Download Recurrent respiratory papillomatosis: pathogenesis to treatment

Recurrent respiratory papillomatosis: pathogenesis to treatment
John H. Lee and Richard J. Smith
Purpose of review
Recurrent respiratory papillomatosis remains a serious
disease and is commonly treated by otolaryngologists. The
goals of this review are to update physicians on current
understandings regarding viral pathogenesis, patient risks,
and current trends in treatment strategies.
Recent findings
Surgical debulking still remains the foundation of
treatment; however, newer surgical approaches
utilizing microdebriders are replacing laser ablation.
Genetic studies have identified individuals with specific
immune cell alleles to be at greater risk for persistent
infection. Our understanding of the viral pathogenesis
has increased by the identification of a viral mechanism
to downregulate antigen expression in cells infected with
human papillomavirus, thus possibly allowing decreased
immune detection. Although the viral types responsible
for recurrent respiratory papillomatosis have been
identified, the mechanism by which they alter cellular
growth has not been identified. Research studies
investigating adjuvant medical therapies aimed at
reducing required surgical therapy intervals and
possibly helping cure the infection are being completed.
A safe, effective adjuvant therapy is still currently not
available.
Summary
Improved surgical approaches have slightly enhanced
patient care; however, more research is needed to
understand how human papillomavirus causes disease so
that these therapies can be developed.
Keywords
laser ablation, microdebriders, papillomatosis, recurrence,
respiratory, viral pathogenesis
Curr Opin Otolaryngol Head Neck Surg 13:354—
—359. ª 2005 Lippincott Williams
& Wilkins.
Department of Otolaryngology — Head and Neck Surgery, University of Iowa,
Iowa City, Iowa, USA
Correspondence to John H Lee, Department of Otolaryngology-HNS,
200 Hawkins Drive, Iowa City, IA 52242, USA
Tel: 319 356 2174; fax: 319 356 4547; e-mail: [email protected]
Current Opinion in Otolaryngology & Head and Neck Surgery 2005,
13:354—
—359
Abbreviations
HPV
IC3
MHC
RRP
human papillomavirus
indole-3-carbinol
major histocompatibility complex
recurrent respiratory papillomatosis
ª 2005 Lippincott Williams & Wilkins.
1068-9508
354
Introduction
Recurrent respiratory papillomatosis (RRP) is a disease
process of the airways that affects persons of all ages
and is characterized by recurrent benign epithelial growths.
The disease course can vary greatly between individuals.
In many instances, spontaneous clearance occurs after
only a few surgical procedures. In other cases, however,
the papillomas continue to grow, spreading throughout
the airway and ultimately affecting surgically inaccessible
and untreatable areas, where eventual degeneration to
squamous cell carcinoma portends the death of these
patients. In this paper, we summarize the epidemiologic
risk factors, viral-related pathogenesis, immunologic risks,
and established treatment regimens for this debilitating
disease.
Epidemiology
Papillomatosis of the human airway tract epithelia is a significant medical problem that has a prevalence rate of 3 to
5 per 100 000 population and accounts for at least $123
million per year in medical expense [1–4]. The etiologic
agent, human papillomavirus (HPV) types 6 and 11, can
infect the entire respiratory tract, although the squamous–
columnar junction of the larynx is the most common site
of involvement [5]. Airway involvement by other subtypes
of HPV is very rare. Infection with HPV11 is more likely to
be associated with the development of aggressive distal
disease than HPV6 [1,6,7]. Another factor associated with
distal spread of disease is diagnosis prior to the age of
three [3,8•].
Although RRP is very rare, exposure of the upper airway to
HPV6 or HPV11 happens frequently during life. In fact, it
is likely that exposure of the upper airway to HPV6 or
HPV11 may be as common as exposure to other viruses
such as rhinovirus; studies have shown that HPV DNA
can be detected in the upper airway of as many as 25%
of normal nonaffected children and adults [9,10]. This frequency of exposure compounds the difficulty in identifying why some persons experience RRP but the majority do
not. For example, exposure of a neonate to HPV during
vaginal delivery to a mother affected with condylomata
does occur [11,12]; however, the relative risk for the development of RRP is 7 in 1000, corresponding to an odds ratio
of 231 compared with children born vaginally without
condylomata [13]. This low risk has fueled a debate over
whether cesarean section should be recommended in the
presence of active condylomata, with some reports suggesting a higher rate of RRP in children delivered vaginally
[13] and others citing a statistically higher rate in children
Recurrent respiratory papillomatosis Lee and Smith 355
delivered by cesarean section [9,14]. For adult-onset RRP,
oral sexual practices have been associated with a slightly
higher risk for the development of papillomas [15] but
have not been definitively implicated in disease pathogenesis. In general, given that the incidence of RRP is rare
compared with the exposure risk to HPV6 or HPV11,
other factors must contribute to the development of persistent papillomatous disease.
Viral pathogenesis
The virus has three vital components that cause human
disease: (1) persistence causing a protracted disease course,
(2) altered cellular growth resulting in airway papillomas,
and (3) viral reproduction allowing the disease to spread.
A clearer understanding of the factors that control viral
genome persistence–associated cellular change and viral
reproduction in human airway epithelium is critical to
our understanding of disease pathogenesis and the development of novel treatment options.
Viral genome replication, maintenance and production
To cause long-standing disease, the HPV genome must
persist during host cell division. In most papillomas, persistence is achieved as an episome (extrachromosomal circular
HPV genome) [16,17•]. The maintenance and replication
of this episomal genome under the nondifferentiating condition requires the expression of at least two early genes,
E1 and E2. This vegetative state of reproduction is thought
to represent the type of replication that occurs in nondifferentiated basal cells [18,19].
Part of the mechanism of episomal maintenance has been
recently clarified. The viral gene E2 binds the viral
genome to host chromosomal DNA so that it is segregated
and maintained during mitosis [20••]. When keratinocytes
differentiate, the viral genome is amplified in the suprabasal cells by way of rolling-circle amplification that synthesizes a sufficient quantity of viral genome for packaging
[21,22]. This differentiation-dependent change in genome
amplification has been linked to the expression of a late
E1–E4 splice isoform. It has been hypothesized that cellular differentiation activates this late viral gene production, thus allowing assembly of virus [23].
Much of what is currently known about HPV has been
reported by the use of high-risk HPV16 and HPV31 in
anogenital keratinocytes; the actual HPV6 or HPV11
mechanism of replication, maintenance, and viral production in airway cells is largely unexplored. For instance, it is
still unknown whether airway cells produce infectious
particles. More research focusing specifically on these
low-risk HPV types in airway cells is needed to determine
whether virus–airway cell interactions are similar to or
different from disease in the anogenital area.
Altered cell growth
The mechanisms by which HPV produces a papillomatous
growth are also poorly understood. In cells with high-risk
HPV16 genomes, the development of condylomata requires
an alteration in cellular growth and differentiation. Two
key viral genes responsible for this change in growth and
differentiation are E6 and E7. These proteins bind to
and alter the function of two key apoptotic proteins, Rb
and P53 [5,24,25]. The E6 and E7 from HPV6 and
HPV11 do not readily degrade these key cellular genes
[26,27,28•], however, which implies that the mechanisms
leading to altered growth in the airway are likely different.
Significant data also suggest that the presence of HPV6 or
HPV11 in airway epithelial cells is not sufficient alone to
induce papillomatous growth, because biopsy specimens
from normal mucosa of the distal airway and separate from
sites of papilloma also contain HPV genomes [29,30•].
Several authors have hypothesized that the virus may
remain in a latent state [29,30•], although the factors that
activate papilloma growth in virus-infected normal cells
remain unknown. Like the factors controlling viral replication, the mechanisms required for altered cellular differentiation by HPV6 or HPV11 in airway cells require more
basic research so that mechanism-specific treatment strategies can be developed.
Immune relationship
It is probable that most persons have been exposed to, or
infected with, low-risk HPV viruses. As with most viruses;
the disease course for each person varies. Most persons
clear the virus exposure completely, but in some individuals the virus persists. In a fraction of this latter group,
disease becomes active and papillomas form. One possible
reason for viral persistence may be the inability to present
viral antigens in major histocompatibility complexes
(MHCs). Population studies have identified certain MHC
alleles that are found in a higher percentage of RRP
patients than in the general population [31,32]. Despite
this association, however, HPV persistence requires more
than a specific MHC allele, because many people with
at-risk alleles do not develop disease.
Part of the answer may be related to the ability of HPV
to downregulate the immune response. Recent work has
shown that the low-risk HPV viral protein E7 interacts
with TAP-1, resulting in a decrease in this protein in
the infected cell. Because TAP-1 plays an important role
in shuttling antigen from a proteasome to the endoplasmic
reticulum, where it assembles with the MHC, a decrease
in TAP-1 may make a cell more tolerant to HPV infection
[33]. These findings suggest that immune modulation is
likely to play a role in the ability of HPV to persist, although
this association also raises the question why so many people are able to clear the virus.
356 Pediatric otolaryngology
Surgical approaches
No disease-specific definitive medical therapy exists for
RRP; therefore, multiple palliative surgical procedures
are required to remove the papillomas. Several principles
hold regarding papilloma removal. First, in contradistinction to malignant lesions, with HPV, margins should not
be obtained. Multiple studies have shown that HPV is
present in the normal mucosa [9,10] and it is currently
not possible to distinguish infected cells with a normal
appearance from unaffected epithelia. Second, although
pathologic confirmation of the diagnosis should be established at the first resection, repeat biopsy is not indicated
with every procedure but should be obtained at defined
intervals to evaluate for disease progression to cancer.
Third, every attempt to maintain laryngeal function is crucial. This dictum may require leaving residual disease to
prevent anterior or posterior web formation. Last, tracheostomy should be avoided because this procedure is associated with a substantially increased risk of distal tracheal
spread [34,35].
The techniques to remove papillomas have evolved over
time. The use of the operating microscope first provided
improved functional outcomes for patients with RRP by
increasing visibility. With the advent of laser surgery, ablation of papillomas in a relatively blood-free field became
possible [36]. Today, a laryngeal and tracheal microdebrider blade has replaced laser ablation as first-line surgical
therapy. This change reflects a safety perspective (there is
no risk of airway fire or inadvertent laser injury with the
debrider), a cost perspective (the microdebrider is much
less expensive to use because operating room time is
decreased and fewer personnel are needed), and an outcome perspective (functional studies have shown improved
functional outcome with the microdebrider in comparison
with the laser [37,38]). A recent survey of pediatric otolaryngologists showed that the majority have embraced
this change [39•].
Adjuvant therapies
Because of the rarity and clinical variability of RRP, proving efficacy for adjuvant therapies requires well-designed
studies that are properly controlled. Unfortunately, most
therapies that are used have not been rigorously tested
and are described only in small series or as anecdotal case
reports without proper controls.
a-Interferon
The use of a-interferon has been the most extensively
investigated adjuvant therapy for RRP. a-Interferon has
the theoretic benefits of modulating both the immune
system and epithelial development. The results of a doubleblinded placebo-controlled study for RRP showed a dosedependent decrease in severity for papilloma growth over
the first 6 months of therapy [40,41]. Unfortunately, cessation of therapy quickly resulted in disease relapse
to pretherapy growth rates. In addition, significant side
affects were encountered with prolonged use [39•].
Indole-3-carbinol
Indole-3-carbinol (I3C) has been approved by the United
States Food and Drug Administration as a nutritional supplement; it is found in high concentrations in cruciferous
vegetables like broccoli, cabbage, and cauliflower. It alters
estrogen metabolism by shifting the p450-dependent
hydroxylation of estrone from 16 a-hydroxyestrone to
2-hydroxyestrone, which in turn alters cellular proliferation and DNA synthesis [42]. In animal models, 2-hydroxyestrone inhibits the estrogen-dependent growth of
tumors [43], and because the viral life cycle is interconnected with epithelial differentiation, several investigators have hypothesized that I3C would decrease RRP
disease burden.
Although several reports have shown that treatment with
I3C may be beneficial, these studies were not prospective
randomized placebo-controlled trials, and the potential
efficacy of I3C should be viewed with caution [44•].
Importantly, the supplement is safe and has virtually no
side affects [44•]. Both the possible benefit and the mechanism of benefit for I3C need well-designed studies
before it can be recommended as a true therapy for RRP
patients.
Cidofovir
Ideally, a drug that specifically targets the HPV genome
for removal would cure RRP without causing concomitant
cell damage to uninfected cells. Currently, a pharmaceutical inhibitor that is approved specifically for HPV infection is not available. Initial trials using the cytosine analog
cidofovir (1-[(S)-3-hydroxy-2 (phosphonomethoxy) propyl]
cytosine dihydrate) have been undertaken [45–49]. Cidofovir has been approved by the United States Food and
Drug Administration to treat cytomegalovirus retinitis in
AIDS patients. The mechanism of action for this drug
in cytomegalovirus is through selective inhibition of the
herpesvirus DNA polymerase [50]. In these cytomegalovirus-infected cells, cidofovir inhibits herpes DNA polymerase at least two times more potently than human
DNA polymerase, thus leading to selective inhibition of
viral replication [50]. HPV does not encode a viral polymerase, however; instead, it uses host cell DNA polymerase to replicate the viral genome. This constraint means
that the mechanism of action of cidofovir in HPV cells
cannot be selective inhibition of a viral polymerase. Nevertheless, an initial trial of cidofovir for treatment of papilloma formation in the cottontail rabbit papillomavirus
model showed promising inhibition of papilloma growth
[51]. Initial reports in small noncontrolled clinical studies
have also suggested some usefulness [47,48,52].
Recurrent respiratory papillomatosis Lee and Smith 357
The utility of this cytosine analog in the treatment of
HPV-infected cells in vitro has been evaluated. Both transformed cells and cancer cells containing integrated HPV
have shown preferential growth inhibition with cidofovir
in comparison with non-HPV cancer cells. These studies
suggest a selective method of cidofovir-mediated toxicity
when cell death in immortalized HPV-positive cells is
compared with that in either HPV-negative immortalized
cells or primary keratinocytes [53–55]. These studies,
however, did not attempt to correlate cell replication rates
to cidofovir toxicity. Recent work has made an attempt
to understand a mechanism of action for cidofovir in
HPV-containing cells [56••]. It has been shown that
cidofovir is incorporated into episomal DNA at a slightly
higher rate than genomic DNA, and cidofovir may slightly
inhibit viral genome replication in comparison with
human genome replication. Replication of the viral
genome quickly returns to baseline after drug removal,
however.
The transient nature of this inhibition suggests that any
clinical application aimed at inhibition of viral genome
replication using cidofovir would require prolonged exposure and frequent administration; thus, the potential
for carcinogenic side effects would be increased. Recent
studies [56••] have shown that papilloma cells were more
sensitive to cidofovir than normal cells; however, the
mechanism was related to incorporation during rapid
cell turnover rather than by way of an HPV-selective
mechanism. Like all cytosine analogs, cidofovir primarily
blocks DNA replication through incorporation into the
genome, thus preferentially targeting rapidly dividing
cells. Multiple rapidly dividing cell lines derived from
cancers not related HPV infection have been shown to
be sensitive to the cytotoxic effects of cidofovir, such
as B16 melanoma, hemangiosarcoma, and nasopharyngeal carcinoma [57–60]. Therefore, it is likely that cidofovir kills papilloma cells more effectively than normal
cells in the surgical wound because the papilloma
cells are dividing more rapidly and are susceptible to
cidofovir.
Clinical therapy of cidofovir to induce non-HPV-specific
cell death in the more rapidly dividing cells of a papilloma
may have clinical utility; however, multiple studies have
challenged the safety of using this compound. Prolonged
therapy has identified several potential adverse effects,
including renal toxicity [61–63] and adenocarcinomas
developed in rats that were given the equivalent human
dose over 26 weeks [63]. Besides these in-vivo results,
several in-vitro assays have predicted that cidofovir is a
carcinogen [64]. Possible additional carcinogenic effects
in HPV-containing cells, lacking normal p53 and pRb, have
not been investigated. Prior to noninvestigational use,
cidofovir needs further studies aimed at elucidating a
potential mechanism of cell death specific to HPV and
properly controlled studies aimed at testing efficacy and
safety.
Vaccine
Recent vaccination trials investigating the persistence of
HPV16 in cervical cells has suggested that immunization with viral coat proteins can protect against infection
[65••–67••]. These breakthrough studies suggest that HPV16
diseases can be prevented with immunization. Although
this approach is promising for prevention, its feasibility
for use with established HPV disease is untested. Many
questions remain before immunization strategies can be
determined to be helpful for RRP. For example, differences between RRP and cervical HPV disease include
age at exposure, viral type, and disease progression, all
issues that must be considered when an immunization
strategy for RRP is designed and planned.
In a recent multi-institution study using a vaccination
strategy to develop an immune response to established
RRP disease [68], participants were vaccinated with an
immune modulating heat shock protein linked to the
E7 protein of HPV16. In preclinical mouse models, similar
strategies were able to eradicate established diseases in
mice by improving cellular and humoral immunity to viral
antigens, thus allowing mice to clear viral-infected cells
[69–71]. In the human trial, 27 RRP patients received
three sequential injections with 500 mcg of HPV-E7 protein, with an observed increase in surgical intervention
time and safety. As with most therapies aimed at RRP,
however, the response varied on an individual basis: two
persons required no further therapy after the vaccination,
and approximately 40% of patients had at least one surgical intervention lengthened [2]. No severe adverse reactions were encountered.
This strategy warrants further study, including a study
design with a placebo–control arm and the creation of a
vaccine composed of heat shock protein linked to the viral
proteins of HPV6 and HPV11. Although HPV16 E7 protein has some similarity (;40%) with the HPV6 or HPV11
protein and antigen crossover may occur, using the correct
antigen would more likely give a stronger and more specific response. As stated earlier, it is likely that the HPV
virus decreases antigen presentation; therefore, immuneenhancing strategies such as these hold great promise
for the treatment of established RRP.
Conclusion
Recurrent respiratory papillomatosis is a rare disease that
carries severe morbidity and occasional mortality. Improvements in surgical approaches have slightly improved the
overall care of these patients; however, cure is possible
only with disease-specific medical therapy. To that end,
more research is needed to understand how HPV causes
disease so that these therapies can be developed.
358 Pediatric otolaryngology
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