recent HPV
infection or its reactivation triggered by hormonal change
and physiological immune suppression. No mothers in our
study reported having had condyloma acuminata before

Table 4
2  2 contingency table showing the distribution of the death rate in patients with RRP in relation to the hysterectomy rate in their mothers
Patients with RRP who died
during the follow-up period

Patients with RRP who

survived the follow-up period

Total

Patients with RRP who had mothers

with a hysterectomy
Patients with RRP who had mothers
without a hysterectomy

16

19

Total

18

25

p = 0.032.

Table 5
2  2 contingency table showing the distribution of the death rate in patients with juvenile-onset RRP in relation to the hysterectomy rate in their mothers
Patients with juvenile-onset RRP who died
from squamous cell carcinoma of the lung
during the follow-up period

Patients with juvenile-onset

RRP who survived the
follow-up period

Total

Patients with juvenile-onset RRP who

had mothers with a hysterectomy
Patients with juvenile-onset RRP who
had mothers without a hysterectomy

15

16

Total

17

21

p = 0.028.

280

V. Gerein et al. / Cancer Detection and Prevention 31 (2007) 276281

pregnancy. Although HPV infection in the genital tract is

often associated with multiple lifetime sex partners [13], in
our study 62% of the women had only one partner before
childbirth. The lifetime number of partners is thought to be
the most important risk factor for oncogenic HPV types;
whereas, the number of partners in the past year and the
occurrence of genital warts were risk factors for the nononcogenic types of HPV [14]. We assume that HPV infection
in the respiratory tract of the child is induced by recent HPV
infection in the genital tract of the mother. Development of
RRP in the child depends upon whether the mother is able to
develop an immune response and to provide the fetus with a
sufficient amount of antibodies. Benign and malignant
lesions in the genital tract are induced by different types of
HPV. A significant correlation between a history of genital
warts and abnormal cervical smear has been noticed [15].
This point is supported by our data. The genital status of
women with a history of condyloma acuminata or with
children with RRP must be carefully monitored, because
they risk developing cervical neoplasia.
Our study revealed that 17.4% of mothers of patients with
RRP had cytological signs of HPV infection, but the results
of mass screening of asymptomatic women has shown that
the prevalence of HPV infection is only 1.04% [16].
Histological indicators of HPV infection were present in
71.4% of mothers of patients with RRP. The rate of
discrepancy between the cytological and histological results
is similar to the published data indicating that specimens
from patients with borderline nuclear abnormality identified
HPV-associated changes by cytological examination in 53%
and by histological examination in 91% [17].
The prevalence of hysterectomy is slightly higher in this
study (24%) than in the general population (15.7%) [18].
The main indication for hysterectomy was submucosal
leiomyoma. The association of death from squamous cell
carcinoma of the lung in juvenile-onset RRP patients with a
gynecological history of hysterectomy in their mothers has
not been previously described. The sample size is relatively
small, so the result should be validated before being used in
clinical management. HPV DNA has been detected in
endometrial adenocarcinoma [19], breast adenocarcinoma
[20], and prostate adenocarcinoma [21]. Although, there is
no indication in published studies on the implication of HPV
in the development of leiomyoma, it is evident that the
development of this disease along with carcinoma of
estrogen-targeted organs is favored by hyperestrogenism,
and this state appears to be a favorable condition for HPV.
Down-regulation of estrogen receptor expression may be the
first alteration to take place in normal epithelium during the
development of cervical dysplasia in women infected with
HPV. The significant decreases in the estrogen receptor/
MIB-1 ratio and the progesterone receptor/MIB-1 ratio in
progressively dysplastic lesions indicates a loss of normal
growth controlled by sex steroid hormones, which is not
observed in normal epithelium [22]. On the other hand, the
HPVoncogenes E6 and E7 are able to induce overexpression

of aromatase, the enzyme responsible for converting

androgen to estrogen, which is the rate-limiting and final
step in estrogen biosynthesis [23].
Our gynecological examination along with cytological
and histological tests of patients with RRP did not reveal any
HPV-related alterations in the genital tract. One woman had
a hysterectomy at the time of the examination because of
squamous cell carcinoma of the cervix. This patient had had
four deliveries. Possible genital HPV infection cannot be
excluded in this patient, because high parity increases the
risk of squamous cell carcinoma of the cervix among HPVpositive women [24].

5. Conclusions
Mothers of children with RRP have indicators of HPV
infection such as condyloma acuminata, koilocytosis, and
koilocytotic dysplasia. Mothers of children with an
aggressive course of RRP tended to suffer a higher incidence
of gynecologic disease than mothers of children who
suffered a mild clinical course of RRP. Death from
squamous cell carcinoma of the lung in children with
juvenile-onset RRP is associated with a hysterectomy of
their mothers.

Conflict of interest
None.

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