Amyloid tumor of the larynx associated with plasma cell infiltration: differential diagnosis.

Abstract

Localized amyloidosis of the larynx is uncommon, accounting for fewer than 1% of all benign laryngeal tumors. We report 2 cases of laryngeal amyloidosis in which dense plasma cell infiltrates were found in the vicinity of the amyloid deposits; in view of this finding, we suspected a hematologic disease--plasmacytoma in particular. However, molecular genetic analysis did not demonstrate any light-chain restriction, indicating that the plasma cells were of polyclonal origin and therefore consistent with chronic inflammation. We also discuss the available literature with respect to diagnostic and therapeutic procedures in patients with amyloidosis of the upper airway.

Introduction

Localized amyloidosis of the larynx is uncommon, accounting for fewer than 1% of all benign laryngeal tumors. (1,2) In 1875, Burow was the first to describe amyloid deposits in the larynx. (3) Since then, numerous cases of solitary laryngeal amyloidosis have been reported in the literature. (4-14) In some cases, the clinical features of laryngeal amyloidosis may lead the clinician to misdiagnose it as a squamous cell carcinoma. (15)

Amyloid is a pathologic protein substance that is deposited between cells in various tissues and organs of the body. Approximately 95% of amyloid is made up of fibrillar proteins, and the remaining 5% is made up of the so-called serum amyloid P component and other glycoproteins. (16-18) Identification of amyloid is based on three criteria: (1) Congo red binding and green birefringence under polarized light, (19) (2) a fibril structure on electro microscopy, (20) and (3) confirmation of the characteristic cross beta-pleated sheet on x-ray crystallography and infrared spectroscopy. (21)

Amyloidosis is classified on the basis of the amyloid protein's constituent chemical fibrils. Eighteen biochemically distinct forms of amyloid protein have been identified. (22) The three most common are AL, AA, and A[beta]. AL (amyloid immunoglobulin [Ig] light chain) is derived from plasma cells, AA (serum amyloid A) is associated with chronic inflammation, and A[beta] is found in cerebral lesions in patients with Alzheimer's disease. Amyloidosis can be systemic (generalized) or localized. Clinically, primary amyloidosis is distinguishable from secondary amyloidosis.

Most amyloid deposits in the larynx are of the AL type. AL deposits appear in both localized and systemic amyloidosis, as well as in hematologic disease and in chronic inflammatory processes. For these reasons, laryngeal amyloidosis should not be considered a single disease; rather, this entity represents a group of diseases that have in common a similar pattern of protein deposition. (16)

The differential diagnosis of laryngeal tumor-shaped amyloidosis can be problematic for both clinicians and pathologists. In this article, we describe 2 cases in which (1) amyloid deposits were found in multiple locations in the larynx, (2) there was no evidence of systemic disease, and (3) the polyclonality of the plasma cells indicated the presence of a chronic inflammatory process rather than a solitary extramedullary plasmacytoma.

Case reports

Patient 1. A 54-year-old woman was referred to the Department of Otorhinolaryngology with a suspected carcinoma of the larynx. She reported a 1-year history of hoarseness, but no pain or swallowing difficulties. Direct rigid laryngoscopy showed an augmented volume of the left false vocal fold with expansion into the anterior commissure (figure 1, A). The true vocal folds and their motility were not affected clinically. Computed tomography (CT) of the neck revealed that the false vocal folds were asymmetric (figure 1, B).

[FIGURE 1 OMITTED]

With the patient under general anesthesia, direct laryngoscopy detected a reddish swelling of the left false vocal fold. Biopsies were taken and fixed in 10% paraformaldehyde. Histologic examination revealed the presence of an amorphous, eosinophilic, hyaline, extracellular substance in the subepithelial layer that affected the supraglottic and glottic larynx bilaterally, even in areas with an unsuspicious macroscopic aspect. The Congo-red-stained deposits reflected a green birefringence under polarized light, thus revealing the specimen's amyloid nature (figure 1, C and D). After the amyloid deposits were treated with KMn[O.sub.4] they retained their green birefringence under polarized light. Based on this finding, we considered the possibility that the deposits belonged to the AL amyloid group. (23)

A dense plasma cell infiltrate surrounded the amyloid deposits. Immunohistochemistry showed that the plasma cells synthesized Ig light chains of the types kappa and lambda in equal numbers. Assessment of IgH gene rearrangement products using genomic DNA obtained from the formalin-fixed and -embedded tumor tissue yielded no distinct bands after polymerase chain reaction (PCR) amplification and electrophoretic separation. This finding implied that the plasma cells were of polyclonal rather than monoclonal origin.

To exclude generalized amyloidosis, a rectal biopsy, echocardiography, and bronchoscopy were performed; they detected no pathology. Further diagnostic steps were performed in the Department of Oncology to exclude a plasmacytoma. Findings on bone marrow biopsy were normal, as were the results of immunologic laboratory analysis, including an assay of Bence Jones proteins. Skeletal roentgenography revealed large diploetic vein canals in the skull, but no osteolytic areas. Moreover, bone marrow scintigraphy showed only a reduced enhancement of the spine, and therefore there was no evidence of bone marrow generalization of any malignant disease. In view of the clinical and histologic amyloid infiltration of several areas of the larynx (including the false vocal folds [primarily the left], both true vocal folds, and the laryngeal surface of the epiglottis), any attempt at a curative resection would have been mutilating. Therefore, we decided to perform trimonthly examinations during a 2-year follow-up. At 2 years, no visible increase in residual laryngeal amyloid had occurred, and the patient exhibited only slight hoarseness and no signs of dyspnea.

Patient 2. In 1995, a 65-year-old man presented to the Department of Otorhinolaryngology with a 4-week history of hoarseness and swallowing difficulty. He denied cigarette smoking and alcohol use. Clinical examination revealed the presence of granulation tissue on both false vocal folds, although the function of the vocal folds themselves was not affected. Direct laryngoscopy was performed and multiple biopsies were taken. Histologic analysis revealed the presence of amyloid deposits in all biopsy specimens; these deposits were surrounded by a lymphocytic plasma cell infiltrate. Immunohistochemistry and molecular genetic analysis, performed in the manner described in the first case, did not reveal a monoclonal plasma cell population, which again implied an inflammatory process rather than a lymphoplasmacytic lymphoma (immunocytoma).

During the next 7 years, no progression of amyloid deposits was evident. In view of the absence of a malignancy and the minor nature of the patient's symptoms, no further intervention was necessary.

However, the patient returned in 2002 when his persistent hoarseness became aggravated. Laryngoscopy with laser excision biopsies was performed to exclude a malignant process (figure 2). The histologic findings did not differ from those in patient 1. Patient 2 underwent the same tests that were performed on patient 1 to exclude a generalized manifestation of amyloidosis, and, again, all findings were negative.

[FIGURE 2 OMITTED]

Management of both patients. Both of these patients were diagnosed with localized amyloidosis of the larynx. Because monoclonality could not be proven and a systemic manifestation of amyloidosis was excluded by skeletal roentgenography and bone marrow biopsy, we excluded a diagnosis of a solitary extramedullary plasmacytoma.

After patient 1 underwent treatment with a bisphosphonate to prevent progression of the augmented volume of the diploetic emissary canals, no deterioration was observed. The residual local amyloids in the larynx did not increase.

Almost 7 years after patient 2 first underwent his first surgical treatment, new amyloid masses were detected in the larynx. After we ruled out a malignant process, we treated the masses surgically.

Discussion

Localized amyloidosis has been described in the orbit, nasopharynx, lips, parts of the mouth and tongue, larynx, and tracheobronchial tree. (24,25) Laryngeal amyloidosis primarily affects men in the fifth decade of life. (2) The nature of symptoms depends on the location of the amyloid deposits. (1) Hoarseness, shortness of breath, and painful deglutition have been described. The predominant symptom of amyloidosis in the glottic area is hoarseness. Our patient 1 complained of long-standing hoarseness and was referred to our clinic with a suspected laryngeal carcinoma. The fact that amyloidosis can mimic a laryngeal carcinoma has been reported in the literature. (26)

The three common features of all types of amyloid are the typical ultrastructure of amyloid fibrils as seen on electron microscopy, (20) confirmation of the characteristic cross beta-pleated sheet on x-ray crystallography and infrared spectroscopy, (21) and the presence of an amyloid serum precursor that already has a high degree of cross beta-pleated sheet structure. Therefore, once amyloid deposits are detected, a generalized manifestation must be excluded. If immunohistochemistry reveals an AL type of amyloid, a diagnosis ofplasmacytoma must be pursued (table).

Physiologically, kappa and lambda light chains are expressed in a ratio of 3:1. In our patient 1, Ig light chains of the kappa and lambda type were equally synthesized. This could suggest a clonal expression of the plasma cells that secrete Ig light chains of the lambda type, but the subsequent PCR test could not prove a monoclonality of lambda-expressing B cells. Because no monoclonality could be demonstrated on immunohistochemistry or by molecular genetic methods, a diagnosis of extramedullary plasmacytoma was not confirmed. Therefore, the patient was diagnosed with localized amyloidosis of the larynx with polyclonal reactive plasma cell infiltration. As this case illustrates, the pathogenesis of local amyloid deposits often remains unclear.

The treatment of choice is management of the underlying disease. (27) Therefore, it is important to classify amyloidosis correctly. The best treatment for localized amyloidosis is local excision. (18) Excision can be performed endoscopically or by the laryngofissure procedure described by Watanabe et al in 1984. (28) In both of our patients, amyloidosis was restricted to the larynx, but it affected multiple sites there. That is why a complete local excision was not possible, especially in patient 2; the inability to perform surgery explains the recurrence he experienced 7 years later. In patient 1, trimonthly examinations during a 2-year follow-up revealed no aggravation, thus confirming that mutilating surgery is not always indicated. Also, generalized amyloidosis did not occur in this patient. Because recurrence may manifest after several years, long-term follow-up is recommended. (7)

Table. Three-step diagnosis of suspected
amyloidosis

Step 1. Biopsy the affected organ

* Congo red binding and green birefringence under
polarized light

* Fibril structure on electron microscopy

* X-ray crystallography and infrared spectroscopy to
confirm the characteristic cross beta-pleated sheet

* Biochemical and/or immunohistochemical identification
of the major amyloid protein

* For patients with the AL type of amyloid:

   Immunohistochemical staining: demonstration of
   kappa and lambda chains in plasma cells

   Molecular genetic methods: differentiation between
   poly- and monoclonal B cells

Step 2. Rule out generalized amyloid deposits

* Rectal biopsy

* Echocardiography

* Bronchoscopy and lung function analysis

* CT of the neck, particularly the trachea

Step 3. Rule out generalized plasmacytoma

* Bone marrow biopsy

* Bone marrow scintigraphy

* Skeletal roentgenography

* Serologic and immunologic examinations: immunoelectrophoresis
and measurements of liver and kidney
function and calcium, paraprotein, and Bence Jones
protein levels in urine and serum

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Susanne Benning, MD; Katja Technau-Ihling, MD; Paul Fisch, MD; Milo Fradis, MD; Joerg Schipper, MD; Wolfgang Maier, MD

From the Department of Otorhinolaryngology (Dr. Benning, Dr. Schipper, and Dr. Maier) and the Department of Pathology (Dr. TechnauIhling and Dr. Fisch), Albert Ludwigs University Medical School, Freiburg, Germany; and the Department of Otolaryngology, B'nai-Zion Medical School, Haifa, Israel (Dr. Fradis).

Originally presented in part at the 4th European Congress of Oto-Rhino-Laryngology-Head and Neck Surgery; May 13-18, 2000; Berlin.

Reprint requests: Wolfgang Maier, MD, Department of Otorhinolaryngology (HNO Klinik), University of Freiburg Medical School, Killianstr. 5, D-79106 Freiburg, Germany. Phone: [phone]; fax: [phone]; e-mail: [e-mail]