Strong transthyretin immunostaining: potential pitfall in cardiac amyloid typing

Abstract

Although systemic amyloidosis commonly presents with renal disease, cardiac involvement usually determines the patient's prognosis. Cardiac involvement is seen in light chain amyloid and transthyretin amyloidosis. Distinguishing between these two is critical because prognosis and treatment differ. Our study demonstrates the unreliability of transthyretin immunostaining in subtyping cardiac amyloid. Between January 2003 and August 2010, we retrieved 229 native endomyocardial biopsies, of which 24 had amyloid. Immunohistochemistry for κ, λ, transthyretin, and serum amyloid A protein was performed on formalin-fixed, paraffin-embedded sections. Staining was graded as weak (trace to 1+) or strong (2 to 3+). Mass spectrometry (MS)-based proteomic typing of microdissected amyloid material was performed on selected cases. Fifteen patients had monoclonal gammopathy/plasma cell dyscrasia with cardiac amyloid. Eight of them (53%) showed strong transthyretin staining in the cardiac amyloid deposits. MS was performed in 5 of these 8 biopsies, and all 5 biopsies revealed light chain amyloid-type amyloid. Two of these 5 light chain amyloid biopsies did not even have concomitant strong staining for the appropriate light chain. Among the 15 cases with plasma cell dyscrasia, only 7 biopsies showed strong staining for the corresponding monoclonal light chain. Strong, false-positive immunostaining for transthyretin in cardiac amyloid is a potential pitfall, augmented by the frequent lack of staining for immunoglobulin light chains. Therefore, the presence of amyloid in the cardiac biopsy should prompt a search for plasma cell dyscrasia irrespective of transthyretin staining. Confirmation with MS should be sought, particularly if there is any discrepancy between κ/λ staining and serum immunofixation results.

Fig.1

Defining the intensity of immunostaining from weak to strong. 1A and 1B show weak staining of amyloid. 1A represents 1+ kappa light chain staining in Case no. 16; 1B represents 1+ transthyretin staining in Case no. 23. Fig.1C and 1D show bright staining of amyloid. 1C represents 3+ lambda staining in Case no. 12; 1D represents 3+ transthyretin staining in Case no. 16.

Fig.2

Biopsy on Case 19 with AL lambda amyloid proven by mass spectrometry. 2A. Congo red positive amyloid deposits surrounding individual myocytes; 2B. Weak staining for lambda light chain; 2C. Weak staining for kappa light chain; 2D. Strong staining for transthyretin.