Recurrent Respiratory Papillomatosis

Recurrent respiratory papillomatosis (RRP) is a chronic disease characterised by benign exophytic squamous papillomas of the upper aerodigestive tract, most often the larynx, caused by HPV types 6 and 11.

• Juvenile onset RRP presents before 12 years (peak 2 to 4 years) and is acquired by perinatal transmission from maternal genital condylomata, usually in first born children delivered vaginally to young mothers. Adult onset RRP presents in the third to fifth decades, probably by orogenital transmission, and tends to be milder and more often male.
• Predilection for squamocolumnar junctions and areas of mucosal turbulence: laryngeal ventricle, undersurface and upper surface of the vocal folds, subglottis, and the laryngeal surface of the epiglottis.
• Clinical course is unpredictable: some patients remit spontaneously, others need dozens of procedures. Juvenile onset disease is more aggressive, with greater risk of airway obstruction.
• Malignant transformation to squamous cell carcinoma occurs in about 1 to 3 percent, related to HPV 11, smoking, and radiotherapy, and in some patients with long standing disease.

• Progressive hoarseness, weak or abnormal cry in infants and children, and voice change that is often wrongly attributed to asthma, croup, or voice abuse.
• Stridor (initially inspiratory, then biphasic) and respiratory distress that worsen with infection.
• Chronic cough, dysphagia, recurrent pneumonia, and failure to thrive in children.
• Life threatening airway obstruction can occur suddenly when a papilloma fragment obstructs the glottis.
• Adults present with persistent hoarseness, sometimes with a cough or dysphonia that fluctuates.
• Most patients have no mucocutaneous warts; examine the mother or partner for genital HPV disease.

• Flexible laryngoscopy shows pink or white, multiple, exophytic, wart like or cauliflower masses on the vocal folds, ventricular folds, subglottis, and epiglottis. Videostroboscopy demonstrates disturbed mucosal wave when the folds are involved.
• Direct microlaryngoscopy and bronchoscopy under general anaesthesia: complete staging, biopsy, and tracheobronchial survey to exclude distal spread.
• Histology: papillary fronds with fibrovascular cores and non-keratinising squamous epithelium, with koilocytosis and acanthosis. HPV DNA typing by PCR (6, 11 versus 16, 18). Severe dysplasia or atypia requires evaluation for carcinoma.
• Severity scoring: a numeric, site weighted endoscopic score and a clinical score (voice quality, stridor, urgency of intervention, respiratory distress) that allow objective comparison before and after treatment.
• Differential diagnosis: laryngeal polyps and cysts, granulomas, papillary carcinoma, laryngeal tuberculosis, granulomatosis with polyangiitis, and laryngeal amyloidosis.
• Maternal history of genital warts, mode of delivery, and birth order are documented.
• Imaging (CT of the chest) is indicated when there are lower airway symptoms or extensive disease.

• There is no cure. The aim is airway patency, voice preservation, and reduction of procedure frequency while avoiding scar and anterior commissure webs.
• Surgical therapy:
  • Microdebrider (powered laryngeal shaver) removal under general anaesthesia with suspended microlaryngoscopy: precise, with less thermal injury to the vocal ligament than laser.
  • CO2 laser, KTP, or pulsed dye laser: photoangiolytic lasers act selectively on vessels in the papilloma core and can be used in the office with topical anaesthesia (lidocaine 4 percent) in cooperative adults.
  • Treat the anterior commissure and both folds in the same sitting only with care, since bilateral raw surfaces predispose to web formation; operate on one side if both anterior commissure surfaces are involved.
  • Intervals are guided by symptoms and examination (every 4 to 12 weeks, lengthening with control).
  • Avoid tracheostomy unless there is critical obstruction; it exposes the trachea and bronchi to papillomatous seeding.
• Adjuvant therapy is considered when more than 4 procedures per year are needed, regrowth is rapid, or there is distal spread:
  • Intralesional cidofovir 5 mg/mL injected into the lesion base (up to about 1 to 2 mL per site) after debulking, repeated every 2 to 4 weeks for several sessions.
  • Bevacizumab 5 mg/mL injected intralesionally (up to 1 mg/kg) or intravenously at 5 mg/kg to 10 mg/kg every 2 to 4 weeks; monitor blood pressure, proteinuria, and wound healing.
  • Interferon alfa-2b 3 million units/m2 subcutaneously daily for 28 days then three times weekly for months (limited by fever, fatigue, neutropenia, and neuropsychiatric effects).
  • Indole-3-carbinol 200 mg to 400 mg orally daily and celecoxib, with limited evidence.
  • Quadrivalent or 9-valent HPV vaccine as an adjuvant, 0.5 mL intramuscularly at 0, 2, and 6 months; reports describe reduced recurrence and longer intervals.
  • Systemic and targeted agents for aggressive or refractory disease, including PD-1 inhibitors, are experimental.
• Treat gastro oesophageal and laryngopharyngeal reflux: omeprazole 20 mg to 40 mg once daily (1 mg/kg/day in children).
• Smoking cessation and voice hygiene; speech therapy for voice rehabilitation after procedures.
• Prevention: HPV vaccination of adolescents and young adults prevents genital HPV 6 and 11 disease and reduces maternal transmission. Caesarean delivery is not routinely recommended for mothers with genital condylomata, as it does not eliminate the risk; the decision is made on obstetric grounds.
• Follow up: regular examination for life, because recurrence can occur after long remission, and early biopsy of any lesion that is firm, fixed, ulcerated, or changed in character.
• Complications: airway obstruction, vocal fold scarring and anterior web, voice impairment, tracheal and pulmonary spread, and malignant transformation.