246 P. Westermark A B 20 µm 20 µm Figure 2. Typical appearance of localized AL amyloidosis with discrete amyloid formation and multiple giant cells. Note the concentric appearance of some amyloid particles (arrows). region is missing (27,29,34,35,37). Small amounts of full-length light chains are usually present as well as small C-terminal fragments (13). The importance of fragmentation in the amyloidogenic process is still not quite settled, since it has been suspected to occur after ﬁbril formation. On the other hand, the almost uni- versal predominance of N-terminal fragments over fragments from the C-terminus has been suggested to indicate a major mechanism in ﬁbrillogenesis (37). Is localized AL amyloid a pseudotumor or a real neoplasm? According to Celsus a tumor originally meant swell- ing, but the designation is nowadays almost only used for neoplasm. Consequently, tumor-like lesions should be non-neoplastic swellings. It is obvious that localized AL amyloidosis appears as a tumor accord- ing to a classical deﬁnition. The descriptions ‘tumor- like’ or ‘pseudotumor’ are often used in order to discriminate from neoplasm. This may be correct for localized AL amyloidosis in the sense that the mass depends on the deposition of amyloid, but, as described below, the basic lesion is nevertheless a neoplasm in the form of a clonal expansion of one plasma cell. A localized production of the amyloid immuno- globulin light chain was suspected at an early date but was difﬁcult to prove. On most occasions, the plasma cell clone is very discrete and even difﬁcult to reco- gnize. Only very exceptionally is the background a clear-cut immunocytoma or plasmacytoma with atypia and mitoses (38). Not only is the number of plasma cells in the amyloid lesion often fairly sparse, but trials to identify monoclonality of the plasma cells by immunohistochemistry have also generally failed (22), although an abnormal overload of kappa or lambda plasma cells sometimes is evident (Figure 3). By means of immunohistochemistry it is often evident that a mixture of plasma cell populations with both kappa and lambda-expressing cells is present. A predominance of one plasma cell type (kappa or lambda) has sometimes been taken as evidence for monoclonality (39). However, gene rearrangement analysis of a few typical localized AL amyloidoses has shown presence of plasma cell clones (40-44). A similar result was obtained by amino acid sequence analysis of the deposited amyloid combined with mRNA extraction and DNA sequencing (33). There- fore it has been suggested that the process can be classiﬁed as a ‘low-grade B cell lymphoproliferative disease’ (44), a somewhat diffuse designation but one which in hematological terminology probably means a neoplasm. GC GC PC PC Amyloid 20 µm Figure 3. ‘Amyloidoma’ immunolabeled with the immunoglobulin light chain lambda-speciﬁc monoclonal antibody pwlam (73). Amy- loid and a majority of plasma cells (PC) are strongly labeled. Note the giant cells (GC) between plasma cells and amyloid. The hypothesis is that plasma cells are synthesizing an amyloidogenic Ig light chain, which is modiﬁed by giant cells to amyloid ﬁbrils.