Acta Oto-Laryngologica
ISSN: 0001-6489 (Print) 1651-2251 (Online) Journal homepage: http://www.tandfonline.com/loi/ioto20
Amyloidosis of the Larynx Henrik Hellquist, Jan Olofsson, Hannibal Sökjer & Lars M Ödkvist To cite this article: Henrik Hellquist, Jan Olofsson, Hannibal Sökjer & Lars M Ödkvist (1979) Amyloidosis of the Larynx, Acta Oto-Laryngologica, 88:1-6, 443-450, DOI: 10.3109/00016487909137191 To link to this article: http://dx.doi.org/10.3109/00016487909137191
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Acta Otolaryngol88: 443-450, 1979 AMYLOIDOSIS OF THE LARYNX Henrik Hellquist, Jan Olofsson, Hannibal Sokjer and Lars M. Odkvist From the Departments of Pathology I , Otolaryngology and Diagnostic Radiology, Linkoping University Hospital, Sweden
Downloaded by [Australian National University] at 02:08 07 May 2016
(Received November 13, 1978)
Abstract. Amyloidosis of the larynx is a rare disease, accounting for less than 1 % of all benign laryngeal ‘tumours’. Three cases of this type of lesion are reported - o n e of the vocal cord, one of the false vocal cord and one of the subglottis and trachea. In 2 of the patients the amyloidosis was localized, while the third was later found also to have an epipharyngeal solitary plasmacytoma with amyloid deposits and in addition amyloidosis of the nasal cavity. However, the amyloidosis in this patient may still be regarded as being localized, as the clinical examination and laboratory tests afforded no evidence of generalized disease. Amyloidosis of the larynx may be manifested as a localized tumour or as a diffuse infiltration. The symptoms and signs will, of course, depend on the site of the amyloid deposit. When the vocal cords are involved hoarseness may result, and this was the most prominent sign in the present cases. The treatment of laryngeal amyloidosis is primarily by endoscopic excision. Amyloid substance has specific staining properties. The Congo red reaction with a green birefringence in polarized light and Phorwhite BBU using fluorescence microscopy are regarded as the most reliable staining reactions. Electron microscopy has revealed a typical fibrillar structure of amyloid.
The pathogenesis of amyloidosis is unknown, the condition is characterized by extracellular deposits of a proteinaceous substance (Glenner & Page, 1976). Amyloidosis was first described by Rokitansky in 1842 and the term ‘amyloidosis’ was coined by Virchow in 1851. The first report of a patient with laryngeal amyloidosis was published by Burow & Neumann in 1875, since when several cases have been described. In a review article McAlpine & Fuller (1964) collected 177 cases. Another 17 have been reported from the Mayo Clinic (Ryan et al., 1977). There are also many case reports (Stark & New, 1949; Juselius & Nyberg, 1960; Vieta & Guraieb, 1964; Heiner, 29 - 79295 I
1968; Eliachar & Lichtig, 1970; Beasley, 1971; Crifo, 1973; Barnes & Zafar, 1977). To elucidate the pathogenesis and clinical behaviour of amyloidosis extensive studies have been carried out with the aid of, for example, electron microscopy and immunochemical techniques (Cohen, 1967; Eliachar & Lichtig, 1970; Franklin & Zucker-Franklin, 1972; Glenner et al., 1972; Glenner & Terry, 1974; Glenner & Page, 1976; Kaiser-Kupfer et al., 1977). Amyloidosis can be either generalized-and then primary or secondary-or localized. The nature of amyloidosis is still an enigma, however. Amyloidosis accounts for less than 1 % of all benign laryngeal ‘tumours’. It occurs slightly &re often in males, and usually between the ages of 40 and 60 (Stark & New, 1949; McAlpine & Fuller, 1964). According to some reports the sites are, in descending order of frequency, the false vocal cords, aryepiglottic folds, and the subglottic region (Leroux-Robert, 1962; D’Arcy, 1972), but the report from the Mayo Clinic (Ryan et al., 1977) gives the vocal cords as the most common location. During the last 10 years 3 cases of laryngeal amyloidosis have been encountered in this hospital.
CASE REPORTS Case 1 (Fig. 1 A, B) History and clinical Jindings. The patient, a woman now 77 years of age, sought medical attention in 1966 for hoarseness, from which Acfli Oto/Lit?figo/ NN
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Fig. / (Case 1). (A) Conventional plain film, lateral view. Subglottic swelling with extension down into the upper trachea (arrows). (B) Microlaryngoscopy. A diffuse subglottic swelling with intact overlying mucosa.
she had been suffering for the past year. Laryngoscopic examination revealed a subglottic swelling, especially posteriorly. HisActrr Otolnrvigol NN
tological examination of biopsy specimens yielded a diagnosis of amyloidosis. A bloodcell count, a bone marrow examination, and liver and renal function tests disclosed no pathological features. ESR was 38 mm. Serum protein electrophoresis showed a slightly elevated gammaglobulin level. Chest radiographs and ECG registrations were unremarkable. Tongue and rectal biopsies disclosed no amyloid deposits. The patient was readmitted in 1967 because of slowly increasing inspiratory difficulty and excisions were performed. Ten years later there was again increasing inspiratory stridor. Radiological examination of the larynx and trachea showed marked soft tissue swelling of the subglottis and the upper 3 cm of the trachea (Fig. 1A). The airway was restored by excisions thr,ough laryngoand bronchoscopes (Fig. 1B). New laboratory tests, including a fine-needle biopsy of the abdominal fat showed no evidence of generalized amyloidosis. Pathological $findings. The histological examination of the excised tissue disclosed a loose connective tissue covered with ordinary,
Amyloidosis of the larynx
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pseudo-stratified columnar epithelium. Within the connective tissue there were diffuse deposits of an amorphous substance staining positively with Congo red: In polarized light a typical green birefringence was seen. Comment. In view of the fact that tongue and rectal biopsies, fine-needle biopsy of the abdominal fat and other laboratory examinations disclosed no abnormality and no evidence of generalized disease, the amyloidosis was classed as localized. Case 2 (Fig. 2A, B) History and clinical findings. In 1973, the patient, a woman of 46, had pansinusitis, and had been suffering from increasing hoarseness for about 2 months. Mirror laryngoscopy revealed a swelling of the right false vocal cord. Radiological examination showed a smooth bulging of this cord, and obliteration of the right ventricle (Fig. 2 A). Histological examination of biopsy specimens yielded a diagnosis of amyloidosis, and further endoscopic excisions were performed using the operating microscope. Microlaryngoscopy (Fig. 2B) in 1974 and 1977 showed that the ‘amyloid tumour’ extended down into the vocal cord muscle. The ESR, a blood-cell count, serum protein electrophoresis, liver and renal function tests and other laboratory examinations disclosed no abnormality. Rectal biopsy (1973) and a fineneedle biopsy of the abdominal fat (1978) were both negative. Pathological findings. Histological examination showed a stromal tissue fairly rich in seromucinous glands and mononuclear leukocytes. Its surface was covered with a stratified squamous non-keratinized epithelium. Dispersed throughout the tissue was an amorphous substance staining with Congo red. The vessel walls and the basement membranes of the seromucinous glands were partly involved. Comment. As the laboratory examinations, including the rectal and abdominal fat biopsies, showed normal conditions, with no sign
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of generalized disease, the amyloidosis must be regarded as being localized. Case 3 (Fig. 3 A-C) History and clinical findings. The patient is a now 61-year-old man with a history of heavy cigarette smoking and abuse of alcohol. From 1966 to 1968 he noticed increasing hoarseness. Laryngoscopy (1968) showed a polypous swelling of the right vocal cord. Histological examination of the excised tissue disclosed amyloidosis. The ESR, a blood-cell count and a bone-marrow examination, serum protein electrophoresis, liver and renal function tests, urography, ECG, chest radiography and other laboratory tests revealed no evidence of pathological conditions. Cholecystography showed a solitary gall stone. Radiography visualized an opaque maxillary sinus. A LucCaldwell operation disclosed a bilocular cyst. Skin, tongue and rectal biopsies were normal. In 1969 a tumour of the upper surface of the soft palate was diagnosed. At histological examination a plasmacytoma with amyloid deposits was identified. Following radiotherapy (60 Gy) the tumour disappeared and there has been no sign of recurrence. In 1969 and 1971 repeated radiological examinations of the skull, thorax, chest and pelvis showed no signs of myelomatosis. In 1972 there were increasing laryngeal symptoms, and the radiological examination and the microlaryngoscopy now showed a right glottic and subglottic tumour (Fig. 3A, B) and more of the amyloid tissue was excised. In 1978 a polypous, easily bleeding swelling of the right nasal cavity was noted and a histological diagnosis of amyloidosis was made. A fine-needle biopsy of abdominal fat did not show any evidence of a generalized disease. Pathological findings. The initial laryngeal polypous lesion was covered with ordinary squamous epithelium. The submucous connective tissue was diffusely infiltrated with an amorphous substance surrounded by leukocytes. It stained with Congo red, and showed Acrci O l o l c i r ~ ~ iXX ~ol
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Fig. 2 (Case 2). (A) Tomogram, a-p view. Bulging of the right false vocal cord and aryepiglottic fold with obliteration of the right ventricle (arrows).(B) Microlaryngoscopy. Smooth swelling of the right false vocal cord with intact overlying mucosa.
filtrated with atypical plasma cells. An amorphous substance staining positively with Congo red was also present. The nasal polyp showed marked oedema, with amyloid deposits. Comment. As the rectal, tongue, skin and abdominal fat biopsies were negative and the other laboratory tests disclosed no generalized disease, the amyloidosis was considered to be primary, being localized to the upper respiratory tract. It might be objected that there was also a solitary plasmacytoma, but there was no myelomatosis.
DISCUSSION
a typical green birefringence when viewed in polarizing light but did not stain with PTAH. For the material examined later the histological findings were similar (Fig. 3 C). The biopsy of the nasopharyngeal tumour was covered with columnar epithelium. The richly vascularized stroma was profusely inA[ ~ C O I t o l ~ i r v ~88 ~~ol
After more than a century’s investigation the nature of the unique proteinaceous amyloid substance remains obscure. Electron micrographs show all amyloid to have the same basic, fibrillar structure, with rigid and unbranched fibrils measuring 50-150 A in diameter (Kyle & Bayrd, 1975; Glenner & Page, 1976). The length of the fibrils has been estimated at about 8000 A (Kyle & Bayrd, 1975). Chemical analysis has distinguished three chemical types of amyloid, one of immuno-
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Amyloidosis of the larynx
Fig. 3 (Case 3). (A) Laryngogram, p a view. Tumour of the right vocal cord with subglottic extension. (B) Microlaryngoscopy. Swelling of the right vocal cord with intact overlying mucosa. (C) Photomicrograph. Infiltration of an amorphous substance (amyloid), staining positively with Congo red, in the submucosa . with intact overlying epithelium ( ~ 3 7 0 ) Inset: Brilliant green birefringence in polarized light ( x 700).
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globulin origin, one of unknown origin and the third apudamyloid (Pearse et al., 1972; Glenner & Page, 1976; Barnes & Zafar, 1977). The amyloid fibrils associated with generalized primary amyloidosis and some forms of localized amyloidosis, and those associated with plasma-cell dyscrasia are derived primarily from the aminoterminal (variable) region of a light chain of a homogeneous immunoglobulin (Glenner & Terry, 1974; Glenner & Page, 1976). The amyloid of unknown origin has fibrils not deriving from immunoglobulin; this type of amyloid is also found in secondary amyloidosis and the familial Mediterranean fever. The third type, apudamyloid, is associated with endocrine polypeptide tumours (Pearse et al., 1972). Congo red, the most commonly used staining reaction for amyloid, gives a bright red colour. In polarizing light an apple-green birefringence is obtained. These tinctorial and polarization properties are due to the presence of P-pleated sheet fibrils (Glenner et al., 1972). The presence of these fibrils is revealed by low-angle X-ray diffraction, which is the third principal method (after light and electron microscopy) for identifying the amyloid substance (Kyle & Bayrd, 1975). The Congo red reaction is sensitive, and false positives and negatives are rare. Evidently still more sensitive, however, is Phorwhite BBU, with even fewer false staining reactions (Waldrop et al., 1973; Glenner & Page, 1976). Crystal violet gives a positive metachromatic reaction. A new potassium permanganate technique for distinguishing between the chemical types of amyloid has been introduced by Wright et al. (1977). The majority of the numerous clinicopathological classifications of amyloidosis are modifications of that published by Symmers in 1956: (1) generalized secondary amyloidosis (amyloidosis associated with an identifiable predisposing disease), (2) generalized primary amyloidosis (no identifiable predisposing disease), and (3) localized amyloidosis. The larynx is rarely involved in generalized sec-
ondary amyloidosis and infrequently in generalized primary amyloidosis. The larynx is, however, the usual site for amyloidosis of the respiratory tract. Amyloidosis within the larynx occurs in two forms: one of them tumour-like and the other displaying diffuse infiltration. The manifestations of the disease will, of course, depend on the site of the amyloid deposit; involvement of the vocal cords will result in hoarseness; subglottic involvement often leads to increasing inspiratory difficulty; and in the case of supraglottic deposits the symptoms prompting the patient to seek medical attention may be more diffuse. The diagnosis is obtained on the basis of laryngoscopic and biopsy findings. Further information on the extent of the lesion may be provided by a radiological examination. Four patterns of extracellular deposit of amyloid in the larynx may be distinguished: ( 1 ) amorphous random masses, (2) in vessel walls, (3) in basement membranes of the seromucinous glands, and (4) as hyaline ‘rings’ in adipose tissue (Barnes & Zafar, 1977). The ‘amyloid tumour’ is, of course, not an actual neoplasm, but rather a localized tumour-like swelling produced by the presence of the amyloid deposit in the submucosal tissue. Two cases (cases 1 and 2) are both examples of localized amyloidosis. The third case (case 3) is questionable, but is probably also to be regarded as localized amyloidosis of the respiratory tract, since fairly exhaustive investigation established no evidence of generalized disease, notwithstanding the presence of a solitary nasopharyngeal plasmacytoma. In a patient with amyloidosis it is necessary to eliminate the possibility of a generalized disease. Among the laboratory tests and other methods that should be used to this end are the ESR, blood-cell count, bone marrow examination, serum protein electrophoresis, liver and renal function tests, and chest radiography. The presence of ECG-anomalies may indicate cardiac amyloid deposits. Biopsy specimens should be taken from either the oral or, preferably, the rectal mucosa (Gafni &
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Amyloidosis of the larynx
Sohar, 1960; Crifo, 1973). A fine-needle technique for procuring specimens of abdominal fat has been introduced by Westermark & Stenkvist (1973). In our 3 cases none of these methods disclosed any significant pathological feature. The following differential diagnoses have to be ruled out: hyalinized myxomatous polyps, benign and malignant tumours with intact overlying mucosa, retention cysts of the false vocal cords, and laryngocele. Histologically, the elimination of the hyalinization of a vocal cord polyp is the most important differential diagnosis, and the possible presence of this condition was considered in Case 3. Two staining methods for amyloid have been recommended besides fibrin staining (PTAH). Plasmacytoma containing amyloid deposits is another condition to be considered (Ryan et al., 1977). The treatment for laryngeal amyloidosis is surgery, consisting in endoscopic excision with the aid of the operating microscope. Localized tumour-like lesions may be removed entirely. In the case of a diffuse submucosal lesion repeated excisions are often necessary to restore the airway and to conserve the voice. For a lesion at the level of the cricoid ring the excision should be performed cautiously and perhaps staged in order to avoid the risk of subglottic stenosis. If the amyloid is extensive an approach through a laryngofissure may be indicated. In amyloidosis of immunoglobulin origin the use of immunosuppressive or cytostatic agents has been suggested (Jones et al., 1972). Melphalan has been tried successfully in some cases, but Kyle & Bayrd (1975) have pointed out the risk of acute leukemia associated with the use of this agent. The cases presented illustrate the diagnostic difficulties in laryngeal amyloidosis. The conservative surgical treatment is stressed. ZUSAMMENFASSUNG Die Larynxamyloidose ist eine seltene Krankheit und macht weniger als 1 % alle gutartigen ,,Geschwulste" des
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Larynx aus. Drei Falle dieser Art der Lasion wird berichtet - einer des Stimmbandes, einer des Tachenbandes und einer des subglottischen Raumes und der Trachea. In zwei der Patienten war die Amyloidose ortlich isoliert, wahrend es bei dem dritten spater auch ein extramedullares Plasmazytom des Nasenrachens mit Amyloidablagerung und ausserdem Amyloidose der Nasenhohle gefunden wurde. Die Amyloidose dieses Patients darf doch als isoliert betrachtet werden, weil sowohl die klinische Untersuchung als die Laboratoriumbefunde keine Beweise einer generalisierten Krankheit gaben. Die Larynxamyloidose kann sich als einen umschriebenen Tumor oder als diffuse Infiltrate aussern. Die Symptome und die Funde werden naturlich von der Lage der Amyloidablagerung abhangig sein. Heiserkeit kann vorhanden sein wenn die Stimmbander betroffen sind und dies was das auffalligste Symptom der vorliegenden Falle. Die Behandlung der Larynxamyloidose ist zuerst eine endoskopische Excision. Das Amyloid zeigt spezifische Eigenschaften der histologischen Farbung. Die Kongorotprobe mit einer griinen Doppelbrechung im polarisierten Licht und Phorwhite BBU bei Verwenden der Fluoreszenzmikroskopie werden als die zuverlassigsten Farbereaktionen angesehen. Die Elektronmikroskopie hat eine typische fibrillare Struktur des Amyloids aufgedeckt.
REFERENCES Barnes, E. L. Jr & Zafar, T. 1977. Laryngeal amyloidosis. Clinicopathologic study of seven cases. Ann Otol86, 856. Beasley, P. 1971. Localized amyloidosis of the larynx. J Laryngol85, 83. Burow, A. & Neumann, L. 1875. Amyloide Degeneration von Laryxtumoren, Canule sieben Jahre lang getragen. Arch Klin Chir 18, 242. Cohen, A. S. 1967. Amyloidosis. New Engl J Med 277, 522. Crifo, S . 1973. Laryngeal idiopathic amyloidosis. ORL 35, 117. DArcy, F. 1972. Localized amyloidosis of the larynx. J Laryngol86, 929. Eliachar, I. & Lichtig, C. 1970. Local amyloid deposits of the larynx. Electron microscopic studies of three cases. Arch Otolaryngol92, 163. Franklin, E. C. & Zucker-Franklin, D. 1972. Current concepts of amyloid. Adv Immunol15, 249. Gafni, J. & Sohar, E. 1960. Rectal biopsy for the diagnosis of amyloidosis. Am J Med Sci 240, 332. Glenner, G . G . , Eanes, E. D. & Page, D. L. 1972. The relation of the properties of Congo red-stained amyloid fibrils to the p-conformation. J Histochem Cyrochem 20, 821. Glenner, G . G . & Page, D. L. 1976. Amyloid, amyloidosis and amyloidogenesis. Intern Rev Exp Pathol15, 1 . Glenner, G . G. & Terry, W. D. 1974. Characterization of amyloid. Annual Rev Med 25, 131. Heiner, E. R. 1968. Primary amyloidosis of the larynx. Arch Otolaryngol87, 413. Acrcr Otolarvnpol 88
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Jones, N. F., Hilton, P. J., Tighe, J. R. & Hobbs, J. R. 1972. Treatment of “primary” renal amyloidosis with melphalan. Lancet ii, 616. Juselius, H. & Nyberg, W. 1960. Primary amyloidosis of the larynx. Actu Otolaryngol (Stockh)52, 79. Kaiser-Kupfer, M. I., McAdam, K . P. W. J. & Kuwabara, T. 1977. Localized amyloidosis of the orbit and upper respiratory tract. Am J Ophthalmol84, 721. Kyle, R. A. & Bayrd, E. D. 1975. Amyloidosis: Review of 236 cases. Medicine 54, 271. Leroux-Robert, J. 1962. “Tumeurs amyloides” du larynx. Ann Otolaryngol (Paris) 79, 249. McAlpine, J. C. & Fuller, A. P. 1964. Localized laryngeal amyloidosis, a report of a case with a review of the literature. J Laryngol78, 296. Pearse, A. G. E., Ewen, S. W. B. & Polak, J. M. 1972. The genesis of apudamyloid in endocrine polypeptide tumours: Histochemical distinction from immunamyloid. Virchows Arch (Zellpathol) 10, 93. Rokitansky, K. F. V. 1842. In Handbuch der Pathologischen Anatomie, Vol. 3. Braunmuller & Siedel, Vienna (cited by Glenner & Page, 1976). Ryan, R. E., Pearson, B. W. & Weiland, L. H. 1977. Laryngeal amyloidosis. Trans Am Acad Ophthalmol Otolaryngol84, 872. Stark, D. B. & New, G. B. 1949. Amyloid tumors of the
larynx, trachea or bronchi. A report of 15 cases. Ann Otol58, 117. Symmers, W. St. C. 1956. Primary amyloidosis: A review. J CIin Pathol9, 187. Vieta, L. J. & Guraieb, S. R. 1964. Laryngeal involvement in amyloidosis. Arch Otolaryngol 79, 490. Virchow, R. 1851. Bau und Zusammensetzung der Corpora amylacea des Menschen. Verh Phys Med Ges Wurzburg 2, 51 (cited by Glenner & Page, 1976). Waldrop, F. S . , Puchtler, H. & Valentine, L. S. 1973. Fluorescence microscopy of amyloid. Using mixed illumination. Arch Pathol95, 37. Westermark, P. & Stenkvist, B. 1973. A new method for the diagnosis of systemic amyloidosis. Arch Intern Med 132, 522. Wright, J. R., Calkins, E. & Humphrey, R. L. 1977. Potassium permanganate reaction in amyloidosis. Histologic method to assist in differentiating forms of this disease. Lab Invest 36, 274.
Jan Olofsson, M.D. Department of Otolaryngology Linkoping University Hospital S-58185 Linkoping Sweden
ISSN: 0001-6489 (Print) 1651-2251 (Online) Journal homepage: http://www.tandfonline.com/loi/ioto20
Amyloidosis of the Larynx Henrik Hellquist, Jan Olofsson, Hannibal Sökjer & Lars M Ödkvist To cite this article: Henrik Hellquist, Jan Olofsson, Hannibal Sökjer & Lars M Ödkvist (1979) Amyloidosis of the Larynx, Acta Oto-Laryngologica, 88:1-6, 443-450, DOI: 10.3109/00016487909137191 To link to this article: http://dx.doi.org/10.3109/00016487909137191
Published online: 08 Jul 2009.
Submit your article to this journal
Article views: 4
View related articles
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=ioto20 Download by: [Australian National University]
Date: 07 May 2016, At: 02:08
Acta Otolaryngol88: 443-450, 1979 AMYLOIDOSIS OF THE LARYNX Henrik Hellquist, Jan Olofsson, Hannibal Sokjer and Lars M. Odkvist From the Departments of Pathology I , Otolaryngology and Diagnostic Radiology, Linkoping University Hospital, Sweden
Downloaded by [Australian National University] at 02:08 07 May 2016
(Received November 13, 1978)
Abstract. Amyloidosis of the larynx is a rare disease, accounting for less than 1 % of all benign laryngeal ‘tumours’. Three cases of this type of lesion are reported - o n e of the vocal cord, one of the false vocal cord and one of the subglottis and trachea. In 2 of the patients the amyloidosis was localized, while the third was later found also to have an epipharyngeal solitary plasmacytoma with amyloid deposits and in addition amyloidosis of the nasal cavity. However, the amyloidosis in this patient may still be regarded as being localized, as the clinical examination and laboratory tests afforded no evidence of generalized disease. Amyloidosis of the larynx may be manifested as a localized tumour or as a diffuse infiltration. The symptoms and signs will, of course, depend on the site of the amyloid deposit. When the vocal cords are involved hoarseness may result, and this was the most prominent sign in the present cases. The treatment of laryngeal amyloidosis is primarily by endoscopic excision. Amyloid substance has specific staining properties. The Congo red reaction with a green birefringence in polarized light and Phorwhite BBU using fluorescence microscopy are regarded as the most reliable staining reactions. Electron microscopy has revealed a typical fibrillar structure of amyloid.
The pathogenesis of amyloidosis is unknown, the condition is characterized by extracellular deposits of a proteinaceous substance (Glenner & Page, 1976). Amyloidosis was first described by Rokitansky in 1842 and the term ‘amyloidosis’ was coined by Virchow in 1851. The first report of a patient with laryngeal amyloidosis was published by Burow & Neumann in 1875, since when several cases have been described. In a review article McAlpine & Fuller (1964) collected 177 cases. Another 17 have been reported from the Mayo Clinic (Ryan et al., 1977). There are also many case reports (Stark & New, 1949; Juselius & Nyberg, 1960; Vieta & Guraieb, 1964; Heiner, 29 - 79295 I
1968; Eliachar & Lichtig, 1970; Beasley, 1971; Crifo, 1973; Barnes & Zafar, 1977). To elucidate the pathogenesis and clinical behaviour of amyloidosis extensive studies have been carried out with the aid of, for example, electron microscopy and immunochemical techniques (Cohen, 1967; Eliachar & Lichtig, 1970; Franklin & Zucker-Franklin, 1972; Glenner et al., 1972; Glenner & Terry, 1974; Glenner & Page, 1976; Kaiser-Kupfer et al., 1977). Amyloidosis can be either generalized-and then primary or secondary-or localized. The nature of amyloidosis is still an enigma, however. Amyloidosis accounts for less than 1 % of all benign laryngeal ‘tumours’. It occurs slightly &re often in males, and usually between the ages of 40 and 60 (Stark & New, 1949; McAlpine & Fuller, 1964). According to some reports the sites are, in descending order of frequency, the false vocal cords, aryepiglottic folds, and the subglottic region (Leroux-Robert, 1962; D’Arcy, 1972), but the report from the Mayo Clinic (Ryan et al., 1977) gives the vocal cords as the most common location. During the last 10 years 3 cases of laryngeal amyloidosis have been encountered in this hospital.
CASE REPORTS Case 1 (Fig. 1 A, B) History and clinical Jindings. The patient, a woman now 77 years of age, sought medical attention in 1966 for hoarseness, from which Acfli Oto/Lit?figo/ NN
H . Hellquist et al.
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Fig. / (Case 1). (A) Conventional plain film, lateral view. Subglottic swelling with extension down into the upper trachea (arrows). (B) Microlaryngoscopy. A diffuse subglottic swelling with intact overlying mucosa.
she had been suffering for the past year. Laryngoscopic examination revealed a subglottic swelling, especially posteriorly. HisActrr Otolnrvigol NN
tological examination of biopsy specimens yielded a diagnosis of amyloidosis. A bloodcell count, a bone marrow examination, and liver and renal function tests disclosed no pathological features. ESR was 38 mm. Serum protein electrophoresis showed a slightly elevated gammaglobulin level. Chest radiographs and ECG registrations were unremarkable. Tongue and rectal biopsies disclosed no amyloid deposits. The patient was readmitted in 1967 because of slowly increasing inspiratory difficulty and excisions were performed. Ten years later there was again increasing inspiratory stridor. Radiological examination of the larynx and trachea showed marked soft tissue swelling of the subglottis and the upper 3 cm of the trachea (Fig. 1A). The airway was restored by excisions thr,ough laryngoand bronchoscopes (Fig. 1B). New laboratory tests, including a fine-needle biopsy of the abdominal fat showed no evidence of generalized amyloidosis. Pathological $findings. The histological examination of the excised tissue disclosed a loose connective tissue covered with ordinary,
Amyloidosis of the larynx
Downloaded by [Australian National University] at 02:08 07 May 2016
pseudo-stratified columnar epithelium. Within the connective tissue there were diffuse deposits of an amorphous substance staining positively with Congo red: In polarized light a typical green birefringence was seen. Comment. In view of the fact that tongue and rectal biopsies, fine-needle biopsy of the abdominal fat and other laboratory examinations disclosed no abnormality and no evidence of generalized disease, the amyloidosis was classed as localized. Case 2 (Fig. 2A, B) History and clinical findings. In 1973, the patient, a woman of 46, had pansinusitis, and had been suffering from increasing hoarseness for about 2 months. Mirror laryngoscopy revealed a swelling of the right false vocal cord. Radiological examination showed a smooth bulging of this cord, and obliteration of the right ventricle (Fig. 2 A). Histological examination of biopsy specimens yielded a diagnosis of amyloidosis, and further endoscopic excisions were performed using the operating microscope. Microlaryngoscopy (Fig. 2B) in 1974 and 1977 showed that the ‘amyloid tumour’ extended down into the vocal cord muscle. The ESR, a blood-cell count, serum protein electrophoresis, liver and renal function tests and other laboratory examinations disclosed no abnormality. Rectal biopsy (1973) and a fineneedle biopsy of the abdominal fat (1978) were both negative. Pathological findings. Histological examination showed a stromal tissue fairly rich in seromucinous glands and mononuclear leukocytes. Its surface was covered with a stratified squamous non-keratinized epithelium. Dispersed throughout the tissue was an amorphous substance staining with Congo red. The vessel walls and the basement membranes of the seromucinous glands were partly involved. Comment. As the laboratory examinations, including the rectal and abdominal fat biopsies, showed normal conditions, with no sign
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of generalized disease, the amyloidosis must be regarded as being localized. Case 3 (Fig. 3 A-C) History and clinical findings. The patient is a now 61-year-old man with a history of heavy cigarette smoking and abuse of alcohol. From 1966 to 1968 he noticed increasing hoarseness. Laryngoscopy (1968) showed a polypous swelling of the right vocal cord. Histological examination of the excised tissue disclosed amyloidosis. The ESR, a blood-cell count and a bone-marrow examination, serum protein electrophoresis, liver and renal function tests, urography, ECG, chest radiography and other laboratory tests revealed no evidence of pathological conditions. Cholecystography showed a solitary gall stone. Radiography visualized an opaque maxillary sinus. A LucCaldwell operation disclosed a bilocular cyst. Skin, tongue and rectal biopsies were normal. In 1969 a tumour of the upper surface of the soft palate was diagnosed. At histological examination a plasmacytoma with amyloid deposits was identified. Following radiotherapy (60 Gy) the tumour disappeared and there has been no sign of recurrence. In 1969 and 1971 repeated radiological examinations of the skull, thorax, chest and pelvis showed no signs of myelomatosis. In 1972 there were increasing laryngeal symptoms, and the radiological examination and the microlaryngoscopy now showed a right glottic and subglottic tumour (Fig. 3A, B) and more of the amyloid tissue was excised. In 1978 a polypous, easily bleeding swelling of the right nasal cavity was noted and a histological diagnosis of amyloidosis was made. A fine-needle biopsy of abdominal fat did not show any evidence of a generalized disease. Pathological findings. The initial laryngeal polypous lesion was covered with ordinary squamous epithelium. The submucous connective tissue was diffusely infiltrated with an amorphous substance surrounded by leukocytes. It stained with Congo red, and showed Acrci O l o l c i r ~ ~ iXX ~ol
H . Hellquist et al.
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Fig. 2 (Case 2). (A) Tomogram, a-p view. Bulging of the right false vocal cord and aryepiglottic fold with obliteration of the right ventricle (arrows).(B) Microlaryngoscopy. Smooth swelling of the right false vocal cord with intact overlying mucosa.
filtrated with atypical plasma cells. An amorphous substance staining positively with Congo red was also present. The nasal polyp showed marked oedema, with amyloid deposits. Comment. As the rectal, tongue, skin and abdominal fat biopsies were negative and the other laboratory tests disclosed no generalized disease, the amyloidosis was considered to be primary, being localized to the upper respiratory tract. It might be objected that there was also a solitary plasmacytoma, but there was no myelomatosis.
DISCUSSION
a typical green birefringence when viewed in polarizing light but did not stain with PTAH. For the material examined later the histological findings were similar (Fig. 3 C). The biopsy of the nasopharyngeal tumour was covered with columnar epithelium. The richly vascularized stroma was profusely inA[ ~ C O I t o l ~ i r v ~88 ~~ol
After more than a century’s investigation the nature of the unique proteinaceous amyloid substance remains obscure. Electron micrographs show all amyloid to have the same basic, fibrillar structure, with rigid and unbranched fibrils measuring 50-150 A in diameter (Kyle & Bayrd, 1975; Glenner & Page, 1976). The length of the fibrils has been estimated at about 8000 A (Kyle & Bayrd, 1975). Chemical analysis has distinguished three chemical types of amyloid, one of immuno-
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Fig. 3 (Case 3). (A) Laryngogram, p a view. Tumour of the right vocal cord with subglottic extension. (B) Microlaryngoscopy. Swelling of the right vocal cord with intact overlying mucosa. (C) Photomicrograph. Infiltration of an amorphous substance (amyloid), staining positively with Congo red, in the submucosa . with intact overlying epithelium ( ~ 3 7 0 ) Inset: Brilliant green birefringence in polarized light ( x 700).
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globulin origin, one of unknown origin and the third apudamyloid (Pearse et al., 1972; Glenner & Page, 1976; Barnes & Zafar, 1977). The amyloid fibrils associated with generalized primary amyloidosis and some forms of localized amyloidosis, and those associated with plasma-cell dyscrasia are derived primarily from the aminoterminal (variable) region of a light chain of a homogeneous immunoglobulin (Glenner & Terry, 1974; Glenner & Page, 1976). The amyloid of unknown origin has fibrils not deriving from immunoglobulin; this type of amyloid is also found in secondary amyloidosis and the familial Mediterranean fever. The third type, apudamyloid, is associated with endocrine polypeptide tumours (Pearse et al., 1972). Congo red, the most commonly used staining reaction for amyloid, gives a bright red colour. In polarizing light an apple-green birefringence is obtained. These tinctorial and polarization properties are due to the presence of P-pleated sheet fibrils (Glenner et al., 1972). The presence of these fibrils is revealed by low-angle X-ray diffraction, which is the third principal method (after light and electron microscopy) for identifying the amyloid substance (Kyle & Bayrd, 1975). The Congo red reaction is sensitive, and false positives and negatives are rare. Evidently still more sensitive, however, is Phorwhite BBU, with even fewer false staining reactions (Waldrop et al., 1973; Glenner & Page, 1976). Crystal violet gives a positive metachromatic reaction. A new potassium permanganate technique for distinguishing between the chemical types of amyloid has been introduced by Wright et al. (1977). The majority of the numerous clinicopathological classifications of amyloidosis are modifications of that published by Symmers in 1956: (1) generalized secondary amyloidosis (amyloidosis associated with an identifiable predisposing disease), (2) generalized primary amyloidosis (no identifiable predisposing disease), and (3) localized amyloidosis. The larynx is rarely involved in generalized sec-
ondary amyloidosis and infrequently in generalized primary amyloidosis. The larynx is, however, the usual site for amyloidosis of the respiratory tract. Amyloidosis within the larynx occurs in two forms: one of them tumour-like and the other displaying diffuse infiltration. The manifestations of the disease will, of course, depend on the site of the amyloid deposit; involvement of the vocal cords will result in hoarseness; subglottic involvement often leads to increasing inspiratory difficulty; and in the case of supraglottic deposits the symptoms prompting the patient to seek medical attention may be more diffuse. The diagnosis is obtained on the basis of laryngoscopic and biopsy findings. Further information on the extent of the lesion may be provided by a radiological examination. Four patterns of extracellular deposit of amyloid in the larynx may be distinguished: ( 1 ) amorphous random masses, (2) in vessel walls, (3) in basement membranes of the seromucinous glands, and (4) as hyaline ‘rings’ in adipose tissue (Barnes & Zafar, 1977). The ‘amyloid tumour’ is, of course, not an actual neoplasm, but rather a localized tumour-like swelling produced by the presence of the amyloid deposit in the submucosal tissue. Two cases (cases 1 and 2) are both examples of localized amyloidosis. The third case (case 3) is questionable, but is probably also to be regarded as localized amyloidosis of the respiratory tract, since fairly exhaustive investigation established no evidence of generalized disease, notwithstanding the presence of a solitary nasopharyngeal plasmacytoma. In a patient with amyloidosis it is necessary to eliminate the possibility of a generalized disease. Among the laboratory tests and other methods that should be used to this end are the ESR, blood-cell count, bone marrow examination, serum protein electrophoresis, liver and renal function tests, and chest radiography. The presence of ECG-anomalies may indicate cardiac amyloid deposits. Biopsy specimens should be taken from either the oral or, preferably, the rectal mucosa (Gafni &
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Sohar, 1960; Crifo, 1973). A fine-needle technique for procuring specimens of abdominal fat has been introduced by Westermark & Stenkvist (1973). In our 3 cases none of these methods disclosed any significant pathological feature. The following differential diagnoses have to be ruled out: hyalinized myxomatous polyps, benign and malignant tumours with intact overlying mucosa, retention cysts of the false vocal cords, and laryngocele. Histologically, the elimination of the hyalinization of a vocal cord polyp is the most important differential diagnosis, and the possible presence of this condition was considered in Case 3. Two staining methods for amyloid have been recommended besides fibrin staining (PTAH). Plasmacytoma containing amyloid deposits is another condition to be considered (Ryan et al., 1977). The treatment for laryngeal amyloidosis is surgery, consisting in endoscopic excision with the aid of the operating microscope. Localized tumour-like lesions may be removed entirely. In the case of a diffuse submucosal lesion repeated excisions are often necessary to restore the airway and to conserve the voice. For a lesion at the level of the cricoid ring the excision should be performed cautiously and perhaps staged in order to avoid the risk of subglottic stenosis. If the amyloid is extensive an approach through a laryngofissure may be indicated. In amyloidosis of immunoglobulin origin the use of immunosuppressive or cytostatic agents has been suggested (Jones et al., 1972). Melphalan has been tried successfully in some cases, but Kyle & Bayrd (1975) have pointed out the risk of acute leukemia associated with the use of this agent. The cases presented illustrate the diagnostic difficulties in laryngeal amyloidosis. The conservative surgical treatment is stressed. ZUSAMMENFASSUNG Die Larynxamyloidose ist eine seltene Krankheit und macht weniger als 1 % alle gutartigen ,,Geschwulste" des
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Larynx aus. Drei Falle dieser Art der Lasion wird berichtet - einer des Stimmbandes, einer des Tachenbandes und einer des subglottischen Raumes und der Trachea. In zwei der Patienten war die Amyloidose ortlich isoliert, wahrend es bei dem dritten spater auch ein extramedullares Plasmazytom des Nasenrachens mit Amyloidablagerung und ausserdem Amyloidose der Nasenhohle gefunden wurde. Die Amyloidose dieses Patients darf doch als isoliert betrachtet werden, weil sowohl die klinische Untersuchung als die Laboratoriumbefunde keine Beweise einer generalisierten Krankheit gaben. Die Larynxamyloidose kann sich als einen umschriebenen Tumor oder als diffuse Infiltrate aussern. Die Symptome und die Funde werden naturlich von der Lage der Amyloidablagerung abhangig sein. Heiserkeit kann vorhanden sein wenn die Stimmbander betroffen sind und dies was das auffalligste Symptom der vorliegenden Falle. Die Behandlung der Larynxamyloidose ist zuerst eine endoskopische Excision. Das Amyloid zeigt spezifische Eigenschaften der histologischen Farbung. Die Kongorotprobe mit einer griinen Doppelbrechung im polarisierten Licht und Phorwhite BBU bei Verwenden der Fluoreszenzmikroskopie werden als die zuverlassigsten Farbereaktionen angesehen. Die Elektronmikroskopie hat eine typische fibrillare Struktur des Amyloids aufgedeckt.
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Jan Olofsson, M.D. Department of Otolaryngology Linkoping University Hospital S-58185 Linkoping Sweden
