Advanced glycation end product-modified beta2-microglobulin is a component of amyloid fibrils of primary localized cutaneous nodular amyloidosis

Primary localized cutaneous nodular amyloidosis is a rare form of cutaneous amyloidosis. Amyloid fibrils in primary localized cutaneous nodular amyloidosis have been reported to be originated from immunoglobulin light chains. Immunohistochemical studies on the lesional skins of four patients with primary localized cutaneous nodular amyloidosis demonstrated that amyloid deposits of all cases showed a positive reaction with the antibodies for beta2-microglobulin and advanced glycation end products as well as immunoglobulin light chain (kappa or lambda). No beta2-microglobulin and advanced glycation end product immunoreactivity was found in the amyloid deposits of other primary localized cutaneous amyloidosis (lichen amyloidosis and macular amyloidosis). Double immunofluorescence study of the lesional skin of primary localized cutaneous nodular amyloidosis showed that anti-kappa light chain, anti-beta2-microglobulin and anti-advanced glycation end product antibodies mostly reacted with the same area of amyloid deposit. Amyloid proteins were sequentially extracted with distilled water from one case of primary localized cutaneous nodular amyloidosis and recovered in the five water-soluble fractions (fractions I-V). Immunoblot assay of amyloid fibril proteins demonstrated that immunoreactive polypeptides with anti-kappa light chain antibody (29 kDa) and with anti-beta2-microglobulin antibody (12 kDa) were detected in fractions I-V, whereas immunoreactive polypeptide with anti-advanced glycation end product antibody (12 kDa) was detected exclusively in fractions III-V but not in fractions I and II. Two-dimensional polyacrylamide gel electrophoresis revealed that 12 kDa polypeptide in fractions I and II was electrophoretically identical with authentic beta2-microglobulin and that beta2-microglobulin in fractions III-V was advanced glycation end product-modified beta2-microglobulin with more acidic pI value. These results indicate that beta2-microglobulin is another major component of amyloid fibrils in primary localized cutaneous nodular amyloidosis and that beta2-microglobulin in primary localized cutaneous nodular amyloidosis is partly subjected to the modification of advanced glycation end product.     

Primary localized cutaneous nodular amyloidosis: case report and biochemical analysis of amyloid.

We report a patient with scalp lesions of primary localized cutaneous nodular amyloidosis. The extensive examination revealed no systemic involvement. Analysis of glycosaminoglycans (GAGs) in amyloid deposits showed a twofold increase as compared with normal skin, which was due to the increase in dermatan sulfate. Local disorders of GAG metabolism may be related to the amyloid fibril formation. Amyloid fibrils were purified and identified electron-microscopically, which consisted of two major 12,000- and 13,000-dalton and minor 29,000- and 48,000-dalton peptides. Western blotting analysis showed a minor 29,000-dalton peptide reactive with antibodies against both kappa and lambda light chains of immunoglobulin. There is a possibility that some components of amyloid in some cases of primary localized cutaneous nodular amyloidosis may consist of both kappa and lambda immunoglobulin light chains.     

Ultrastructural localization of amyloid P component in primary localized cutaneous amyloidosis

Amyloid P component (AP) was specifically localized to dermal amyloid deposits in the papular and nodular variants of primary localized cutaneous amyloidosis by an immunoperoxidase technique using an antibody to serum amyloid P component (SAP). Specific staining with anti-SAP of elastic fibre microfibrils which has previously been observed in normal skin, was also present and was noted in close proximity 10 deposits of amyloid material. AP associated with normal elastic fibre microfibrils may be involved in the deposition of amyloid fibrils in vivo.     

Localized primary cutaneous nodular amyloidosis: case report

Amyloidosis results from deposition of fibrous and insoluble amyloid protein in extracellular spaces of organs and tissues. Amyloid deposition can be localized or systemic and either primary or secondary. We report a case of localized primary cutaneous nodular amyloidosis manifested by papular-nodular, reddish-brown lesions affecting the nasal area, without evidence of systemic involvement. Immunohistochemistry showed the presence of immunoglobulin kappa light chain.     

Unusual primary cutaneous localized amyloidosis

The case of a 41-year-old female patient with an unusual type of primary localized cutaneous amyloidosis is reported. Clinical examination revealed lesions typical for macular cutaneous amyloidosis, while histology and histochemistry, in contrast, revealed the presence of nodular amyloidosis of the skin with deposition of lambda light chain amyloid.     

Secondary localized cutaneous amyloidosis in solar elastosis

A case of secondary localized cutaneous amyloidosis in solar elastosis was studied by light and electron microscopy. Amyloid deposition was restricted to areas with elastotic changes, and in some areas both changes were intermingled with each other. The amyloid was permanganate-sensitive, and proved to be protein AA. Ultrastructurally it was composed of fine tubular filaments. It is suggested that the amyloid deposition in this case was related to sunlight damage of the skin.     

Nodular localized primary cutaneous amyloidosis: a bullous variant

Primary cutaneous amyloidosis describes a group of disorders in which amyloid is deposited in the skin without evidence of systemic involvement. Nodular localized primary cutaneous amyloidosis (NLPCA) is a rare form of these skin‐restricted amyloidoses. We present an unusual case of NLPCA in a 51‐year‐old man, who had clinical and histopathological evidence of subepidermal bullous formation, a unique feature in NLPCA. The possible pathogenesis of this change is discussed.     

Nodular primary localized cutaneous amyloidosis: immunohistochemical evaluation and treatment with the carbon dioxide laser

Nodular primary localized cutaneous amyloidosis is an uncommon disorder for which there is no consistently satisfactory treatment. The amyloid fibrils are thought to have an immunoglobulin light chain derivation and systemic involvement must be excluded in all cases. We report a patient with a large scalp lesion of nodular primary localized cutaneous amyloidosis whose immunohistochemical evaluation revealed lambda light chain deposits and who thus far has no apparent systemic involvement. The lesion was treated by the carbon dioxide (CO2) laser with excellent cosmetic results and minimal morbidity.     

Gene rearrangement studies in the diagnosis of primary systemic and nodular primary localized cutaneous amyloidosis

Difficulties may arise in the diagnosis of patients with clinical features suggestive of plasma cell dyscrasia-related amyloidosis (amyloidosis L), but without evidence of a paraprotein. We have employed gene rearrangement methodology to demonstrate the clonality of bone marrow cells not only in a patient with myeloma-associated systemic amyloidosis, but also in a patient with "primary" systemic amyloidosis without overt myeloma or a detectable paraprotein. Furthermore, we have shown the clonality of the amyloid-producing plasma cells within a skin nodule of a patient with primary localized cutaneous amyloidosis; by contrast, clonal rearrangement was not detected in bone marrow cells from this patient. This finding provides definitive proof that organ-limited nodular primary localized cutaneous amyloid deposits arise in relation to cutaneous plasmacytomas. Gene rearrangement studies may enable early diagnosis and initiation of treatment in patients with systemic amyloidosis L, as well as their differentiation from patients with organ-limited nodular cutaneous amyloidosis, who do not require aggressive therapy.     

Nodular localized primary cutaneous amyloidosis: a long-term follow-up study

We present long-term follow-up data on patients with nodular localized primary cutaneous amyloidosis (NLPCA) seen at the St John's Institute of Dermatology between 1968 and 1999. This is the largest clinical follow-up study of this type of amyloid to date. Based on these cases we estimate the rate of progression of NLPCA to systemic amyloidosis to be only 7%, much lower than the 50% rate currently quoted in the literature.     

Typing of infiltration cells in primary, localized, nodular, cutaneous amyloidosis]

Amyloid tumours in two patients with primary localized nodular cutaneous amyloidosis contained very dense infiltrates consisting mainly of plasma cells and lymphocytes. In one case IgM was detected on many cells of the infiltrate, while in the other IgA was found in morphologically apparently normal plasma cells. Immunohistochemical investigations did not reveal any immunoglobulin light chain restriction in either of the tumours. Numerous cells expressed B cell markers, such as CD20 or CD38. Rearrangement studies on material from the amyloid tumour of one of the patients confirmed the monoclonality of plasma cells. This observation indicates that the nodules of primary localized nodular cutaneous amyloidosis indeed represent an extramedullary plasmocytoma, which consists of amyloid-producing plasma cells. Of special interest was the unexpectedly high proportion of cells expressing T cell markers (CD3, CD5, CD4 greater than CD8) in the amyloid nodules of both patients. After excluding co-expression of B and T cell markers on identical cells by immunohistochemical studies on serial sections and also after molecular biological studies, we assume that this is a separate T cell population that may have a regulatory effect on the production of amyloid.     

Primary localized cutaneous nodular amyloidosis successfully treated with cyclophosphamide

Primary localized cutaneous nodular amyloidosis (PLCNA) is a rare subtype of localized cutaneous amyloidosis and can be associated with various connective tissue disorders. It can be difficult to treat and past therapies include surgical excision, dermabrasion, electrodessication and curettage, cryotherapy and laser therapy. We present a case of a middle‐aged woman with PLCNA associated with CREST (calcinosis, Raynaud phenomenon, oesophageal motility disorders, sclerodactyly and telangiectasia) syndrome and Sjögren's syndrome responding to cyclophosphamide with no new amyloid deposits and resolution of skin ulceration after many years of resistance to drug therapy. It is important to monitor these patients for progression into systemic amyloidosis.     

Nodular localized primary cutaneous amyloidosis

The most common forms of localized primary cutaneous amyloidosis are lichen (papular) and macular amyloidosis. Nodular or tumefactive amyloidosis is rare and demonstrates important clinical, historical, pathogenic and prognostic differences from the lichen and macular variants. We report two cases of nodular localized primary cutaneous amyloidosis.     

Deposition of complement CIq in primary localized cutaneous amyloidosis

Deposition of immunoglobulins and complement components was studied in twelve cases of primary localized cutaneous amyloidosis by direct immunofiuorescence microscopy. CIq was detected in amyloid islands in ten cases but immunoglobulins and C3 were found in only a few cases. It is suggested that CIq may be one of the nonepidermal components of cutaneous amyloid.     

Primary localized cutaneous nodular amyloidosis and CREST syndrome: a case report and review of the literature

Primary localized cutaneous nodular amyloidosis (PLCNA) is a form of primary localized cutaneous amyloidosis (PLCA) that presents as yellowish waxy nodules on the extremities, face, trunk, or genitalia. We report the case of a patient with PLCNA and CREST (calcinosis, Raynaud phenomenon, esophageal motility disorders, sclerodactyly, and telangiectasia) syndrome. A diagnosis of her extensive PLCNA was made after biopsy specimens from the bilateral shins stained positive for amyloid extending from the superficial papillary dermis to the subcutis. Results of a workup were negative for paraproteinemia or signs of systemic amyloidosis and have remained so after 8 years of follow-up. We present a review of the literature describing the presentation and histopathology of the varying forms of amyloidosis.     

Nylon cloth macular amyloidosis

In primary localized cutaneous amyloid, deposition of amyloid is confined to the skin without the involvement of any internal organs. Amyloid deposition in the skin is often scanty, and electron microscopy may be needed to confirm the presence of the typical amyloid fibrils. There have been several case reports of cutaneous amyloidosis associated with friction or rubbing of the skin. We report a case of primary localized cutaneous amyloid associated with the habitual use of a nylon cloth.     

Immunofluorescence and histochemical studies of localized cutaneous amyloidosis

Lichen amyloidosus (LA) and macular amyloidosis (MA) are two forms of localized cutaneous amyloidosis in which the amyloid occurs as larger and smaller deposits respectively in the papillary dermis. The histogenesis of the amyloid of these conditions is unknown. By using an indirect immunofluarescence technique we showed that LA and MA do not react with antibodies against different previously characterized amyloid fibril proteins. These results indicate that the amyloid of LA and MA is different from other known types of amyloid. Protein AP, which was demonstrated in amyloid of MA and LA, is known to be present in all forms of amyloid and is of unknown significance. Antiserum against keratin did not react with the larger homogeneous amyloid bodies, but showed a weak reaction with some small deposits. Histochemical staining failed to show keratin in any of the tissues containing LA or MA.     

Lamina densa malformation involved in histogenesis of primary localized cutaneous amyloidosis.

Skin lesions of lichenoid amyloidosis and macular amyloidosis were immunohistochemically investigated using five monoclonal antibodies against basement membrane zone (BMZ) components. A hemidesmosomal component did not contribute to amyloid deposits, but components of the lamina densa and anchoring fibrils were associated with amyloid deposits in the uppermost dermis. Immunoelectron microscopy revealed that these BMZ components were not only aggregated in the BMZ and dermis, but were also involved in the individual amyloid islets. The lamina densa was disrupted in the interface areas just above the amyloid deposits, where cytoplasm of the basal cells directly faced the aggregate of amyloid filaments. Aggregates of some BMZ components were continuous to the amyloid islets from the lamina densa area. These findings suggest that a lamina densa malformation is involved in amyloid production in the interface of the BMZ, and support the secretion theory rather than the fibrillar body theory of amyloidogenesis in these types of primary localized cutaneous amyloidosis.     

Histopathological and immunohistochemical study of amyloidosis cutis nodularis atrophicans—Comparison with systemic amyloidosis

Three cases of amyloidosis cutis nodularis atrophicans (ACNA) were investigated histologically and immunohistochemically to determine the nature and origin of the deposited amyloid. A pulmonary lesion from a case of nodular pulmonary amyloidosis, and cutaneous lesions from three cases of primary systemic amyloidosis, two cases of secondary systemic amyloidosis and three cases of secondary cutaneous amyloidosis following basal cell epithelioma were also examined for comparison. Histology showed infiltration of numerous plasma cells adjacent to amyloid deposits in ACNA and nodular pulmonary amyloidosis, but not in systemic amyloidosis. Immunohistochemically, the cytoplasm of the plasma cells was stained with anti-immunoglobulin light chain or anti-Bence-Jones protein antisera or both, and amyloid material stained with anti-AL antiserum in ACNA and nodular pulmonary amyloidosis. These results suggest that, in ACNA, the plasma cells may produce and secrete immunoglobulin light chains or Bence-Jones protein or both, which undergo proteolysis to protein AL or amyloid fibril proteins which have the same immunoglobulin determinants as protein AL. The product is then deposited locally to form nodules in the dermis.     

Epidermal origin of the amyloid in localized cutaneous amyloidosis

A case of localized cutaneous amyloidosis which developed after a lichen planus-like skin reaction is reported. The amyloid consisted of amyloid fibrils enveloped by heparan sulphate granules. These amyloid fibrils reacted to anti-human keratin antibody, indicating an epidermal origin for the fibrils.