Laryngeal Amyloidosis: Occurrence Long After Radiation Therapy for Laryngeal Cancer

Significant Statement

Amyloidosis is an infrequent condition where fibrillar protein accumulates in the tissues. Laryngeal amyloidosis (LA) occurs at about 9% to 15% of all cases of amyloidosis, accounting for less than 1% of benign tumors of the larynx. We present a rare clinical report of LA that developed 27 years after radiation therapy for laryngeal cancer. It is only the third case of amyloidosis of the larynx associated with laryngeal carcinoma described in the literature.

A 72-year-old male patient presented with a 2-year history of hoarseness of voice. According to his medical history, the patient had laryngeal cancer of the right vocal fold in 1994, which was managed with a course of radiotherapy (a total of 33 sessions). Investigation with flexible nasoendoscopy revealed 2 lesions in the anterior third of the right vocal fold and left vestibular fold (Figure 1). Examination of the neck was unremarkable. Direct rigid laryngoscopy and biopsy with CO₂ laser were performed, followed by histologic analysis of all biopsy specimens. The analysis showed fragments of laryngeal mucosa with deposits of amorphous eosinophilic material, consistent with amyloid (Figure 2). The deposits were stained with Congo red and had characteristic greenish birefringence when examined under polarized light. Immunohistochemical stains for kappa and lambda light chains, as well as amyloid A component, were negative, confirming the diagnosis of amyloidosis. It is noteworthy that these were isolated findings, as there was no manifestation of amyloidosis in any other system, which was further supported by investigation with positron emission tomography-computed tomography and blood tests were clear. Four months after the surgery, the patient complained of dysphonia, and endoscopy of the larynx showed a laryngeal web in the anterior commissure. A new surgery was performed to remove the tissue using CO₂, and mitomycin was applied topically to prevent recurrence. Follow-up of the patient at 2 years found no evidence of amyloidosis recurrence.

Figure 1.

Image showing 2 lesions (yellow arrows) arising from the anterior third of the right vocal fold and left vestibular fold, respectively.

Figure 2.

Histopathological examination showing laryngeal biopsy specimens with amyloid deposits. (A) The overlying squamous epithelium of the right true vocal fold shows keratosis, with dysplasia (H&E, 10×). (B) The lamina propria of the anterior commissure displays a moderate inflammatory infiltrate, composed of lymphocytes and plasma cells (H&E, 40×). H&E, hematoxylin and eosin.

Amyloidosis is a relatively uncommon benign clinical condition, and the larynx is the most frequently affected site for localized amyloidosis in the head and neck area. ¹ It is characterized by extracellular deposition of insoluble abnormal fibrous proteins (amyloid) in tissues, which disrupt the normal function of the organ. ² The term “amyloid,” derived from the Greek “amylon” meaning starch, was introduced by the pathologist Virchow in 1854. ³ LA accounts for about 0.2% to 1.2% of all benign laryngeal tumors, with slow and progressive growth. ⁴ It is classified into systemic and localized forms and further sub-divided into primary and secondary forms. ⁵ Localized amyloidosis is notably more infrequent than systemic, accounting for only 10% to 20% of cases. ³ When the head and neck area is involved in the systemic form, macroglossia is the prevailing sign (found in approximately 20% of patients). Moreover, hereditary and acquired forms have been described. ³ Further to the larynx, involvement of the nasopharynx, oral cavity, oropharynx, salivary glands, eyes, paranasal sinuses, and tracheobronchial tree has also been reported. ¹ LA affects patients aged between 50 and 70 years, with a male predominance (male to female ratio 3:1). ³ The most common sites of LA are, with decreasing frequency, the ventricles, false vocal folds, true vocal folds, aryepiglottic folds, and subglottis.

There are only 2 clinical reports in the literature related to laryngeal carcinoma that involve LA. One report associated long-standing localized LA with laryngeal squamous cell carcinoma, while the other found LA to conceal carcinoma in situ. ^5,6 However, in our report, there is no evidence to suggest a causal relationship between the development of LA and prior radiation and laryngeal cancer.

Symptomatology includes dysphonia, hoarseness, dyspnea, cough, stridor, and hemoptysis. ⁷ Clinical examination usually reveals a yellow, orange, or grey submucosa, a discrete nodule, or pedunculated lesions. ⁸

When amyloidosis of the head and neck is confirmed, patients are recommended to undergo tests, such as blood tests (including renal and liver function), cardiological investigations, and imaging. Imaging with computed tomography or magnetic resonance imaging (MRI) is a very helpful tool, with characteristic skeletal muscles intensity in MRI. ² Sometimes, patients undergo core biopsy from abdominal fat tissue to rule out systemic amyloidosis, while previously bone marrow and rectal biopsies were also performed. ^1,3,4 Localized LA very rarely progresses to systemic amyloidosis.

Treatment of choice is complete endoscopic resection of the lesion(s) with either cold instruments or CO₂ laser, while open procedures are also performed. ^1,3,8 The benefit of corticosteroids and radiotherapy remains controversial. ^1,9 Diagnosis is suspected when histopathological investigation with hematoxylin and eosin shows acellular eosinophilic nodules and is confirmed when specimens are stained with Congo red (apple-green birefringence). ³ Observation is suggested when lesions are small and asymptomatic. Long-term follow-up is of paramount importance due to high rates of recurrent disease, as well as after the primary surgery for LA. ^8,10

Prognosis is excellent for LA. ² Differential diagnosis includes tumors such as squamous cell carcinoma, medullary carcinoma of thyroid with laryngeal invasion, chondrosarcoma, lymphoma, polyps, as well as inflammatory disorders (eg, sarcoidosis). ¹¹