Review Therapy for Recurrent Respiratory Papillomatosis

Antiviral Therapy 7:1–9

Review Therapy for recurrent respiratory papillomatosis

Karen J Auborn1,2

1Department of Otolaryngology, Long Island Jewish Medical Center, The Long Island Campus of Albert Einstein College of Medicine, New Hyde Park, NY, USA 2North Shore-Long Island Jewish Research Institute, BoasMarks Biomedical Science Research Building, Manhasset, NY, USA

Corresponding author: Tel: +1 516 562 1184; Fax: +1 516 562 1022; E-mail: [email protected]

Human papillomaviruses types 6 or 11 are aetiological medical treatments, aimed at containing the virus and agents of recurrent respiratory papillomatosis, a disease growth of tumours, include indole-3-carbinol or its dimer characterized by benign exophytic tumours usually on diindolylmethane, interferon, photodynamic therapy and the vocal cords. Surgery debulks the tumours, but these others. Preventive and therapeutic vaccines hold promise growths generally recur at regular intervals. Adjunct for eliminating the virus.

Recurrent respiratory papillomatosis Figure 1. Laryngeal papilloma

Certain types of human papillomaviruses (HPVs), mainly HPV types 6 and 11, cause recurrent respiratory papillomatosis (RRP) [1,2]. These HPV types are considered to have a low oncogenic potential. In the early 1980s, HPV DNA was detected in laryngeal papillomas by Southern hybridization with related HPV types and HPV capsid antigen [1,2]. These same types of HPVs, the closely related HPV types 6 and 11, cause exophytic lesions in the genital tract [3]. Kreider et al. were able to produce typical papillomas cysts in xenografts in immunodeficient mice using laryngeal tissue infected with HPV-11 virus particles [4,5]. High- risk oncogenic types of HPVs – HPV-16 and HPV-18 – which are commonly found in the genital tract, have been identified only rarely in RRP [6]. Subsequently, Steinberg et al. were able to show that HPV DNA is not only present in the laryngeal papillomas, but can be found in tissue that appears histologically normal, adjacent to lesions, establishing the presence of tissue with the potential to produce papillomas [7]. The disease RRP results in benign hyperplastic epithelial tumours (Figure 1) that are typically found on the vocal folds. However, the lesions can occur in all parts of the respiratory tract, including the orapharynx and the lungs. The primary symptom of the disease is hoarseness because the lesions interfere with vocal cord function, and bulky lesions can cause life-threatening airway obstruction. Other symptoms include respira- Tumour growth with grape-like appearance on vocal cords of patient with tory fatigue, chronic cough and episodes of choking. recurrent respiratory papillomatosis.

Figure 2. Histology picture from a laryngeal papilloma A hallmark of the disease is the tendency of the papil- showing papillary fronds (lower arrow) and numerous koilo- lomas to recur after removal, hence the name [8–10]. cytes (upper arrow) Generally, the disease is classified as juvenile onset (diagnosed before adolescence) or adult onset. In fact, most children with RRP have recurrences that require treatment every 2–3 months [11]. RRP is considered an orphan disease. In the USA, a recent survey from the Centers for Disease Control estimates the incidence for juvenile onset RRP to be 4.3/100 000 [11]. Similarly, the prevalence in Denmark is estimated at 3.6/100 000 and 3.9/100 000 for juvenile and adult onset, respectively [12]. Although the prevalence of RRP in juvenile disease is equal between boys and girls, men have a much higher ratio (4:1) than women in adult onset disease (RRP Foundation ques- tionnaire). Evidence indicates that juvenile onset RRP results from vertical transmission from mother to child [13,14]. However, most babies exposed to maternal HPV do not develop RRP. The origin of the adult onset disease is not known. Many more individuals harbour latent HPVs in the respiratory tract than those who have ever had signs of RRP [15]. Papillomas tend to occur at the junction of squamous and ciliated epithelia, such as vocal cords, subglottis, laryngeal surface of the epiglottis and even the trachea [16]. The lesions themselves (Figure 2) typically exhibit a papillary growth pattern, metaplasia, koilocytes and dysplasia similar to condylomata in the genital tract [17]. The disease course is highly variable. The severity of The discovery that RRP has a viral aetiology, disease is usually greatest in children. The frequency of together with the growing knowledge of the molecular recurrence and need for removal or debulking of papil- biology of HPVs improves the prospect for better lomas varies greatly between individuals. Clinically, management and treatment of RRP. Most new adjunct papillomas are often described as looking like a clump treatments have led to somewhat more effective treat- of grapes (Figure 1). For most individuals, surgery is ments. These adjunct treatments are generally an required at regular intervals that can vary from every approach to control expression of the virus and keep few weeks to every few years. Some individuals with the virus quiescent. However, none of these treatments severe cases may require a tracheotomy to maintain an have been effective in eradicating the latent HPV. airway. Spread of papillomas can occur, usually to the When little understanding of RRP existed, many treat- trachea, but also to more distal bronchopulmonary ment regimens were tried empirically with little areas [8–10]. A tracheotomy may exacerbate this success. Such treatments usually did not ameliorate the spread [16]. Malignant transformation is infrequent disease and often caused harm to the patient, and and more common when there is pulmonary involve- included irradiation, antibiotics, vaccines, podopyllin ment [18–21]. Irradiation and other DNA-damaging and steroids [8]. Increasingly, better management of agents predispose individuals with RRP to malignant the disease with surgery plus adjunct treatments aimed transformation [18]. Spontaneous remission is highly at keeping the virus quiescent have helped many people variable and unpredictable, and some individuals never with RRP. The ultimate goal would be to eradicate the obtain remission. The reasons for remissions, severity virus. of disease or why most people infected with HPVs do not develop disease are unknown, but are probably Management by surgery multiple. Latent HPV is probably the source of recurrent lesions [7]. Hormonal, immunlogical and RRP is primarily managed by surgery. Removal of endocrine factors appear to influence the patho- papillomas assures an adequate airway and typically genecity of a relevant HPV infection. For example, improves the voice. The CO2 laser offers the advan- pregnancy appears to exacerbate RRP [22]. tages of minimal thermal injury to underlying tissues

and haemostasis [23]. Various methods of airway product DIM occurs in acid environments, such as the management have been employed to manage these stomach. I3C and DIM are commercially available and difficult airways during anaesthesia, including endotra- are sold separately as supplements. The quality of these cheal intubation, spontaneous ventilation and jet compounds has generally improved as clinical studies ventilation [24]. Complications include scarring, have required precise documentation of their formula- webbing and alteration of the normal vocal cord tion. The rationale for this therapy is that these mobility, all of which affect voice quality and may phytochemicals could induce a better oestrogen compromise the airway. Some surgeons prefer the metabolite balance, and hence a cellular environment traditional surgical tools to debulk papillomas since a that discourages pathology caused by papillo- vapour plume with infectious virus [25] is not created, maviruses. Certain HPV types, including HPV-6 and and there is no possibility of laser burns. Either method HPV-11, have a predilection for causing lesions in requires a surgeon that is skilled in the specific proce- certain tissues that are either hormonally sensitive, dure in order to minimize damage to the vocal cords. such as the transformation zone of the cervix [26,27], Some individuals require a tracheotomy to maintain an or relevant to RRP, such as the vocal cords in the airway. Unfortunately, a tracheotomy often results in larynx [9,28]. Oestrogen binds to membranes derived the subsequent development of tracheal and stomal from laryngeal tissue (both men and women), and this papillomas. binding is increased in membranes derived from laryngeal papillomas [29]. 16α-hydroxylation of oestrone, a Medical therapy type of oestrogen metabolism that prolongs oestro- genic activities, is constitutively high in the larynx [30] A variety of medical treatments, usually as adjunct and the transformation zone of the cervix [31], and therapy used along with surgical excision of papil- increased in laryngeal papillomas and genital cells lomas, have become available. The goal of these transformed by HPVs [31]. I3C or DIM (the dimer of adjunct therapies is to reduce or eliminate the need for I3C) induces an alternative oestrogen metabolism [32], future surgeries. The relatively few individuals with namely 2-hydroxylation of oestradiol, resulting in RRP coupled with very different disease courses and 2-hydroxyoestrone, a metabolite that is not oestro- responses to therapies have made evaluation of these genic (see Figure 3). Moreover, 2-hydroxyoestrone is therapies difficult. However, the RRP Foundation has rapidly O-methylated to 2-methoxy-oestradiol and made a concerted effort to keep statistics and evaluate 2-methoxy-oestrone, compounds that are antiprolifer- the effectiveness of such therapies (see Table 1). ative, apoptotic and anti-angiogenic [33]. After studies with mice indicated that a diet supplemented with I3C Indole-3-carbinol/diindolylmethane prevented papilloma cysts in xenografts of laryngeal Indole-3-carbinol/diindolylmethane (I3C/DIM) is the tissue infected with HPV-11 [30], several studies deter- most popular adjunct therapy, because of its virtual mined that a diet rich in cruciferous vegetables or absence of toxicity. These compounds are derived from supplements of I3C/DIM [34–36] was a useful adjunct eating cruciferous vegetables (broccoli, cabbage, cauli- therapy for RRP. flower, and so on) and are generally used at While more beneficial oestrogen metabolism concentrations that people could achieve eating a diet appears to be a factor for prevention of RRP [30,35], rich in these vegetables, that is 200–400 mg per day. I3C/DIM does have other activities that should not I3C results from autolysis of glucobrasscin, a storage only help prevent the recurrence of papillomas, but product in these vegetables, and the condensation also be useful in treatment of papillomatosis and

Table 1. Impact of adjuvant therapies for recurrent respiratory papillomatosis

Therapy Number of users No response (%) Improved (%) Complete remission (%) Partial response (%)

I3C/DIM 121 44.6 55.4 19.0 36.4 Interferon 56 42.9 57.1 7.1 50.0 Acyclovir 31 64.5 35.5 12.9 22.6 Photodynamic therapy 19 68.4 31.6 5.3 26.3 Ribavirin 3 33.3 66.7 0.0 66.7 Retinoic acid 16 62.5 37.5 0.0 37.5 Cidofovir 12 8.3 91.7 25.0 66.7 Mumps vaccine 14 21.4 78.6 21.4 57.1

Data courtesy of the Recurrent Respiratory Papillomatosis Foundation (RRPF). The RRPF surveys recurrent respiratory papillomatosis patients/families via question- naire regarding their therapy and disease history. I3C/DIM, indole-3-carbinol/diindolylmethane.

Antiviral Therapy 7:1 3 KJ Auborn

Figure 3. Oestrogen metabolism

16αα-Hydroxyoestrone α

Oestrdiol Oestrone

2-Hydroxyoestrone

Indole-3-carbinol induces 2-hydroxylation of E1 thus changing the ratio of 2-OHE to 16α-OHE. prevention of malignant conversion. I3C/DIM is unpublished observation). In addition, I3C does not antiproliferative, down regulating CDK6 [37], and appear to cause problems with reproduction [43]. induces apoptosis in abnormally proliferating cells in However, a few patients have anecdotally reported the absence of p53 [38] – a pathway of apoptosis that some bone loss that might have been caused by long- can be made defective by the papillomaviruses [39]. term use of I3C/DIM, thus suggesting that bone loss Furthermore, I3C/DIM can prevent DNA damage by should be evaluated before and during treatment. acting as a free radical scavenger [40,41]. Another oestrogen metabolite, 4-hydroxyoestrone, Side-effects have been few. I3C/DIM induces many which was shown to cause kidney cancer in hamsters, phase I and phase II enzymes [42–44], which is why can sometimes be induced by I3C/DIM [44]. Most rele- many carcinogens are inactivated and oestrogen vant for the use of I3C/DIM in the treatment of RRP is metabolism is rerouted, and because of this induction the fact that some patients are refractory to the bene- certain drugs can also be inactivated, which occurred fits of I3C/DIM for unknown reasons (Table 1). A with dilantin in the case of several RRP patients [36]. recent placebo-controlled study using I3C for treat- Specifically, medications that are metabolized by ment of cervical intraepithelial neoplasia (CIN) II and CYP1A1 or CYP1A2 (information provided by the III, found a statistically significant regression of CIN in drug manufacturer) should not be used in conjunction patients treated with 200 or 400 mg/day I3C, given with I3C/DIM. DIM should be used if a patient takes orally, compared with placebo, as determined by a antacids because I3C may not be converted to DIM in 12-week biopsy [45]. None of the placebo group had the stomach. Because of the anti-oestrogen activities, complete regression compared with 47% of the treated I3C/DIM may cause osteoporosis or other problems groups. I3C/DIM should be effective for treatment of associated with lower oestrogen levels. However, mice condylomata acuminata, the presumed source of juve- on diets supplemented with I3C for more than 1 year nile RRP by vertical transmission [13,14]. DIM and did not show bone loss (G Gronowitz & K Auborn, several proteins induced by DIM decrease expression

driven by HPV-11 regulatory sequences (K Auborn, Preliminary results show that six of the seven patients unpublished observation). Because of the low toxicity to date with 1 or more years of follow-up are free of associated with I3C/DIM, other adjunct treatments laryngeal disease. One patient with tracheal disease has tend to be used for patients with severe RRP that have shown some improvement, but did not achieve failed to respond to I3C/DIM. complete remission (M Shikowitz, Long Island Jewish Medical Center, personal communication). mTHPC has Interferon a much shorter exit time from tissue than HPD [51], Interferon has proved effective in ameliorating RRP by and a patient is only light sensitive for 2 weeks. RRP slowing down the recurrence rate. Most studies evalu- initially worsens after treatment, but a delayed ated interferon α (IFN-α) including recombinant forms improvement occurs, with the possibility of complete [46–48], and effectiveness appeared to be related to remission. The reasons for this bi-phasal effect are not dosage [47]. When IFN-α binds to a specific cell- known. Theoretical concerns about light sensitivity and surface receptor, an active factor composed of two singlet oxygen reactions remain, since the resulting proteins forms and translocates to the cell nucleus, oxidation reactions have the potential to damage stimulating specific transcription. The cell then healthy cells. To date, the most significant side-effects becomes resistant to a variety of viruses. The growth of have been sunburn reactions in patients that do not use some cells is slowed, and immunomodulatory actions precautionary measures [52]. occur. The side-effects of interferon are not pleasant, with serious complications reported in a subset of Cidofovir patients [49]. Flu-like symptoms usually occur, and Cidofovir [(S)-1-(3-Hydroxy-2-phosphonylmeth- liver function abnormalities may develop. Leukopenia oxypropyl)cytosine; HPMPC] appears to be very and other serious problems are infrequent. Specifically effective in the treatment of RRP, although the for RRP, when interferon is discontinued, the disease number of individuals treated with it remains small. recurs more severely than before the treatment. This Cidofovir is a nucleoside analogue, and has a broad ‘rebound’ effect can be mitigated by titrating down- spectrum of activity against a wide variety of DNA ward when ending therapy problems. Although viruses by interfering with viral DNA synthesis, interferons have been effective in trials, the Food and inhibiting angiogenesis and inducing apoptosis [53]. Drug Association (FDA) has not approved their use for In animal studies, cidofovir causes regression of large the treatment of this disease. lesions caused by the cottontail rabbit papillomavirus [54]. Cidofovir is used systemically, intralesionally Photodynamic therapy and topically as an antiviral. For RRP, intralesional Photodynamic therapy (PDT) has been in trials for RRP injections are used, and this method avoids some of for over 10 years. Most studies have been carried out at the toxicity (kidney damage) associated with the the Long Island Jewish Medical Center, NY, USA [50]. compound [55]. The largest study of cidofovir as a A photosensitizing dye is given to the patient, and when treatment for RRP comes from Belgium [56], where the dye is exposed to light of a certain wavelength, a investigators reported the complete disappearance singlet oxygen reaction occurs resulting in the killing of of papillomas in 14 out of 17 patients with severe cells. The dye has a predilection for tumours, including RRP. Smaller studies in the USA have yielded equally papillomas. It localizes to vascularized structures and is impressive results [57,58], including a case of RRP therefore retained longer in papillomas and other where the papillomavirus lesions had spread to the tumours because they typically become more vascular- lungs [59]. A recent placebo-controlled study ized than normal tissue. Hence, the cell killing exhibits evaluated the efficacy of cidofovir topical gel for an anti-angiogenic effect. Each agent has a different treatment of condylomata acuminata [60]. None of ‘wash-out’ time where the dye leaves the normal cells the patients in the placebo group had a complete allowing a safe window for treatment. Older studies response whereas 47% of the treated group experi- used the photosensitizing drug haematoporphyrin enced complete recovery. Adverse reactions to derivative (HPD). Unfortunately, this dye left the cidofivir are kidney toxicity, which is associated with patient light sensitive for up to 2 months. Although systemic use, and some irritation to laryngeal tissue. improvement of RRP occurred in some patients with Cidofovir is adsorbed by papilloma cells to a greater this regimen, trials with HPD did not result in a statis- extent than normal cells and converted to the tically significant number of extended remissions. Trials active nucleotide analogue. In theory, a certain now underway with a different photosensitizing dye – amount of DNA damage would result in cells exposed Foscan or meso-tetra hydroxyphenyl chlorin (mTHPC) to, but not killed by cidofovir. Long-term follow-up – are much more encouraging. In an ongoing study of of patients should carefully evaluate possible PDT with mTHPC, patients received a single treatment. malignant conversion.

Antiviral Therapy 7:1 5 KJ Auborn

Acyclovir preventative and therapeutic vaccines or combinations Acyclovir [9-(2-hydroxyethoxymethyl)guanine; ACV] [77–79]. The emphasis for HPV vaccines has been for is a purine analogue that is phosphorylated into its cervical cancer and genital warts. However, the same active form by thymidine kinases coded by herpes viruses that cause many genital warts (HPV-6 or -11) viruses [61]. Human thymidine kinases do not activate are also the aetiological agents of laryngeal papillomas. acycolvir, which is why this compound specifically kills The design of most preventative vaccines uses recom- cells with an active herpes virus infection. The binant L1 viral capsid protein that reassembles into analogue incorporates into DNA causing strand breaks viral-like particles (VLPs). These VLPs produce in the viral DNA. The papillomaviruses, much smaller neutralizing antibodies against the specific HPV type as viruses than herpes viruses, do not code for any thymi- shown with VLPs made from L1 of HPV-11 [80,81]. dine kinase. Therefore, the rationale for using acyclovir The protective effect of VLPs has been demonstrated in to treat RRP is uncertain. However, some clinical a number of animal models. For example, VLPs made response was observed in a number of trials [62,63]. from cottontail rabbit papillomavirus recombinant L1 The hypothesis is that the clinical response may be protein protects rabbits from this virus [82]. A VLP correlated to co-infection with herpes simplex virus. vaccine against HPV-11 was well tolerated and Side-effects from acyclovir are uncommon. induced high levels of neutralizing antibodies in a Phase I study [83]. Therapeutic vaccines target some Other therapies non-structural virus proteins, usually the E6 or E7. A very small number of patients have been treated with Various candidate HPV vaccines are being tested using cis-retinoic acid or isotretinoin (accutane), ribavirin non-structural virus proteins. These vaccines are and cimetidine – an H2-receptor antagonist commonly administered in vectors, peptides, or nucleic acids, or used to treat peptic ulcers. as components of chimeric VLPs. TA-GW is a vaccine that has the potential to be effective as both a thera- Retinoids peutic and a prophylactic vaccine [84]. TA-GW Retinoids induce cell differentiation, inhibit prolifera- consists of a fusion protein L2 and E7 proteins coded tion and angiogenesis – processes incompatible with by HPV-6. When administered together with an adju- tumour growth – providing a basis for their use as vant, this vaccine shows considerable efficacy in the adjunct therapy for RRP [64]. While success using cis- clearance of genital warts in Phase II trials [85]. retinoic acid for RRP has been documented [65–67], Different from most therapies, the vaccine approach is one study was suspended because patients experienced clearly aimed at eliminating the virus, and holds toxicity, and the therapy was ineffective [68]. promise not only for treating RRP, but also for reducing the number of individuals infected with the Ribavirin relevant HPVs. Ribavirin is an antiviral commonly used for certain RNA viruses such as hepatitis C and respiratory syncy- Acknowledgements tial virus [69,70]. Ribavirin is a guanosine analogue and inhibits synthesis of GTP by an effect on inosine This study was supported by grant P50DC00203 from monophosphate dehydrogenase, thus limiting RNA the National Institute on Deafness and Other synthesis. A small, randomized study in Minnesota, Communications Disorders. We wish to thank Mark USA showed that ribvirin resulted in an increased Shikowitz for his assistance with this manuscript. interval between surgery [71]. Side-effects are common, and include headache, fatigue and anaemia. References

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Received 19 February 2001; accepted 14 November 2001

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