Original Articles Should the Reporting of Bone Marrow Positivity for Amyloid Be Revised? A Critical Assessment Based on 66 Biopsies From a Single Institution Sara Javidiparsijani, MD; Maria M. Picken, MD, PhD  Context.—Amyloidoses are rare but heterogeneous disorders for which diagnosis is contingent upon the detection of deposits by Congo red stain and amyloid protein typing determines the treatment options. Objective.—To address the reporting of bone marrow (BM) involvement by amyloid in relation to the spatial distribution of deposits and to explore whether the location of deposits may have clinical relevance. Design.—We examined 66 BM biopsies positive for amyloid with regard to the location and type of amyloid, the percentage and clonality of plasma cells, other organ involvement, and relevant clinical information. Results.—In 21 cases, amyloid deposits involved BM stroma, whereas 45 cases were nonstromal. All cases of stromal involvement were typed as amyloid light chain (AL) amyloidosis (or presumed AL), whereas nonstromal involvement was associated with at least 3 types of amyloidosis: AL, amyloid transthyretin (ATTR), and amy- loid A (AA). The initial diagnosis of amyloidosis was made in a BM specimen in 21 of 66 cases (31.8%). Plasma cells ranged from 1% to 80% (mean, 13.4%; median, 8%; ,10% in 44 of 66 specimens [66.6%]) and were monoclonal in 58 of 66 cases (87.8%), and in 54 of 66 cases (81.8%) amyloid deposits were documented in at least one other organ. Conclusions.—This study demonstrates that there is significant heterogeneity in the spatial distribution of amyloid in BM biopsy specimens with medullary, extra- medullary, purely vascular, or combined involvement. Whereas stromal deposits were associated exclusively with AL, nonstromal and purely vascular deposits were seen in at least 3 types of systemic amyloidosis (AL, AA, and ATTR). We discuss the reporting of BM biopsy tissue positivity for amyloid deposits. (Arch Pathol Lab Med. 2020;144:967–973; doi: 10.5858/ arpa.2019-0324-OA) A myloidoses are a heterogeneous group of disorders that are characterized by the deposition of abnormal proteins in tissues. In this process, globular, soluble proteins misfold and aggregate into insoluble fibril (‘‘amyloid’’) aggregates that lead to progressive organ damage. 1 By electron microscopy, amyloid deposits consist of rigid, nonbranching fibrils that typically measure 8–12 nm in diameter. The fibrils possess a cross–b-pleated structure, in which b-strands are oriented perpendicularly to the fibril axis. To date, 36 proteins have been identified to be amyloidogenic in humans. 1,2 Amyloid deposits may be localized, as in Alzheimer disease or type II diabetes, or systemic, affecting various organs or tissues throughout the body. The clinical manifestations of amyloidosis are heterogeneous and may be influenced by both genetic and environmental factors. The most common type of systemic amyloidosis is amyloid light chain (AL) amyloidosis, where fibrils are derived from the immunoglobulin light chain or its fragment. 1,3–5 Approximately 2200 new cases of AL are diagnosed every year in the United States, and there has been a 2.6-fold increase between 2007 and 2015, from 15.5 to 40.5 cases per million. 3 Other systemic amyloidoses include AA, ALECT2, and hereditary amyloidoses. 1 AA (amyloidosis derived from serum amyloid A protein, acute- phase reactant) is typically associated with an underlying chronic inflammatory process, whereas the pathogenesis of ALECT2 (amyloidosis derived from leukocyte chemotactic factor 2) is unclear; no genetic component has emerged as yet, despite a strong association with Mexican American ethnicity. Among the hereditary amyloidoses, most types are individually rare, but collectively hereditary amyloidoses constitute approximately 10% of all systemic amyloidoses currently diagnosed. This may, however, represent under- diagnosis. 6–9 Of this group, amyloidosis derived from a transthyretin variant (ATTRv) has begun to emerge as a significantly underdiagnosed cause of cardiac failure and polyneuropathy; ATTR derived from the wild type Accepted for publication November 5, 2019. Published online January 16, 2020. From the Department of Pathology, Loyola University Medical Center, Maywood, Illinois. Dr Javidiparsijani is now with the Department of Hematopathology, NYU-Langone Health, New York, New York. The authors have no relevant financial interest in the products or companies described in this article. Presented in part at the annual meeting of the United States and Canadian Academy of Pathology; March 16–21, 2019; National Harbor, Maryland. Corresponding author: Maria M. Picken, MD, PhD, Department of Pathology, Bldg 110, Room 2242, Loyola University Medical Center, 2160 S First Ave, Maywood, IL 60173 (email: mpicken@lumc.edu). Arch Pathol Lab Med—Vol 144, August 2020 Amyloidosis in Bone Marrow Biopsy Specimens—Javidiparsijani & Picken 967