Anatomic Pathology / CRYOFIBRINOGENEMIA IN FOUR ANATOMIC SITES

Although the histologic characteristics of cryofibrinogenemia have been described in skin lesions, the literature is largely devoid of descriptions of this disorder in other organs. This series is the first to document the histopathologic manifestations of intrapulmonary, intramuscular, and renal cryofibrinogenemia. We describe the histopathologic manifestations of cryofibrinogenemia in 10 cases with manifestations in 4 organ systems: skin in 7 cases, skeletal muscle in 2, lung in 2, and kidney in 1. Irrespective of anatomic site, all lesions showed an occlusive thrombotic diathesis comprising eosinophilic refractile deposits within vessel lumina with extension into the intima, with or without an accompanying characteristic granulomatous vasculitic component. Ultrastructural examination of the renal deposits showed fibrillary material within glomerular capillary lumina with unique morphologic features not previously described. Analysis of plasma from several cases revealed a cold-precipitable protein, which in most cases included a monoclonal paraprotein. The laboratory and histologic distinctions between cryofibrinogenemia and cryoglobulinemia are addressed. We provide guidelines for the proper handling of patient specimens in the workup of cryofibrinogenemia. Cryofibrinogenemia refers to the presence in plasma of cryoproteins mainly comprising fibrinogen, fibrin, and fibrin split products, which may be primary, with no identifiable cause, or secondary to certain autoimmune, malignant, thrombotic, inflammatory, and infectious disorders.1-3 Although the pathogenesis of cryofibrinogenemia is not well understood, the associated cutaneous and systemic manifestations have been documented.1-3 The literature describing the histopathologic manifestations of cryofibrinogenemia is limited, with most reports being in the context of skin lesions; cryofibrinogenemia-associated lesions of other organ systems are not described. We describe the histopathologic manifestations in 10 patients with cryofibrinogenemia from 4 separate sites, namely, skin, muscle, lung, and kidney. The aim of our study was to detail the histologic manifestations of cryofibrinogenemia in the skin and in organ sites not previously described. Also included are the novel ultrastructural findings of glomerular deposits seen in a renal biopsy specimen from 1 patient with cryofibrinogenemia. The distinction of cryofibrinogenemia from cryoglobulinemia is discussed as it pertains to histopathologic features and laboratory testing. The analysis of blood samples for cryoproteins requires that samples be kept at 37°C during the entire processing period to prevent false-negative results. We provide methodologic guidelines used in our laboratory for cryofibrinogen screening. Materials and Methods We prospectively encountered 10 patients with cryofibrinogenemia manifest in skin (7 cases), lung (2 cases), muscle (2 cases), and kidney (1 case) biopsy specimens. In all cases, we used light microscopy to study 5-μm, H&Eand periodic Anatomic Pathology / ORIGINAL ARTICLE Am J Clin Pathol 2003;119:114-122 115 11 DOI: 10.1092/KB5ARGWVL1R2BPBN 115 © American Society for Clinical Pathology acid–Schiff (PAS)-stained sections of paraffin-embedded, formalin-fixed tissue. Direct immunofluorescence (DIF) studies for IgG, IgA, IgM, and C3 were performed in 3 cases by overlay of a commercially prepared fluorescein-conjugated antibody on sections cut from frozen (–70°C) biopsy material and examined with a fluorescent microscope. An indirect immunofluorescence method with a fluoresceinconjugated, rabbit antimouse antibody was used to detect the presence of C5b-9 in frozen sections of these same 3 cases using anti-C5b-9 (aE11 clone, DAKO, Carpinteria, CA). Serum and plasma samples were studied to confirm the presence and nature of the cryoprecipitate using the technique described in ❚Appendix 1❚. In 6 cases, immunofixation electrophoresis was performed on the cryoprecipitate. After the cryoprecipitate was electrophoresed on an SPIFE IFE gel (Helena Laboratories, Beaumont, TX) to resolve the constituent proteins, antisera to human IgG, IgA, IgM, kappa light chains, and lambda light chains were applied.