Pathogenesis of the amyloidogenic plasma cell clone Given that the most common localization of localized AL amyloidosis is at mucous membranes in contact with the environment, it has been suggested there is an antigenic induction of amyloidogenic plasma cell clones (17). A chronic inﬂammation has often been encountered (15). It seems likely that similar plasma cell clones without amyloid deposits may appear as commonly when the cells do not produce an amyloi- dogenic Ig light chain. It is noteworthy that a number of cases with localized AL amyloidosis have been associated with Sjögren’s syndrome (24,45). Giant cells in localized AL amyloidosis Foreign giant cells are very often mentioned in plen- tiful case reports on localized amyloidosis (e.g. (17,18,22,36,39,44,46-55)). Their occurrence is usu- ally explained as a reaction to the amyloid deposits (54). However, amyloid in general does not induce a foreign body reaction, and there are almost never any giant cells present in the amyloid masses in systemic AL amyloidosis. Furthermore, amyloid ﬁbrils close to giant cells are organized in the same way as seen at sites where cells participate in amyloid production, e.g. in the spleen in AA amyloidosis (56) or in the islets of Langerhans in IAPP amyloidosis (14). This is often suggested already when using polarization microscopy where a clear-cut orientation of amyloid ﬁbril bundles against giant cells is evident (Figure 4). Therefore, we proposed that giant cells in localized AL amyloidosis directly participate in the transfor- mation of the soluble full-length light chains into GC Amyloid GC GC Figure 4. Amyloid adjacent to giant cells (GC). An organization of amyloid ﬁbrils is apparent when in contact with giant cells. This organization is interpreted as assemblage of protein, probably after some modiﬁcation, into ﬁbrils on or at the surface of the cells. Congo red stained section in polarized light with crossed polars. Localized AL amyloidosis: A suicidal neoplasm? 247 insoluble ﬁbrils formed from N-terminal light chain fragments (34). The genesis and function of multinuclear giant cells, typical of certain infections and inﬂammations, are still poorly understood. They develop by fusion of macrophages and are generally thought of as cellular elements that try to perform phagocytosis of particular structures, e.g. larger foreign particles. However, this simplistic explanation has been questioned, and giant cells may exhibit novel functions that are not yet understood (57). Experimentally, giant cells have been reported to be induced by cultivation of mono- cytes in the presence of interleukin 3 (IL-3) and interferon-gamma (58,59), IL-4 (60-64), or IL-13 (65). Plasma cells can express IL-4 (66). Although T cells may be a more important source of IL-4, there is a normal foreign body response in T cell- deﬁcient mice (67). The inducer in localized AL amyloid is unknown, and giant cells do not appear in the bone-marrow in systemic AL amyloidosis in spite of presence of neoplastic plasma cells. It should also be pointed out that the bone-marrow is usually not particularly affected in the systemic disease, although the ﬁbril protein is synthesized there. Hypothesis and conclusion From the current knowledge, it is only possible to create a hypothesis for the pathogenesis of localized AL amyloidosis. A benign small plasma cell clone is formed at one site, perhaps after prolonged antigenic stimulation. The clonal plasma cells produce an immunoglobulin light chain which is amyloidogenic but needs to be modiﬁed. Only clones that can recruit macrophages, which fuse to giant cells by mechanisms yet to be elucidated, can form amyloid. The modiﬁ- cation of the light chains may take place within giant cells which take up the soluble light chain molec- ules by endocytosis and process them so that the N-terminal parts can aggregate into ﬁbrils. Alter- natively, protein modiﬁcation may occur on the cell surface. Most likely, the assembly take place on the cell surface, e.g. after lysosomal secretion, which is a regulated secretory pathway (68). Such a scenario would explain the evident organization of amyloid ﬁbrils close to giant cells, very different from what is seen in deposits in systemic amyloidosis. Another fact which points to a pathogenesis different from systemic amyloidosis is that localized AL amyloid of kappa type is common. Although it is only possible to speculate, this may depend on a lower propensity of kappa chains to form beta-sheet ﬁbrils, overcome in the localized situation where the protein concentra- tion close to plasma cells likely is high. The hypothetical