Lichen Amyloidosis

Primary localized cutaneous amyloidosis (PLCA) is characterized by extracellular deposition of heterogenic amyloid proteins in the skin without systemic involvement. Types of PLCA include the following:

• Lichen amyloidosis
• Macular amyloidosis
• Nodular amyloidosis

Lichen amyloidosis is believed to be more prevalent among Southern Chinese and South American populations.[1]  It is more common in males than in females and occurs most frequently in persons aged 50-60 years.

Lichen amyloidosis accounts for approximately 10% of cases of PLCA. The pathogenesis remains undetermined, but it is considered a secondary process following chronic scratching associated with primary disease.[2]

A rare variant of multiple endocrine neoplasia type 2A (MEN 2A) is associated with lichen amylosidosis[3] ; it is almost exclusively associated with RET codon 634 mutation.[4]  The cardinal triad of this autosomal dominant syndrome is medullary thyroid carcinoma, pheochromocytoma, and hyperparathyroidism. The lichen amyloidosis in this syndrome is usually localized to the interscapular region consisting of lichenoid papules, with hyperpigmentation and fine scaling. The histopathologic and immunohistochemistry findings are similar to those in isolated lichen amyloidosis, pointing to keratin-derived amyloidosis.[5]

Maddison et al suggest a possible cause of the severe pruritus associated with lichen amyloidosis in relation to nerve fiber density. They suggest that the hypersensitivity of the remaining nerve fibers is a response to an unexplained neurodegeneration of the absent nerve fibers.[6]

The diagnosis can usually be made clinically, particularly in patients with the classic presentation. Both macular and lichen amyloidosis can occur in the same patient; this is sometimes called biphasic amyloidosis. A skin biopsy should be reserved for evolving lesions. 

Lichen amyloidosis is a chronic condition without potential for malignant transformation or increase in mortality. Treatment is not required but can be employed for symptomatic or cosmetic complaints. Many therapeutic modalities have been suggested, including topical and systemic medications, phototherapy, electrodessication, dermabrasion, cryosurgery, and lasers, but no standardized treatment has been established.[7]  Complications are usually related to pruritus with bleeding from excessive scratching. 

Amyloidosis is a generic term that signifies the abnormal extracellular tissue deposition of one of a family of biochemically unrelated proteins that share certain characteristic staining properties, including apple-green birefringence of Congo red–stained preparations viewed under polarizing light. Under electron microscopy (EM), amyloid deposits are composed of linear, nonbranching, aggregated fibrils that are 7.5-10 nm thick and of indefinite length and arranged in a loose meshwork.

X-ray diffraction crystallography and infrared spectroscopy revealed that these fibrils have a meridional, antiparallel, beta-pleated sheet configuration with polypeptide chains arranged perpendicular to the long axis of the fibrils.[8]

Amyloid deposits contain (in addition to the fibrillar component) a nonfibrillar protein referred to as amyloid-P (Am-P). This protein is identical to normal plasma globulin, known as serum amyloid-P (SAP). Am-P constitutes 14% of the dry weight of amyloid. This protein is also found in the microfibrillar sheath of elastic fibers. SAP is closely related to the acute-phase reactant C-reactive protein (CRP) and has been shown to be an elastase inhibitor.

SAP and the beta-pleated sheet configurations are thought to protect amyloid deposits from degradation and phagocytosis, leading to persistence of the deposits.

Basal keratins are the primary elements of the amyloid deposits.[9] Amyloid deposits in macular amyloidosis and lichen amyloidosis bind to antikeratin antibodies. These deposits contain sulfhydryl groups, pointing to altered keratin as a source for these deposits. Apaydin et al found no differences in staining characteristics of cytokeratins between macular amyloidosis and lichen amyloidosis.[10] Interestingly, in their study, all the cytokeratins detected in amyloid deposits were of basic type (type II). This may be because, in amyloidogenesis, acidic cytokeratins such as cytokeratin 14 are degraded faster than basic types.

Weyers et al presented a convincing argument that the deposition of amyloid in lichen amyloidosis is not the cause but the result of itching and scratching. This argument was based on several lines of evidence.[2]

Amyloid deposition per se does not cause itching. Systemic amyloidosis is not associated with pruritus. Nonpruritic lichen amyloidosis has also been described. Pruritus usually precedes the development of lichen amyloidosis by years. Amyloid cannot be detected in clinically healthy skin of patients with lichen amyloidosis.

Small-fiber neuropathy (SFN) has been found in patients with lichen amyloidosis and pruritus. An increase in epidermal expression of IL-31 receptors in the skin was also found. SFN results in a reduction of intraepidermal nerve fibers (IENF), and pruritus may be associated with hypersensitivity of cutaneous nerve fibres related to the increased expression of epidermal IL-31 receptors.[1]

Striking similarities, both clinically and histopathologically, exist between lichen amyloidosis and lichen simplex chronicus.

The genetic basis of familial primary localized cutaneous amyloidosis and, potentially, the sporadic form appears to involve mutations in the oncostatin M receptor (OSMR) and IL-31 receptor A (IL31RA) genes.[11] A pathogenic missense mutation was identified in the OSMR gene that encodes the OSMR β (OSMR-β) in a Brazilian pedigree.[12]  Lin at al found a point mutation in the IL31RA gene in a family with hereditary autosomal dominant primary localized cutaneous amyloidosis.[13]  

Although it is usually an isolated finding, lichen amyloisosis may be associated with multiple endocrine neoplasia type 2A (MEN 2A), primary biliary cirrhosis, systemic lupus erythematosus (SLE), and Sjogren’s syndrome. 

The classic presentation of lichen amyloidosis includes multiple pruritic, hyperpigmented, hyperkeratotic papules that may coalesce to form plaques in a rippled pattern. The most common site is the shins and lower limbs, but involvement of the upper extremities and trunk is possible.[11, 14] (See the image below.)

Lichen Amyloidosis. Courtesy of DermNet New Zealand (http://www.dermnetnz.org/assets/Uploads/systemic/amyloid1.jpg).

The most common dermoscopic finding of lichen amyloidosis is a white central hub surrounded by various configurations of brownish pigmentation, including fine radiating streaks, dots, leaf-like projections, and bulbous projections.  Additionally, the central hub may be replaced by a scar-like area (which may be the only feature in larger and thicker lesions), and a rim of white collarette (resembling a volcanic crater) may sometimes be present.[15]

The diagnosis can usually be made clinically, particularly in patients with the classic presentation. A skin biopsy should be reserved for evolving lesions. Many stains can demonstrate amyloid deposits in the skin. The best known is the Congo-red stain, which under polarizing light gives apple-green birefringence. Other stains include periodic acid-Schiff (PAS); methyl violet; crystal violet; various cotton dyes (eg, pagoda red, Sirius red); and the fluorescent dyes thioflavin-T and Phorwhite BBU.

Amyloid deposits in lichen amyloidosis are found in the papillary dermis, usually at the tips of the dermal papillae. Lichen amyloidosis is distinguished from macular amyloidosis by the presence of marked epidermal changes, including hyperkeratosis and acanthosis.

Many therapeutic modalities have been suggested, including topical and systemic medications, phototherapy, electrodessication, dermabrasion, cryosurgery, and lasers, but no standardized treatment has been established.[7]  Because of the growing appreciation of the importance of pruritus as the primary trigger for the deposition of amyloid, treatment modalities are often directed toward the relief of pruritus. 

Sedating antihistamines have been found to be moderately effective. Menthol, in combination with other agents (eg, antihistamines), has been used successfully to relieve the pruritus associated with lichen amyloidosis.[16]

Topical and intralesional steroids are beneficial if combined with other modalities. Costanedo-Cazares et al reported improvement in lichen amyloidosis using treatment with 0.1% topical tacrolimus ointment.[17]  Topical dimethyl sulfoxide (DMSO), a chemical solvent, was used with moderate success, but failures have also been reported.[18, 19, 20] Pandhi et al reported a lack of effect with DMSO treatment for cutaneous amyloidosis.[21]

Acitretin has been used successfully to relieve pruritus and flatten hyperkeratotic papules in 3 patients with lichen amyloidosis.[22, 23, 24] In a report emphasizing the localization of lichen amyloidosis in body regions with lower temperatures, narrow-band UVB was used to treat the patient; marked improvement of pruritus and clearing of the amyloid deposits was reported.[25]

Terao et al evaluated the effects of topical tocoretinate on lichen amyloidosis and macular amyloidosis lesions. The outcome was very good for 4, good for 2, moderate for 2, and poor for 2 of 10 treated patients.[26]  Koh et al reported successful clearance of amyloid deposition and near normalization of epidermal changes following a 6-month course of daily oral alitretinoin 30 mg in a 49-year-old woman with lichen amyloidosis and atopic dermatitis.[27]  Yew and Tey reported significant reduction in pruritus in 2 patients after administration of amitriptyline 10 mg for 6 weeks.[28]

Aggressive strategies proposed for the removal of amyloid include laser vaporization, dermabrasion, and excision of individual lesions. However, both the lesions and the pruritus usually promptly recur after these treatments. Sawamura et al reported satisfying improvement of lichen amyloidosis with pulsed dye laser. Both pruritus and the papular eruption of lichen amyloidosis improved.[29]

Aoki and Kawana reported successful treatment of lichen amyloidosis of the auricular concha using electrodessication.[30]  Significant improvements were observed in lichen amyloidosis treated with carbon dioxide laser in 2 studies.[31, 32]

The goal of pharmacotherapy for lichen amyloidosis is to reduce morbidity.

Class Summary

These agents act by competitive inhibition of histamine at the H1 receptor. They may control itching by blocking effects of endogenously released histamine.

Chlorpheniramine (Chlor-Trimeton)

Chlorpheniramine competes with histamine or H1 receptor sites on effector cells in blood vessels and the respiratory tract.

Diphenhydramine (Benadryl)

Diphenhydramine is used for symptomatic relief of symptoms caused by the release of histamine in allergic reactions.

Class Summary

This agent is an industrial solvent.

Dimethyl sulfoxide (Rimso-50)

Dimethyl sulfoxide may help relieve symptoms. DMSO, an oxidation product of dimethyl sulfide, is an exceptional solvent possessing a number of commercial uses. This not an FDA-approved indication.