Nodular Localized Cutaneous Amyloidosis

Localized cutaneous amyloidosis (LCA) refers to a condition characterized by the deposition of amyloid or amyloid-like proteins in the dermis. Localized cutaneous amyloidosis encompasses several conditions characterized by amyloid deposition, including macular amyloidosis, lichen amyloidosis, and biphasic amyloidosis (both forms are present).  Nodular localized cutaneous amyloidosis (NLCA) is the rarest type of localized cutaneous amyloidosis and is distinct from the other forms. By definition, nodular localized cutaneous amyloidosis describes a primary disease of the skin, although lesions occasionally appear similar to the skin manifestations of systemic amyloidosis.

As a term, "amyloid" was used historically to define proteins that shared similar microscopic characteristics and affinity for certain stains. Research has revealed that "amyloid" proteins are heterogeneous. The various diseases characterized by deposition of "amyloid" proteins are similarly heterogeneous but have in common the deposits of fibrillar proteins characterized as "amyloid" in the dermis. In nodular localized cutaneous amyloidosis, the amyloid is believed to derive from local plasma cells, in contrast to lichenoid or macular amyloidosis, which have keratinocyte-derived amyloid.

In nodular localized cutaneous amyloidosis, plasma cells produce immunoglobulin γ light chains as well as β2-microglobulin, which are precursors to the amyloid fibril protein(s) termed amyloid L. Reports differ regarding the clonality of this population of plasma cells. In some instances, plasma cells have been monoclonal, suggesting that nodular localized cutaneous amyloidosis is a neoplastic disorder.[2] On the other hand, cutaneous plasma cell clonality has been observed in the absence of a monoclonal plasma cell population in the bone marrow.[2, 3] In other cases, plasma cells demonstrated polyclonality, which usually is a feature of a more reactive process.

United States data

The incidence and prevalence of localized cutaneous amyloidosis in the United States are not known; however, the scarcity of reported patients with localized cutaneous amyloidosis indicates that the condition may be rare.

International data

Despite a paucity of reported patients, localized cutaneous amyloidosis, although rare, is represented in the American, Asian, and European literature.

Morbidity/mortality

Nodular localized cutaneous amyloidosis typically is benign and limited to the skin. However, lesions are more often persistent. Reported rates of progression to systemic disease are derived from case series with small numbers of patients; these rates vary from 7% to nearly 50%.[4, 5] Progression to fatal systemic amyloidosis has been reported, although this is a rare occurrence.[6] As many as 25% of reported cases have been associated with Sjögren syndrome. Some speculate that these 2 disorders may have a shared pathogenesis.[7, 8, 9, 10, 11]

Case reports have also correlated nodular localized cutaneous amyloidosis with other autoimmune disorders such as CREST syndrome (calcinosis, Raynaud phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia syndrome), primary biliary cirrhosis, rheumatoid arthritis, and systemic lupus erythematosus.[12] Other rare associations described in the case report literature include alcoholic cirrhosis[13] and severe atopic dermatitis.[14]

Race-, sex-, and age-related demographics

Epidemiologic data can be difficult to establish when so few patients are reported. No specific racial, ethnic, or geographic group appears more prone than another to developing nodular localized cutaneous amyloidosis.

Of the first 13 patients described in the Japanese literature, 12 were women; however, this disproportionate ratio has not been seen consistently. In a subsequent series of 12 patients, the male-to-female ratio was equal. Other series have reported equal or nearly equal male-to-female ratios.

Patients reportedly range in age from 33-86 years. The mean age of onset has been reported to be 55 years. Although numbers are small, reports indicate that nodular localized cutaneous amyloidosis is likely to occur during adulthood.

The patient history may include the following:

• Nodular localized cutaneous amyloidosis lesions usually are asymptomatic.

• Patients can present with single or multiple lesions.

• In some reports, lesions were present for several years before patients sought medical attention.

• Troublesome aspects of nodular localized cutaneous amyloidosis primarily result from patient concerns about appearance, although plaques eventually fissured in one patient in whom the plantar aspects of the feet were affected.

• Up to 25% of reported cases of NLCA have been in patients with Sjögren syndrome.[15]

• In some cases, patients have given a history of preceding trauma.[4, 16, 17]

Physical examination may reveal the following:

• Firm nodules can present at any cutaneous site including the face, scalp, extremities, trunk, and genitalia; however, acral areas are preferentially involved.[18, 19, 20, 21]

• Nodules vary from a few millimeters to a few centimeters and may coalesce to form larger plaques.

• Disseminated cases have been described.[22]

• Nodules appear pink to brown or red.

• Underlying epidermal atrophy has been described.

• Other terms that describe the various lesions of nodular localized cutaneous amyloidosis include waxy, purpuric, yellowish, or bullous.

• Lesions tend not to ulcerate, although a case of localized ulcerative nodular amyloidosis with deep involvement was described.[23]

• Nodular localized cutaneous amyloidosis lacks extracutaneous findings by definition; however, one patient reported to have nodular localized cutaneous amyloidosis had amyloid deposits in the rectum.

• Macroglossia, a typical feature of systemic amyloidosis, is not seen in nodular localized cutaneous amyloidosis.

Normal serum protein electrophoresis and urine protein electrophoresis studies help to exclude multiple myeloma, which can also cause amyloid deposits made up of immunoglobulin light chains.

Positive antinuclear, anti-Ro, and anti-La antibody tests suggest Sjögren syndrome.

Laboratory studies, such as a complete blood cell count, serum chemistry profile, and liver function tests, often were part of a general workup in several case reports of patients with nodular localized cutaneous amyloidosis. Nodular localized cutaneous amyloidosis does not cause any abnormal findings in these studies.

Urinalysis or 24-hour urine testing can be performed to check for protein. Proteinuria is not a feature of localized cutaneous disease but can be seen in systemic amyloidosis.

In some patients, imaging studies have included chest radiography, electrocardiography, and abdominal ultrasonography.

Screening for amyloid within organs can be accomplished using scintigraphy with radioiodinated serum amyloid P component (ie, SAP scanning). This is a very sensitive test for detecting early systemic amyloidosis.

Skin biopsy provides the definitive diagnosis. No special tissue preparation or handling is required before delivering the specimen to the laboratory. Special stains and immunohistochemistry are helpful.

An optimal biopsy specimen includes the epidermis, papillary dermis, and reticular dermis. The amyloid in nodular localized cutaneous amyloidosis is located in the reticular dermis and subcutaneous fat, and this finding clearly differentiates nodular localized cutaneous amyloidosis from other forms of amyloidosis. A shave biopsy or other superficial sample may not include enough reticular dermis to complete the diagnosis.

Consider bone marrow biopsy with gene rearrangement studies (if available) to exclude multiple myeloma.

Despite their biochemical heterogeneity, all "amyloid" deposits demonstrate a similar light microscopic appearance. They are eosinophilic and homogeneous when stained with hematoxylin and eosin and viewed with standard optics. When stained with Congo red and viewed with polarized light, deposits exhibit a characteristic apple-green birefringence. Pagoda red is even more specific for amyloid, and staining with thioflavin T is very sensitive.

In nodular amyloidosis, amyloid is not limited to the papillary dermis but is present in the entire dermis and may extend to subcutaneous fat. Amyloid deposition may be particularly prominent in walls of small blood vessels and surrounding individual lipocytes (see the images).

The bright pink homogeneous-appearing material seen is amyloid stained with Congo red. A distinguishing feature of amyloid in the skin is an affinity to take up Congo red stain.

Amyloid shows apple green when examined with polarized light.

This transmission electron micrograph of amyloid deposited in the tissue shows loosely interwoven straight filaments.

Plasma cells, which most likely produce the amyloid, occur within an adjacent and intermingled inflammatory infiltrate. They can be sparse or numerous (similar plasma cell infiltrate occurs in nodular pulmonary amyloidosis but usually is absent in cutaneous lesions of primary systemic amyloidosis). When eosinophilic amyloid material is exposed to potassium permanganate prior to staining with Congo red, the amyloid retains its congophilia, similar to systemic amyloidosis but in contradistinction to secondary amyloidosis. Kappa or lambda light chains (or both) may be present on immunohistochemical staining.[6]

When viewed with a transmission electron microscope, the apparently homogeneous deposits of amyloid are composed of loosely interwoven 6- to 10-nm–thick straight filaments. The amino acids of the filament proteins are arranged in a characteristic beta-pleated sheet tertiary structure. Amyloid deposits in the skin also contain small amounts of a plasma-derived, nonfibrillar, amyloid-P protein.

Various methods attempt to improve the appearance of the nodular localized cutaneous amyloidosis lesions, including topical and intralesional corticosteroids, cryotherapy, dermabrasion,[24] shaving, curettage and electrodesiccation, carbon dioxide laser,[25, 26, 27] and pulsed dye laser.[28] However, lesions frequently recur after treatment. Topical and intralesional corticosteroids and cryotherapy usually are not helpful. One attempt at cryotherapy produced pinpoint bleeding. A solitary report has described successful treatment with cyclophosphamide in a patient with both CREST (calcinosis, Raynaud phenomenon, esophageal dysmotility, sclerodactyly, telangiectasia) and Sjögren syndrome.[29]  One patient responded to intralesional methotrexate.[30]

Rarely, patients with nodular localized cutaneous amyloidosis develop systemic amyloidosis or multiple myeloma years later, suggesting the need for follow-up care.

Procedures may include the following:

• Procedures such as excision and curettage and electrodessication have provided satisfactory cosmetic results for nodular localized cutaneous amyloidosis.[31]

• Laser treatment has been described in nodular localized cutaneous amyloidosis.

• Excessive tissue friability and difficulty with intraoperative hemostasis were described while treating one nasal lesion with carbon dioxide laser; however, a good cosmetic result was achieved.

• A patient treated with a tunable dye laser had a good result, and clinical improvement was maintained over 6 months.

None of these treatment methods totally eradicates lesions, which can recur.