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Overview of recurrent respiratory papillomatosis

Wiatrak, Brian J.

Current Opinion in Otolaryngology & Head & Neck Surgery: December 2003 - Volume 11 - Issue 6 - pp 433-441
Pediatric otolaryngology

Purpose of review: The purpose of this article is to review recent literature regarding pediatric recurrent respiratory papillomatosis (RRP) published within the last year. By reviewing and assessing these articles, a more clear understanding regarding the etiology and management of pediatric RRP can be obtained, allowing physicians to better care for their pediatric RRP patients.

Recent findings: Pediatric RRP continues to be an extremely difficult management problem for otolaryngologists. This disease process continues to be a significant burden on the health care system and is a significant cause of morbidity in affected patients and their families. The incidence of RRP continues to be approximately 3.96 per 100,000 in the pediatric population. It has been noted recently that approximately 7 of every 1000 children born to mothers with vaginal condyloma develop pediatric RRP. Although the mainstay of surgical management has traditionally been the CO2 laser, newer surgical techniques have demonstrated efficacy in the management of pediatric RRP patients, including powered instrumentation and the pulse-dye laser. The traditional adjuvant medical therapies used for pediatric RRP continue to be commonly used, including interferon-α2a, retinoic acid, and indol-3-carbinol/diindolylmethane (I3C/DIM). Recently cidofovir has demonstrated efficacy in selected patients. In addition, current research regarding vaccine therapy for pediatric RRP has shown promise. Basic science research in the field of immunology has demonstrated multiple defects in cell-mediated immunity, which has shed further light on the etiology of pediatric RRP.

Summary: Pediatric RRP continues to be a highly morbid disease process. New surgical and medical therapies offer hope for better control of this disease in affected patients. Recent advances in immunologic research offer the hope of immune system modulation and augmentation as potential future treatment modalities to better control this disease process.

Abbreviations:RRP recurrent respiratory papillomatosis, I3C/DIM indol-3-carbinol/diindolylmethane, HPV human papillomavirus, GERD gastroesophageal reflux disease

Recurrent respiratory papillomatosis (RRP) is the most common benign laryngeal neoplasm to occur in children. This potentially highly morbid condition has continued to defy most medical and surgical treatments, causing untold physical and emotional suffering in infected patients. The health care system in the United States has incurred a significant financial burden managing these patients. RRP is an unusual condition, often considered an orphan disease; however, it continues to be ubiquitous within the pediatric population. Three clinical subgroups of RRP patients are known, including pediatric cases, adult-onset cases, and pediatric cases that persist into adulthood.

Recurrent respiratory papillomatosis typically manifests as progressive hoarseness and stridor related to the growth of exophytic lesions within the larynx and trachea (Fig. 1). Currently, the mainstay for therapy is endoscopic surgical debridement in the operating room with the option of various adjuvant medical therapies that have demonstrated variable response rates in the literature. In rare cases, RRP is fatal because of severe airway obstruction, diffuse bronchopulmonary spread with pulmonary failure, or malignant transformation (Fig. 2). Hormonal influences on the papilloma growth rate have been detected, particularly in cases of vaginal condyloma; however, a case of maternal death related to obstruction by papillomas in a pregnant woman has been reported [1]. The most common sites of involvement are within the larynx; however, extralaryngeal sites may become involved, including the trachea, esophagus, lungs, parenchyma, oropharnx, oral cavity, nasal cavity, and other head and neck sites. For reasons that are unclear, RRP has a particular preponderance toward aggressive disease in the pediatric population, with the most severe cases in children presenting under the age of 3 [2,3]. It has been suggested that childhood-onset RRP is more aggressive than its adult counterpart. Histologically, the papillomas appear as pedunculated masses of slender projection of nonkeratinizing stratified squamous epithelium supported by a core of highly vascular connective tissue stroma. Cellular differentiation has been noted to be abnormal, with altered expression and production keratins. The papillomatous lesions usually arise at anatomical sites that contain juxtaposed epithelium [4]. These sites include the limen vestibule, the nasopharyngeal surface of the soft palate, the midline of the laryngeal surface of the epiglottis, the upper and lower margins of the ventricle, the under surface of the true vocal folds, the carina, and the bronchial spurs [5]. Although papillomas are histologically benign, dysplasia and malignant changes may occur [6,7•,8•].

We know that RRP is caused by human papilloma virus (HPV), which consists of double-stranded DNA with an icosahedral-shaped virion protein capsid with a diameter of 55 nn [3]. In 1982, Mounts, et al. implicated HPV types 6 and 11 in the pathogenesis of laryngeal RRP [9]. The relationship between maternal genital condyloma acuminata in children with RRP was first noted in 1956 [10]. It is interesting to note that pediatric RRP and vaginal condyloma acuminata are both caused primarily by HPV subtypes 6 and 11, thus leading most researchers to believe that vertical transmission from mother to child is taking place in most cases [3,11••,12••]. Although unusual, vertical transmission to children born by cesarean section of mothers with vaginal warts has also been documented [13,14]. To date, more than 90 subtypes of HPV are known, although many vary only slightly in their DNA sequence. Only viral subtypes 6, 11, and, rarely, 16 and 18 have been noted in cases of RRP [9,11••,15]. High-risk subtypes, that is, 16 and 18, have been associated with malignant transformation in the laryngotracheal airway in cases of RRP [16]. Although cutaneous warts are typically caused by HPV types 2 and 3, a recent case of simultaneous laryngotracheal RRP and cutaneous warts in the same patient caused by HPV-11 has been reported [17•]. The HPV virus has been detected in adjacent nonaffected tissues in cases of RRP, and it has also been detected in the plume of laser smoke during surgical cases [18–20]. There are no reported cases of transmission of RRP to health care workers. The high-risk triad of teenaged mother, vaginal delivery, and first-born child has been identified in the development of RRP [21].

Clinically, patients with RRP usually present initially with hoarseness or aphonia, subsequently developing airway obstruction manifesting as stridor. Less commonly, children may present with chronic cough, recurrent pneumonia, failure to thrive, dysphagia, or acute life-threatening events [3]. Children with a history of chronic hoarseness should undergo flexible laryngoscopy to rule out RRP or other laryngeal pathology. In severe cases, emergency tracheotomy may be required. It has been suggested that tracheotomy may predispose children to distal tracheobronchial spread [22,23]; however, it is unclear whether this is truly the case, since many patients are successfully decannulated after debulking of their obstructive papillomas without the development of tracheal disease [23]. Patients with high-risk viral subtypes may be more prone to develop tracheal disease related to tracheotomy [24,25].

Recently published literature regarding RRP-related issues are discussed, considering the topics of epidemiology, medical therapy, and surgical management.

Department of Pediatrics and Surgery, Division of Otolaryngology-Head and Neck Surgery, University of Alabama at Birmingham, Birmingham, Alabama, USA

Correspondence to Brian J. Wiatrak, MD, FAAP, FACS, Pediatric ENT Associates/Children's South, 1940 Elmer J. Bissell Road, Birmingham, AL 35243, USA

Fax: 205-824-4983; e-mail:

© 2003 Lippincott Williams & Wilkins, Inc.