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Irradiation of recurrent respiratory papillomatosis causing spinal cord compression
Irradiation of Recurrent Respiratory Causing Spinal Cord Compression
Papillomatosis
Charles H. Shelton, MD, Paul A. Levine, MD, Chris H. Crane, MD, and Tyvin A. Rich, MD
(Editorial Comment: This is an important reminder for the clinician who may underestimate papillomatosis or fail to consider radiation in such a setting.) Recurrent respiratory papillomatosis (RRP) was originally described in children by MacKenziel and termed juvenile laryngeal papillomatosis. Subsequently, it has been described in adults with benign and aggressive variants2 and has a potential for malignant degeneration.3 In addition to the more common involvement of the larynx, endotracheal and endobronchial involvement has also been described.4 Although histologically benign, papilloma can invade soft tissue and lead to respiratory arrest and fatal pulmonary hemorrhage.3 Our case shows an unusual presentation of spinal cord compression occurring in the setting of histologically benign disease and supports the use of radiotherapy in the setting of unusual progressive intrathoracic papillomata in the adult. CASE REPORT A 50-year-old white woman with a 47-year history of RRP and no prior history of radiation therapy presented with chest and back pain. Her past history began at 3 years of age when she presented with dysphonia, resulting in the diagnosis of laryngeal papilloma. Numerous recurrences were treated with multiple resections, culminating in a tracheostomy. She was successfully decannulated at the age of 8 years, but later had an episode of respiratory distress requiring a second tracheostomy. She first had evidence of pulmonary paren-
From the Departments of Radiation Oncology and Otolaryngoiogy-Head and Neck Surgery, University of Virginia Health Sciences Center, Charlottesville, VA. Address reprint requests to Tyvin A. Rich, MD, Department of Radiation Oncology, PO Box 383, University of Vii$~” Health Sciences Center, Charlottesville, VA Copyright 0 1999 by W.B. Saunders 0196-0709/99/2003-OOOi$i 0.00/O 180
Company
American Journal of Otolaryngology,
chymal involvement at the age of 41 years, and at that time was asymptomatic, with several small soft-tissue densities in the right upper and lower lobes. Fluoroscopic-guided biopsy results showed pulmonary papillomatosis. This was followed up radiographically for approximately 7 years until progression was noted. Computed tomography (CT) scan at that time showed a large right upper and lower lobe mass, as well as mediastinal lymphadenopathy. A CT-directed biopsy of the lung mass showed papilloma with focal dysplasia. At the age of 49 years, because of progressive intrathoracic disease, she underwent thoracotomy, with multiple wedge biopsy samples showing well-differentiated keratinizing papillary squamous proliferation. Areas of focal dysplasia were seen, but no invasive disease was found in multiple sectioning of many wedge incisional biopsy samples (Fig 1). She continued to present with tracheal recurrences of her papillomata, and multiple laser ablative procedures were required. Histopathological analysis of multiple specimens showed mild dysplasia only. At the age of 51 years, she developed fever, worsening dyspnea, leukocytosis [white blood cell count, 25,OOO/pL), and hypercalcemia (serum calcium, 11.7 mg/dL) and was admitted for pneumonitis. A chest radiograph showed, in addition to an opacified right lung, bony destruction of the right sixth and seventh ribs, a paraspinous mass at T5 to T7, and bony destruction of several vertebral bodies. CT scan confirmed a large intrathoracic mass with erosion into the ribs and scapula (Fig 2). Physical examination at that time showed a posterior chest wall mass measuring 11 X 8 cm, with palpable tenderness in the area of her thoracotomy scar at approximately the level of the fifth rib. Neurological examination showed paresthesias in the right hand and anesthesia involving the right seventh thoracic dermatome. Multiple core biopsy samples of this posterior chest wall mass showed keratinizing squamous epithelium with minimal atypia, consistent with prior open biopsies. Magnetic resonance imaging confirmed a large mass filling the right hemithorax with direct contiguous spread of tumor into the spine at the level of T6 and T7. A large amount of epidural tumor, with narrowing of the canal and anterior displacement of the spinal cord, was noted (Fig 3). Intravenous dexamethasone and emergent radiation therapy were started. Her radiotherapy treatment consisted of external-beam anterior and poste-
Vol20, No 3 (May-June), 1999: pp 180-l 83
RADIOTHERAPY
FOR
AGGRESSIVE
PAPILLOMATOSIS
181
Fig 1. Representative section from an open biopsy of a large intrathoraclc mass showing well-differentiated keratinizing squamous epfthelium with mild dysplasia. Note the absence of basement membrane invasion, cytologic atypia, and pleomorphism. (Hematoxylin and eosin, original magnification x300.)
rior fields (measuring 15 x 21 cm) to include the right hemithorax and spine, using 6-MV photons daily to both fields to a prescribed midplane dose of 3,000 cGy in 10 days. Within 1 week of the completion of radiation therapy, an objective response in the size of the chest wall mass was noted (decreasing to 6 X 6 cm), as well as expansion of part of the right lung on chest radiograph and complete resolution of all neurological symptoms. She had the unfortunate complication of a traumatic hip fracture (pathologically negative for metastases) and was stabilized orthopedically and underwent anticoagulation. Four weeks later, she presented with bleeding around her tracheostomy site, having developed a coagulopathy secondary to mismanagement of her coumadin therapy, resulting in bilateral aspiration pneumonitis and death. An autopsy was not performed.
Fig 2. CT scan panel with intrathoracic disease. Note the bony erosion of the transverse process and pedicle of the thoracic vertebra.
Fig 3. Magnetic resonance (A) coronal image and (6) sagittal image showing a large intrathoracic mass with direct contiguous involvement of the spine and spinal cord encroachment.
182
DISCUSSION
RRP is a disease entity that has evolved from earlier classifications of adult and juvenileonset and aggressive and nonaggresive types to the current designation RRP, signifying the occurrence of papillomata in any part of the respiratory system and the recurrent nature of these tumors in adults and children. Tracheobronchial involvement occurs in approximately 2% to 17% of the cases4 and is associated with multiple airway manipulations and tracheostomy.5 More distal airway involvement is exceedingly rare (less than 1%).4*6 The cause of this disease is the human papilloma virus7 Histologically benign papillomata can invade surrounding structures with no cytologic features of malignancy.8 Such cases have been described to grossly invade soft tissues of the neck or lung parenchyma, and the distinction between well-differentiated squamous cell carcinoma and this more benign histology, termed invasive laryngeal papilloma, can be difficult.a We could find no referenced cases of RRP causing spinal cord compression, although one case report described autopsy findings of tumor deposits in the spinal canal of a IT-yearold patient with dysphagia secondary to squamous cell carcinoma that developed 14 years after the diagnosis of laryngeal papillomatosisg Malignant transformation can occur both in irradiated and unirradiated patient&l0 along the entire respiratory tract and must be considered in the differential diagnosis. Well-differentiated squamous cell carcinoma is the predominant histological type and may be discovered incidentally at autopsy in patients dying of pneumonia or respiratory failure.ll In the current case, multiple open biopsies of the thoracic mass failed to show malignant degeneration, and although malignant degeneration was suspected, no cytological proof could be obtained. Furthermore, clinical findings could be explained by direct contiguous extension of intrathoracic papillomata, and distant metastases were distinctly absent. Several investigators have emphasized the need to consider malignancy despite negative cytopathological findings,8J2J3 and Keim12 has suggested the importance of a clinical or biological diagnosis of cancer, rather than relying on specific cytologic criteria. Singh and Ramsaroop13 cor-
SHELTON ET AL
related clinical features suggestive of malignant transformation in patients with histopathological features that were nondiagnostic. These included sudden rapid exhuberant growth requiring excisions at intervals of less than 2 months, sudden need for tracheostomy, dysphagia, laryngeal edema, limitation of vocal cord mobility, and cervical lymphadenopathy. Historically, radiation therapy was advocated by some investigators for cases of refractory laryngeal papillomata, but was discouraged in the treatment of this benign disease after several reports of secondary malignancies appeared in the 1940s to 1960s.l" By the early 1970s, radiotherapy was contraindicated in RRP, with literature reports of laryngeal and bronchogenic carcinomas in 3% to 14% of the cases treated with radiation,14 with latency periods from 1 to 34 years after treatment.1°J5 Other complications cited from radiotherapy included arrested development of the larynx, laryngeal stenosis, fistulas, and necrosis.1o Despite its infrequent use, several historical reports indicate the efficacy of radiotherapy in the active stages of disease,16 with radiation reserved for cases showing very aggressive biological behavior. The role of radiotherapy in the modern era is limited to cases of malignant degeneration or surgically unresectable disease with an unusually invasive growth pattern in the adult and disease with aggressive behavior in children. One recent report shows the efficacy of treatment in patients with progressive intrapulmonary papillomata, with complete clearance of the lesions clinically and radiographically after 50 Gy of external-beam therapy.17 This is acceptable, particularly when the beneficial effects of treatment in a symptomatic patient far outweigh the unlikely possibility (and delayed outcome) of a radiation-induced malignancy. Radiotherapy for recurrent papillomatosis in the pediatric population is not recommended because of the high association of secondary malignancies (16 times increased risk in one study).15 Previous reports describing radiotherapy in this condition have not been able to identify a dose-response curve for laryngeal papilloma, although radiation therapy for curative intent in secondary malignancies has been successful.= The present report is an unusual case of spinal cord compression secondary to RRP.
RADIOTHERAPY
FOR
AGGRESSIVE
PAPILLOMATOSIS
Although the possibility exists for an elusive diagnosis of malignant transformation, the other plausible explanation is that locally aggressive respiratory papillomata were resnonsible for the observed clinical findings. Whereas surgery is the mainstay of treatmint for RRP, radiotherapy appears to be efficacious in a limited number of reports and should be considered for refractory cases of RRP and for cases with unusually aggressive variants that preclude surgical removal.
REFERENCES 1. Mackenzie M: A Manual of Diseases of the Throat and Nose, vol 1. Diseases of the Pharynx, Larynx and Trachea. New York, NY, William Wood and Co, 1880, p 305 2.
Doyle DJ, Gianoli GJ, Espinola T, et al: Recurrent respiratory papillomatosis: Juvenile versus adult forms. Laryngoscope 104:523-527,1994 3. Bewtra C, Krishnan R, Lee SS: Malignant changes in nonirradiated juvenile laryngotracheal papillomatosis. Arch Otolaryngol 108:114-117,1982 4. Gaylis B, Hayden RE: Recurrent respiratory papillomatosis: Progression to invasion and frank malignancy. Am J Otolaryngol 12:104-112,199l 5. Gruden JF, Webb WR, Sides DM: Adult-onset disseminated tracheobronchial papillomatosis: CT features. J Comput Assist Tomogr 18:640-642,1994 6. Helmuth RA, Strate RW Squamous carcinoma of the lung in a nonirradiated, nonsmoking patient with juvenile
183
laryngotracheal
papillomatosis.
Am J Surg Path01 11:643-
650,1987
7. Mounts P, Shah KV, Kashima H: Viral etiology of juvenile and adult-onset squamous papilloma of the larynx. Proc Nat1 Acad Sci U S A 179:5425-5429,1982 8. Fechner RE, Goepfert H, Alford BR: Invasive laryngeal papillomatosis. Arch Otolaryngol99:147-151,1974 9. Dallimore NS: Squamous bronchial carcinoma arising in a case of multiple juvenille papillomatosis. Thorax 40:797-798,1985
10. Rabbett WF: Juvenile laryngeal papillomatosis: The relation of irradiation to malignant degeneration in this disease. Ann Otol Rhino1 Laryngol74:1149-1163,1965 11. Byrne JC, Tsao MS, Fraser RS, et al: Human papillomavirus-ll DNA in a patient with chronic laryngotracheobronchial papillomatosis and metastatic squamous cell carcinoma of the lung. N Engl J Med 317:873-878,1987 12. Keim RJ: Malignant change of laryngeal papillomas: A case report. Otolaryngol Head Neck Surg 88:773-777, 1980 13. Singh B, Ramsaroop R: Clinical features of malignant transformation in benign laryngeal papillomata. J Laryngol Otol108:642-648,1994 14. Majoros M, Parkhill EM, Devine KD: Papilloma of the larynx in children. Am J Surg 108:470-475, 1964 15. Lindeberg H, Elbrond 0: Malignant tumours in patients with a history of multiple laryngeal papillomas: The significance of irradiation. Clin Otolaryngol 16:149151,1991 16. Bjork
H, Weber C: Papilloma of the larynx. Acta Otolaryngol46:499-516,1956 17. Byhardt RW, Almagro U: The role of radiation therapy in the treatment of recurrent adult laryngeal papillomatosis. Am JClin Oncol11:131-137, 1988
Papillomatosis
Charles H. Shelton, MD, Paul A. Levine, MD, Chris H. Crane, MD, and Tyvin A. Rich, MD
(Editorial Comment: This is an important reminder for the clinician who may underestimate papillomatosis or fail to consider radiation in such a setting.) Recurrent respiratory papillomatosis (RRP) was originally described in children by MacKenziel and termed juvenile laryngeal papillomatosis. Subsequently, it has been described in adults with benign and aggressive variants2 and has a potential for malignant degeneration.3 In addition to the more common involvement of the larynx, endotracheal and endobronchial involvement has also been described.4 Although histologically benign, papilloma can invade soft tissue and lead to respiratory arrest and fatal pulmonary hemorrhage.3 Our case shows an unusual presentation of spinal cord compression occurring in the setting of histologically benign disease and supports the use of radiotherapy in the setting of unusual progressive intrathoracic papillomata in the adult. CASE REPORT A 50-year-old white woman with a 47-year history of RRP and no prior history of radiation therapy presented with chest and back pain. Her past history began at 3 years of age when she presented with dysphonia, resulting in the diagnosis of laryngeal papilloma. Numerous recurrences were treated with multiple resections, culminating in a tracheostomy. She was successfully decannulated at the age of 8 years, but later had an episode of respiratory distress requiring a second tracheostomy. She first had evidence of pulmonary paren-
From the Departments of Radiation Oncology and Otolaryngoiogy-Head and Neck Surgery, University of Virginia Health Sciences Center, Charlottesville, VA. Address reprint requests to Tyvin A. Rich, MD, Department of Radiation Oncology, PO Box 383, University of Vii$~” Health Sciences Center, Charlottesville, VA Copyright 0 1999 by W.B. Saunders 0196-0709/99/2003-OOOi$i 0.00/O 180
Company
American Journal of Otolaryngology,
chymal involvement at the age of 41 years, and at that time was asymptomatic, with several small soft-tissue densities in the right upper and lower lobes. Fluoroscopic-guided biopsy results showed pulmonary papillomatosis. This was followed up radiographically for approximately 7 years until progression was noted. Computed tomography (CT) scan at that time showed a large right upper and lower lobe mass, as well as mediastinal lymphadenopathy. A CT-directed biopsy of the lung mass showed papilloma with focal dysplasia. At the age of 49 years, because of progressive intrathoracic disease, she underwent thoracotomy, with multiple wedge biopsy samples showing well-differentiated keratinizing papillary squamous proliferation. Areas of focal dysplasia were seen, but no invasive disease was found in multiple sectioning of many wedge incisional biopsy samples (Fig 1). She continued to present with tracheal recurrences of her papillomata, and multiple laser ablative procedures were required. Histopathological analysis of multiple specimens showed mild dysplasia only. At the age of 51 years, she developed fever, worsening dyspnea, leukocytosis [white blood cell count, 25,OOO/pL), and hypercalcemia (serum calcium, 11.7 mg/dL) and was admitted for pneumonitis. A chest radiograph showed, in addition to an opacified right lung, bony destruction of the right sixth and seventh ribs, a paraspinous mass at T5 to T7, and bony destruction of several vertebral bodies. CT scan confirmed a large intrathoracic mass with erosion into the ribs and scapula (Fig 2). Physical examination at that time showed a posterior chest wall mass measuring 11 X 8 cm, with palpable tenderness in the area of her thoracotomy scar at approximately the level of the fifth rib. Neurological examination showed paresthesias in the right hand and anesthesia involving the right seventh thoracic dermatome. Multiple core biopsy samples of this posterior chest wall mass showed keratinizing squamous epithelium with minimal atypia, consistent with prior open biopsies. Magnetic resonance imaging confirmed a large mass filling the right hemithorax with direct contiguous spread of tumor into the spine at the level of T6 and T7. A large amount of epidural tumor, with narrowing of the canal and anterior displacement of the spinal cord, was noted (Fig 3). Intravenous dexamethasone and emergent radiation therapy were started. Her radiotherapy treatment consisted of external-beam anterior and poste-
Vol20, No 3 (May-June), 1999: pp 180-l 83
RADIOTHERAPY
FOR
AGGRESSIVE
PAPILLOMATOSIS
181
Fig 1. Representative section from an open biopsy of a large intrathoraclc mass showing well-differentiated keratinizing squamous epfthelium with mild dysplasia. Note the absence of basement membrane invasion, cytologic atypia, and pleomorphism. (Hematoxylin and eosin, original magnification x300.)
rior fields (measuring 15 x 21 cm) to include the right hemithorax and spine, using 6-MV photons daily to both fields to a prescribed midplane dose of 3,000 cGy in 10 days. Within 1 week of the completion of radiation therapy, an objective response in the size of the chest wall mass was noted (decreasing to 6 X 6 cm), as well as expansion of part of the right lung on chest radiograph and complete resolution of all neurological symptoms. She had the unfortunate complication of a traumatic hip fracture (pathologically negative for metastases) and was stabilized orthopedically and underwent anticoagulation. Four weeks later, she presented with bleeding around her tracheostomy site, having developed a coagulopathy secondary to mismanagement of her coumadin therapy, resulting in bilateral aspiration pneumonitis and death. An autopsy was not performed.
Fig 2. CT scan panel with intrathoracic disease. Note the bony erosion of the transverse process and pedicle of the thoracic vertebra.
Fig 3. Magnetic resonance (A) coronal image and (6) sagittal image showing a large intrathoracic mass with direct contiguous involvement of the spine and spinal cord encroachment.
182
DISCUSSION
RRP is a disease entity that has evolved from earlier classifications of adult and juvenileonset and aggressive and nonaggresive types to the current designation RRP, signifying the occurrence of papillomata in any part of the respiratory system and the recurrent nature of these tumors in adults and children. Tracheobronchial involvement occurs in approximately 2% to 17% of the cases4 and is associated with multiple airway manipulations and tracheostomy.5 More distal airway involvement is exceedingly rare (less than 1%).4*6 The cause of this disease is the human papilloma virus7 Histologically benign papillomata can invade surrounding structures with no cytologic features of malignancy.8 Such cases have been described to grossly invade soft tissues of the neck or lung parenchyma, and the distinction between well-differentiated squamous cell carcinoma and this more benign histology, termed invasive laryngeal papilloma, can be difficult.a We could find no referenced cases of RRP causing spinal cord compression, although one case report described autopsy findings of tumor deposits in the spinal canal of a IT-yearold patient with dysphagia secondary to squamous cell carcinoma that developed 14 years after the diagnosis of laryngeal papillomatosisg Malignant transformation can occur both in irradiated and unirradiated patient&l0 along the entire respiratory tract and must be considered in the differential diagnosis. Well-differentiated squamous cell carcinoma is the predominant histological type and may be discovered incidentally at autopsy in patients dying of pneumonia or respiratory failure.ll In the current case, multiple open biopsies of the thoracic mass failed to show malignant degeneration, and although malignant degeneration was suspected, no cytological proof could be obtained. Furthermore, clinical findings could be explained by direct contiguous extension of intrathoracic papillomata, and distant metastases were distinctly absent. Several investigators have emphasized the need to consider malignancy despite negative cytopathological findings,8J2J3 and Keim12 has suggested the importance of a clinical or biological diagnosis of cancer, rather than relying on specific cytologic criteria. Singh and Ramsaroop13 cor-
SHELTON ET AL
related clinical features suggestive of malignant transformation in patients with histopathological features that were nondiagnostic. These included sudden rapid exhuberant growth requiring excisions at intervals of less than 2 months, sudden need for tracheostomy, dysphagia, laryngeal edema, limitation of vocal cord mobility, and cervical lymphadenopathy. Historically, radiation therapy was advocated by some investigators for cases of refractory laryngeal papillomata, but was discouraged in the treatment of this benign disease after several reports of secondary malignancies appeared in the 1940s to 1960s.l" By the early 1970s, radiotherapy was contraindicated in RRP, with literature reports of laryngeal and bronchogenic carcinomas in 3% to 14% of the cases treated with radiation,14 with latency periods from 1 to 34 years after treatment.1°J5 Other complications cited from radiotherapy included arrested development of the larynx, laryngeal stenosis, fistulas, and necrosis.1o Despite its infrequent use, several historical reports indicate the efficacy of radiotherapy in the active stages of disease,16 with radiation reserved for cases showing very aggressive biological behavior. The role of radiotherapy in the modern era is limited to cases of malignant degeneration or surgically unresectable disease with an unusually invasive growth pattern in the adult and disease with aggressive behavior in children. One recent report shows the efficacy of treatment in patients with progressive intrapulmonary papillomata, with complete clearance of the lesions clinically and radiographically after 50 Gy of external-beam therapy.17 This is acceptable, particularly when the beneficial effects of treatment in a symptomatic patient far outweigh the unlikely possibility (and delayed outcome) of a radiation-induced malignancy. Radiotherapy for recurrent papillomatosis in the pediatric population is not recommended because of the high association of secondary malignancies (16 times increased risk in one study).15 Previous reports describing radiotherapy in this condition have not been able to identify a dose-response curve for laryngeal papilloma, although radiation therapy for curative intent in secondary malignancies has been successful.= The present report is an unusual case of spinal cord compression secondary to RRP.
RADIOTHERAPY
FOR
AGGRESSIVE
PAPILLOMATOSIS
Although the possibility exists for an elusive diagnosis of malignant transformation, the other plausible explanation is that locally aggressive respiratory papillomata were resnonsible for the observed clinical findings. Whereas surgery is the mainstay of treatmint for RRP, radiotherapy appears to be efficacious in a limited number of reports and should be considered for refractory cases of RRP and for cases with unusually aggressive variants that preclude surgical removal.
REFERENCES 1. Mackenzie M: A Manual of Diseases of the Throat and Nose, vol 1. Diseases of the Pharynx, Larynx and Trachea. New York, NY, William Wood and Co, 1880, p 305 2.
Doyle DJ, Gianoli GJ, Espinola T, et al: Recurrent respiratory papillomatosis: Juvenile versus adult forms. Laryngoscope 104:523-527,1994 3. Bewtra C, Krishnan R, Lee SS: Malignant changes in nonirradiated juvenile laryngotracheal papillomatosis. Arch Otolaryngol 108:114-117,1982 4. Gaylis B, Hayden RE: Recurrent respiratory papillomatosis: Progression to invasion and frank malignancy. Am J Otolaryngol 12:104-112,199l 5. Gruden JF, Webb WR, Sides DM: Adult-onset disseminated tracheobronchial papillomatosis: CT features. J Comput Assist Tomogr 18:640-642,1994 6. Helmuth RA, Strate RW Squamous carcinoma of the lung in a nonirradiated, nonsmoking patient with juvenile
183
laryngotracheal
papillomatosis.
Am J Surg Path01 11:643-
650,1987
7. Mounts P, Shah KV, Kashima H: Viral etiology of juvenile and adult-onset squamous papilloma of the larynx. Proc Nat1 Acad Sci U S A 179:5425-5429,1982 8. Fechner RE, Goepfert H, Alford BR: Invasive laryngeal papillomatosis. Arch Otolaryngol99:147-151,1974 9. Dallimore NS: Squamous bronchial carcinoma arising in a case of multiple juvenille papillomatosis. Thorax 40:797-798,1985
10. Rabbett WF: Juvenile laryngeal papillomatosis: The relation of irradiation to malignant degeneration in this disease. Ann Otol Rhino1 Laryngol74:1149-1163,1965 11. Byrne JC, Tsao MS, Fraser RS, et al: Human papillomavirus-ll DNA in a patient with chronic laryngotracheobronchial papillomatosis and metastatic squamous cell carcinoma of the lung. N Engl J Med 317:873-878,1987 12. Keim RJ: Malignant change of laryngeal papillomas: A case report. Otolaryngol Head Neck Surg 88:773-777, 1980 13. Singh B, Ramsaroop R: Clinical features of malignant transformation in benign laryngeal papillomata. J Laryngol Otol108:642-648,1994 14. Majoros M, Parkhill EM, Devine KD: Papilloma of the larynx in children. Am J Surg 108:470-475, 1964 15. Lindeberg H, Elbrond 0: Malignant tumours in patients with a history of multiple laryngeal papillomas: The significance of irradiation. Clin Otolaryngol 16:149151,1991 16. Bjork
H, Weber C: Papilloma of the larynx. Acta Otolaryngol46:499-516,1956 17. Byhardt RW, Almagro U: The role of radiation therapy in the treatment of recurrent adult laryngeal papillomatosis. Am JClin Oncol11:131-137, 1988