2014, Volume 30, Number 2, Page(s) 133-136
Metastatic Squamous-Cell Carcinoma of the Lung Arising in a 12-Year-Old Boy with Juvenile Recurrent Respiratory Papillomatosis of Neonatal Onset
Sabah BOUDJEMAA1, Nicolas LEBOULANGER1, Linda DAÝNESE1, Patricia DE CREMOUX1, Hubert DUCOU LE POINTE2, Aurore COULOMB1
1Department of Pathology, Hopital Armand Trousseau, PARIS, FRANCE
2Department of Radiology, Hopital Armand Trousseau, PARIS, FRANCE
Keywords: Human papillomavirus, Squamous cell carcinoma, Recurrent respiratory papillomatosis, Children
Juvenile recurrent respiratory papillomatosis is the most common
benign neoplastic disease of the larynx in children, characterized by
numerous squamous papillomas caused by Human Papilloma Virus
type 6 and 11. HPV is thought to be acquired at the time of vaginal
delivery from maternal genital condylomas. Juvenile recurrent
respiratory papillomatosis can be protracted by surgical interventions
performed to avoid airway obstruction and extend below the vocal
cords as far as the main stem bronchi. Lung involvement in Juvenile
recurrent respiratory papillomatosis seems to be more prevalent than
non-systematic reviews have reported until now and progression to
cancer occurs in a significant proportion of these cases at a younger
age than previously reported. This would suggest that closer attention
should be paid to these children. We report a case of malignant
transformation in a 12 year-old boy followed-up since the birth for an
invasive juvenile recurrent respiratory papillomatosis with pulmonary
involvement. The presence of HPV 6/11 was demonstrated by PCR
analysis performed on material obtained from a metastatic vertebral
Juvenile recurrent respiratory papillomatosis (JRRP) is
the most frequent benign neoplasic disease of the larynx
in children and adolescents1
. JRRP is characterized by
numerous benign squamous papillomas of the respiratory
tract, usually confined to the larynx and self-limited.
Occasionally, the behaviour is more aggressive, with
persistent, recurrent papillomas and spread to the inferior
. This distal involvement has been reported to occur in the trachea in 2-26% of cases and in the lungs in
2.3 % of cases3,4
The strongest risk factor for JRRP is a maternal history of
genital papillomas transmitted during delivery. JRRP is due
to infection with Human Papilloma Virus (HPV) mainly
of type 6 and 112,5,6,7. Although these HPV types are
thought to be of «low risk» in the genitary tract, patients
with JRRP can develop broncho-pulmonary carcinoma,
especially those who receive radiation or cytotoxic drugs or
We report a new case of metastatic squamous cell carcinoma
associated with HPV6/11 in a 12 year-old boy managed
for a neonatal onset JRRP with pulmonary involvement.
Clinical data, since the birth of the child were available and
reviewed. A Guyanese child presented with respiratory
symptoms, shortly after birth. He was born at full-term and
delivered vaginally. It is not known whether his mother had
genital condylomas. These respiratory symptoms leaded
to the discovery of papillomatosis affecting the whole
upper airways (nose, trachea and bronchi). At the age of 4
months, he underwent a tracheotomy due to upper airway
obstruction. A biopsy performed in Guyana confirmed
benign papillomatosis. The patient referred to our
institution at the age of 6 months and underwent a surgical
management consisting in airway desobstruction with laser
procedures and XPS shaver, without any improvement.
Medical therapy consisting in 15 cycles of intravenous
administration of cidofovir was started in January 2001,
followed by local injections into the larynx every month
since April 2002 (7,5 mg/ml, from 10 to 20 ml each time).
Between July and September 2007, he weekly received
aerosols of cidofovir (30 mg each). No clinical response
was obtained despite surgical and medical management,
requiring 234 hospitalizations and 150 endoscopies under
general anesthesia between 1997 and 2008. The tracheotomy
could not be removed at any time.
At the age of 12 year-old, a follow-up computed tomography
(CT) scan demonstrated a large pulmonary mass with
mediastinal lymphadenopathies (Figure 1) and a lumbar
spine (L2) lytic lesion (Figure 2). The pulmonary tumor was not accessible to biopsy or surgical resection and persisted
after a broad-spectrum intravenous antibiotherapy. A fine
needle aspiration (FNA) and a CT-guided fine needlebiopsy
were then performed on the L2 lytic lesion. The
cytologic material obtained was analyzed after MGG stain.
Tissue for microscopic examination was fixed in formalin
and processed routinely. Sections (5 μm) were cut from
the paraffin blocks and stained with haematoxylin-eosinsaffron.
FNA showed numerous differentiated squamous
cells. Biopsies measured 10 mm in greatest length.
Microscopic examination showed infiltration of bone
by a carcinoma composed of sheets of polygonal tumor
cells with abundant eosinophilic cytoplasm and vesicular
nuclei, mild atypia and a low mitotic rate. Keratinization
was focally present. A bone metastasis from pulmonary well differentiated squamous cell carcinoma was diagnosed
(Figure 3). A few weeks after the diagnosis, the patient
condition continued to deteriorate and he died of multiples
Click Here to Zoom
|Figure 1: Thoracic TDM showing pulmonary mass with
Click Here to Zoom
|Figure 3: Bone infiltration by well differentiated squamous cell
carcinoma. (H&E Saffron; x40).
To extract total DNA, 4 sections of 10 μm were cut from a
formalin-fixed tissue block using a commercially available
kit (QIA amp DNA mini kit, Qiagen, Valencia, CA).
Samples were screened for HPV specific types 16, 18,
33, 45, 6 and 11 DNA and consensus HPV DNA (HPV
X) using GP5+/GP6+primers in five independent PCR.
PCR amplification was performed in a 50 μL volume and
included 5 mM MgCl2, 0.2 mole of dNTP, 1.25 U Taq Gold
DNA polymerase (Applied Biosystems, Foster City, CA,
USA) and 1 μmol/L of each HPV type 3' and 5' primers.
The amplification ramp included 1 min at 94°C, 1 min at
55°C and 1 min at 72°C for 30 cycles, except consensus PCR
where annealing temperature was 42°C for 40 cycles. PCR
products were visualized on 0.5% agarose, 2% Nusieve gel
stained with ethydium bromide. Positive control-plasmids
and two independent negative controls were amplified in
each run. All samples were tested for DNA integrity by PCR
using primers for the human GAPDH gene9. The presence
of HPV 6/11 was demonstrated by five independent PCR
analysis, on formalin-fixed paraffin-embedded tumor tissue
from the bone metastatic lesion. The viral load was low, but
HPV 6/11 HPV DNA was constantly found in all samplings,
attesting the infection of the tumor (Figure 4). No material
from papillomas was available in our laboratory, as the
initial biopsy was performed in Guyana.
Juvenile recurrent respiratory papillomatosis (JRRP) remains
a mysterious disease and is very difficult to manage.
The median age of JRRP is 2 years, with a range of 2 months
to 19 years. Eighty three percent of cases are diagnosed before
4 years of age4
. In this case, JRRP was diagnosed in
the first 4 months of life.
The course of the disease is unpredictable. Papillomas
may regress spontaneously. An aggressive course may occur when papillomas spread to the distal airways and
to the lungs, probably protracted by iterative surgical
interventions performed to avoid airway obstruction. A
systematic review of the literature analyzed 11 publications
on 161 cases of lung involvement in JRRP. The pooled data
showed the incidence of lung involvement in JRRP at 3.3%
(from a cohort studies) and the incidence of malignant
transformation at 16%. The median interval between the
diagnosis of JRRP and that of lung involvement is 8 years
(range <1-45 years)4.
Malignant transformation may occur, either at the laryngeal,
bronchial or pulmonary level. The median interval between
the diagnosis of JRRP and that of cancer is 19 years (12
years in this case). The youngest child reported to die of
lung cancer was 6 years old and 31% of the reported cases
are diagnosed before the age of 18 years. The strongest
risk factor for JRRP is a history of genital condyloma
transmitted from the mother during delivery. HPV is the
etiologic agent of respiratory papillomatosis. The virus is
a 55 nm nonenveloped, icosahedron containing an 8 kb
circular, covalently closed, double-strand genome. The
genome consists of three regions: the long control region
(LCR), which contains transcription regulatory sequences,
the early and the late regions which are related to the phase
of infection in which they are expressed10. Gabott et
al. evaluated HPV type and viral mutation occurring
during the course of juvenile-onset recurrent respiratory
papillomatosis in 199 papillomas excised from 47 children.
Forty four children had HPV-induced papillomas, with
type 11 accounting for 55%, type 6 for 43% and both type 6
and 11 for 2%11.
Despite the epidemiological classification of type 6 and 11
HPV as low risk HPVs, it has been reported in the literature
that children with lesions containing HPV 11 have a more
aggressive course than patients with HPV 6-associated
lesions. HPV11 is associated with squamous cell carcinoma
although HPV11 is uncommonly associated with the
development of invasive carcinoma at other sites12.
Patients affected by HPV11 papillomatosis as in our case
are younger, with a longer period of disease activity, require
more surgical procedures and are less likely to go into
remission than HPV 6-infected patients. These data suggest
that HPV 11 may play a significant role in carcinogenesis
in the larynx and respiratory tract, particularly in patients
with JRRP. In summary, JRRP aggressiveness is in relation
with two strong risk factors: the age at diagnosis of JRRP
(laryngeal involvement) and HPV type.
Rady et al. demonstrated that the p53 genetic mutation
was associated with integration of HPV-11 in histologically
malignant lesions. This association may promote a progressive genetic instability that can lead to the development and
clonal expansion of malignant lesions in JRRP2. In our
case, immunohistochemical analysis showed positive nuclear
staining for p53.
Patients who receive radiation or cytotoxic drugs or those
who subsequently smoke may be predisposed to the
development of broncho-pulmonary carcinoma8.
In this observation, HPV may be an important risk factor
in the development of squamous cell carcinoma as the child
did not receive radiation or cytotoxic drugs. In addition,
HPV 6/11 DNA was detected by PCR-analysis in the
metastatic tumor cells.
Clearly, to date, not enough data are available on the
association of HPV type, the possible variation in HPV or
the development of mutations and progression to cancer.
To conclude, many issues need to be improved in JRRP:
the understanding of the mechanisms underlying the
lung involvement as well as the risks associated with
different HPV types and the risk of progression to cancer,
strategies for early diagnosis of malignant transformation
and adequate follow-up. Randomized control trials and
prospective cohort studies are warranted12. Significant
vaccine research is being pursued for JRRP13. In the
future, the incidence of JRRP and squamous cell carcinoma
may be reduced by the wild use of quadrivalent HPV
vaccine for prevention of HPV 6/11.
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