Human papillomavirus infections of the oral mucosa and upper respiratory tract.

Epidemiology and Clinical Manifestations Ramírez-Fort MK, Khan F, Rady PL, Tyring SK (eds): Human Papillomavirus: Bench to Bedside. Curr Probl Dermatol. Basel, Karger, 2014, vol 45, pp 132–153 (DOI: 10.1159/000357904)

Human Papillomavirus Infections of the Oral Mucosa and Upper Respiratory Tract Harrison P. Nguyen a · Kayla L. McNiece b · Angela A. Duong c · Farhan Khan d

a Baylor College of Medicine, b University of Texas Health Science Center at Houston and c University of Texas at Austin, Austin, Tex., and d Center for Clinical Studies, Houston, Tex., USA

Abstract Human papillomaviruses (HPVs) are frequently detected in a variety of lesions in the oral mucosa and upper respiratory tract. The pathogenesis in these areas is not as clearly elucidated as in other anatomical regions, but most experts agree that HPVs are responsible for the commonly observed benign lesions, such as squamous papillomas, verruca vulgaris and recurrent respiratory papillomatosis. Transformation of these benign lesions is well described, but it is not clear what role the virus plays, if any, in carcinogenesis. HPV types 6 and 11 are most frequently detected in oral cavity and respiratory tract lesions, though several other types have also been reported. Despite an opaque understanding of these lesions’ pathogeneses, it is essential for the clinician to recognize these diseases, to provide appropriate treatment and to promote patient awareness of potential oral transmission. In this paper, we review the major HPV-associated diseases of the oral mucosa and upper respiratory tract, focusing specifically on clinical features, histopathological characteristics and dis© 2014 S. Karger AG, Basel ease management.

Since human papillomavirus (HPV) DNA can frequently be detected in the normal oral mucosa (1–43%) as well as in a variety of benign, premalignant and malignant oral lesions, the specific role of HPV in oral pathogenesis has been difficult to pinpoint and continues to be debated [1]. To date, 36 types (HPV types 1, 2, 3, 4, 6, 7, 10, 11, 13, 16, 18, 30, 31, 32, 33, 35, 40, 42, 45, 52, 54, 55, 57, 59, 61, 62, 64, 69, 71, 72, 73, 81, 83, 84, 89 and 120) are associated with benign lesions of the oral cavity while 27 types (HPV types 2, 3, 6, 11, 13, 16, 18, 26, 31, 33, 35, 39, 45, 51, 52, 53, 56, 57, 58, 59, 66, 67, 68, 69, 70, 73 and 82) have also been implicated in malignant oral disease [2–5]. While oral HPV can be transmitted perinatally, it is most commonly transmitted horizon-

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Human Papillomavirus Infection of the Oral Cavity

tally through oral exposure, orogenital contact, nonsexual fomite transfer or autoinoculation from other infected body sites [6–9]. Oral HPV infection can result in different clinical presentations – including benign, papillomatous, hyperplastic, verrucous and carcinomatous lesions. While an immunosuppressed status increases vulnerability to HPV-related disease, it should be noted that oral lesions are not always pathognomonic of underlying systemic conditions [10].

Histopathological Features Squamous papilloma consists of papillary proliferation of keratinized stratified squamous epithelium and fibrovascular connective tissue on a pedunculated base. These lesions are typically hyperorthokeratinized, hyperparakeratinized or both; however, there is no change to the maturation pattern of surface epithelium. Occasionally, a candidal superinfection of the superficial epithelium can be detected among the papillary fronds. Chronic secondary lesional trauma frequently occurs, leading to an inflammatory infiltrate within the underlying connective tissue stroma. Less commonly observed features of squamous papilloma include: koilocytosis as a result of perinuclear cytoplasmic vacuolization of cells in the spinous layer, mild atypia, increased mitotic activity, independently keratinizing cells, increased nucleus/cytoplasm ratio and the presence of large multinucleated epithelium cells [20].

HPV Infections of the Oral Mucosa and Upper Respiratory Tract Ramírez-Fort MK, Khan F, Rady PL, Tyring SK (eds): Human Papillomavirus: Bench to Bedside. Curr Probl Dermatol. Basel, Karger, 2014, vol 45, pp 132–153 (DOI: 10.1159/000357904)

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Squamous Papilloma Squamous papillomas are the most common benign epithelial neoplasms of the oral cavity, comprising 2% of all oral lesions submitted to oral and maxillofacial pathology services [11]. Though the disease can occur at any age and does not show any predilection for gender, individuals between the ages of 30 and 50 years appear to be at the highest risk for developing the disease [11, 12]. HPV types 6, 11 and 16 are primarily associated with the disease, and less frequently, DNA from HPV types 2, 13, 16, 31, 32, 33 and 35 is detected [13–16]. Although commonly considered to be a nuisance, the lesion is typically asymptomatic and presents as a solitary, soft, pedunculated, papillary or verrucous exophytic mass. The lesion results from a proliferation of the keratinized squamous epithelium and may be white, pink or reddish in color, depending on the amount of surface keratinization and the degree of secondary inflammation [17]. The most common sites of infection are the palatal complex and tongue, but any oral mucosal site can be infected. HPVs associated with squamous papilloma lie latent for 3–12 months before becoming active and virulent, but even during active infection, the virulence factor and infectivity rate are believed to be relatively low [18]. Hyperplasia occurs within a short period of time, and growth typically stops once the maximum size of 0.2–1.0 cm is reached. The rate of recurrence for solitary lesions is low in contrast to cases with multiple lesions. Immunohistochemical assays for p53 protein in solitary lesions are overwhelmingly negative, suggesting a benign nature of solitary lesions with little indication of malignant transformation potential [19].

Fig. 1. Verruca vulgaris on the tongue.

Treatment and Prognosis Squamous papilloma may be removed surgically by excision or, less commonly, by laser ablation. Once removed, recurrence is rare, except in HIV-positive patients; this is based on the largest series studied to date, where there was a 4% recurrence rate in immunocompetent patients [11, 19]. Mild epithelial atypia may be observed in as high as 25% of lesions [11, 21]. Fortunately, there is no record of malignant transformation, progressive enlargement or spread of infection to other oral mucosal sites.

Histopathology Verruca vulgaris is characterized by a papillomatous proliferation of hyperkeratotic stratified squamous epithelium – which is generally a combination of orthokeratinization and parakeratinization – with acanthosis and hypergranulosis [25]. The exo-

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Nguyen · McNiece · Duong · Khan Ramírez-Fort MK, Khan F, Rady PL, Tyring SK (eds): Human Papillomavirus: Bench to Bedside. Curr Probl Dermatol. Basel, Karger, 2014, vol 45, pp 132–153 (DOI: 10.1159/000357904)


Verruca Vulgaris Verruca vulgaris, also known as the common wart, can occur orally (fig. 1) but occurs at a lower incidence than its cutaneous counterpart; oral verruca vulgaris is observed in a mere 0.03% of schoolchildren [22]. DNA from HPV types 1, 2, 4, 7 and 57 has been detected in 55–75% of oral warts – this parallels the types associated with cutaneous verruca vulgaris occurring on the hand [12, 23, 24]. This observation has led to the hypothesis that infection is primarily transmitted orocutaneously via autoinoculation. Within the population, HPV infection displays a slight predilection toward males. Listed in decreasing incidence, sites of infection include the vermilion, labial mucosa of the lips, palate, anterior tongue and gingiva. The lesions present as white, rough, firm papules or nodules with a papillary, conical or heavily stippled surface. Morphologies of the lesions can vary by location; for example, lesions on the vermilion border of the lip or perioral skin are usually tan and scaly. The infection typically appears as a cluster of warts with sessile bases, but infrequently, it presents as a solitary intraoral lesion. At maturation, a wart is between 0.5 and 1.0 cm and, without trauma, maintains this size for several months to years.

phytic lesion consists of an underlying connective tissue core with many blunted and/ or acutely angulated hyperkeratotic projections. If the lining of the surface is parakeratotic, the vertical tiers of nucleated cells will usually appear smudgy and will overlie the papillary crests. Elongated rete ridges radiating toward the center of the lesion give the appearance of discrete margins as well as a ‘cupping’ effect [26]. Another common characteristic is a diffuse chronic inflammatory infiltrate within the underlying stroma. Less frequent features include koilocytosis in the upper spinous and granular cell layers, eosinophilic intranuclear viral inclusions in the granular layer, and minimally exophytic papillary projections exhibiting acanthotic bulbous rete ridges. Mild epithelial atypia can be observed in the early proliferative phase [27]. Ultrastructurally, many viral particles in paracrystalline arrangement may be visualized in the nuclei [28].

Condyloma Acuminatum Condyloma acuminatum, commonly known as anogenital wart, is the most common viral sexually transmitted disease in the USA. Although it is rarely reported, condyloma acuminatum can develop in the oral cavity through orogenital sex or hand-to-mouth self-inoculation. Among infants who are delivered by cesarean section, rare cases of vertical transmission transplacentally or via amniotic fluid infection have been reported [29, 30]. Most cases of condyloma acuminatum occur on the labial mucosa, tongue, floor of the mouth or gingiva of white males aged 30–50 years, but cases have also been reported in children [23, 31, 32]. Several studies attempting to show a concomitant presence between oral and anogenital HPV infection in healthy adults have not yielded consistent results [33–35]. In contrast, most cases in children have been associated with concomitant genital lesions or with the presence of maternal genital warts during gestation [36]. Clinically, the lesions have a sessile, pink, well-demarcated appearance and bear a surface that is characterized by multiple, short, blunted projections resembling cauliflowers, mulberries or cockscombs. In the early stages, condyloma acuminatum may have a flat-topped papular or nodular presentation with a striped surface. The lesions tend to grow rapidly and can be differentiated at maturity from squamous papillomas based on their enormous size (1–3 cm). The most common HPV types associated with oral condyloma acuminatum are types 6 and 11, which have been isolated in up to 90% of analyzed oral lesions [23, 32]. HPV types 2, 16, 18, 31, 33


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Treatment and Prognosis Similar to squamous papilloma, oral verruca vulgaris is treated by surgical excision, laser ablation, electrocautery or cryotherapy. Recurrence is uncommon, but to ensure the effectiveness of treatment, the base of the lesion should be carefully removed. If the patient has cutaneous warts, these lesions should be treated as well to minimize the possibility of reinfection. There have been no reports of malignant transformation of oral warts [26].

and 35 have also been identified in oral condyloma acuminatum [23, 33, 34, 37]. The incubation period is usually 1–3 months but has been reported to be as long as 20 months [26, 38]. Histopathology Microscopically, condyloma acuminatum lesions are characterized by mild parakeratosis and a broadly papillomatous proliferation of squamous epithelium with prominent acanthosis. Mitotic figures are almost always present, involving both the basal and spinous cell layers; occasionally, koilocytes can be seen in the keratinized and spinous layers. Condyloma acuminatum can be differentiated from squamous papilloma and verruca vulgaris by an increased bluntness and broadness of the papillary projections. Unlike the horizontal anastomosis pattern observed in focal epithelial hyperplasia, oral condyloma acuminatum contains bulbous rete ridges that impart a vertical branching pattern of anastomosis. The stroma usually contains dilated capillaries and a variably dense inflammatory infiltrate of lymphocytes and stromal cells. Mild to moderate epithelial atypia is observed in approximately 30% of biopsied lesions.

Focal Epithelial Hyperplasia Focal epithelial hyperplasia, also known as Heck’s disease (fig. 2), is a benign disease of the oral cavity that is associated with HPV types 13 and 32 [40, 41]. HPV types 13 and 32 are detected in 90% of focal epithelial hyperplastic lesions, and except for cases of perianal bowenoid papulosis, focal epithelial hyperplasia is the only pathology associated with these two viral types [16]. The disease is most frequently observed in Native Indians from North and South America, Eskimos, and South Africans of Khoi Shan extraction [42, 43]. This epidemiological trend suggests a genetic component to disease susceptibility [38, 43]. The disease preferentially affects women under the age of 20 years, and is also associated with a higher disease risk in immunocompromised individuals – as is common with any HPV infection [42, 43]. Focal epithelial hyperplasia is characterized by multiple soft, circumscribed, sessile, nontender papules, plaques and nodules, each topped with a flat, pink to pale, grainy surface. The lips, lateral bor-

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Treatment and Prognosis Unfortunately, like their anogenital counterparts, oral condylomata acuminata are often refractory to multiple therapies and have a high recurrence rate. Nevertheless, to minimize transmission or reinoculation, lesions are generally managed with conservative surgical excision and, in the setting of multiple lesions, with electrocautery, laser ablation or cryotherapy. In the highly recalcitrant cases, interferon and retinoids have been used with varying success [39]. Treatment can be supplemented with antiviral drugs, such as podofilox and 5-fluorouracil cream [32]. Fortunately, anogenital condyloma acuminatum rarely becomes cancerous; to date, there have been no documented cases of malignant transformation of these lesions in the oral cavity.

Fig. 2. Focal epithelial hyperplasia (Heck’s disease).

ders of the tongue, and labial and buccal mucosa are the classic sites of infection, but palatal and gingival lesions are occasionally observed. A 2004 study investigating the prevalence of focal epithelial hyperplasia among Waimiri Atroari Indians found that 21% of the population were positive for the disease with younger patients predominantly presenting with multiple nodular lesions while older patients presented with fewer flat or papular lesions [44]. Papular presentations are often misdiagnosed as condyloma acuminatum. Some studies have speculated that the lesions of focal epithelial hyperplasia are able to malignantly transform in immunosuppressed patients, but this is still debated. It is currently considered to be a benign disease [45–47].

Treatment and Prognosis The diagnosis of focal epithelial hyperplasia is done by biopsy. Some patients experience spontaneous regression of the disease while others suffer from lesions that persist until adulthood – occasionally present for 10 years or more [46]. Treatment options are inconsistently effective and include surgical excision, cryotherapy, topical 25% podophyllin resin, carbon dioxide laser ablation and vitamin therapy [38]. CO2 lasers provide excellent, fast results with no local bleeding, and treatment sites are allowed to heal independently – no sutures or dressings are needed. Thanks to the mechanical design of the CO2 laser, no trauma is inflicted to adjacent tissues. In addition to therapeutic uses, CO2 lasers can be used to biopsy lesions. Recurrence of this disease is rare.


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Histopathology Focal epithelial hyperplasia displays clear acanthosis of the epithelium and mild parakeratosis. Due to the irregular elongation and horizontal anastomosis, the rete ridges are widened – usually confluent – and may be club-shaped. Vacuolated cells are frequently found in the upper spinous cell or superficial keratinocyte layers. Found in the spinous layer are binucleated and multinucleated epithelial cells along with mitosoid figures which are believed to result from viral alteration of the squamous cells. Virus-like particles can also be visualized within the cytoplasm and nuclei of the cells in this layer [26]. A scant inflammatory infiltrate of mostly lymphocytes is typically present in the lamina propria.

Human Papillomavirus-Associated Oral Epithelial Dysplasia (Koilocytic Dysplasia) HPV-associated oral epithelial dysplasia, or koilocytic dysplasia, is an infection of the oral cavity with similar microscopic features as the intraepithelial neoplasia of the female genital tract [48]. Koilocytes – literally meaning ‘empty cells’ in reference to their microscopic morphology – are now known to be pathognomonic for HPV infection; their cytological abnormalities represent the lethal cellular effects of viral reproduction in host cells [49]. The disease presents as flat or slightly elevated white lesions that may have a cobblestone or papillary surface. The infection is most frequently found on the tongue, lips and buccal mucosa of middle-aged men [50]. The infection may be somewhat opportunistic since over 20% of reported lesions occur in confirmed HIV-positive patients [50]. Koilocytic dysplastic lesions are often positive for either high-risk HPV types 16/18 or intermediate-risk HPV types 31/33/35, and, occasionally, dual infection with HPV types 6/11 occurs [50]. Histopathology Koilocytic dysplastic lesions are characterized by acanthotic epithelium covered by orthokeratin or parakeratin, a flat or papillary surface architecture, broad-based or tear-drop-shaped rete pegs and usually anastomosis. Since the lesions are associated with HPV infection, koilocytosis, binucleated or multinucleated keratinocytes, mitosoid figures, acanthosis, atypical mitoses and dyskeratosis can be found microscopically. In some cases, there is swirling disorganization of the cells within the partial or full thickness of the epithelium. Importantly, all grades of epithelial dysplasia may be observed in these lesions [50–52].

Oral Warts Associated with HIV Infection Immunosuppression leads to an increased susceptibility to HPV-induced oral lesions – including verruca vulgaris, condyloma acuminatum, focal epithelial hyperplasia and koilocytic dysplasia. Only koilocytic dysplasia seems to be associated with specific HIV-induced immunosuppression since the prevalence rates of the other oral diseases in the HIV population are thought to be relatively low (1–4%) [54–57]. HPVrelated oral lesions in HIV infection have been mainly reported in men who have sex

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Treatment and Prognosis Liquid-based cytology and hybrid capture can be performed to confirm the histological diagnosis of koilocytic dysplasia [48]. Once the diagnosis is confirmed, it is recommended that the lesions be excised since the biological potential of these oral lesions is still unknown [50]. Koilocytic dysplasia can easily be confused with bowenoid papulosis of the oral mucosa since the latter condition also has a red, dysplastic appearance, is associated with HPV-16 and is frequently observed in immunosuppressed patients [53]. It is still not known whether koilocytic dysplasia and bowenoid papulosis share the same disease process and whether or not these oral mucosal lesions have similar treatment responses and biological behavior as their anogenital counterparts.

with men as well as heterosexual parenteral drug users [53, 55, 57, 58]. Clinical patterns in immunosuppressed patients include cauliflower-like, spiky/conical, flat, stippled or corrugated warts located on the lip vermilion, tongue, gingiva or labial/buccal mucosa [58, 59]. Multifocal presentation is commonly reported since a number of patients also have concurrent infection or a previous history of cutaneous warts – usually facial, digital and/or anogenital [56, 58]. The most common viral types associated with these oral warts include HPV types 7 and 32, but types 2, 6, 11, 13, 16, 18, 55, 59, 69, 72 and 73 have all been reported [51, 59, 60]. Oral lesions in the immunosuppressed population frequently contain multiple HPV types; this contrasts with the singular infection pattern typically seen in healthy patients [37, 50, 60]. HPV-7 papillomas, commonly seen on the hands of meat handlers, have also been found in the oral and facial cutaneous warts of HIV-positive individuals [60, 61]. Individuals who are positive for HPV-13 and -32 and, to a lesser extent, HPV-6/11 and -16/18, exhibit flat oral warts and papules that are similar to focal epithelial hyperplasia or flat condylomata [51, 59]. Histopathology The histopathological features are the same as previously discussed for each respective disease. The main differences in HIV-associated oral warts are the novel types of HPV (types 72/73) and the occasional presence of epithelial atypia [50–52, 59, 62]. Epithelial atypia can be mild to severely dysplastic and may have premalignant potential. Unfortunately, the significance of HPV types 72/73 is still unknown; this is based on the fact that 60% of clinically normal oral mucosa from immunosuppressed individuals are also positive for mucosatropic HPV-16 [63].

Oropharyngeal Squamous Cell Carcinoma Expression of HPV DNA in oral and oropharyngeal squamous cell carcinoma (SCC; fig. 3) has been recognized for several years, but only in the last decade has it been considered a positive prognostic factor in HPV-positive SCC tumors. When compared to subjects with HPV-cytonegative oropharyngeal SCC, HPV-cytopositive tumors usually affect the palatal tonsils of younger individuals who are more engaged


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Treatment and Prognosis As recommended for other HPV-induced oral lesions, the usual management entails surgical removal of the lesion by scalpel, laser ablations, electrocautery or cryotherapy. Topical podophyllin resin can be used before surgery to decrease lesion size and, theoretically, lessen the viral load and recurrences. Despite therapeutic attempts, oral and perioral recurrences are still common among immunocompromised individuals [58]. For recalcitrant lesions, surgical excision and interferon (IFN) therapy – intralesionally or systemically – are indicated [64]. Other possible treatments include a histamine H2 antagonist, cimetidine, and intralesional cidofovir. Unfortunately, even with multimodal treatment, the recurrence rate remains high at 35% [58, 62].

Fig. 3. Verruca vulgaris and oral SCC of the tongue.

in high-risk sexual behavior, have higher HPV-16 antibody titers and use less tobacco [65]. These HPV-cytopositive carcinomatous cells have a distinct molecular profile and are associated with better survival rates [66]. However, the precise role of HPV in squamous cell carcinogenesis is still unknown. It is currently believed that HPV is an etiological factor in oropharyngeal squamous cell tumors since these cancerous cells tend to show viral integration, have high viral loads (>1 copy/cell), overexpress functional p16INK4A, possess unmutated p53 gene and have decreased levels of retinoblastoma protein [65]. In contrast, cells of HPV-cytopositive oral SCC typically have a low viral load, infrequent viral integration, and absent transcriptionally active E6/ E7 mRNA – suggesting that HPV has limited biological significance in oral squamous cell carcinogenesis [67, 68]. This remains only a hypothesis since it is entirely possible that HPV employs a ‘hit-and-run’ carcinogenic mechanism or participates in the initial stages of transformation but is phased out in the later stages [69]. Unfortunately, reliable markers for the progression of high-risk HPV-infected epithelium into malignant lesions are not currently available. Since transmission likely occurs through orogenital contact, the best management strategy for oral and oropharyngeal SCC is advocating responsible sexual behavior. The quadrivalent HPV vaccination campaign is expected to decrease the prevalence of HPV-mediated SCC. It is recommended that both men and women receive prophylactic treatment for HPV prior to the onset of sexual activity [70].

Recurrent respiratory papillomatosis (RRP) is defined as HPV infection of the upper aerodigestive tract (fig. 4–7). Although HPV infection can occur anywhere along the tract, the larynx is the most common site followed by the oral cavity, trachea, bronchus, lung parenchyma and esophagus in decreasing frequency [71–73]. Although rarely fatal, RRP can be devastating with significant morbidity. The disease process is characterized by benign papillomatous (exophytic, squamous, wart-like) growths

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Human Papillomavirus Infection of the Upper Respiratory Tract

Fig. 4. Obstructing laryngeal papillomas in a child.

Fig. 5. Isolated vocal cord papilloma in an adult.

Fig. 7. Manifestations of laryngeal papillomas in an adult.


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Fig. 6. Mild laryngeal papilloma disease in a child.

The Pathogenesis of HPV Infection RRP is the result of HPV stem cell infection in the mucosal basal layer of the aerodigestive tract. HPV activates the epidermal growth factor receptor pathway and inactivates tumor suppressor proteins necessary for growth regulation. This leads to a derangement in cellular proliferation/differentiation and results clinically in papilloma formation [71]. The recurrence of this disease is based on the virus’s ability to persist within a host cell in an active or latent state [73, 74]. HPV types 6, 11, 16, 18, 31 and 33 have been reported in cases of RRP, but the majority of cases are caused by types 6 and 11 [71, 73, 74]. HPV-11 is the more common and aggressive of the two subtypes with earlier presentation, longer disease course, more frequent surgical interventions, and a higher mortality rate [71, 74]. The viral types are also divided into low-risk and high-risk categories based on their potential for malignant transformation. The high-risk types in RRP are HPV-16 and HPV-18; just as in cases of cervical dysplasia, papillomas infected with either of these two types are at an increased risk of malignant conversion [77]. The more common culprits of RRP, HPV types 6 and 11, are considered low risk with less than a 1% risk of malignant transformation in juvenile cases and a 3–7% risk in adult cases. Transformation secondary to these low-risk agents typically occurs in adults with other risk factors such as radiation exposure or tobacco use and children with extensive, prolonged courses [73, 76]. Clinical cases have demonstrated that HPV-11 is associated with an increased risk of lung cancer development in comparison to HPV-6, but rarely HPV-6 can result

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in the larynx and tracheobronchial tree that can lead to airway involvement, recurrence, dissemination and a risk of malignant transformation [74–76]. Despite being considered a benign condition, malignant transformation has been known to occur in 3–5% of patients [74]. It is typically considered a pediatric condition but can occasionally present in adulthood [76, 77]. Even though RRP is a rare disease, it has a significant emotional impact on patients and their families due to the unpleasant symptoms, the necessity of recurrent surgical interventions, and the possibility of malignant conversion [77]. Diagnosis is made by visualization of papillomas in the aerodigestive tract using flexible nasolaryngoscopy or direct laryngobronchoscopy; biopsy and histological examination are used to confirm the diagnosis and to assess for possible malignant transformation [74]. Derkay et al. [75] established a staging/scoring system to standardize the evaluation of RRP in order to accurately assess a patient’s disease status, detect subtle changes in the patient’s course over time, assure complete data collection, facilitate physician-to-physician communications, standardize reports of adjuvant therapies for data analysis, and better describe the natural course of the disease. The staging system is based on the extent of papillomatosis at defined aerodigestive subsites and a subjective assessment of the patient’s clinical course (interval of surgery, total number of surgeries within the past 12 months, quality of voice, stridor and level of respiratory distress) [75].

Epidemiology A pilot study that compared the incidence of RRP in privately and publicly insured patients in the USA concluded that the incidence of RRP was higher in publicly insured patients compared to privately insured patients by greater than 150%. Consequently, people of lower socioeconomic status are at greater risk of HPV infection and subsequent RRP [73]. The presentation of RRP occurs in a bimodal distribution – it presents in children under 5 years of age and in adults during the second and third decades of life [74]. Its presentation is based on the mode of infection and varies according to the host’s age and comorbidities. Currently, the papillomas of juvenile-onset RRP (JORRP) are the most common benign neoplasms in the larynx of children [77]. The infection can be vertically transmitted from a mother to a child in utero or during the birthing process. In fact, the increased incidence of cervical HPV infections has been mirrored by an


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in bronchial carcinomas [71, 76]. Cancers secondary to either type are associated with a dismal prognosis [76]. Although the direct mechanism of oncogenesis is unknown, 1 case demonstrated integration of the HPV-11 DNA into a host cell’s genome and subsequent mutation of the p53 proto-oncogene. The presence of HPV-11 in malignant lesions has been consistently proven, but the presence of the p53 mutation has been variable [73]. To date, 20% of all investigated lung cancer cases secondary to RRP have evidence of HPV DNA – with HPV-16 and HPV-18 being the most frequently detected. A recent study demonstrated that the E6 and E7 oncogenes and their transcripts were prerequisites for transformation in HPV-positive lung cancer cases; this further supported the theory that HPV is a cofactor in bronchial carcinogenesis. Also evidenced in this same study, 18F-fluoro-2-deoxy-D-glucose (FDG) positron emission tomography and computed tomography was determined to be very useful in the early detection of malignancies arising from RRP; malignant lesions showed a considerable increased uptake of 18F-FDG upon imaging [76]. The pathogenesis of HPV infection may also be determined by a host’s innate and adaptive immune systems. Only a small percentage of individuals exposed to HPV will present with RRP, and even fewer will go on to develop severe disease. On a molecular level, comparison of the immune response gene expression between papillomatous tissue and adjacent normal-appearing tissue suggests that patients with RRP are unable to elicit an adequate HPV-specific T cell response; specifically, there is a Th1/Th2 cytokine imbalance and an altered CD8+ response [73]. There is also evidence to suggest that HPV-11 E6 shunts resources to increase interleukin-10 expression (Th2) at the expense of IFN-γ (Th1) expression in patients with RRP. Another mechanism by which HPV increases its pathogenicity is by evading a host’s immune system through the downregulation of the transporter (transporter associated with antigen processing 1) responsible for presenting antigens to immune-responsive cells; thus, HPV alters the major histocompatibility complex cell surface expression of the host’s cells and attenuates the immune response mounted against it [73].

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increased incidence of JORRP [76]. It has been determined that babies born to mothers with active condylomata have an increased risk – up to 231 times – of contracting the virus in comparison to babies of disease-free mothers. The risk increases with prolonged delivery, protracted labor following rupture of the membranes and newly acquired infection (in comparison to chronic infection) [71, 73]. The virus can also be transmitted transplacentally from the mother to her neonate; a recent study estimated that 12% of neonates contracted HPV via this mechanism. Despite the high prevalence of HPV, the infectious nature of the virus and the close proximity of a neonate to maternal active condylomata, the risk of a vertical transmission is actually quite low – approximately 1 in 400 potentially affected births. Further, RRP is an uncommon complication in HPV-exposed neonates. Thus, other factors such as immunity, extent of viral exposure (timing and viral load) and local traumas (intubation, extraesophageal reflux) must play a role in the development of RRP [73]. Adult-onset RRP can represent a reactivation of latent infection or a newly acquired sexually transmitted infection following oral-genital contact [71, 74, 77]. Although difficult to determine precisely, the incidence of RRP in the USA is estimated to be 4.3/100,000 children and 1.8/100,000 adults [73, 77]. Since there is no cure for RRP, the goal of treatment is reducing laryngeal tissue compromise, maintaining an adequate airway and preserving vocal function. Based on the proliferative nature of the disease, patients are prone to recurrences and typically undergo numerous surgical treatments. The National Registry of Children with RRP reports that the typical pediatric patient will require nearly 19.7 surgical procedures in his/her lifetime; this equates to approximately 4.4 procedures per child per year and totals more than 10,000 surgeries annually for American children [78, 79]. Nineteen percent of children with RRP have a more aggressive form of the disease and will require upwards of 40 procedures in their lifetime [73]. Beyond the risks and complications of surgery, the consequences of repeated anesthetic use in children of developmental age must be thoroughly considered. There are concerns of behavioral changes and possible learning delays with repeated exposure to anesthesia [79]. Age seems to be one of the few predictors for the severity of disease. It has been shown that children who present with RRP before versus after 3 years of age are 3.6 times more likely to need more than 4 surgical procedures in a year and are twice as likely to have 2 or more affected anatomical sites [79]. Coinfection of HPV with other viruses such as herpes simplex virus, cytomegalovirus and Epstein-Barr virus can also be predictive of an aggressive clinical course [74]. In addition, lower respiratory tract involvement typically follows a more tumultuous course and is directly correlated with the presence of a tracheotomy. One clinical study of 208 JORRP patients suggested that the epithelial trauma produced by tracheotomy facilitates seeding of the virus to new sites and creates a new squamocolumnar junction at the sites of healing that is prone to HPV infection [72]. Fortunately, involvement distal to the larynx is rare with only 5% of patients experiencing tracheal papillomas and less than 1% acquiring disease in the lung parenchyma [76].

Clinical Presentation Even though pediatric patients may be exposed to HPV before or during birth, most patients are not immediately symptomatic [73]. Hoarseness is typically the first presenting symptom but usually goes unnoticed due to its subtle manifestation in a child or infant. Other symptoms reflect upper airway involvement and include dyspnea, persistent cough, recurrent upper respiratory infections, pneumonia, respiratory distress, stridor, dysphonia, dysphagia and failure to thrive. Often there is a low index of suspicion for RRP in children who present with upper respiratory symptoms, and more common etiologies such as allergies, croup, bronchitis, asthma and acid reflux are worked up prior to the diagnosis of RRP – unless there is a specific reason to suspect RRP [73, 74, 78]. Thus, the diagnosis of RRP is frequently established approximately 1 year after the initial presentation of symptoms. Diagnosis is common between the ages of 2 and 4 years [73]. The course of this disease can vary from the most aggressive forms that require frequent debridement to more indolent courses that wane and spontaneously remit; the majority of patients will fall in between these two extremes. The unpredictable nature of this disease can be further affected by the introduction of a tracheotomy or endotracheal tube. Although these devices secure a patent airway, they disrupt the surrounding mucosa – increasing the reactivation of latent HPV, the colonization of new sites and the possible spread of HPV to the tracheobronchial tree. Around 30% of children with these tubes experience extralaryngeal spread of RRP [73]. Tracheotomy is indicated only in the severest cases when the airway is threatened or in cases refractory to multiple surgical debulkings. If necessitated, decannulation should be achieved at the earliest opportunity [72, 73]. If RRP reaches the lungs, the prognosis is poor. Computed tomography of the chest will show noncalcified peripheral nodules with central cavitations and air fluid levels. Pulmonary RRP is among the most aggressive forms of RRP. Patients will often struggle with recurrent bouts of pneumonia and bronchiectasis, and will eventually progress to pulmonary failure secondary to HPV’s destructive effect on the lung parenchyma. Severe RRP can further develop into SCC via malignant transformation of infected cells. Because this risk is ever-present, yearly biopsies should be performed to monitor for malignant degeneration [73, 77].


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In addition to the huge emotional burden on patients and their families, the economic burden of this disease is great. It is estimated that there are 80–1,560 new cases of JORRP annually with treatment costs ranging from USD 72,000 to 387,000 per patient per year. The annual cost of adult-onset RRP is estimated to be 40% that of JORRP [80]. Based on this data, the annual national economic burden of this disease reaches approximately 15,000 surgical procedures (performed in adults and children) and nearly USD 171 million [73, 79, 80]. This equals 2.1% of the total annual costs of preventing and treating HPV-associated diseases in the USA [80].

Immunotherapy and Pharmacotherapy In addition to surgical management, adjuvant pharmacotherapy can enhance treatment and lengthen the interval between surgical interventions. It is suggested that adjuvant therapy be used in patients who require 4 or more surgical procedures annually, those who experience rapid regrowth of papillomata with airway compromise and those who show evidence of multisite spread [76, 79]. Currently, the cornerstone of RRP adjuvant therapy is IFN-α, a human cytokine with antiviral, antiproliferative and immunomodulatory properties. Among its modulatory roles, IFN-α inhibits angiogenesis necessary for papilloma growth [73, 81, 82]. It also stimulates host cells to increase the expression of major histocompatibility complex molecules essential to the presentation of HPV antigens and results in amplification of the immune response. Of notable importance, IFN-α also prevents viral penetration into host cells and further disrupts viral replication, maturation and release [82]. Before beginning IFN-α therapy, a treating physician should be particularly cognizant of its associated toxicities. IFN-α toxicity can present as a ‘flu-like’ syndrome with symptoms of fatigue, headache, anorexia, fever, chills, myalgias, arthralgias and nausea [73, 82, 83]. More concerning symptoms include depression, mood disorders, confusion, seizure, weight loss, rash, alopecia, tinnitus, reversible hearing loss, retinopathy and pneumonitis. IFN-α therapy has also been shown to have abortifacient properties in primates

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Treatment Surgery The treatment of RRP is based on surgical management and aims to thoroughly debulk the papillomas, to spare the integrity of the underlying laryngeal tissues, to increase the interval between interventions and to improve the quality of life [73, 77]. Surgical options include the use of microdebriders, cold knife endolaryngeal incision with or without phonosurgical technique and lasers – including the CO2, 532nm pulsed KTP (potassium titanyl phosphate), flashed pumped-dye and pulsed-dye lasers [73, 77, 79]. CO2 lasers have been preferred in the past, but recent, newer lasers – the KTP and pulsed-dye lasers – are angiolytic and result in less thermal damage to underlying tissue [73]. Pulsed KTP lasers can remove sessile lesions and papillomas in sensitive areas like the anterior portion of the vocal cords and the interarytenoid region; they also provide an increased thermal relaxation time, in comparison to CO2 and pulsed-dye lasers, which decreases thermal injury to underlying structures [77, 79]. Microdebriders are effective at removing bulky lesions and do not risk thermal insult to tissues. Their limited precision poses a challenge for the removal of papillomas in tight areas such as the anterior commissure and ventricle [77]. Despite this restriction, they have become more popular due to their selective suction function that allows for better precision and preservation of normal tissues. Due to the recurrent nature of this disease that necessitates frequent surgical interventions, both of these benefits increase the popularity of this surgical modality [73].


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and should not be prescribed for pregnant patients or those desiring to become pregnant [82]. Overall, the toxic risks of this treatment must be carefully weighed against its benefits before therapy initiation [73]. The results of adjuvant IFN-α therapy in RRP are varied and unpredictable. One multicenter study showed no persisting decrease in disease progression after 2 years of surgery with adjuvant IFN-α versus surgery alone. Another study declared a 75% response rate and complete remission in a third of participating patients who underwent continuous IFN-α augmentation. Generally, the consensus is to initiate IFN-α treatment and reassess a patient’s response in 6 months. If the response is positive, therapy should be continued. A lack of response or evidence of toxicity should prompt discontinuation of the drug [73]. Another option for adjuvant pharmacotherapy includes antiviral agents such as cidofovir and ribavirin. Although ribavirin has no observed benefit in the treatment of RRP, cidofovir, a cytosine analog, offers some hope. Cidofovir boosts the host’s immune system through unknown mechanisms and targets DNA viruses by inducing apoptosis in affected cells [73]. Traditionally, this drug has been injected intralesionally at the time of surgery, but recently, inhalation has been used as a mode of delivery. Intralesional injection of cidofovir has been observed to induce partial to complete remission of papillomas and to decrease the number of necessary debulking procedures. Despite the popularity of this adjuvant treatment, a recent 12-month, double-blind, randomized control trial of intralesional cidofovir versus placebo (normal saline) at the time of surgical debulking showed no significant improvement in the quality of life. At the 12-month mark, both arms of the study showed significant improvement in the Derkay Severity Score, but neither showed a change in health-related and voice-related quality of life. This suggests that the natural history of this disease is marked by gradual improvement of severity over time. Therefore, improvements in disease status that were once attributed to intralesional cidofovir may actually be explained by natural disease progression or simply injection of a fluid volume in a papilloma (which was a common procedure in both arms of the study) [74]. Further large, well-executed, randomized, placebo-controlled studies are needed to resolve the discrepancies between reports, patient experiences and physicians’ standard of treatment [74]. Toxicities of this treatment include nephrotoxicity, bone marrow toxicity, iritis and uveitis. Based on animal studies, cidofovir may also be carcinogenic, embryotoxic and teratogenic [73]. Case reports have also demonstrated progressive dysplasia in patients treated with cidofovir – thus necessitating careful patient and family counseling before the initiation of this therapy [79]. For aggressive cases of RRP refractory to cidofovir or cases where cidofovir is impossible due to toxicity, use of intralesional bevacizumab (Avastin) up to 88 mg shows potential for regression and remission of papillomas [83]. Bevacizumab is a recombinant, human immunoglobulin G1 monoclonal antibody that binds vascular endothelial growth factor (VEGF) and neutralizes its angiogenic activities [84]. In RRP, the

Photodynamic Therapy Photodynamic therapy potentially shows great promise in the treatment of RRP based on its capacity to selectively treat tumor cells while avoiding violation of normal cells. It is particularly efficacious in superficial lesions with a high cell turnover rate, such as the papillomas of RRP. Prior to laser treatment, a photosensitizer, such as Photofrin, is injected into papillomatous lesions to induce apoptosis after laser excitation. Photodynamic therapy results in sensitization of the immune system to lower viral loads. The benefits of this treatment modality are still to be confirmed [73].

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papillomas have an abundant vascular supply that is mediated by VEGF. The angiogenesis induced by VEGF contributes to the pathogenesis of the disease and is the target of bevacizumab treatment. Bevacizumab prevents VEGF-stimulated angiogenesis essential to papilloma growth and maintenance. Aggressive cases of RRP characterized by rapid growth and rapid neovascularization can also be slowed by this treatment modality [83]. In 3 pediatric cases, it was proven that the interval between operative interventions was prolonged by intralesional bevacizumab following microdebrider debulking and pulsed KTP laser treatment [79]. Another prospective investigation in adults showed single-site efficacy without local or systemic complications. Further investigation is needed to define optimal dosing and route of drug delivery [83]. The adverse effects of bevacizumab must be weighed against its potential benefits; possible adverse effects include bleeding, poor local wound healing, blood clotting, elevated blood pressure, hypothyroidism, and other common complications secondary to any laryngeal injectables – vocal cord scarring, local inflammatory responses and resultant airway obstruction [79, 83]. Other pharmacotherapeutic options include indole-3-carbinol (I3C), heat shock protein (HSP) E7, and the mumps vaccine. I3C is an FDA-approved nutritional supplement abundant in cruciferous vegetables such as broccoli, cauliflower and cabbage. It has been shown to alter estradiol metabolism in papillomas so that production of a genotoxic metabolite that promotes unscheduled DNA synthesis and hyperproliferation of epithelial cells is shifted to a more amenable metabolite that decreases the risk of hormone-dependent tumors [78]. In a small clinical trial, 4 out of 9 patients achieved partial or complete remission on I3C therapy; no adverse effects were observed [73]. Other studies have shown complications such as tremor, imbalance and nausea [83]. The effectiveness of I3C in the pediatric population needs further investigation [78]. HSP E7 is a recombinant protein combining heat shock protein 65 of Mycobacterium bovis and the E7 protein of HPV-16; subcutaneous HSP E7 is known to decrease the frequency and absolute number of surgical interventions for patients with RRP. Mild, local reactions were the only noted adverse events [73]. Furthermore, injection of the mumps vaccine at the bases of papillomas before treatment with a CO2 laser has been correlated with a prolonged length of remission in children. Causality cannot be solidified, however, until a prospective, randomized control trial proves this hypothesis [73].

Laryngopharyngeal Reflux Disease Management of laryngopharyngeal reflux disease seems to show added benefit to patients with RRP. Mucosal damage and inflammation caused by refluxed acid or gastric enzymes can irritate and disrupt aerodigestive tract epithelium and trigger papilloma growth and spread. Treatment of laryngopharyngeal reflux disease with antireflux medications carries fewer side effects than some of the other adjuvant therapies and can help promote/maintain remission. It has also been shown to decrease the laryngeal web formation and to benefit patients with vocal dysfunction [73]. Vaccination There are currently 2 vaccines against HPV on the market. Cervarix is a bivalent vaccine targeting the L1 capsid proteins of HPV types 16 and 18, the 2 most common agents of cervical cancer. This vaccine fails to provide coverage for the most common causes of RRP, HPV types 6 and 11. Gardasil remedies this problem by providing coverage against HPV-6, HPV-11, HPV-16 and HPV-18; this quadrivalent vaccine contains recombinant virus-like particles that mimic the L1 capsid protein [73]. Vaccines provide the greatest hope of reducing the incidence of HPV and, thus, the incidence of RRP [73, 80]. In the future, eradication of HPV is possible based on the principles of disease prevention, herd immunity and passive immunity via the transmission of maternal antibodies to a neonate in utero [73].

Recurrent respiratory papillomatosis is a benign but complex disease with considerable potential for significant morbidity. Its bimodal distribution within the US population reflects the modes of its transmission. Vertical transmission from a mother to her neonate or infant may be accomplished transplacentally or during the birthing process. The presence of RRP in adults suggests reactivation of latent disease or recent infection secondary to sexual encounters. Although the clinical course of the disease is variable, many factors play a role in the severity of disease such as age at onset, type of HPV infection, presence of a tracheotomy, and immune status of the patient. Because of the recurrent nature of this disease and the frequency of dissemination, treatment is difficult. Treatment is largely surgical and is based on debulking papillomas to provide symptomatic relief and preserving the integrity and function of the aerodigestive anatomy. Adjuvant pharmacotherapy may augment surgical management and is indicated in patients who require more than 4 surgical procedures per year or have signs of airway compromise or distal spread. The future of this disease will be largely affected by the use of vaccinations in the prevention of HPV infection; until then, the increasing incidence of the disease and the exorbitant costs of treating recurrences will promote research in the specific mechanisms of infection and the discovery of efficacious treatments for RRP.


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Conclusion

Acknowledgements Figure 1 was provided by Robert Brodell, MD, and Maureen Offiah, MBA, University of Mississippi Medical School. Figures 4–7 were provided by Michael Underbrink, MD, University of Texas Medical Branch, and have been previously published by Venkatesan et al. [73].

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