Amyloidosis

* Context.-Localized laryngeal amyloidosis is an uncommon condition with limited long-term follow-up studies. The precise etiology and pathogenesis are not entirely clear.

Objective.-To further characterize the histopathologic features and possible pathogenesis of localized laryngeal amyloidosis.

Design.-Three cases of primary localized laryngeal amyloidosis were identified at our institutions from 1980 to 2003. The clinical features and histologie and immunohistochemical patterns were evaluated. Systemic workups were pursued during the long-term follow-up.

Results.-The common presentation of the patients was hoarseness. The lesions involved vocal cords, anterior commissure, and ventricle. Microscopically, the amyloid was present within the submucosa with an adjacent lymphoplasmacytic infiltrate. The plasma cells and amyloid demonstrated monoclonal light chain restriction in all 3 cases (2 λ, 1 κ). No evidence of systemic amyloidosis or an overt B-cell lymphoma was found in these patients. Two patients with long-term follow-up underwent subsequent surgical removals for multiple recurrences, which occurred within 1 year of the initial diagnosis.

Conclusions.-The demonstration of monoclonal light chain expression in the plasmacytic infiltrate and amyloid component in the absence of systemic lymphomas indicates that localized laryngeal amyloidosis may represent a form of benign monoclonal plasma cell dyscrasia. A close follow-up of the patients may be indicated for early detection of recurrences.

(Arch Pathol Lab Med. 2005;129:215-218)

Amyloidosis is a group of disorders in which an extracellular deposition of an abnormal amount of proteins occurs in a variety of organs, including the larynx, von Rokitansky1 first described such deposits in 1842, but it was not until 1851 that Virchow2 applied the term amyloid to describe this deposition. Clinically, amyloidosis is divided into 2 categories: systemic and localized. Approximately 9% to 15% of amyloidosis is of the localized type. Localized amyloidosis in the head and neck is a rare and benign disease. The larynx is the most common site of involvement and accounts for 0.2% to 1.5% of benign Iaryngeal tumors. Within the larynx, the vocal folds and ventricle are more commonly affected. Presenting symptoms include hoarseness, sometimes cough, and sensation of fullness. Stridor and dyspnea may occur in patients with extensive involvement. Laryngeal involvement could be either diffuse subepithelial deposition (diffuse type) or discrete tumor nodules (nodular type).3 Histologically, the presence of amyloid can be confirmed by the characteristic Congo red staining under polarized light microscopy, through immunohistochemical stains, or by electron microscopic findings of laryngeal biopsy specimens. In this report, we examined 3 cases of localized laryngeal amyloidosis in our institutions from 1980 to 2003 and reviewed clinical, pathologic, histochemical, and immunohistochemical aspects of the disease.

REPORT OF caseS

Patient 1 (Table) was a 36-year-old man who presented with several months of hoarseness at the end of 1989. He was neither a smoker nor drinker. His medical history was unremarkable. Laryngoscopic examination at initial presentation revealed small nodular lesions that involved the anterior two thirds of both vocal cords and the anterior commissure. Microdirect laryngoscopy with forceps excision was performed. The lesion was biopsied and diagnosed as laryngeal amyloidosis. All other laboratory findings, including chest x-ray examination, blood workup, and serum and urine protein electrophoresis, were normal. The first recurrence was 1 year later in the beginning of 1991, involving the same location. Later there were multiple recurrences, and the patient underwent subsequent microdirect laryngoscopy and forceps excisions in 1992, 1993, 1997, and 1999. With each additional procedure, the size of the lesion increased from 1.5 to 3.0 cm in greatest dimension. In 2000, the patient care was transferred to one of the authors (S.B.L.), and laryngoscopic examination revealed that the endolarynx was filled with multiple large polypoid lesions that involved the entire supraglottis and anterior commissure, with a compromised endolaryngeal lumen. The lesions were treated with a combination of forceps excision and carbon dioxide laser. Two additional similar procedures were performed in 2000 and again in 2002. During the last procedure, the patient experienced an intraoperative pneumothorax that was treated with a thoracostomy tube and tracheotomy. Six weeks later, the lesion was debulked using a powered laryngeal microdebrider, permitting the surgeon to achieve a more extensive debulking than had previously been performed. The tracheotomy was decannulated, and the site healed without incident. A second debulking with the microdebrider and standard endotracheal intubation was performed 5 months later. No further procedures have been performed in the subsequent 12 months. Despite the repeated recurrences, his disease remains limited to the larynx only (Figure 1).

Patient 2 (Table) was a 50-year-old man who presented with a 2-year history of hoarseness, which was worsening with use and unresponsive to steroid therapy. His medical history included mitral valve prolapse, status post appendectomy, and bilateral nephrolithotomy. Medication included aspirin. He did not smoke and was only a social drinker. He had no radiation or major trauma to this site. Indirect laryngoscopy showed thickened and lobulated vocal cords, particularly on the right side, with normal movement of the vocal cords. The lesions were removed during microdirect laryngoscopy with a carbon dioxide laser, and he was diagnosed as having laryngeal amyloidosis in 1986. Results of urine and serum protein electrophoresis performed in the same year were negative. Serum antinuclear antibody test results were negative. A year later, a large amount of amyloid was seen in the subglottic pads (bilateral) and anterior commissure. Most of the amyloid was removed at that time. The amyloid in the anterior commissure was excised a few months later. In 1988, the patient was noted to have subglottic amyloid anteriorly on the left side and posteriorly on the right side, which was again removed with a carbon dioxide laser. The patient tolerated the procedures well and was followed up by a speech therapist. In 1993, his follow-up laryngoscopy showed a small white mass on the right vocal cord, which did not require excision. Since then, he was lost to follow-up.

Patient 3 (Table) was a 56-year-old man who presented with a 5-month history of hoarseness. Past medical history included hypertension and hypercholesterolemia. He was treated with steroid and antibiotics with no improvement. Laryngoscopic examination revealed a 1.0-cm polypoid lesion in the right false vocal cord and ventricle. The extensive search for other locations of amyloidosis was negative. No lymphoproliferative disorder was detected. The polypoid lesion was removed by a carbon dioxide laser.

PATHOLOGIC FINDINGS

Grossly, the specimens from all 3 patients were similar and consisted of multiple friable, gray to tan soft tissue fragments, ranging in size from 1.0 to 3.0 cm. Histologie examination of the specimens from all 3 patients revealed diffuse submucosal globular deposition of amorphous, acellular, eosinophilic material on hematoxylin-eosinstained slides (Figure 2, A). Sparse mixed chronic inflammatory infiltrate, which consisted predominantly of mature plasma cells and lymphocytes, was present at the periphery of the amyloid deposits (Figure 2, A). Some of the amyloid material was observed around the stromal blood vessels (Figure 2, B) and the residual submucosal glands (Figure 2, C). The overlying squamous mucosa occasionally showed reactive changes and mucosal ulceration with secondary microthrombi in submucosal vessels (patient 3; Figure 2, D). Foreign-body giant cell reactions were easily identified adjacent to the amyloid deposits (patient 1; Figure 2, E). Congo red stains revealed apple-green birefringent material under polarized light (Figure 2, F), confirming the diagnosis of amyloidosis.

Immunohistochemical staining for λ and κ demonstrated light chain restriction in the infiltrating plasma cells and the amyloid substance in all patients, indicating the nature of the amyloid deposits being monoclonal immunoglobulins. Patients 1 and 3 showed solely λ light chain staining (data not shown), whereas patient 2 displayed κ light chain restriction (Figure 3). Electron microscopy was performed on the specimen from patient 1 and revealed characteristic interlacing meshwork of nonbranching fibrils (data not shown).

COMMENT

The first case of localized laryngeal amyloidosis was documented by Borow in 1873.4 Until 1990, only approximately 300 cases of upper airway amyloidosis were reported in the literature." This condition most commonly occurs in the fourth to sixth decades of life, with a malefemale predominance of 3:1.

In 1980, Glenner6,7 proposed the following classification system for amyloidosis: (1) the type of amyloid protein, such as AL (immunoglobulin light chain amyloid) and AA (secondary amyloidosis); (2) the protein precursor, such as κ or λ light chains, frans-thyretin, or β^sub 2^-microglobulin; and (3) clinical presentations, such as primary, secondary, myeloma associated, familial, localized, aging, or hemodialysis associated. Laryngeal amyloidosis is usually a localized and primary disease and is classified as AL/κ or λ/primary. In agreement with previously reported series, all cases of our laryngeal amyloidosis occurred as localized lesions without systemic involvement. The disease occurred in true and false vocal cords, subglottis and supraglottis, and anterior commissure, which are the common locations in laryngeal amyloidosis. Even in patients with multiple recurrences (patients 1 and 2), the disease is still limited to the larynx, indicating the benign nature of the disease.

The precise etiology and pathogenesis of laryngeal amyloidosis remain unknown. There is no definite established link with smoking, drinking, vocal abuse, or recurrent infection. In the 1980s, Preud'Homme et al8 demonstrated immunoglobulin light chains in some of their amyloid specimens. Since then, restricted light chain staining (λ or κ) in both plasma cells and the amyloid has been observed in more cases of laryngeal amyloidosis.9 Furthermore, Westermark et al10 and Berg et al11 discovered several unusual amino acid substitutions in κ1 light chain from cases of laryngeal amyloidosis. Some of these substitutions are located at highly conserved region of light chain and therefore could substantially change the configuration of the protein and result in the amyloid formation. This evidence further elucidates the pathogenic mechanism of localized amyloidosis. Compared with κ chain, λ light chain restriction was reported with greater frequency in the literature, because the variable region of λ light chain is known to be the most amyloidogenic. Perhaps certain amino acid residues that occur at particular positions in the λ sequence render them particularly amyloidogenic.12 All of our cases showed a population of plasma cells intimately associated with amyloid deposits. Immunohistochemical studies revealed κ (n = 1) or λ (n = 2) light chain restrictions for both amyloid deposits and plasma cells, suggesting a localized plasma cell dysfunction or dyscrasia. Our findings support the speculation that monoclonal plasma cells at this location are probably responsible for producing excessive or structurally abnormal immunoglobulins, which our body fails to remove.

Although it is rare, laryngeal amyloidosis may occur in patients with an underlying lymphoid neoplasm or in association with systemic amyloidosis. A number of reports have demonstrated a relationship between extramedullary plasmacytoma or multiple myeloma and localized laryngeal amyloidosis.13 Pribitkin et al14 described 2 patients who experienced systemic involvement (rectum, lung, and heart) among 16 patients with upper aerodigestive tract amyloidosis. Therefore, most authors believe that an evaluation for systemic disease is necessary because of the morbidity of systemic disease. Complete blood cell count, liver and renal function tests, urinary test for Bence-Jones protein, chest radiography, electrocardiogram, echocardiogram, and abdominal ultrasound may be warranted. A rectal biopsy or simple needle biopsy of abdominal fat may be performed to exclude systemic involvement." During the long period of follow-up, none of our patients developed plasmacytoma or multiple myeloma or systemic amyloidosis, although all of them had monoclonal expression of the plasmacytic infiltrate and amyloid component in the laryngeal lesion. In this regard, localized laryngeal amyloidosis may represent a form of benign monoclonal plasma cell dyscrasia.

Currently, the most popular and highly effective treatment available is microdirect laryngoscopy with a carbon dioxide laser excision. The goal is to maintain an adequately patent airway with as few procedures as possible, since each procedure potentially creates additional intralaryngeal scar and webbing. In nearly half of the cases reported in literature, the surgery had to be repeated due to localized recurrent or large lesions. Therefore, regular follow-up with laryngoscopy is crucial for early diagnosis of recurrence. Adjuvant therapies, such as irradiation, chemotherapy, and steroids, have shown no proven benefit in the treatment of this disorder.

Recently, an experimental small-molecule drug called CPHPC was developed by Pepys et al.15 CPHPC depletes serum amyloid P component, which binds to and stabilizes amyloid fibrils. Therefore, the decrease of serum amyloid P component in amyloid fibrils leads to the degradation of amyloid fibrils. Human trials for this molecule are currently under way.

References

1. von Rokitansky KF. Handbuch der pathologischen Anatomie. Vienna, Austria: Braumuller & Seidel; 1842:209-249.

2. Virchow R. Bav and Zussmmersetzying der Corpora Amalacca des Menschen. Vehr Phys Med Geswurzlurg. 1851;2:51-53.

3. Chow LT, Chow WH, Shum BS. Fatal massive upper respiratory tract haemorrhage: an unusual complication of localized amyloidosis of the larynx. I Laryngol Otol. 1993:107:51-53.

4. Borow A. Amyloide Degenaeration von Larynxtumoren: Canule seiber jahre lang Getrager. Arch Klin Chir. 1873)15:242-246.

5. Kennedy TL, Patel NM. Surgical management of localized amyloidosis. Laryngoscope. 2000;110:918-923.

6. Glenner GG. Amyloid deposits and amyloidosis: the beta-fibrilloses (first of two parts). N Engl J Med. 1980;302:1283-1292.

7. Glenner GG. Amyloid deposits and amyloidosis: the beta-fibril loses (second of two parts). N Engl I Med. 1980;302:1333-1343.

8. Preud'Homme JL, Ganeval D, Grunfeld JP, et al. Immunoglobulin synthesis in primary and myeloma amyloidosis. CHn Exp Immunol. 1988:73:389-394.

9. Lewis IE, Olsen KD, Kurtin PJ, KyIe RA. Laryngeal amyloidosis: a clinicopathologic and immunohistochemical review. Otolaryngol Head Neck Surg. 1992;106:372-377.

10. Westermark P, Sletten K, Pitkanen P, Natvig J, Lindholm C. Localized Iaryngeal amyloidosis: partial characterization of an amyloid fibril protein AL. MoI lmmunol. 1982:19:447-450.

11. Berg AM, Troxler RF, Gril lone G, et al. Localized amyloidosis of the larynx: evidence for light chain composition. Ann Otol Rhinol Laryngol. 1993;! 02:884-889.

12. Solomon A, KyIe RA, Frangione B. Light chain variable region subgroups of monoclonal immunoglobulins in amyloidosis AL. In: Amyloidosis. New York, NY: Plenum Press; 1986:449-462.

13. Nagasaka T, Lai R, Kuno K, Nakashima T, Nakashima N. Localized amyloidosis and extramedullary plasmacytoma involving the larynx of a child. Hum Pathol. 2001 ;32:132-134.

14. Pribitkin E, Friedman O, O'Hara B, et al. Amyloidosis of the upper aerodigestive tract. Laryngoscope. 2003;113:2095-2101.

15. Pepys MB, Herbert J, Hutchinson WL, et al. Targeted pharmacological depletion of serum amyloid P component for treatment of human amyloidosis. Nature. 2002;41 7:254-259.

Linglei Ma, MD, PhD; Bizhan Bandarchi, MD; Clarence Sasaki, MD; Steven Levine, MD; Young Choi, MD

Accepted for publication September 29, 2004.

From the Departments of Pathology (Drs Ma, Bandarchi, and Choi) and Head and Neck Surgery (Drs Sasaki and Levine), Yale University School of Medicine, New Haven, Conn.

The authors have no relevant financial interest in the products or companies described in this article.

Reprints: Linglei Ma, MD, PhD, Dermatopathology section, 530 First Ave, Suite 7J, New York University Medical Center, New York, NY 10016 (e-mail: lingleim@yahoo.com).

Copyright College of American Pathologists Feb 2005
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