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Recurring laryngeal papilloma
RecurringLm3mgeal Papilloma ARNOLD M. GO/IN, M.D.,* JOHN T. KOS, II, M.D.,~" LARRY H. TABER, M.D.,$ AND ERVIN ADAM, M.D.{}
A prospective study of 31 children born of mothers with condylomata acuminata at parturition or during pregnancy was undertaken to test the hypothesis that la~ngeal papilloma could be associated with venereal warts and could be acquired perinatally. None of the children born of mothers with condylomas at delivery or during their pregnancies had developed symptoms, signs, or observable lesions of laryngeal papilloma, whether delivered vaginally or by cesarean section. Nevertheless we do not know the true incidence of this disease or the infectivity of the causative micro-organism. Although it appears that the correlation between laryngeal papilloma in children and the presence of condylomata acuminata in the mother during pregnancy or parturition is not as strong as our retrospective study had suggested, it should not be disregarded.
Recurring laryngeal papilloma is the most c o m m o n benign laryngeal n e o p l a s m in children. ~ The condition was first recognized as "warts in the throat" by Marsellus Donalus ~ in the seventeenth century. Morel MacKenzie s diff e r e n t i a t e d the l e s i o n f r o m o t h e r laryngeal masses and coined the name papilloma in 1871. Laryngeal papillomatosis continues to be a distressing problem to the physician and patient alike. The magnitude of the problem is reflected in the conflicting reports regarding the etiology of the lesion and effective treatment. Clinically laryngeal papillomatosis is thought of as a disease of infancy and childhood, but it is frequently found in adults. Hoarseness or an abnormal cry is the initial manifestation in the young infant; dyspnea, cough, stridor, and respiratory distress m a y subsequently develop. The symptoms and signs may occur singularly or in combination. In children the disorder tends to have a progressive course, papillomas often showing robust growth and rapid recurrence w h e n removed. In adults the recurrence rates
have been lower. Spontaneous remission is frequent, particularly approaching puberty, but remission remmns unpredictable. A recent study failed to identify puberty as an influence on the age of remission; indeed remission m a y not be maintained, since late recurrence occasionally can occur? Occurring most frequently in the larynx, multiple papillomas have also been encountered in the trachea, bronchi, and lung parenchyma with and without laryngeal disease# -7 Morphologically the lesion originates as an exophytic proliferation of squamous cell epithelium and stroma. The stroma consists of sparse connective tissue with few l y m p h o c y t e s and plasma cells. The overlying epithelium is a hyperplastic, well differentiated, stratified squamous cell epithelium of varying thickness. The epithelium is nonkeratinized, this feature distinguishing it from that of isolated keratinizing papilloma occasionally seen in adults. Some cellular atypia may be observed, 4' 8 but malignant degeneration is rare. 9-11 The etiology of this disorder remains elusive,
Accepted for publication February 5, 1981. *Professor, Department of Otolaryngology, Wayne State University School of Medicine,Detroit, Michigan. #Otolaryngologist, Lincoln, Nebraska. ~:Associate Professor,Department of Pediatrics and Infectious Diseases, Baylor College of Medicine. Staff, Ben-Taub Hospital, Jefferson-Davis Hospital, cmd Texas Children's Hospital, Houston, Texas. ~Associate Professor, Department of Virology and Epidemiology and Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, Texas. American Journal of Otolaryngology--Volume 2, Number 2, May 1981
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a l t h o u g h m a n y theories have been proposed. T h e greater i n c i d e n c e in males a n d the frequently observed spontaneous regression near p u b e r t y have s u g g e s t e d a hormonal factor in papillogenesis and a possible electrolytic abnormality. 12-14 Other associated factors that have b e e n evaluated include chronic irritation, race, geography, and socioeconomic status. 1~ By far the greatest interest has been focused on the possibility of a viral etiology and immunologic deficiency or a combination of the two. Stimulated b y MacKenzie's observation of the c o m m o n coexistence of laryngeal papilloma and skin warts, s U h l m a n 16 in 1923 transplanted a laryngeal papilloma to his arm and implanted the resulting papilloma into the vaginal m u c o s a of a dog. This a c c o m p l i s h m e n t was duplicated by Ishikawa ~7 in 1936, although others have failed. Resler and S n o w is w e r e able to transplant papilloma to dog vaginal m u c o s a and sMn using a cell free filtrate from laryngeal papillomas; however, transfer of the lesion to the larynx or oral m u c o s a was not successful. Laryngeal papillomas are thought to be prod u c e d b y tumorigenic viruses containing double s t r a n d e d DNA b e l o n g i n g to t h e p a p o v a v i r u s group, but attempts to grow the virus in tissue culture have failed. ~", 1, Identification of virus particles in laryngeal papillomas awaits conclusive agreement. A l t h o u g h virus-like particles have been identified in extracts of laryngeal papilloma in some studies, 2~ examination by others has not confirmed their presence. ~5' 24-2, The observation of skin warts in patients with laryngeal papillomas has b e e n reported, 2~ 2Ob and two reports of laryngeal papillomas occurring in infants w h o s e mothers h a d condylomata acuminata at the time of delivery stimulated our r e t r o s p e c t i v e s t u d y to t e s t t h e s e a s s o c i a tions 25, 29~. ~d The mothers of five of nine children with laryngeal papillomas had abundant c o n d y l o m a t a a c u m i n a t a at the time of delivery; in another two mothers genital warts were noted in the gestational history. 25 Of further interest was the observation that these children became s y m p t o m a t i c earlier than other children whose mothers had no history of genital warts: these i n f a n t s o f t e n d e v e l o p e d s y m p t o m s b y six m o n t h s of age. This suggested transmission of a virus to the child during parturition. Similar findings have since been reported by others 4, 24, 30 A prospective study was attempted to examine the link b e t w e e n these two disorders. The objective of this study was to test the hypothesis that laryngeal papillomas could be as-
sociated with venereal warts and acquired perinatally. 25 It w a s t h o u g h t t h a t i d e n t i f y i n g children born to mothers with venereal w a r t s and following them prospectively might m a k e possible an estimation of the risk of acquiring the disease.
METHODS AND CLINICAL MATERIAL The study population was derived from t h e obstetrical service of a large city hospital that a v e r a g e s 10,000 d e l i v e r i e s p e r year. O n e hundred seven w o m e n with condylomas during pregnancy were identified; 31 of these w o m e n were enrolled in our program. The diagnosis of condyloma was made clinically. Nineteen m o t h ers had condylomas at the time of delivery; 12 were free of venereal warts at the time of delivery. Seventeen of the 19 mothers with condylomas at the time of delivery gave birth vaginally; two mothers underwent cesarean section. The addresses of the children to be f o l l o w e d were kept by a nurse-epidemiologist. T w e n t y nine of the 31 infants were examined b e t w e e n six and eight months of age, and five infants were re-examined b e t w e e n 10 months and 12 months of age. A clinical history of s y m p t o m s of laryngeal disease was taken and direct lary n g o s c o p y was performed as part of the evaluation in the 29 children. Further serial surveillance was possible in 19 children, 17 of w h o m had undergone direct laryngoscopies and two of w h o m could not be examined directly. Three children were f o l l o w e d for an additional 12 months, one child for two years, and 15 children for three to six years after direct laryngoscopy. Twelve children w h o had undergone direct laryngoscopy were not available for subsequent follow-up. Surveillance in these 12 children c o n sisted of periodic queries regarding the nature of the cry, change in voice, hoarseness, respiratory difficulty, asthma, w h e e z i n g , and o t h e r symptoms of laryngeal disease, Clinic charts a n d reports of emergency room visits were examined to identify possible laryngeal disorders.
RESULTS
All the 29 infants examined b y direct laryngoscopy had a normal larynx. None showed evidence of laryngeal papillomas regardless of w h e t h e r the mother h a d c o n d y l o m a s d u r i n g pregnancy or at the time of delivery, or w h e t h e r
RECURRING LARYNGEAL PAPILLOMA
delivery was effected vaginally or by cesarean section. None of the Ig children capable of being followed for one to five years after direct laryngoscopy developed symptoms to suggest an existent or progressive laryngeal disorder. Four children developed isolated or transient minor symptoms. One patient whose mother had condylemas at delivery and w h o was delivered vaginally developed "choMng" at age 30 months. Examination was negative and neither voice change nor other sequelae followed. Another patient also delivered vaginally from a mother with condylomas at term experienced recurring upper respiratory tract infections and developed asthma; indirect laryngoscopy at age five years was negative for papilloma. A third patient delivered vaginally from a mother without condylemas at delivery developed an upper respiratory tract infection and wheezing at 30 months of age; she had moved away from the area, but follow-up by her family physician indicated recovery without sequelae. A fourth patient whose mother had condylomas at the time of vaginal delivery had what the mother c o n s i d e r e d a " f u n n y little voice," but by 36 months of age there was no abnormality in the voice quality, unusual upper respiratory tract infections, or respiratory distress. Neither direct nor indirect laryngoscopy could be performed, however.
DISCUSSION Laryngeal papillomas are epithelial hyperplastic tumors that tend to resist therapy, often recur after removal, and tend to involve and to be t r a n s p l a n t e d to adjoining structures. Although the etiology of these lesions has not been established conclusively, the prevailing view is that papillomas are caused by a member of the papovavirus group. Although common h u m a n skin warts were presumed to be infectious throughout the nineteenth century, the viral etiology of common skin warts was established in 1919 by Wile and Kingery) ~ The human wart virus is a member of the papovavirus A group. It was initially believed that all human papillomas were the result of a common etiologic agent, but significant differences in the epidemiology, clinical features, ultrastructure, and serologic tests suggest that at least two different types of papovavirus are responsible for verrucae vulgaris and condyloma acuminata.2S. 32-a6 Laryngeal papillomas may re-
ARNOLD M. COHN ET AL.
suit from either of these agents or another related agent. The clinical behavior of recurring laryngeal papillomas, their remissions and recurrences, is compatible with that of a viral disease, Our previous study suggested that laryngeal papilloma may be caused by the agent responsible for venereal warts and may be acquired perinata]ly7 ~ Among nine children with laryngeal papillomas, all became symptomatic by two years of age, and five of the nine were symptomatic before one year of age. The mothers of all five patients who were symptomatic by age one year recalled having had genital warts at the time of delivery. Of the remaining four mothers, two recalled having condylomas during their pregnancy but not at the time of delivery. Thus, seven of these nine children with laryngeal papillomas were born to mothers with genital warts. This concept has been reinforced in other reports. Stephens and her colleagues ~4report three of 17 patients with this association. Strong and his coworkers 4 report that 50 per cent of 30 patients younger than the age of five were born of mothers who had condylomas at the time of delivery; and Quick et a12~ reported that 60 per cent of their patients had a history of maternal condylomas during pregnancy or at parturition. Strong et el. 4 suggest a variable if not low infectivity of the disease and do not know of secondary cases of the disorder among older siblings of the patients or subsequent children of mothers of patients with the disease. We also have not found laryngeal papillomas in older siblings of patients with the disease or in children of subsequent pregnancies of mothers of our patients with laryngeal papillomas. ]n the present study none of the children born of mothers with condylomas at delivery or during pregnancies have developed signs, symptoms, or observable lesions of laryngeal papillomas, w h e t h e r delivered vaginally or b y cesarean section, although only 23 of these children could be followed beyond one year of age. Nevertheless we do not know the true incidence of this disease or the infectivity of the responsible micro-organism. Although all previous studies have suggested an early age of onset of the disease in children horn of mothers with venereal warts at delivery, the age of onset or presentation of this disorder extends well into childhood and the disorder occurs in adults. Although it appears that the correlation between laryngeal papillomas in children and the presence of condyloma acuminata in the mother dur-
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ing pregnancy or parturition is not as strong as our retrospective s t u d y suggests, it should not be disregarded.
References 1. MacKenzie, M.: Diseases of the Pharynx, Larynx and Trachea. New York, William Wood & Co., 1880, p. 226. 2. Donalus, M. Cited by Webb, W. W.: Papilloma of the larynx. Laryngoscope, 55:980-984, 1956. 3. MacKenzie, M.: Essays on Growths in the Larynx with Reports and an Analysis of One Hundred Consecutive Cases Treated by the Author. Philadelphia, Lindsay & Blakeston, 1871. 4. Strong, M. S., et al.: Recurrent respiratory papillomatosis. Ann. Otol. Rb_inol. Laryngol., 85:508-516, 1976. 5. Al-Sa]eem, T., Peals, A. R., and Norris, C. N.: Multiple papillomatosis of the lower respiratory tract. Cancer, 22:1173-1184, 1968. 6. Smith, L., and Gooding, C.: Pulmonary involvement In laryngeal papillomatosis. Pediatr. Radiol., 2:161-164, 1974. 7. Fechner, R. E., Goepfert, H., and Alford, B. R.: Invastve laryngeal papillomatosis. Arch. Otolaryngol., 99:147-151, 1974. 8. HoUnger, P. H., et el.: Studies of papilloma of the larynx. Ann. Otol. Rhinol. Laryngol., 74:443--447, 1962. 9. Zehnder, P. R., Jr., and Lyons, G. D.: Carcinoma and juvenile papil]omatosis. Ann. Otol. Rhinol. Laryngol., 84:614-618, 1975. 10. Shapiro, R. S., Marlowe, F. l., and Butcher, J.: Malignant degeneration of nonirradiatad juvenile laryngeal papillomatosis. Ann. Otol. Rhinol. Laryngol., 85:101-104, 1976. 11. Siegel, S. E., et el.: Malignant transformation of tracheobronchial juvenile papillomatosis without prior radiotherapy. Ann. Otol. Rhinol. Laryngol., 88:192-197, 1979. 12. Broyles, E. N.: Treatment of laryngeal papilloma in children. South. Mad. J., 34:239-242, 1941. 13. Holinger, P. H., Schild, ]. A., and Mauriz, D. G.: Laryngeal papilloma; review of etiology and therapy. Laryngoscope, 78:1462-1474, 1968. 14. Shilovtseva, A. S.: The complex treatment of patients affected with papillomatosis of the larynx and trachea. Vesta. Otorinola.rIngol., 29:74-79, 1967. 15. One, S., Saito, H., and Igarashi, M.: The etiology of papi]loma of the larynx. Ann. Otol. R.hinol. Laryngol., 66:1119-1142, 1957. 16. Uhlman, E. V.: On t_ha etiology of the laryngeal papilloma. Acta Otolaryngo]., 5;317-325, 1923. 17. Ishikawa, K.: Experimentalle studien fiber die transplantation des papilloma. Fukuoka Otol., 8:68-76, 1936. 18. Resler, D. R., and Snow, J. B.: Cell-free filtrate transplantation of human laryngeal papilloma to dogs. Laryngoscope, 77:397-416, 1967. 19. West, R. A., Boggs, J. D., and Holinger, P. H.: Studies in tissue growth of laryngeal papilloma. Acta Otolaryngal., 48:14-15, 3.957,
~2
20. Maassen, H., and Schulz, H.: E:ektronenmlkroskepiseher nachineis des virus in kehlkopfpapillam des mensehen. Klin. Wschr., 35:771-774, 1957. 21. Dmochowski, L., et al.: Study of subnfiaroscopic structure and of virus particles in cells of human laryngeal papillomas. Tex. Rep. Biol. Med., 22:454-401, 1984. 22. Boyle, W. F., Riggs, ]. L., and Oshno, L. S.: Electron microscopic identification of papova virus in laryngeal papilloma. Laryngoscope, 83:1102-1108, 1973. 23. Incze, J. S., et al.: The morphology of human papillomas of the upper respiratory tract. Cancer, 38 ..1634-1646, 1977.
24. Stephens, C. B., et al.: Autogenous vaccine treatment of j u v e n i l e laryngeal papillomatosis. Laryngoscope, 89:1689-1696, 1979. 25. Cook, T. A., st al.: Laryngeal papilloma: etiologic and therapeutic consideration. Ann. Otol. Rhinol. Laryngel., 62:649-655, 1973. 26. Svoboda, D. J., Kirchner, F. R., and Proud, G. O.: Electron microscopic study of human laryngeal papillomatosts. Can. Res., 23:1084-1089, 1963. 27. Oriel, J. D., and Almaida, J. D.: Demonstration of virus particles in human genital warts. Br. J. Vener. Dis., 46:37--42, 1970. 28. Barrora-Ora, J. G., Smith, K. O., and Melnick, f. L.: Quantitation of papovavirus particles in human warts. J. Natl. Cancer Inst., 29:583-593, 1962. 29. Butel, J. S.: Studies with human papilloma virus modeled after known papovavirus systems. J. Natl. Cancer Inst., 48:285-299, 1972. 29a. Bjork, H., and Weber, C.: Papilloma of the larynx. Acta Otolaryngol., 46:499-516, 1956. 29b. Majoras, M., Parknell, E. M., and DeVine, K. D.: Papi l l o m a of the l a r y n x in children. Am. J. Surg., 108:470-475, 1964. 29c. Hajek, E.: Contribution to the etiology of laryngeal papilloma in children. J. Laryngol., 70:166-168, 1956, 29d. Kaufman, R. S., and Balogh, K.: Verrueas and Juvenile laryngeal papillomas. Arch Otolaryngol., 89:748-749, 1969. 30. Quick, C. A., Faras, A., and Krzysek, R.: The etiology of laryngeal papillomatosis. Laryngoscope, 88:1789-1795, 1978. 31. Wile, U. J., and Kingery, L. B.: The etiology of common warts. ~. A. M. A., 73:970, 1919. 32. Pass, F., and Maizel, J. V., Jr.: Wart-associated antigens. II. Human immunity to viral structural proteins. 1. Invest. Dermatol., 60:307-311, 1973. 33. Spira, G., et el.: Papovavirus structural polypeptides: comparison of human and rabbit papilloma virus with simian virus 40. Intervirology, 3:220-231, 1974. 34. Almeida, J. D., Oriel, J. D., and Stannard, L. N.: Characterization of the virus found in human genital warts. Microbios, 1 ;225-232, 1989. 35. Oriel, ]. D.: Natural history of genital warts. Br. ].Vener. Dis., 47:1-13, 1971. 36. Conner, J.: Vermcae vulgaris. II. Demonstration of a comp l i m e n t fixation reaction. Acta Derm. Venereol. [Stockh.), 51:365-373, 1971, Department of Otolaryngology 5E Wayne State University School of Medicine 540 East Canfield Street
Detroit,Michigan 48201 (Dr.Cohn]
RECURRING L A R Y N G E A L PAPILLOMA
A prospective study of 31 children born of mothers with condylomata acuminata at parturition or during pregnancy was undertaken to test the hypothesis that la~ngeal papilloma could be associated with venereal warts and could be acquired perinatally. None of the children born of mothers with condylomas at delivery or during their pregnancies had developed symptoms, signs, or observable lesions of laryngeal papilloma, whether delivered vaginally or by cesarean section. Nevertheless we do not know the true incidence of this disease or the infectivity of the causative micro-organism. Although it appears that the correlation between laryngeal papilloma in children and the presence of condylomata acuminata in the mother during pregnancy or parturition is not as strong as our retrospective study had suggested, it should not be disregarded.
Recurring laryngeal papilloma is the most c o m m o n benign laryngeal n e o p l a s m in children. ~ The condition was first recognized as "warts in the throat" by Marsellus Donalus ~ in the seventeenth century. Morel MacKenzie s diff e r e n t i a t e d the l e s i o n f r o m o t h e r laryngeal masses and coined the name papilloma in 1871. Laryngeal papillomatosis continues to be a distressing problem to the physician and patient alike. The magnitude of the problem is reflected in the conflicting reports regarding the etiology of the lesion and effective treatment. Clinically laryngeal papillomatosis is thought of as a disease of infancy and childhood, but it is frequently found in adults. Hoarseness or an abnormal cry is the initial manifestation in the young infant; dyspnea, cough, stridor, and respiratory distress m a y subsequently develop. The symptoms and signs may occur singularly or in combination. In children the disorder tends to have a progressive course, papillomas often showing robust growth and rapid recurrence w h e n removed. In adults the recurrence rates
have been lower. Spontaneous remission is frequent, particularly approaching puberty, but remission remmns unpredictable. A recent study failed to identify puberty as an influence on the age of remission; indeed remission m a y not be maintained, since late recurrence occasionally can occur? Occurring most frequently in the larynx, multiple papillomas have also been encountered in the trachea, bronchi, and lung parenchyma with and without laryngeal disease# -7 Morphologically the lesion originates as an exophytic proliferation of squamous cell epithelium and stroma. The stroma consists of sparse connective tissue with few l y m p h o c y t e s and plasma cells. The overlying epithelium is a hyperplastic, well differentiated, stratified squamous cell epithelium of varying thickness. The epithelium is nonkeratinized, this feature distinguishing it from that of isolated keratinizing papilloma occasionally seen in adults. Some cellular atypia may be observed, 4' 8 but malignant degeneration is rare. 9-11 The etiology of this disorder remains elusive,
Accepted for publication February 5, 1981. *Professor, Department of Otolaryngology, Wayne State University School of Medicine,Detroit, Michigan. #Otolaryngologist, Lincoln, Nebraska. ~:Associate Professor,Department of Pediatrics and Infectious Diseases, Baylor College of Medicine. Staff, Ben-Taub Hospital, Jefferson-Davis Hospital, cmd Texas Children's Hospital, Houston, Texas. ~Associate Professor, Department of Virology and Epidemiology and Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, Texas. American Journal of Otolaryngology--Volume 2, Number 2, May 1981
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a l t h o u g h m a n y theories have been proposed. T h e greater i n c i d e n c e in males a n d the frequently observed spontaneous regression near p u b e r t y have s u g g e s t e d a hormonal factor in papillogenesis and a possible electrolytic abnormality. 12-14 Other associated factors that have b e e n evaluated include chronic irritation, race, geography, and socioeconomic status. 1~ By far the greatest interest has been focused on the possibility of a viral etiology and immunologic deficiency or a combination of the two. Stimulated b y MacKenzie's observation of the c o m m o n coexistence of laryngeal papilloma and skin warts, s U h l m a n 16 in 1923 transplanted a laryngeal papilloma to his arm and implanted the resulting papilloma into the vaginal m u c o s a of a dog. This a c c o m p l i s h m e n t was duplicated by Ishikawa ~7 in 1936, although others have failed. Resler and S n o w is w e r e able to transplant papilloma to dog vaginal m u c o s a and sMn using a cell free filtrate from laryngeal papillomas; however, transfer of the lesion to the larynx or oral m u c o s a was not successful. Laryngeal papillomas are thought to be prod u c e d b y tumorigenic viruses containing double s t r a n d e d DNA b e l o n g i n g to t h e p a p o v a v i r u s group, but attempts to grow the virus in tissue culture have failed. ~", 1, Identification of virus particles in laryngeal papillomas awaits conclusive agreement. A l t h o u g h virus-like particles have been identified in extracts of laryngeal papilloma in some studies, 2~ examination by others has not confirmed their presence. ~5' 24-2, The observation of skin warts in patients with laryngeal papillomas has b e e n reported, 2~ 2Ob and two reports of laryngeal papillomas occurring in infants w h o s e mothers h a d condylomata acuminata at the time of delivery stimulated our r e t r o s p e c t i v e s t u d y to t e s t t h e s e a s s o c i a tions 25, 29~. ~d The mothers of five of nine children with laryngeal papillomas had abundant c o n d y l o m a t a a c u m i n a t a at the time of delivery; in another two mothers genital warts were noted in the gestational history. 25 Of further interest was the observation that these children became s y m p t o m a t i c earlier than other children whose mothers had no history of genital warts: these i n f a n t s o f t e n d e v e l o p e d s y m p t o m s b y six m o n t h s of age. This suggested transmission of a virus to the child during parturition. Similar findings have since been reported by others 4, 24, 30 A prospective study was attempted to examine the link b e t w e e n these two disorders. The objective of this study was to test the hypothesis that laryngeal papillomas could be as-
sociated with venereal warts and acquired perinatally. 25 It w a s t h o u g h t t h a t i d e n t i f y i n g children born to mothers with venereal w a r t s and following them prospectively might m a k e possible an estimation of the risk of acquiring the disease.
METHODS AND CLINICAL MATERIAL The study population was derived from t h e obstetrical service of a large city hospital that a v e r a g e s 10,000 d e l i v e r i e s p e r year. O n e hundred seven w o m e n with condylomas during pregnancy were identified; 31 of these w o m e n were enrolled in our program. The diagnosis of condyloma was made clinically. Nineteen m o t h ers had condylomas at the time of delivery; 12 were free of venereal warts at the time of delivery. Seventeen of the 19 mothers with condylomas at the time of delivery gave birth vaginally; two mothers underwent cesarean section. The addresses of the children to be f o l l o w e d were kept by a nurse-epidemiologist. T w e n t y nine of the 31 infants were examined b e t w e e n six and eight months of age, and five infants were re-examined b e t w e e n 10 months and 12 months of age. A clinical history of s y m p t o m s of laryngeal disease was taken and direct lary n g o s c o p y was performed as part of the evaluation in the 29 children. Further serial surveillance was possible in 19 children, 17 of w h o m had undergone direct laryngoscopies and two of w h o m could not be examined directly. Three children were f o l l o w e d for an additional 12 months, one child for two years, and 15 children for three to six years after direct laryngoscopy. Twelve children w h o had undergone direct laryngoscopy were not available for subsequent follow-up. Surveillance in these 12 children c o n sisted of periodic queries regarding the nature of the cry, change in voice, hoarseness, respiratory difficulty, asthma, w h e e z i n g , and o t h e r symptoms of laryngeal disease, Clinic charts a n d reports of emergency room visits were examined to identify possible laryngeal disorders.
RESULTS
All the 29 infants examined b y direct laryngoscopy had a normal larynx. None showed evidence of laryngeal papillomas regardless of w h e t h e r the mother h a d c o n d y l o m a s d u r i n g pregnancy or at the time of delivery, or w h e t h e r
RECURRING LARYNGEAL PAPILLOMA
delivery was effected vaginally or by cesarean section. None of the Ig children capable of being followed for one to five years after direct laryngoscopy developed symptoms to suggest an existent or progressive laryngeal disorder. Four children developed isolated or transient minor symptoms. One patient whose mother had condylemas at delivery and w h o was delivered vaginally developed "choMng" at age 30 months. Examination was negative and neither voice change nor other sequelae followed. Another patient also delivered vaginally from a mother with condylomas at term experienced recurring upper respiratory tract infections and developed asthma; indirect laryngoscopy at age five years was negative for papilloma. A third patient delivered vaginally from a mother without condylemas at delivery developed an upper respiratory tract infection and wheezing at 30 months of age; she had moved away from the area, but follow-up by her family physician indicated recovery without sequelae. A fourth patient whose mother had condylomas at the time of vaginal delivery had what the mother c o n s i d e r e d a " f u n n y little voice," but by 36 months of age there was no abnormality in the voice quality, unusual upper respiratory tract infections, or respiratory distress. Neither direct nor indirect laryngoscopy could be performed, however.
DISCUSSION Laryngeal papillomas are epithelial hyperplastic tumors that tend to resist therapy, often recur after removal, and tend to involve and to be t r a n s p l a n t e d to adjoining structures. Although the etiology of these lesions has not been established conclusively, the prevailing view is that papillomas are caused by a member of the papovavirus group. Although common h u m a n skin warts were presumed to be infectious throughout the nineteenth century, the viral etiology of common skin warts was established in 1919 by Wile and Kingery) ~ The human wart virus is a member of the papovavirus A group. It was initially believed that all human papillomas were the result of a common etiologic agent, but significant differences in the epidemiology, clinical features, ultrastructure, and serologic tests suggest that at least two different types of papovavirus are responsible for verrucae vulgaris and condyloma acuminata.2S. 32-a6 Laryngeal papillomas may re-
ARNOLD M. COHN ET AL.
suit from either of these agents or another related agent. The clinical behavior of recurring laryngeal papillomas, their remissions and recurrences, is compatible with that of a viral disease, Our previous study suggested that laryngeal papilloma may be caused by the agent responsible for venereal warts and may be acquired perinata]ly7 ~ Among nine children with laryngeal papillomas, all became symptomatic by two years of age, and five of the nine were symptomatic before one year of age. The mothers of all five patients who were symptomatic by age one year recalled having had genital warts at the time of delivery. Of the remaining four mothers, two recalled having condylomas during their pregnancy but not at the time of delivery. Thus, seven of these nine children with laryngeal papillomas were born to mothers with genital warts. This concept has been reinforced in other reports. Stephens and her colleagues ~4report three of 17 patients with this association. Strong and his coworkers 4 report that 50 per cent of 30 patients younger than the age of five were born of mothers who had condylomas at the time of delivery; and Quick et a12~ reported that 60 per cent of their patients had a history of maternal condylomas during pregnancy or at parturition. Strong et el. 4 suggest a variable if not low infectivity of the disease and do not know of secondary cases of the disorder among older siblings of the patients or subsequent children of mothers of patients with the disease. We also have not found laryngeal papillomas in older siblings of patients with the disease or in children of subsequent pregnancies of mothers of our patients with laryngeal papillomas. ]n the present study none of the children born of mothers with condylomas at delivery or during pregnancies have developed signs, symptoms, or observable lesions of laryngeal papillomas, w h e t h e r delivered vaginally or b y cesarean section, although only 23 of these children could be followed beyond one year of age. Nevertheless we do not know the true incidence of this disease or the infectivity of the responsible micro-organism. Although all previous studies have suggested an early age of onset of the disease in children horn of mothers with venereal warts at delivery, the age of onset or presentation of this disorder extends well into childhood and the disorder occurs in adults. Although it appears that the correlation between laryngeal papillomas in children and the presence of condyloma acuminata in the mother dur-
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ing pregnancy or parturition is not as strong as our retrospective s t u d y suggests, it should not be disregarded.
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20. Maassen, H., and Schulz, H.: E:ektronenmlkroskepiseher nachineis des virus in kehlkopfpapillam des mensehen. Klin. Wschr., 35:771-774, 1957. 21. Dmochowski, L., et al.: Study of subnfiaroscopic structure and of virus particles in cells of human laryngeal papillomas. Tex. Rep. Biol. Med., 22:454-401, 1984. 22. Boyle, W. F., Riggs, ]. L., and Oshno, L. S.: Electron microscopic identification of papova virus in laryngeal papilloma. Laryngoscope, 83:1102-1108, 1973. 23. Incze, J. S., et al.: The morphology of human papillomas of the upper respiratory tract. Cancer, 38 ..1634-1646, 1977.
24. Stephens, C. B., et al.: Autogenous vaccine treatment of j u v e n i l e laryngeal papillomatosis. Laryngoscope, 89:1689-1696, 1979. 25. Cook, T. A., st al.: Laryngeal papilloma: etiologic and therapeutic consideration. Ann. Otol. Rhinol. Laryngel., 62:649-655, 1973. 26. Svoboda, D. J., Kirchner, F. R., and Proud, G. O.: Electron microscopic study of human laryngeal papillomatosts. Can. Res., 23:1084-1089, 1963. 27. Oriel, J. D., and Almaida, J. D.: Demonstration of virus particles in human genital warts. Br. J. Vener. Dis., 46:37--42, 1970. 28. Barrora-Ora, J. G., Smith, K. O., and Melnick, f. L.: Quantitation of papovavirus particles in human warts. J. Natl. Cancer Inst., 29:583-593, 1962. 29. Butel, J. S.: Studies with human papilloma virus modeled after known papovavirus systems. J. Natl. Cancer Inst., 48:285-299, 1972. 29a. Bjork, H., and Weber, C.: Papilloma of the larynx. Acta Otolaryngol., 46:499-516, 1956. 29b. Majoras, M., Parknell, E. M., and DeVine, K. D.: Papi l l o m a of the l a r y n x in children. Am. J. Surg., 108:470-475, 1964. 29c. Hajek, E.: Contribution to the etiology of laryngeal papilloma in children. J. Laryngol., 70:166-168, 1956, 29d. Kaufman, R. S., and Balogh, K.: Verrueas and Juvenile laryngeal papillomas. Arch Otolaryngol., 89:748-749, 1969. 30. Quick, C. A., Faras, A., and Krzysek, R.: The etiology of laryngeal papillomatosis. Laryngoscope, 88:1789-1795, 1978. 31. Wile, U. J., and Kingery, L. B.: The etiology of common warts. ~. A. M. A., 73:970, 1919. 32. Pass, F., and Maizel, J. V., Jr.: Wart-associated antigens. II. Human immunity to viral structural proteins. 1. Invest. Dermatol., 60:307-311, 1973. 33. Spira, G., et el.: Papovavirus structural polypeptides: comparison of human and rabbit papilloma virus with simian virus 40. Intervirology, 3:220-231, 1974. 34. Almeida, J. D., Oriel, J. D., and Stannard, L. N.: Characterization of the virus found in human genital warts. Microbios, 1 ;225-232, 1989. 35. Oriel, ]. D.: Natural history of genital warts. Br. ].Vener. Dis., 47:1-13, 1971. 36. Conner, J.: Vermcae vulgaris. II. Demonstration of a comp l i m e n t fixation reaction. Acta Derm. Venereol. [Stockh.), 51:365-373, 1971, Department of Otolaryngology 5E Wayne State University School of Medicine 540 East Canfield Street
Detroit,Michigan 48201 (Dr.Cohn]
RECURRING L A R Y N G E A L PAPILLOMA