O r i g i n a l   a r t i c l e Adjuvant  therapy  for  laryngeal  papillomatosis

Adjuvant therapy
for laryngeal papillomatosis
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A B S T R A C T
K E Y
Respiratory papillomatosis affects the larynx in most cases. It is a relatively rare disease, with po-
WORDS tentially devastating consequences for the patient. Many studies have proven the viral etiology of
the disease. Surgery is the most successful mode of treatment. Adjuvant therapy is used in cases
respiratory
of aggressive disease. The most successful adjuvant drugs are interferon, various virostatics (e.g.,
papillomatosis,
acyclovir, valacyclovir, and cidofovir) and indole-3-carbinol. Vaccination with a quadrivalent vacci-
adjuvant therapy, ne against HPV will probably decrease the incidence of respiratory papillomatosis or help in the
surgery, treatment treatment of the disease in the future. The results of adjuvant therapy of laryngeal papillomatosis at
success the University Department of ORL & HNS in Ljubljana are comparable to the results in other centers
around the world.

Introduction SULDWH 7KH WHUP ´DJJUHVVLYH IRUP RI WKH GLVHDVHµ LV
5HVSLUDWRU\SDSLOORPDWRVLV53ZKLFKPRVWRIWHQ used when a total of more than 10 surgical procedures,
DIIHFWV WKH ODU\Q[ LV D UHODWLYHO\ UDUH EHQLJQ GLVHDVH RUPRUHWKDQWKUHHSURFHGXUHVDQQXDOO\DUHUHTXLUHG
that can, however, have an aggressive clinical course LQRUGHUWRLPSURYHWKHSDWLHQW·VFRQGLWLRQ
7KHDJHGLVWULEXWLRQRISDWLHQWVKDVWZRSHDNV Human papilloma virus (HPV) has been found in
WKHÀUVWLVDWDQDJHRIOHVVWKDQ\HDUVDQGWKHVHFRQG WKHJUHDWPDMRULW\RISDWLHQWVZLWK530RUHWKDQ
LQWKHWRDJHEUDFNHW,QWKH86WKHLQ GLIIHUHQWW\SHVKDYHDOUHDG\EHHQIRXQGDOWKRXJK53
FLGHQFHRIWKHGLVHDVHLVDVVHVVHGDWDSSUR[LPDWHO\ LVPRVWRIWHQFDXVHGE\W\SHVDQG([SHUWV
WRFKLOGUHQRUDGXOWV presume that infection most often occurs in children
/LQGHEHUJ HW DO SURSRVHG D FODVVLÀFDWLRQ RI WKH XSRQELUWKRUHYHQGXULQJJHVWDWLRQ7ZRSRVVLELOLWLHV
disease into juvenile and adult forms in relation to RILQIHFWLRQH[LVWLQSDWLHQWVLQZKRPWKHGLVHDVHDS
WKHÀUVWDSSHDUDQFHRIWKHGLVHDVH,QWHUPVRIWKH SHDUVLQDGXOWKRRGHLWKHULQIHFWLRQRFFXUUHGGXULQJ
FOLQLFDOFRXUVHRIWKHGLVHDVHDFODVVLÀFDWLRQLQWR´DJ birth and the outbreak of the disease only appeared
JUHVVLYHµDQG´QRQDJJUHVVLYHµIRUPVLVPRUHDSSUR later because of a breakdown of the immune system

Acta  Dermatoven  APA  Vol  20,  2011,  No  3 175

Adjuvant  therapy  for  laryngeal  papillomatosis O r i g i n a l   a r t i c l e

GHÀFLHQF\ RI FHOO LPPXQLW\ RU LQIHFWLRQ RFFXUUHG SURWHFWV DJDLQVW LQIHFWLRQ ZLWK +39  DQG  :LWK
ODWHU WKURXJK RUDO RU VH[XDO FRQWDFW HJ RUDO VH[XDO wider use of vaccination in the future, a reduction in
FRQWDFW²² WKHLQFLGHQFHRI53PD\DOVRSHUKDSVEHH[SHFWHGLQ
%RWKFKLOGUHQDQGDGXOWVPRVWRIWHQVHHNPHGLFDO ERWKMXYHQLOHDQGDGXOWIRUPV
KHOS EHFDXVH RI LQFUHDVLQJ KRDUVHQHVV :LWK JURZWK The purpose of our research was to establish how
RI WKH SDSLOORPDV EUHDWKLQJ GLIÀFXOWLHV DQG VWULGRU successful adjuvant therapy was in patients treated at
RFFXU ZKLFK IRUWXQDWHO\ UDUHO\ UHTXLUH WUDFKHRWRP\ the University Department of Otorhinolaryngology
,QUDUHFDVHVWKHSDSLOORPDVDOVRVSUHDG DQG &HUYLFRIDFLDO 6XUJHU\ 25/  &)6 LQ WKH ODVW
to the lower respiratory tract, a development normally \HDUV
DVVRFLDWHGZLWKDSRRUSURJQRVLV(YHQPRUHUDUHO\
LQWRWKHSDSLOORPDVXQGHUJRPDOLJQDQWFKDQJ
HV2QWKHRWKHUKDQGLQGLYLGXDOFDVHVKDYH
also been known in which the papillomas spontane
ously regress, which could be connected with hor
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Patients and methods
$PRQJ WKH SDWLHQWV WUHDWHG DW WKH 25/  &)6
'HSDUWPHQWLQ/MXEOMDQDEHWZHHQDQGZH
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 HDVH LQ WHUPV RI WKH FULWHULD SURSRVHG E\ 'R\OH 
$SSUR[LPDWHO\HTXDOSURSRUWLRQVRISDWLHQWVZLWK :H H[WUDFWHG GDWD IURP WKH PHGLFDO GRFXPHQWDWLRQ
juvenile and adult forms of the disease have an ag RQWKHH[WHQWRIWKHGLVHDVHDFFRUGLQJWRWKH'HUND\
JUHVVLYHFRXUVHDQGUHVSHFWLYHO\6RPH HWDOSURWRFROWKHPHWKRGRIWUHDWPHQWDQGWKH
factors associated with an aggressive disease course SHULRGVEHWZHHQLQGLYLGXDOVXUJLFDORSHUDWLRQV,QDOO
KDYH EHHQ HVWDEOLVKHG LQIHFWLRQ ZLWK +39  HDUO\ patients treated after 2001, we determined the level
spread of the disease to the subglottis, appearance of RI DQWLERGLHV WR KHUSHV VLPSOH[ YLUXV +69  +69
WKHGLVHDVHEHIRUHDJHJDVWURHVRSKDJHDOUHÁX[DQG  F\WRPHJDORYLUXV &09 DQG (SVWHLQ %DUU YLUXV
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7KHEDVLFPRGHRIWUHDWPHQWRI53LVVWLOOVXUJHU\
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surgeon attempts to remove as many of the papillomas
as possible in order to improve the respiratory path
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able to have as little damage to the mucous membranes
DQGRWKHUVWUXFWXUHVLQWKHODU\Q[DVSRVVLEOHVRDVQRW
WRLQGXFHVFDUULQJ7KH&22 laser has been the most
successful tool in surgical treatment for a number of
\HDUVDQGUHFHQWO\D´PLFURGHEULGHUµKDVEHHQLQFUHDV
LQJO\XVHG7KHOLNHOLKRRGRIWKHIRUPDWLRQRIVFDUVLQ
WKH ODU\Q[ LQFUHDVHV ZLWK WKH QXPEHU RI RSHUDWLRQV
Dye lasers have also been successful in the treatment
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(%9 LQ RUGHU WR GHFLGH ZKHWKHU WR WUHDW ZLWK DF\
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ease course was aggressive and that were treated with
adjuvant therapy, we compared the periods between
individual operations before and after the start of
WKHDGMXYDQWWKHUDS\:HIROORZHGWKHSDWLHQWVIRU 
WRPRQWKVDIWHUWKHVWDUWRIDGMXYDQWWKHUDS\:H
considered treatment to have been completely success
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treatment, the intervals between surgical procedures
ZHUHDWOHDVWWZLFHDVORQJDVEHIRUHWKHWUHDWPHQW,I
the growth of the papillomas did not slow by at least
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$GMXYDQW WKHUDS\ LV UHTXLUHG LQ  RI SDWLHQWV VXFFHVVIXO
ZLWKWKHDJJUHVVLYHIRUPRIWKHGLVHDVH7ZHQW\\HDUV
ago, interferon was most commonly used but it has a
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Results
clovir, valacyclovir, and cidofovir) are also used as ad )URPWRSDWLHQWVPDOHVIH
MXYDQWGUXJVDQGDFWRQ+39DVZHOODVRWKHUYLUXVHV PDOHVZHUHWUHDWHGDWWKH25/ &)6'HSDUWPHQW
,QGROH FDUELQRO DQG LWV PHWDEROLWHV LQÁXHQFH WKH ,QSDWLHQWVER\VJLUOVWKHGLVHDVHDSSHDUHG
metabolism of estrogen and thus decrease the growth before age 15, and in the others it appeared during
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clinical trials that, after treatment of gastroesophageal
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erations took place with the aid of a CO2 laser, but the
DJJUHVVLYHIRUPRIWKHGLVHDVH4XDGULYDOHQW SDSLOORPDV ZHUH VWLOO H[FLVHG PLFURVXUJLFDOO\ GXULQJ
vaccination against HPV, which has been shown to be WKHLQLWLDOSURFHGXUH,QRQHWKLUGRISDWLHQWVWKHGLV
successful in preventing HPV genital infections, also HDVHDSSHDUHGRQO\RQFHZKHUHDVWKHRWKHUVUHTXLUHG

176 Acta  Dermatoven  APA  Vol  20,  2011,  No  3

O r i g i n a l   a r t i c l e
from 2 to 43 surgical procedures, with an average of
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53 KDG DQ DJJUHVVLYH FRXUVH LQ  SDWLHQWV 
males, 12 females) ranging in age from 5 months to 53
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months to 53 years at the time of diagnosis of the dis
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Adjuvant  therapy  for  laryngeal  papillomatosis
In the cases of nine individuals (one child, eight
adults) we decided to inject cidofovir into the site of
the papillomas following laser ablation, in a concen
WUDWLRQUDQJLQJIURPWRPJPO7KHSDWLHQWV
were injected with the drug from one to nine times
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juvenile patient, after nine injections of cidofovir with
DWRWDOGRVHRIPJWKHSDSLOORPDVVWRSSHGJURZ
ing and did not reappear in the following 2 years of
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:KHQWKHUHZDVDÀQGLQJRI+69RU+69LQ
fection, as was the case in 14 patients (12 adults, two
children) with the aggressive form of the disease, the
patients were treated with acyclovir or valacyclovir
DW D VWDQGDUG GRVH IRU  PRQWKV 7KH H[WHQW RI WKH
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uals with the aggressive form of the disease or very
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disease and time periods between individual surgical
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dures doubled and in three children growth of the
papillomas ceased after 2 years of taking the medica
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IROORZXSSHULRGDUHVKRZQLQ7DEOHVDQG
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one of the adjuvant drugs were further treated with
another adjuvant drug or received a vaccination, and
two patients were vaccinated after the failure of two
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Table 1. Comparison of the extent of respiratory papillomatosis, interval between surgical procedures, and
number of surgical procedures before and after adjuvant therapy.
Interval between
Extent of disease Procedures (n)
Adjuvant drug procedures (months)
Before After Before After Before After
Acyclovir/valacyclovir      
,QGROHFDUELQRO      
Cidofovir      
HPV vaccination      

Table 2. Review of success of treatment with different adjuvant drugs in patients with aggressive forms of
respiratory papillomatosis.

Follow-up Complete Partial Not

Adjuvant drug Patients (n)
time (months) response response successful

Acyclovir/valacyclovir 14 ²  4 3
,QGROHFDUELQRO 5 48–84 1 2 2
Cidofovir  ² 1  1
HPV vaccination 8 24–32 2 4 2

Acta  Dermatoven  APA  Vol  20,  2011,  No  3 177

Adjuvant  therapy  for  laryngeal  papillomatosis O r i g i n a l   a r t i c l e

Discussion JUHVVLYHIRUPVRIWKHGLVHDVH,QSDWLHQWVZKRVHORZHU
respiratory tracts are affected, cidofovir is given also
53LVDUDUHGLVHDVHDIIHFWLQJDVPDOOQXPEHURI V\VWHPLFDOO\7KHVXFFHVVRIFLGRIRYLULQWKHWUHDWPHQW
patients, and so statistical evaluation of success does
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after adjuvant therapy did not differ greatly, which is
evidence that we always decided on surgical interven
tion when patients were in relatively the same clinical
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our patients, we observed partial or complete success
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injections of cidofovir, the papillomas stopped grow
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increase the survival of cells and induce changes in
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operations before and after adjuvant therapy is also
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of adjuvant therapy was essentially longer than after
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38 operations before adjuvant therapy, for an average
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WKHVH GDWD DQG WKH GUXJ PDQXIDFWXUHU·V UHTXLUHPHQW
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redirects it into a metabolite that decreases the growth
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the average number of operations before adjuvant
WKHUDS\
A better method of evaluating the success of treat
ment is determination of the interval between indi
vidual surgical procedures before and after adjuvant
therapy, or an overall clinical evaluation of the suc
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growth of the papillomas, and number of operations
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success of treatment in our patients was comparable
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Since establishing the success of vaccination
against HPV for preventing uterine cancer, vaccina
tion has been recommended for girls 11 to 12 years
old, or also women up to age 26, and in some countries
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protects against infection with HPV 6 and 11, a re
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summary we found a complete response to therapy in YDFFLQDWLRQ LQ WKH IXWXUH FDQ SUREDEO\ EH H[SHFWHG
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According to data from the few studies available, KDYHDOVREHHQSXEOLVKHG:HGHFLGHGRQYDF
acyclovir or valacyclovir have been used successfully cination in patients with the most aggressive course of
as adjuvant therapy after surgical removal of papillo the disease or those in whom one or even two adju
PDVLQRIFDVHV7KHVHGDWDFRXOGFRQÀUP
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rostatic is similar to that described in the literature be
cause we recorded complete success of adjuvant thera
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aggressive form of the disease in whom simultaneous
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In recent years there have been some reports of
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Conclusion
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ease of the upper respiratory tract with possible dev
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In aggressive forms of the disease adjuvant therapy is
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analogue of the cytosine nucleotide, which is built
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illomas after their prior surgical removal in very ag
178
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This is the best way to bring about improvement in
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Acta  Dermatoven  APA  Vol  20,  2011,  No  3
O r i g i n a l   a r t i c l e Adjuvant  therapy  for  laryngeal  papillomatosis

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Acta  Dermatoven  APA  Vol  20,  2011,  No  3 179

Adjuvant  therapy  for  laryngeal  papillomatosis O r i g i n a l   a r t i c l e

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A U T H O R S ’ 3URI,UHQD+RþHYDU%ROWHåDU0'3K'FRQVXOWDQW'HSDUWPHQWRI
A D D R E S S E S Otorhinolaryngology  and  Cervicofacial  Surgery,  Ljubljana  University  
Medical  Center,  Slovenia
Maja  Šereg  Bahar,  MD,  MS,  same  address
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University  of  Ljubljana,  Slovenia
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Febrile  Illnesses,  Ljubljana  University  Medical  Center,  Slovenia
Prof.  Mario  Poljak,  MD,  PhD,  Institute  of  Microbiology,  Medical  Faculty,  
University  of  Ljubljana,  Slovenia

180 Acta  Dermatoven  APA  Vol  20,  2011,  No  3