|Year : 2003 | Volume
| Issue : 1 | Page : 30-34
Amyloidosis of the larynx and pharynx
AA Kochhar1, ME Baraka2
1 Clinical Assistant, Department of Otolaryngology, The Royal Lancaster Infirmary, Lancaster -, England
2 Consultant, Department of Otolaryngology, The Royal Lancaster Infirmary, Lancaster -, England
|Date of Web Publication||11-Jul-2020|
A A Kochhar
Dept. of Otolaryngology, The Royal Lancaster Infirmary, Lancaster
Source of Support: None, Conflict of Interest: None
Amyloidosis is a disturbance of metabolism characterized by a deposition of proteinaceous material in different organs and results in a wide range of clinical manifestations. Involvement of the pharynx and larynx is a rare and benign process. We report two cases involving the pharynx and larynx separately. This is an update of the literature review, the classification of amyloidosis, its pathogenesis and its management.
Keywords: Amyloidosis, pharynx, larynx
|How to cite this article:|
Kochhar A A, Baraka M E. Amyloidosis of the larynx and pharynx. Saudi J Otorhinolaryngol Head Neck Surg 2003;5:30-4
| Introduction:|| |
Amyloidosis is a disease process characterized by the extracellular deposition of protein fibrils in a (pleated fashion. Although it was first reported byVon Rokitansky in 1842 , the word amyloid (meaning “starchlike”) was first coined by Virchow in 1851 . This was because it responded in a starchlike fashion when treated with iodine and sulphuric acid (Amylon is Greek for “starch” and eidos for resemblance). Hooper, in 1891  was the first to report laryngeal amyloidosis in the English literature. Head and neck amyloid may represent local or systemic disease. Systemic disease can involve virtually any organ system, with serious clinical sequelae and a grave prognosis. Localized amyloidosis is an uncommon disorder of unknown cause that occurs in the absence of systemic amyloidosis or associated disease. It can involve the head and neck, aerodigestive tract, lower respiratory tract, urinary bladder as well as the skin. In the head and neck, the larynx, is the most commonly affected site. Amyloidosis involving the Waldeyers ring is very rare and only one such case has been reported before , We report the second case of amyloid deposition in the Waldeyers ring.
| Case reports:|| |
Case report 1 - A 69-year-old gentleman presented to the Respiratory Physicians with a six-week history of shortness of breath. He also complained of a lump at the back of his throat. He had no stridor, dysphagia or hemoptysis. He smoked for thirty years and had stopped smoking five years ago. He was also being treated for hypertension but had no other problems. The respiratory physicians noted that he had enlarged lymph nodes in the right submandibular region and both axillae. The chest X- ray revealed a right-sided pleural effusion. Pleural aspiration was performed under local anesthesia and 300 mlof fluid was drained. The cytology did not reveal any malignant cells and the fluid was negative for acid-fast bacilli. A pleural biopsy showed fibrosis only. Three weeks later he was readmitted with the same complaints. The repeat chest X-ray showed a right-sided pleural effusion. Repeat pleural aspirate contained 1-4 lymphocytes but no malignant cells. Other than a persistently raised erythrocyte sedimentation rate, all the other laboratory investigations were within normal limits. In view of his recurrent pleural effusion a bronchoscopy was planned. The bronchoscopist noted that the access was very difficult due to oropharyngeal bleeding. However, the bronchoscopy was reported as normal and the brush biopsies were negative. The patient was subsequently referred for an ENT opinion.
The patient was noted to have hot-potato speech. The throat examination revealed an extensive smooth, non-ulcerated, submucosal mass involving the palatine and lingual tonsils and extending to the postnasal space. There was no cervical lymphadenopathy.
A CT Scan showed a soft tissue mass in the pharynx. The mass was irregular and was extending posteriorly to the prevertebral soft tissue [Figure 1]. An urgent pharyngoscopy was carried out. A large growth was found. It was involving the palatine tonsils, base of tongue, and valleculae and was extending along the lateral pharyngeal wall to the lymphoid tissue on the posterior surface of the oropharynx (essentially involving the Waldeyers ring). Debulking was carried out. An elective tracheostomy was performed. Post-operatively the patients swallowing improved dramatically and on the seventh postoperative day the patient was successfully decanulated. The histology showed an extensive subcutaneous deposition of acellular eosinophilic materials consistent with amyloidosis [Figure 2].
|Figure 1: CT Scan showing a soft tissue mass in the pharynx. The mass is irregular and is extending posteriorly to the prevertebral soft tissue|
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|Figure 2: The histology shows an extensive subcutaneous deposition of acellular eosinophilic materials consistent with amyloidosis|
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The patient was investigated further for any systemic cause of amyloidosis. A bone marrow biopsy was normal, and the serum protein electrophoresis revealed no evidence of multiple myeloma. However, it was pointed out that he had an elevated level of an IgM lambda paraprotein. A review of the histology sections showed an excess of IgM and lambda positive lymphoplasmacytoid cells in the residual islands of lymphoid tissue adjacent to the amyloid deposits and a diagnosis of lymphopasma- cytoid B cell malignant lymphoma was made. The patient was treated with Chlorambucil and he showed a noticeable improvement.
Case Report 2 - A 66 year-old man was referred to the ENT clinic with a two-year history of hoarseness. There was no dysphagia, weight loss or any other symptoms. He was a non-smoker and consumed about 8 units of alcohol per week. He did give a history of rheumatoid arthritis to which he did not receive any treatment. Indirect Laryngoscopy revealed a growth involving the left aryepiglottic fold and left false cord. There was no cervical lymphadenopathy. A chest X-ray was normal. Direct Laryngoscopy was performed and biopsies were taken from the left aryepiglottic fold and false cord. The histology report suggested amyloidosis. The patient was referred to the immu- nologists, where systemic amyloidosis was ruled out and treatment in the form of Colchicine 500 micrograms twice daily was commenced.
The patients voice improved for sometime. However, the hoarseness recurred 2 years later. A repeat direct Laryngoscopy showed a growth involving the right ventricle and the right anterior commissure. The left vocal cord was free of disease. The lesion was biopsied and a diagnosis of amyloidosis was confirmed. He was fine till 2 years later when his symptoms recurred. Laryngoscopy revealed a pale, firm material replacing the entire right hemilarynx. The left vocal cord was normal but the left supraglottis was infiltrated. The deposits were debulked again only to recur again one year later. This time a massive right supraglottic deposit of amyloid was found jeopardizing the airway and accordingly a tracheostomy was performed. Subsequently a laryn- gofissure was carried out and the amyloid deposits were excised from the right supraglottis and left subglottis. A silastic roll was placed between the vocal cords. Four weeks later the silastic roll was removed and the patient was successfully decanulated. The patient has been well since with no recurrence for the last 5 years.
| Discussion:|| |
Amyloidosis is a spectrum of diseases that have in common the extracellular accumulation of protein fibrils in a unique and characteristic beta-pleated sheet polymer. These protein subunits are derived from normally occurring serum proteins such as various immunoglobulins. Berg et. al.  confirm the immunoglobulin origin of localised laryngeal amyloidosis. The cause of localised amyloidosis of the respiratory tract remains unknown. In contrast to systemic amyloidosis, in which little amyloid is found adjacent to plasma cells in the bone marrow (the presumed site of amyloid synthesis), localised amyloid deposits are found surrounded by plasma cells that synthesize immunoglobulin , It is possible that the plasma cells in the tracheobronchial tree produce amyloid in response to an inhaled allergen . Another theory is that the monoclonal plasma cells produce structurally abnormal immunoglobulins or an excessive amount of amyloid that exceeds local clearing mechanisms. The reason for these fibrils to accumulate has not been fully explained. There appears to be a chronically elevated serum precursor concentration coinciding with a predilection, possibly genetic, for amyloid deposition , Once the formation ofamyloid has occurred, and if the patient is susceptible to it, deposition occurs as there seems to be a reduced capacity to degrade and mobilize amyloids .
The classification of amyloidosis has undergone many changes in past years owing to an improved understanding of its biochemical nature. The old system still accepted by some, uses criteria developed by Kyle and Bernard  and modified by Gertz and Kyle . The patients are divided into the following categories:
- Primary amyloidosis: several organs were affected with amyloid but there was no evidence of a B-cell dyscrasia such as multiple myeloma or any underlying chronic disease.
- Amyloidosis associated with multiple myeloma.
- Secondary amyloidosis: This is also systemic with amyloid deposition occurring in patients with an underlying chronic disease such as tuberculosis, rheumatoid arthritis or other granulomatous infection.
- Localised Amyloidosis: Solitary deposition of amyloid usually affecting one anatomic site. These patients had no identifiable systemic manifestation of amyloidosis; results of serum and urine electrophoresis were negative for gammapathies; and rectal biopsy specimens or abdominal fat aspirations were negative for amyloid.
In the current nomenclature scheme , amyloidosis is classified by three essential parameters: (1) the name of the fibrillar protein making up the amyloid deposit, eg, AL, A A, ATTR, or AB2M; (2) the name of the precursor protein (usually serum- derived) from which the fibrillar protein was constituted, e.g., lambda light chain, apoSSA, transthyretin, or beta2 microglobulin and  the clinical description of the resultant disease process, e.g., primary, secondary, myeloma associated, familial, etc. Readers are referred to the references for further discussion of this complex classification system , , . Laryngeal amyloidosis is usually a localised, idiopathic, primary process and is classified as AL/k or lambda light chain/idiopathic. The most common form of amyloidosis affecting the body is a systemic process due to multiple myeloma . Pharyngeal involvement may be a manifestation of systemic disease.
The clinical manifestations of amyloidosis are varied and depend entirely on the system involved. It could affect the kidney, liver, heart, skin, gastrointestinal tract, nervous system, endocrine system, joints, respiratory tract or the haemopoietic system . Renal and cardiac disease is seen in both primary and secondary amyloidosis, and renal failure is the most common cause of death. 10% to 20% of patients with multiple myeloma develop amyloidosis and according to Kyle and Bayrd 26% of these could have amyloid macroglossia . The larynx is the commonest site of amyloidosis of the head and neck and is also the most common site of localized idiopathic amyloidosis in the body. Laryngeal amyloidosis comprises less than 1 % of benign laryngeal tumours and is not a neoplasm. It is rare in association with systemic amyloidosis, but it may be the first site involved in this disease. The onset is insidious with symptoms progressing slowly over months to years before the diagnosis is actually made. The commonest symptom is hoarseness although the patient can have dyspnoea on exertion. Dysphagia, hemoptysis, throat fullness and a choking sensation have also been reported. There is a male predominance with a male to female ratio of 3:1. Laryngeal amyloid may be a tumour like nodule, or it may diffusely infiltrate the submucosal of the larynx. It has a predilection for the supra- glottic larynx, with the false vocal cords most commonly affected, followed by the subglottis, ventricle, true vocal cords, and aryepiglottic folds. It must be emphasized that multiple sites in the respiratory tract are commonly affected.
Amyloidosis affecting the tonsil and Waldeyers ring has been reported by Beiser et al . This is extremely rare and the first case presented will be the second to be reported in world literature. Glenner and Page  have suggested this to be a localised, organ limited amyloidosis, where the eor- gani is the continuous lymphatic tissue comprising Waldeyers ring. Beiser et al  made attempts to identify possible etiological factors but could draw no conclusions. They did note that this ring of lymphatic tissue is unique in being exposed to the external environment. The specific topography suggests an immune local response.
When amyloidosis is suspected, biopsy is the gold standard for diagnosis. If possible, the primary organ involved should be biopsied. Diagnostic efforts must be directed at evaluating the extent of local disease and ruling out systemic causes of amyloidosis such as multiple myeloma, tuberculosis and rheumatic diseases. A thorough endoscopic evaluation of the entire respiratory tract should be conducted, including the nose, nasopharynx, larynx, and tracheobronchial tree, given the high incidence of multifocality. According to O’Hailoran et al  the recommended work-up includes a complete blood count, blood urea and creatinine levels, liver function tests, erythrocyte sedimentation rate, urinalysis, Rh factor testing, antinuclear antibody testing, serum and urine electrophoresis, a tuberculin skin test, and chest radiography. Because of the difference in prognosis between systemic and local disease, it is important to evaluate for systemic involvement. In the past rectal biopsy was performed. Recent studies have shown abdominal fat aspirates to be as sensitive as rectal biopsy. This easily tolerated test is highly specific but sensitivity is estimated to be between 75% and 90% . Bone marrow biopsy can be performed to rule out multiple myeloma; the results were normal in our patient. Serum and urine electrophoresis can also be done and immunohistochemical techniques can sometimes identify the protein precursor subtype
On gross examination, amyloid appears grey to yellowish in colour and firm to rubbery in consistency. Histologically it is a homogenous, acellular, eosinophilic extracellular infiltrate especially filling extensive areas of subepithelial regions. Cells containing numerous vacuoles surround these deposits. Lymphocytes and plasma cells are also found. Amyloid is distributed preferentially to the perivascular areas, smooth muscle, and connective tissue and in the basement membrane of seromuci- nous glands. Amyloid may be differentiated from other eosinophilic infiltrates with a number of his- tochemical stains. Amyloid stains dark brown with iodine and purple red with crystal or methyl violet. Staining with Congo red, the classic and most specific histochemical test, produces apple green birefringence and dichromism in polarized light. A modified potassium permanganate stain will allow reasonably accurate differentiation of the AA type from AL amyloid. Immunohistochemistry reveals symbol 108 \f “Symbol” \s 12 1 chains in 60% and symbol 107 \f “Symbol” \s 12 k chains in 25 % of the patients studied, suggesting a polyclonal source of immunoglobulins .
Electron microscopy of these deposits shows linear, non-branching fibrils, about 100 A wide, arranged in a random array. On X-ray diffraction a (pleated configuration is seen, which is responsible for amyloids insolubility and resistance to proteolysis under physiologic conditions, as well as its characteristic staining properties . Each fibril has a backbone composed of a distinct protein. The cells surrounding these deposits may be considered phagocytes by their ultrastructural characteristics .
The treatment of patients would largely depend on whether systemic disease is present. Associated diseases should be sought out and treated if possible. There have been reports of amyloidosis regression with successful treatment of underlying disease , , Medical treatments, including systemic corticosteroids and chemotherapy with drugs like melphalan and colchicine have been tried but largely been unsuccessful , , , Radiotherapy has been ineffective except in local control of myeloma and plasmacytoma , However, neither modality has made a significant difference in the overall survival of patients with systemic amyloidosis , In selected cases observation may be indicated, because there may be slow or no progression of disease over many years. Lesions have been reported stable in size for 17 years, and no case of malignant degeneration has ever been reported . Consequently, the treatment for primary localized amyloid of the larynx and pharynx is surgical . The treatment goals are twofold: maintenance of an adequate airway and improving or maintaining voice quality. The surgical removal may be carried out endoscopically or by open techniques. In both the cases reported endoscopic excision of amyloid was carried out. Laser excision has been reported and may be favoured due to its haemostatic capability , , Nevertheless, recurrence may manifest after several years so long term follow-up is necessary , . Eradicative laryngofissure or supraglottic laryngectomy, as performed in case 2, is possibly a very effective approach to avoid the recurrence of amyloid and the ensuing repeated resections in the same region. Total laryngectomy and tracheal resection have been reported, but it is rare that such radical therapy is required , Tracheostomy may be necessary for airway compromise or as a temporary adjunct to resection. In the series of Lewis et al , multiple surgical procedures were required in 10 of 22 (45%) patients, and 11 of 22 (50%) patients had persistent disease at follow-up ranging from 4 months to 25 years. As recurrence may manifest after several years long term follow-up is recommended. Development of generalised amyloidosis did not occur in our cases and has not been reported in literature , .
The prognosis of patients with amyloidosis depends on the presence of systemic disease. In the Mayo Clinic series of patients with primary or secondary amyloidosis, mean survival was 15 months without multiple myeloma, and 5 months with multiple myeloma. Kerner et al  document that localized forms of amyloidosis can be successfully treated’without major sequelae, and most patients remain symptom and disease free, as did the patients in our case reports.
| Conclusions:|| |
Amyloidosis refers to many diseases that are unified by the abnormal extracellular accumulation of protein fibrils in a characteristic configuration. Head and Neck surgeons should be able to understand and recognize localized and systemic amyloidosis as each has a different prognosis. More importantly, patients with symptomatic local deposits of amyloid in the larynx and pharynx can be successfully treated surgically. If repeated endoscopic excision fails to control the disease Laryngofissure or supraglottic laryngectomy offers the best chance of long term control of this disease while preserving vocal function. Further recurrences may occur, hence long-term follow-up is recommended.
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[Figure 1], [Figure 2]