Systemic AL amyloidosis is a proteotoxic clonal plasma cell disorder in which amyloid-forming immunoglobulin light chains produced by the clonal plasma cells cause cellular toxicity and deposit as fibrils, leading to organ dysfunction and death, usually of a cardiac cause. Distinguishing AL from other types of amyloidosis such as senile systemic due to wildtype (ATTRwt), or hereditary due to mutant transthyretin (ATTRm), can be challenging and has significant clinical ramifications. The incidence of monoclonal gammopathies (MG) is increased in African-Americans and in older patients; patients in those categories who have ATTRwt or ATTRm are more likely to have MG and are therefore at increased risk of being misdiagnosed with AL and receiving cytotoxic chemotherapy inappropriately.
Over a 6 year period at Memorial Sloan-Kettering Cancer Center, 369 consecutive patients with systemic amyloidosis were evaluated for clonal plasma cell disease and 30% of them were screened for hereditary ATTRm based on African-American race, dominant peripheral neuropathy or having been referred with a tissue diagnosis of amyloidosis without apparent MG. A mutant transthyretin was identified in 5.4% (20/369; 7 Ala60Thr, 4 Ile122Val (one homozygote), 4 Phe64Leu, 4 Val30Met and 1 Glu89Gln). In addition, ATTRwt was diagnosed in 4% (15/369). Of the 20 consecutive patients with mutant TTR, 10 had an associated gammopathy, 6 monoclonal and 4 polyclonal. Those with MG had 2 potential sources of amyloidogenic proteins - the light chains associated with the MG and the mutant TTR. We used several available approaches to establish a conclusive diagnosis, including immunohistochemistry (IHC) and more definitive typing via mass spectrometry (MS) and immunogold electron microscopy (IEM). Ultimately, 4 of the 6 with MG and mutant TTR were diagnosed with ATTRm, while the other 2 had AL amyloidosis and were treated with chemotherapy. Of note, one patient was initially thought to have ATTRm based on IHC, but then shown to have AL based on MS. Interestingly, none of the 15 consecutive patients with SSA had a gammopathy despite being an older cohort (med age 76.5 vs 64). This lends credence to the hypothesis that patients with TTR mutations may be at increased risk of developing gammopathies (50% in this series). The significance of this rate of coincidence is two-fold. First, the mutant TTR protein may be immunogenic, as has been suggested.1 Second, this heightens the need for diagnostic vigilance and willingness to perform direct tissue typing. Kindreds with hereditary disease may be at greater risk of being misdiagnosed and treated for AL then would be expected based on population wide incidence. Clinical diligence and use of the newest techniques for pathologic typing are essential.2
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Comenzo:Millenium Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Elan Pharmaceuticals: Consultancy; Genzyme: Research Funding; Celgene: Research Funding; Ortho: Research Funding.
Asterisk with author names denotes non-ASH members.