Diagnosis and management of pulmonary metastasis from recurrent respiratory papillomatosis

Diagnosis and management of pulmonary metastasis from recurrent respiratory papillomatosis ROBERT D. SILVER,

MD,

FRANK L. RIMELL,

MD,

GEORGE L. ADAMS,

MD,

CRAIG S. DERKAY,

MD,

and RYAN HESTER,

MD,

Minneapolis, Minnesota, and Norfolk, Virginia OBJECTIVE: We sought to review the current and proposed management, as well as bring about discussion, of managing the patient with distal tracheal and pulmonary parenchymal involvement by recurrent respiratory papillomatosis (RRP). DESIGN, SETTING, AND PATIENTS: We conducted a review of 6 patients with pulmonary metastasis from RRP at 3 academic tertiary care hospitals. Interventions included surgical and medical management with antiviral, chemotherapeutic, and/or immunemodulating agents. RESULTS: Although treatment with ␣–2-␤ interferon, isotretinoin, and methotrexate have not proved to eradicate pulmonary involvement by RRP, possible epithelial stabilization and slowing of disease progression are noted. CONCLUSIONS: The rates of distal tracheal and pulmonary metastasis as seen in our cohort were higher than previously reported. Approximately 12% of our patients with RRP have distal tracheal spread and as many as 7% of all patients with RRP at our institutions have pulmonary dissemination. Also, high suspicion for malignant conversion to squamous carcinoma in the patient with pulmonary spread should be maintained. In addition, aggressive treatment, although not proved to eradicate the pulmonary disease, should be undertaken due to the high morbidity and mortality associated with pulmonary dissemination of RRP in our cohort. (Otolaryngol Head Neck Surg 2003;129:622-9.)

T he

purpose of this report was to review our experience, as well as the current state of manage-

From the Department of Otolaryngology–Head and Neck Surgery, University of Minnesota (Drs Silver, Rimell, and Adams), and the Department of Otolaryngology, Eastern Virginia Medical School, Children’s Hospital of the King’s Daughters, Norfolk, VA (Drs Derkay and Hester). Reprint requests: Frank L. Rimell, MD, Department of Otolaryngology, Box 396, 420 Delaware St SE, Minneapolis, MN 55455; e-mail, [email protected]. Copyright © 2003 by the American Academy of Otolaryngology–Head and Neck Surgery Foundation, Inc. 0194-5998/2003/$30.00 ⫹ 0 doi:10.1016/j.otohns.2003.08.018 622

ment, in distal tracheal spread (DT) and pulmonary metastasis (PM) of recurrent respiratory papillomatosis (RRP). Additionally, a discussion of the rate of disease prevalence and proposed factors influencing disease progression is provided. In the majority of cases, RRP remains isolated to the larynx and immediate subglottic region. In a low percentage of cases, however, papillomatous lesions spread to the distal third of the trachea as well as into healthy lung tissue. Early age at presentation appears to be a negative prognostic factor,1 and while causation for DT/PM is unknown, it has often been blamed on tracheostomy placement.2-4 Twenty-five percent of our patients had documented DT before tracheostomy and one patient had PM before tracheostomy. These multiple metastatic foci result in alveolar destruction, restrictive parenchymal lung disease, multiple abscesses, transformation to squamous cell carcinoma, and death. The following cases are from the authors’ experience and illustrate a common pattern seen in patients with PM from RRP. In addition, the current and proposed management of these difficult patients, including the use of transbronchial biopsies, surgical resection, various drug cocktails, and other therapies, is intended to bring about discussion for managing the patient with distal trachea and pulmonary parenchymal involvement by RRP. CASE REPORTS Case 1 A male child presented to us at 20 months of age when the diagnosis of RRP was made.5 Pulmonary metastasis was first noted in the right upper lobe at 3 years of age. Four months after diagnosis, the pulmonary nodules began to cavitate as they increased in size and number. By age 5, all areas of the right lung were involved radiologically and the child had been put on individual trials of bleomycin, methotrexate, and ␣–2-␤ interferon. By the age of 7, both lung fields were involved.

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Fig 1. Multiple bilateral nodules in a patient with pulmonary dissemination of recurrent respiratory papillomatosis.

Case 2 A female child was transferred to us at 24 months of age on interferon therapy because of severe distal tracheal disease. Distal tracheal disease was noted before tracheostomy at 22 months of age. She had an obstructed right lung at the time of transfer and underwent laser ablation and removal of mucopus with eventual reexpansion of her right lung. At 6 years of age, computed tomography (CT) scan noted multiple bilateral pulmonary nodules (Fig 1). This was determined to be consistent with PM from RRP. Over a 6-month period, these began to enlarge and cavitate (Fig 2). CT-guided transthoracic needle biopsies of the nodules determined no malignant degeneration. It was decided to begin this 15-kg child on a 3-drug cocktail of 1.75 million units of ␣–2-␤ interferon, isotretinoin 10 mg each day on even days and 10 mg twice a day on odd days, and methotrexate 15 mg each week. She continued to undergo resection of the laryngeal and tracheal papillomas every 4 to 8 weeks and presently is on the above 3-drug combination with ␣–2-␤ interferon at 3 million units 3 times per week. This patient’s bilateral pulmonary papillomas are noted to have slowly

increased in number, as confirmed over the past 4 years by CT scanning. She has recently undergone trial injections of the antiviral drug cidofovir6 directly into her larger pulmonary lesions under CT guidance (Fig 3). After 6 months, 3 injections were complicated by 2 pneumothoraces, and no improvements were seen in her pulmonary lesions, although continued improvement is seen in the distal tracheal disease. It should be noted that her distal tracheal disease is vaporized by a potassium titanyl phosphate (KTP) laser and then injected with cidofovir via endoscopic sclerotherapy needle. Case 3 A female child had a history of RRP initially diagnosed at 6 months of age. She presented to us at 19 months of age after respiratory arrest during tracheostomy change. Before this, she underwent multiple laser ablations of her laryngeal papillomas and has subsequently required laser ablation on a monthly basis. Due to the extensive nature of her papillomas, the patient was started on isotretinoin, methotrexate, and ␣–2-␤ interferon therapy. A chest CT scan revealed multiple nodules bilat-

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Fig 2. Enlargement and cavitation of pulmonary nodules in the same patient over a six month period.

Fig 3. Cidofovir injection into pulmonary lesions under CT guidance.

erally consistent with PM from RRP. At 2.5 years of age, she moved out of the state. On returning 2 months later, a 50% distal tracheal obstruction was

visualized and excised using KTP laser. The 3-drug regimen was again started. At 3 years of age, a chest CT scan demonstrated no definitive

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change in the size or distribution of the bilateral pulmonary nodules. Case 4 This female patient’s history reveals diagnosis of RRP at age 18 months. She had multiple surgical and laser treatments of her papillomas and by 15 years of age underwent tracheostomy. A chest radiograph at that time was negative for pulmonary disease. At 15.5 years of age, distal tracheal involvement extending to the level of the carina was noted. She was started on an ␣–2-␤ interferon protocol at that time. The patient elected to discontinue interferon therapy after 3 months due to side effects, particularly fever and lethargy. She continued to receive outpatient laser excision of her papillomas on an approximately monthly basis for the next several years. At 23 years of age, the patient presented 4 days postpartum with a right lung abscess. Follow-up CT scanning revealed an increase in the previously identified density in the right lower lobe, multiple parenchymal cysts that were unchanged, and a calcified nodule in the right upper lobe. Frozen section demonstrated squamous cell carcinoma involving the hilum, upper, and lower lobes of the right lung. Pneumonectomy, along with resection of the posterior chest wall and involved spinal column, was performed approximately 1 month later. Oncologic follow-up included radiation therapy as well as concurrent chemotherapy with vinblastine and cisplatin. Isotretinoin and ␣–2-␤ interferon were added shortly after starting chemotherapy. The lung nodules continued to enlarge with no demonstrable response to treatment. Case 5 A female patient first presented to us at 38 years of age with papillomatous overgrowth at the left main stem bronchus and a history significant for more than 110 resections of laryngeal papillomas. After extirpation of the papillomatous mass, antiviral treatment with ribavirin was initiated and continued for 5 months. She demonstrated a positive response characterized by a 10-month papilloma-free interval. The patient was restarted on ribavirin therapy and again demonstrated a prolonged period requiring no surgical intervention. Approximately 2 years later, she was enrolled in a Food and Drug Administration–approved doubleblind ribavirin study and demonstrated a decrease

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in the rate and bulk of papillomatous growth. A chest radiograph obtained in the initial consultation for this study revealed a 1.5-cm nodular density in the right lung. CT scanning revealed a 3-cm mass in the superior segment of the right lower lobe as well as multiple small pulmonary nodules bilaterally. Several thin-walled cavities were also noted. Comparison CT scans obtained 5 years earlier revealed increased prominence in the pulmonary nodularity. Transformation to squamous cell carcinoma was suspected, but autopsy was declined at the time of the patient’s death. Case 6 A female child was born at 27 weeks and required ventilator support for the first 3 weeks of life. She presented to us at 7 months of age with a 2-month history of hoarseness and progressive respiratory distress. Direct laryngoscopy and bronchoscopy revealed extensive laryngeal involvement by papillomas without any evidence for subglottic or distal disease. She required surgical intervention at 1-month intervals for the next year, each time presenting with extensive papillomatous regrowth. Subglottic disease was first noted at the third month after diagnosis. Six months after diagnosis, she was initiated on a trial of ␣–2-␤ interferon at a dose of 1.7 million units 3 times a week. Treatment was discontinued at 7 months due to lack of any apparent response. A methotrexate regimen was then begun at a dosage of 1 mg/kg twice a week. At 2.5 years of age, she was found to have extensive tracheal disease with several satellite papillomas extending from the subglottis to the carina with bulky obstructive lesions at the carina and the right main stem bronchus. At 4.5 years of age, a chest CT scan revealed multiple cystic cavities bilaterally, as well as multiple noncavitary nodules. This patient remains on combined interferon and methotrexate therapy with slowing of glottic and supraglottic disease but with unarrested progression of distal tracheal and pulmonary disease. DISCUSSION Prevalence One of the most feared complications of RRP is PM. The literature on this topic is sparse with regard to prevalence, diagnosis, and management. It has been estimated that DT occurs in 5% of patients, whereas PM occurs in 1% of patients

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with RRP.7 To date, there have been no clinical trials to study this group of patients because they are so few in number. Over the past several years, a database has been established by the Centers for Disease Control and Prevention and the Recurrent Respiratory Papillomatosis Task Force. The goals are to (1) establish a cohort of patients with RRP, (2) determine the extent and severity of disease in these patients, and (3) assess the most commonly used types of surgical and pharmacologic treatments.8 According to data available at the time this article was written, there were a total of 35 (6.20%) of 564 patients reported to the RRP database with tracheal disease (inclusive of bronchial or pulmonary involvement).9 The Recurrent Respiratory Papilloma Foundation also keeps a database of its members and reports 63 (17.10%) of 367 patients with tracheal involvement, 33 (8.99%) of 367 with bronchial involvement, and 22 (5.99%) of 367 with lung/pulmonary involvement independent of tracheal involvement. The 106 patients reviewed by the senior authors (F.L.R. and C.D.) include patients from the University of Pittsburgh (1982-1995), the University of Minnesota (1980-1997), and the Children’s Hospital of the King’s Daughter (1996-2000). The combined patient cohort reveals 12% of patients with DT and 7% with PM. Inclusion in one group excludes patients from the other and it should be noted that percentages are based on all papilloma patients. It is also important to consider that these institutions are tertiary in nature and slanted toward taking care of more severely ill patients. Of the 4 patients with PM at the University of Minnesota, 2 were referred with disease already in the lung. Similarly, of the 7 patients with DT, 5 presented after this had developed. The actual rate of DT/PM is not clear, but the RRP Task Force’s current report of 6.2% for DT is likely more accurate compared with our rate of 12% or that of the 17% stated by the RRP Foundation’s selfreported survey. At this time, a range from 6% to 17% of patients are likely to develop DT, with major referral institutions experiencing a 12% rate. The previously proposed rate of 1% of patients having PM, however, may be too low. Improved support and intervention, even without complete eradication of disease, may allow for advanced disease progression and an increase in

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the prevalence of patients with PM from RRP over the past 2 decades. Causation We do know the human papilloma (HPV) virus grows in squamous epithelium and therefore, for distal spread to occur squamous metaplasia, needs to be present in the distal trachea or lung. Factors that promote squamous metaplasia include tracheostomy, repeated intubations, and aggressive bronchoscopy. These factors, however, explain only distal tracheal spread and not pulmonary alveolar spread. Tracheostomy has been blamed repeatedly for DT/PM, yet the University of Minnesota/Children’s Hospital of Pittsburgh experience shows that these patients truly have a more aggressive disease process before their tracheostomy.2 This is further illustrated by many of the case histories presented in this article. We have previously documented patients with DT/PM before their tracheostomy.2 However, we still strongly support the notion of avoiding tracheostomy placement if at all possible. Venturi ventilation has also been blamed as promoting DT/PM. The University of Minnesota and Children’s Hospital of Pittsburgh uses venturi or jet ventilation extensively, whereas the Children’s Hospital of the King’s Daughter does not. Although the University of Pittsburgh and Minnesota have a higher rate of patients with DT/PM than the Children’s Hospital of the King’s Daughter, many of the patients seen in the former institutions already had DT/PM at the time of referral. It is interesting to note that the only patient from the Children’s Hospital of the King’s Daughter to develop PM did leave that institution for a few years before returning with DT/PM and was treated elsewhere, where venturi ventilation was used. However, most patients seen at the University of Minnesota and Pittsburgh with DT/PM already present were treated in places where venturi or jet ventilation was not used. There are 3 ways in which papillomatous disease has been reported to occur in the lung.10 The first type are inflammatory polyps, the second are solitary papillomas, and the third type are multiple papillomas. Inflammatory polyps are not caused by HPV and are not further discussed in this report. Solitary pulmonary papillomas may be

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Table 1. Patients, interventions, and disease progression Patient

Age at diagnosis Sex Treatment Age with evidence of distal tracheal disease Age with evidence of pulmonary metastasis

1

2

3 months Male Bleomycin, Methotrexate, ␣-2-␤ interferon unknown

24 months Female Isotretenoin, Methotrexate, ␣-2-␤ interferon, intra-lesion cidofovir 22 months

3 years

6 years

problematic with regard to respiratory mechanics but have a tendency toward decreased incidence of recurrence after treatment by lobectomy, thereby avoiding further pulmonary involvement.5,11 Solitary squamous papillomas may occur in the absence of previous laryngotracheal findings,11 whereas multiple metastatic papillomas appear on a continuum with previous laryngotracheal disease. Pulmonary metastasis begins with small solitary nodules that enlarge and cavitate over time, destroying healthy parenchymal lung tissue (Figs 1 and 2). These cavitations demonstrate rapid DNA turnover representing active viral infection and are likely areas to eventually undergo malignant degeneration. Solitary and multiple pulmonary papillomatous lesions have been shown by in situ hybridization, polymerase chain reaction, and restriction fragment length polymorphism analysis to contain several human papilloma subtypes. Types 6 and 11 have been most frequently isolated in tissue samples obtained from patients with aggressive RRP.3,12,13 Type 11 is highly associated with malignant conversion to squamous cell carcinoma,3,4,13-16 and our experience is that the majority of patients with DT/PM were infected with HPV 11. Bonagura et al10 further demonstrated that the T-cell response of RRP patients exhibits an increase in TH2-like cytokine mRNA, suggesting that immunologic findings correlate with disease severity. In light of this, it is necessary to consider the use of transbronchial or transthoracic biopsy in assessing prognosis and care. Our opinion is to take biopsy samples of rapidly growing segments. This may require the use of CT-guidance needle biopsy for distal pulmonary lesions. A positive biopsy for squamous cell carcinoma would change the management to a course of more aggressive

chemotherapy. A biopsy positive for carcinoma in situ also allows for consideration of more aggressive treatment. Presently, HPV type is not a determinant in the medical management of parenchymal involvement by RRP, although viral typing may provide better insight over grading of dysplasia for assessing prognosis at the onset of the disease process.3,17 Adjuvant Therapies Adjunctive medical therapies have questionable benefit in prolonging and improving the quality of life in patients with disseminated RRP. Photodynamic therapy has been reported in a child with DT/PM18,19 but is limited to endobronchial lesions only. The antiviral agent ribavirin demonstrated some palliation of more proximal and tracheal disease but had no observable benefit in parenchymal disease. Similarly, intralesion injections of the antiviral drug cidofovir demonstrated no improvement in pulmonary disease. In our experience, treatment with a pharmacologic protocol of ␣–2-␤ interferon, isotretinoin, and methotrexate has been initiated in 4 cases of DT/PM (Table 1). The goal of this therapy is not a cure of disease but rather palliation in the hope of less frequent surgical debulking and potentially alternative pharmacologic management in the near future. There is a discussion among some to begin the use of stronger antineoplastic agents on initial findings of PM because the development of this process is almost always fatal. In our experience, as well as in the cases noted by Kramer et al,7 mortality with PM will probably occur in a 4- to 10-year period after the diagnosis of pulmonary metastasis.

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Table 1. (Continued) 3

4

5

6

6 months Female Isotretenoin, Methotrexate, ␣-2-␤ interferon 19 months

18 months Female Isotretenoin, Vinblastine, cislatin, ␣-2-␤ interferon, Radiation Tx 151⁄2 years

Unknown Female Ribavirin Unknown

7 months Female ␣-2-␤ interferon, methotrexate 21⁄2 years

19 months

23 years

35 years

41⁄2 years

CONCLUSIONS DT/PM is still a relatively rare complication in a rare disease. The frequency of DT/PM is greater than previously thought, however, with 6% to 12% of patients having DT and up to 7% of all patients with RRP manifesting PM. There is currently no recommended form of treatment once such spread occurs. Severe overgrowth of the papillomatous mass necessitates frequent operative debulking, and approximately 35% of cases require tracheostomy to maintain airway patency.2,19 It is our recommendation to follow patients with DT closely for early signs of PM. High suspicion for malignant conversion should be maintained particularly in those cysts that are rapidly growing. Once PM is demonstrated by CT scanning, adjuvant long-term chemotherapy with methotrexate, interferon, and isotretinoin is considered with the intent to stabilize the epithelium and slow progression of the disease process. Surgical resection for isolated disease may be an option, as well as more aggressive chemotherapy directed toward squamous cell carcinoma.20 Mortality from pulmonary metastasis of RRP is likely to occur within 10 years of diagnosis.

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and parenchymal juvenile laryngotracheobronchial papillomatosis. effect of photodynamic therapy. Chest 1991; 100:1458-61. 18. Rimell FL, Shoemaker DL, Pou AM, et al. Pediatric respiratory papillomatosis: prognostic role of viral subtyping and cofactors. Laryngoscope 1997;107:915-8. 19. Shikowitz MJ, Abramson AL, Freeman K, et al. Efficacy

of DHE photodynamic therapy for respiratory papillomatosis: immediate and long-term results. Laryngoscope 1998;108:962-7. 20. Sakopoulos A, Kesler KA, Weisberger EC, et al. Surgical management of pulmonary carcinoma secondary to recurrent respiratory papillomatosis. Ann Thorac Surg 1995;60:1806-7.

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