ADJUVANTNO ZDRAVLJENJE PAPILOMATOZE GRLA
ADJUVANT THERAPY OF LARYNGEAL PAPILLOMATOSIS
Assoc. Prof. Dr. Irena Hočevar Boltežar, MD, consultant *, Maja Šereg Bahar, MD, MSc*,
Prof. Dr. Miha Žargi, MD, senior consultant*, Prof. Dr. Nina Gale, MD**, Assoc.Prof. Mojca
Matičič, MD***, Prof. Dr. Mario Poljak, MD****
*Department of Otorinolaryngology and Cervicofacial Surgery, University Medical Center
**Institute of Pathology, Medical Faculty, University of Ljubljana, Slovenia
***Department of Infecious Diseases and Febrile Illnesses, University Medical Center
****Institute of Microbiology, Medical Faculty, University of Ljubljana, Slovenija
Papilomatoza grla je relativno redka bolezen zgornjih dihal, katere klinični potek pa je lahko
za bolnika usoden. Številne raziskave so potrdile virusno etiologijo bolezni. Doslej najbolj
uspešno zdravljenje je kirurško, za adjuvantno zdravljenje pa se odločimo v primerih
agresivne oblike bolezni. Kot adjuvantna zdravila za papilomatozo grla so bili doslej
najuspešnejši interferon, različni virostatiki (aciklovir, valaciklovi, cidofovir) in indol-3
karbinol. Cepljenje s štirivalentnim cepivom proti humanemu papiloma virusu bo v
prihodnosti morda zmanjšalo incidenco papilomatoze grla, morda pa tudi pomagalo pri
zdravljenju že razvite bolezni. Uspehi zdravljenja agresivne oblike bolezni na Kliniki za ORL
in CFK, UKC Ljubljana so primerljivi z uspehi drugod po svetu.
Respiratory papillomatosis in most cases affects the larynx. It is a relatively rare disease,
with possible devastating consequences for the patient. Many studies have proven the
viral aetiology of the disease. Surgery is the most successful mode of treatment.
Adjuvant therapy is used in cases of aggressive disease. The most successful adjuvant
medicaments are interferon, various virostatics (acyclovir, valacyclovir, cidofovir) and
indole-3-carbinol. Vaccination with a quadrivalent vaccine against HPV will probably
decrease the incidence of respiratory papillomatosis or help in the treatment of the
disease in the future. The results of adjuvant therapy of laryngeal papillomatosis at the
University Department of ORL & HNS in Ljubljana are comparable to the results in
other centers in the world.
Key words: respiratory papillomatosis, adjuvant therapy, surgery, treatment success
Respiratory papillomatosis (RP), which most often affects the larynx, is a relatively rare
benign disease but which can have an aggressive clinical course (1, 2). The age distribution of
patients has two peaks: the first is at an age of less than 5 years and the second in the 20-40
age bracket (3, 4). In the United State of America, the incidence of the disease is assessed at
approximately 1.7 – 4.3/100,000 children, or 1.8/100,000 adults (5, 6).
Lindeberg et al. proposed a classification of the disease into juvenile and adult forms in
relation to the first appearance of the disease (3). In terms of the clinical course of the disease,
a classification into »aggressive« and »non-aggressive« forms is more appropriate. The term
aggressive form of the disease is used when a total of more than 10 surgical procedures, or
more than 3 procedures annually, are required in order to improve the patient's condition (7).
Human papilloma virus (HPV) has been found in the great majority of patients with RP. More
than 120 different types have already been found, although RP is most often caused by types 6
and 11 (5, 8). Experts presume that infection most often occurs in children during birth or
even already during pregnancy. Two possibilities of infection exist in patients in whom the
disease appears in the adulthood: either infection occurred during birth and the outbreak of the
disease only later because of a breakdown of the immune system (deficiency of cell
immunity) or infection occurred later orally or through sexual contact (e.g., oral sexual
contact) (4-6, 9-12).
Both children and adults most often seek medical help because of increasing hoarseness. With
growth of the papillomas, breathing difficulties and stridor occur, which fortunately rarely
require tracheotomy (1, 3, 5, 12). In rare cases, the papillomas also spread to the lower
respiratory tract, what is normally associated with a poor prognosis of the disease (6). Even
more rarely (in 3%-7%) the papillomas undergo malignant change (5, 9, 12). On the other
hand, individual cases have also been known in which the papillomas spontaneously
disappear, what could be connected with hormonal or immunological changes in the patient
(5, 7, 10, 12, 13).
Approximately equal proportions of patients with juvenile (17%) and adult (19%) forms of
the disease have an aggressive course (6). Some factors have so far been established,
associated with an aggressive disease course: infection with HPV 11, early spread of the
disease to the subglottis, the appearance of the disease before the age of 3, gastroesophageal
reflux and simultaneous infection with other viruses (5, 10, 12-14).
The basic mode of treatment of RP is still surgery under general anaesthesia. During the
operation, the surgeon attempts to remove as much of the papillomas as possible, in order to
improve the respiratory paths and the quality of voice. At the same time, as little damage to
the mucous membrane and other structures in the larynx as possible is desired, so as not to
induce scarring. CO2 laser has been most successful in surgical treatment for a number of
years and, recently, a »microdebrider« has been increasingly used. The possibility of the
formation of scars in the larynx increases with the number of operations. Dye lasers have also
been successful in the treatment of RP because of their angiolithic effect on the blood vessels
in the papillomas (5, 10, 12, 13, 15).
Adjuvant therapy is required in 10% of patients with the aggressive form of the disease.
Twenty years ago, interferon was most commonly used but it has a number of adverse effects
(16). Virostatics (acyclovir, valacyclovir, cidofovir) are also used as adjuvant medicaments
and act on HPV as well as other viruses. Indole-3 carbinol and its metabolites influence the
metabolism of estrogen and thus decrease the growth of the papillomas (10, 12, 17-21). It has
been found in clinical trials that after treatment of gastroesophageal reflux in children with
RP, the number of recurrences is significantly reduced. The authors therefore recommend
treatment of reflux mainly in patients with an aggressive form of the disease (22, 23).
Quadrivalent vaccination against HPV, which has been shown to be successful in preventing
HPV genital infections, also protects against infection with HPV 6 and 11. With wider use of
vaccination in the future, a reduction in the incidence of RP may also perhaps be expected –
in both juvenile and adult forms (12).
The purpose of our research was to establish how successful adjuvant therapy was in patients
treated at the University Department of Otorhinolaryngology and Cervicofacial Surgery
(Univ. Dept. of ORL & CFS) in the last 32 years.
PATIENTS AND METHODS
Among patients treated at the Univ. Dept. of ORL & CFS Surgery in Ljubljana in the period
1979-2011, we identified the patients with an aggressive form of the disease in terms of the
criteria proposed by Doyle (7). We extracted from the medical documentation data on the
extent of the disease according to the protocol of Derkay et al. (24), the method of treatment
and the periods between individual surgical operations. In all patients treated after 2001, we
determined the level of antibodies against herpes simplex virus (HSV 1, HSV 2),
cytomegalovirus (CMV) and Epstein Barr virus (EBV), in order to decide about possible
treatment with acyclovir or valacyclovir. In patients in whom the disease course was
aggressive and who were treated with adjuvant therapy, we compared the periods between
individual operations before and after the start of the adjuvant therapy. We followed the
patients for 7 to 103 months after the start of adjuvant therapy. We considered treatment to
have been completely successful if after completed treatment a maximum of one operation
was required and the papillomas did not then reappear throughout the period of observation.
Partial success meant that after the end of the treatment, the intervals between surgical
procedures became at least twice as long as before the treatment. If the growth of the
papillomas did not slow by at least 50%, we considered the treatment to have been
In the period from 1979 to 2011, 182 (125 men, 57 women) patients were treated at the Univ.
Dept. of ORL and CFS. In 31 patients (14 men, 17 women), the disease appeared at an age up
to 15 years, and in adulthood in the others. Patients were aged from 9 months to 82 years at
the time of diagnosis of the disease.
All patients were treated surgically. Until 1996, papillomas were removed microsurgically.
Later operations took place with the aid of CO2 laser, only at the first procedure the
papillomas were excised microsurgically. In one third of patients, the disease appeared only
once, in the others, from 2 to 43 surgical procedures were required, on average 2.3 operations
RP had an aggressive course in 27 patients (15 men, 12 women), aged from 5 months to 53
years at the first appearance of symptoms, and from 9 months to 53 years at the time of
diagnosis of the disease. After 1999 all patients with an aggressive form of the disease were
treated with proton pump inhibitors, specifically with esomeprasol, omeprasol or pantoprasol
in a standard dose twice daily until improvement (slower growth of papillomas).
When there was a finding of HSV 1 or HSV 2 infection, as was the case in 14 patients (12
adults, 2 children) with the aggressive form of the disease, the patients were treated with
acyclovir or valacyclovir in a standard dose for two months. The extent of the disease and
time periods between individual surgical procedures are shown in Table 1.
Five children with the aggressive form of the disease received indole-3 carbinol for 6 months
to three years. The interval between required surgical procedures doubled, and in three
children, growth of the papillomas ceased after two years of taking the medicine (Tables 1
In the case of nine persons (1 child, 8 adults) we decided to inject cidofovir into the site of the
papillomas after laser ablation of them, in a concentration from 2.5-7.5 mg/ml. The patients
were injected with the medicine from 1-9 times and received a total dose of 10 mg - 75 mg. In
the child, after 9 injections of cidofovir with a total dose of 26.25 mg the papillomas stopped
growing and did not appear in the following two years of follow-up (Tables 1 and 2).
We decided on vaccination with three doses of quadrivalent vaccine (HPV 6, 11, 16, 18) in
persons with the aggressive form of the disease or very quickly growing papillomas, and
above all in patients in whom other adjuvant medicaments had not helped. We vaccinated 7
adults and 1 child, 6 female and 2 male. The results of treatment at the end of the follow-up
period are shown in Tables 1 and 2.
Nine patients, due to the lack of success of one of the adjuvant medicaments were further
treated with another adjuvant medicament or received a vaccination, and two patients were
further vaccinated after the failure of two adjuvant medicaments.
Table 1. Comparison of extent of respiratory papillomatosis, interval between surgical
procedures and number of surgical procedures before and after adjuvant therapy.
Table 2. Review of success of treatment with different adjuvant medicaments in patients with
aggressive forms of respiratory papillomatosis.
RP is a rare disease, affecting a small number of patients, therefore statistical evaluation of
success does not have real value. In this paper in which we have summarised the results of
adjuvant therapy in 27 patients with aggressive RP, we decided on a presentation of results
without statistical evaluation.
Estimates of the extent of papillomas before and after adjuvant therapy did not differ greatly,
which is evidence that we always decided on surgical intervention with relatively the same
clinical condition. Only after vaccination the extent of the papillomas reduced by a good third.
The number of operations before and after adjuvant therapy is also difficult to compare, since
the time before the start of adjuvant therapy was essentially longer than after it. The group of
patients with an aggressive form of RP included 4 patients who had from 10 to 38 operations
before adjuvant therapy, on average 22.5 operations, which undoubtedly also influenced the
average number of operations before adjuvant therapy.
A better method of evaluating the success of treatment is determination of the interval
between individual surgical procedures before and after adjuvant therapy, or an overall
clinical evaluation of the success, which covers the extent of the disease, speed of growth of
the papillomas and number of operations required (complete or partial response to therapy or
lack of success). In terms of the latter evaluation, it could be summarised that we found a
complete response to therapy in 31%, partial response in 47% and, in the case of 22% of
patients, adjuvant therapy was unsuccessful.
According to data from the rare studies, acyclovir or valacyclovir have been successful
adjuvant therapy after surgical removal of papillomas in 50% of cases (21). These data could
confirm the importance of simultaneous infection with other viruses during the course of RP,
mainly infection with HSV. The success of therapy of our patients with this virostatic is
similar to that described in the literature, since we recorded complete success of adjuvant
therapy in one half of the patients. Only those patients with the aggressive form of the disease
in whom simultaneous infection with HSV 1 or HSV2 was confirmed were given the
In recent times, there have been some reports of the use of cidofovir (10, 12, 17, 18).
Cidofovir is an analogue of the cytosine nucleotide, which is built into the DNA chain of the
virus. It is most commonly injected directly into the larynx at the site of the papillomas after
their prior surgical removal, with very aggressive forms of the disease. In patients with lower
respiratory tract affected, cidofovir is given also systemically. The success of cidofovir in the
treatment of RP was even more than 60% (10, 12, 17-19). In our patients, we observed partial
or complete success in the case of 8 of 9 treated patients. We also injected the medicament
only locally at the site of the papillomas. We achieved the greatest success in a 2-year old girl,
in whom an operation was required practically every two months because of the fast growth
of the RP. After 9 injections of cidofovir, the papillomas stopped growing. In 2009, a warning
appeared that cidofovir can increase the survival of cells and induce changes in gene
expression, which is known to be connected with malignant transformation in cells (25). In
view of these data and the requirement of the manufacturer of the medicine that cidofovir can
be used exclusively for CMV infection of the eyes, we stopped using cidofovir.
Indole-3 carbinol affects estrogen metabolism and redirects it into a metabolite that decreases
the growth of papillomas. We have used the medicament in children with partial or complete
success in 75% of cases (22). The success of treatment in our patients was comparable with
Since establishing the success of vaccination against HPV for preventing uterine cancer,
vaccination has been recommended for girls aged 11-12, or also women up to the age of 26, in
some countries even for boys. That quadrivalent vaccination also protects against infection
with HPV 6 and 11, therefore a reduction of the incidence of RP with more widespread
vaccination in the future can probably be expected (12). Individual reports of the success of
the use of quadrivalent HPV vaccine also for the treatment of RP have been published (26,
27). We decided on vaccination in patients with the most aggressive course of the disease or
those in whom one or even two adjuvant medicaments had not been successful. The course of
the disease improved in 6 of 8 vaccinated patients. Only with further follow-up the exact role
of vaccination against HPV in the treatment of RP will be proved.
Respiratory papillomatosis is a relatively rare disease of the upper respiratory tract with
possible devastating consequences for the patient in some cases. In aggressive forms of the
disease adjuvant therapy is used. It is necessary to consider carefully which medicament to
use in order to achieve the best possible results. Only in this way the improvement of the
health condition and thus the quality of life of patients with respiratory papillomatosis can be
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