The Classification and Typing of Amyloid Deposits

Abstract

The diagnosis of amyloidosis, unlike many other diagnoses that fall on the shoulders of the pathologist, is based on a simple tinctorial property. Binding of the cotton wool dye Congo red, demonstrating green birefringence when viewed under polarized light, fulfills all diagnostic criteria for amyloid. Reporting amyloidosis in a pathologic specimen is reminiscent of a histologic diagnosis of “lymphoma.” The demonstration of amyloid in and of itself is not particularly helpful to the clinician, and an accurate determination of the type of amyloid is just as important as recognizing the presence of amyloid. The clinician will have many questions for the pathologist. Is the amyloid systemic or localized? Is the amyloidosis primary, secondary, or inherited? The former question is important because the majority of patients with localized disease do not require systemic therapy and the long-term prognosis is excellent. The latter question is important because the prognoses for the 3 forms of systemic amyloid and the treatment of the 3 disorders are vastly different. One often involves chemotherapy and stem cell transplantation; another might lead to liver transplantation. Accurate classification becomes imperative. Some forms of localized amyloid are light chain–derived, but the light chain production is local and not part of a systemic plasma cell dyscrasia.1 Localized forms of amyloid might be suspected because of the organ involved. When deposits of amyloid are found in the bladder, urethra, and ureter, it is virtually always a localized process. Most cases of amyloid in the skin and conjunctivae are localized. Amyloidosis of the larynx and tracheobronchial tree is not a systemic disorder, although it may cause troublesome complications. Amyloid deposits in the atria of the heart, pleura, and the articular cartilage generally are localized, and the diagnosis of systemic amyloidosis should not be made unless there is other evidence of visceral involvement. The majority of patients seen in the United States with systemic amyloid have immunoglobulin light chain amyloid (AL) or primary type. The origin of the fibril is an immunoglobulin light chain or immunoglobulin heavy chain fragment. Virtually all patients have a demonstrable clonal plasma cell dyscrasia, and this fact can be used to advantage in classifying the amyloid. These patients will have a detectable monoclonal light chain in the serum or urine shown by immunofixation or an elevation of the immunoglobulin free light chain level revealed by nephelometry.2 Bone marrow examination will demonstrate clonal plasma cells as the source of the light chain production.3 The finding of a monoclonal protein is helpful, but it is not sufficient to diagnose AL. Occasionally a patient will have an incidental monoclonal gammopathy of undetermined significance and a form of amyloid that is not immunoglobulin light chain in origin.4 Finding amyloid deposits on biopsy in the presence of monoclonal immunoglobulins is strong but not conclusive evidence of AL. Clinically, it is difficult to distinguish primary, secondary, familial, and senile forms of amyloid from one another. In the Mayo Clinic (Rochester, MN) experience, half of the patients with inherited amyloidosis do not have a positive family history. Patients with secondary amyloidosis typically have nephrotic syndrome. Renal biopsies demonstrate amyloid deposits. These patients also might have significant gastrointestinal involvement. Patients with hereditary systemic amyloidosis can have renal involvement