Recurrent Respiratory Papillomatosis
November 16, 1991
Susan A. Eicher, M.D.

Recurrent respiratory papillomatosis is a disease of viral etiology that is characterized by recurrent proliferations of benign squamous papillomas within the respiratory tract. Histologically, the papillomas consist of multiple finger-like projections with a central fibrovascular core, which are typically covered by stratified squamous epithelium. Although benign histologically, respiratory papillomas may behave very aggressively and can precipitate sudden airway obstruction. The actual incidence of this disease is unknown, but the estimate of 1500 new cases diagnosed annually has been propagated throughout the literature since 1964. Between 60 and 80% of cases are thought to be of childhood onset, usually before the age of three years.

The natural history of recurrent respiratory papillomatosis is highly variable. Clinical presentation is usually with hoarseness or with symptoms of airway obstruction. After presentation, the disease may undergo spontaneous remission or persist in a stable state, requiring only periodic endoscopies. It also may take a progressive form, with distal spread down the tracheobronchial tree. Remissions and exacerbations of RRP are extremely common in both juvenile and adult onset disease and are unpredictable. Recurrent disease has been reported to develop after as long as 31 years of complete remission. Despite much speculation in the past that remissions and even permanent regression of respiratory papillomatosis often correlate with puberty, this does not in fact appear to be the case. On the other hand, pregnancy is associated with accelerated papilloma growth and reactivation of latent disease.

The etiologic agents of respiratory papillomas are human papillomaviruses 6 and 11. These HPV's are tissue-specific, targeting stratified squamous epithelium of the oropharynx, larynx, and anogenital region but not targeting epidermis. In juvenile onset RRP, up to 50% of patients have been reported to have a family history of genital tract papillomaviral infection in their parents. However, patients delivered by Cesarean section are not immune to developing RRP, and so infection may occur transplacentally or be acquired postnatally.

When one considers the number of adults of child-bearing age who are infected with HPV, the risk of a child's contracting respiratory papillomatosis must be exceptionally low. HPV's 6 and 11 induce abnormal differentiation of epithelium, resulting in relative hyperplasia of the parabasal layers and papillomatous formation. Of particular significance is that HPV 6 and 11 viral DNA as well as HPV capsid antigen have been found in both papilloma tissue and in macroscopically normal tissues. These viral elements have also been found in the respiratory epithelium of patients in complete remission. This implies that the virus exists in the latent form and explains the tendency for papillomas to recur and to occur in previously uninvolved sites. Purely surgical intervention will clearly never completely eradicate the infection.

The most common site of involvement by respiratory papillomas is the true vocal cord. Supra- and subglottic extension does occur frequently. Other areas of involvement, in order of decreasing frequency, are the trachea and bronchi, palate and nasopharynx, and pulmonary parenchyma. Involvement of the lung parenchyma leads to pulmonary nodules, atelectasis, pneumonia, bronchiectasis, cavitations, neoplasia, and even death.

An association is thought to exist between tracheotomy and distal spread of papillomas, and tracheotomy, should be avoided if possible. Whether a true cause-and-effect relationship exists is unclear. One mechanism of distal spread could be distal seeding of the virus after tracheotomy to previously uninvolved mucosa. Alternatively, since HPV does exist in a latent form in a large segment of respiratory mucosa, it is possible that tracheotomy somehow induces distal papilloma growth by activating latent infection. When tracheotomy is unavoidable, it is important to decannulate the patient as soon as it is feasible. Adjuvant therapy such as interferon should also be considered.

The potential exists for respiratory papillomas to behave aggressively and even undergo malignant transformation. Fechner, in 1974, introduced the term invasive laryngeal papillomatosis to describe the presence of extramucosal invasion by papillomatous disease, but without evidence of cytologic atypia suggestive of squamous cell carcinoma. Invasion into the soft tissues of the neck, esophagus, and pulmonary parenchyma have all been described. Such aggressive behavior may herald the potential for malignant transformation. The degree of epithelial atypia, which has been positively correlated with the frequency of disease recurrence and with distal spread, may indicate the potential for malignant transformation as well. It is estimated that 2-3% of all cases of respiratory papillomatosis degenerate spontaneously into squamous cell carcinoma. The incidence of such degeneration is reportedly higher after irradiation.

A multitude of both real and purported therapies for respiratory papillomatosis have been employed over the years. They have traditionally been divided into three categories: medical, physical, and immunological. All of these approaches have been met with variable success and sometimes questionable success.

Historically, medical modalities have included the use of podophyllum, hormones, broad-spectrum antibiotics, chemotherapeutic agents, and electrolytes. None of these have been shown to be of any significant benefit.

A variety of physical modalities have also been employed. Cup forceps removal was the mainstay of therapy prior to the advent of lasers and did little to alter the course of disease. Thyrotomy with skin, mucosal, or vein grafts were plagued by the recurrence of papillomas. More drastic measures such as laryngeal diversion and laryngectomy have been undertaken, but distal recurrences were common. Other methods of eradication have also been tried, such as ultrasound. Radiation should not be used for treating benign papillomas due to its potential for injuring the laryngeal skeleton and the potential for inducing malignant transformation.

At the present time, the control of respiratory papillomatosis is best achieved with periodic microsuspension laryngoscopy and carbon dioxide laser vaporization. This method has proved superior to other endoscopic techniques such as cup-forceps removal, cryosurgery, and suction diathermy. The laser permits a more precise and complete removal of disease, while providing effective hemostasis. These factors help minimize the chance of acute postoperative airway obstruction, which had discouraged regular eradication of papillomas prior to the introduction of the CO2 laser. Removing the disease on a periodic basis before extensive growth occurs or obstructive symptoms develop is essential to minimizing the complications of RRP. It is also likely that effective reduction of the tumor burden may help encourage disease remission. The laser should be used judiciously to improve the airway and restore laryngeal contour, bearing in mind that it can be destructive to normal tissues and lead to scarring and anatomic distortion.

Despite the improvement over other endoscopic modalities, laser vaporization is certainly not without its risks. Aside from the attendant risks of hypoxia and airway obstruction during any endoscopic procedure on these patients, complications such as airway fire, pneumothorax, laryngeal and tracheal stenosis, and tracheocutaneous fistula have all occurred with this therapy. Airway fires can be prevented by proper protection of the endotracheal tube, maintaining the F102 below 35%, and by avoiding nitrous oxide. It is also important to mention that HPV 6 and 11 viral DNA have been detected in the laser plume, which theoretically may pose a risk to health care workers. Specialized masks are available to help filter out viral particles.

Adjuvant immunotherapy for respiratory papillomatosis is extremely promising. In the past, autogenous vaccine, transfer factor, lymphokines, and BCG were tried in an attempt to augment the patient's immune response to the viral infection. However, these had very inconsistent degrees of success. After the recognition of interferon's antiproliferative and antiviral effects, it became the most widely used form of adjuvant therapy for respiratory papillomas. Although useful in patients with frequent recurrences, interferon will not cure the infection. HPV DNA is still expressed by the respiratory epithelium even in patients without visible disease.

Other forms of therapy have also had some success against respiratory papillomatosis. The most recent modality being studied is photodynamic therapy with dihematoporphyrin ether (DHE). Although DHE appears to be effective against RRP, it induces generalized photosensitivity, which will likely limit its utility. Retinoids have also been shown to be of some benefit in RRP. Retinoids are believed to promote normal epithelial differentiation and may induce normal differentiation of HPV infected cells. Because retinoids have also been shown to be effective in preventing the development of secondary squamous cell carcinomas of the head and neck, they may even have a role in the prevention of malignant transformation of respiratory papillomas in those patients at risk.

Case Presentation

A 10-year-old white female with recurrent respiratory papillomatosis (RRP) was diagnosed at seven months of age. Her family history is significant for juvenile-onset RRP in her maternal grandfather. Shortly after birth, she was noted to be hoarse with symptoms of respiratory obstruction. She was unsuccessfully treated for reactive airway disease and was referred for otolaryngologic evaluation. At that time, extensive laryngeal papillomatosis was found, and endoscopic carbon dioxide laser vaporization of these lesions was performed. Because of persistent recurrences, she required endoscopic procedures one to two times per month to maintain patency of her airway. However, the disease continued to progress, and she required tracheotomy for airway obstruction, at the age of 19 months. Endoscopic excisions were still necessary every two to four weeks to remove extensive laryngotracheal papillomatosis. She was subsequently started on interferon therapy, and the frequency of endoscopy declined slightly to four to six week intervals. An attempt to discontinue the interferon after a six month initial trial resulted in rapid progression of the disease, and therapy was resumed. However, despite interferon therapy distal spread of the papillomas continued, and disease was present in the trachea, bronchi, and pulmonary parenchyma. Cavitary lesions were noted on plain radiographs and computed tomograms of the chest. Laryngeal scarring and stenosis also developed. Interferon therapy was discontinued without sequelae because continued benefit was no longer evident over time.

Since then, she has required the tracheotomy to maintain her airway. She currently undergoes endoscopic procedures on a monthly basis. She experiences occasional bouts of pneumonia and peristomal infections, and the laryngotracheobronchial and pulmonary parenchymal disease continues to slowly progress. Biopsies have only shown benign squamous papillomas without cytologic atypia.

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