Are You Confident of the Diagnosis?

Characteristic findings on physical examination

Macular amyloidosis typically presents as gray-brown pruritic macules, which gradually coelesce into patches with a rippled pattern involving the upper back (Figure 1) and less often the arms, chest and thighs. Macular amyloidosis is one of the more common types of primary localized cutaneous amyloidoses. The three main forms of primary localized cutaneous amyloidosis are lichen amyloidosis, macular amyloidosis, and nodular amyloidosis. Patients can sometimes have physical findings of both lichen amyloidosis and macular amyloidosis, known as biphasic amyloidosis.

Figure 1.

Macular amyloid on the back.

Figure 2.

Representative biopsy of macular or lichen amyloid. (Courtesy of Bryan Anderson, MD)

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Expected results of diagnostic studies

A skin biopsy stained with hematoxylin and eosin typically demonstrates amorphous deposits of eosinophilic material (amyloid deposits) within the papillary dermis. In order to differentiate macular amyloidosis from other skin disorders, the presence of amyloid must be confirmed.

The detection of amyloid is often made by the following staining patterns: methyl and crystal violet metachromasia, yellow-green birefringence under a fluorescence microscope after thioflavin T staining, or apple-green birefringence under a polarized light after Congo red staining. However, small amounts of amyloid may not be detected by methyl violet and Congo red staining, which can complicate the diagnosis of macular amyloidosis. It is also important to know that both lichen amyloidosis and macular amyloidosis share the ability to stain positive for antikeratin antibodies.

Diagnosis confirmation

The differential diagnosis for macular amyloidosis includes notalgia paresthetica (chronic, sensory neuropathy typically involving an area of the back, postinflammatory hyperpigmentation (increased melanin production resulting from inflammation/trauma, pityriasis (tinea) versicolor (chronic fungal infection typically presenting with hyperpigmented or hypopigmented patches on the upper part of the body, erythema dyschromicum (hyperyperpigmented [brown-gray-blue] on the upper part of the body with a resolving eythematous border, phototoxic dermatitis (hyperpigmentation due to photosenisitve skin, and drug-induced pigmentation (skin discoloration from drug exposure).

Who is at Risk for Developing this Disease?

Macular amyloidosis occurs more commonly in Central and South American, Asian, and Middle Eastern populations. There is some evidence in the literature that macular amyloidosis is more common in women who are between the ages of 20 to 50 years. Family history is important because hereditary forms of macular amyloidosis do exist.

What is the Cause of the Disease?

The amyloid deposits in macular amyloidosis are keratinocyte-derived. The exact pathogenesis leading to the apoptosis of keratinocytes is not clear but trauma such as friction (rubbing and scratching), genetic predisposition, infectious agents, and ultraviolet radiation are possible causes.

Systemic Implications and Complications

Macular amyloidosis has not been reported to progress to systemic disease with the amyloid deposits exclusively localized to the skin. However, there is evidence linking primary localized cutaneous amyloidoses to a variety of immune disorders including systemic sclerosis, CREST syndrome, rheumatoid arthritis, systemic lupus erythematosus, primary biliary cirrhosis, autoimmune cholangitis, Kimura disease, ankylosing spondylitis, autoimmune thyroiditis, IgA nephropathy, and sarcoidosis.

In some families with the hereditary forms of primary localized cutaneous amyloidoses, an association with multiple endocrine neoplasia (MEN) type 2A, also known as Sipple syndrome, has been established. MEN type 2A is an autosomal dominant disorder including the triad of medullary carcinoma of the thyroid, pheochromocytoma, and hyperparathyroidism.

It is essential that any individual in such a kindred who presents with either macular amyloidosis or lichen amyloidosis be assessed for the RET protooncogene; if the mutation is present, a prophylactic thyroidectomy should be strongly considered.

Treatment Options

Medical options

  • Topical corticosteroids

  • Topical calcineurin inhibitors

  • Intralesional corticosteroids

  • Systemic retinoids

  • Systemic cyclophosphamide

Physical modalities

  • Ultraviolet (UV) B phototherapy (narrow band and broadband)

  • PUVA (psoralen with UVA) phototherapy

Surgical options

  • Dermabrasion

  • CO2 laser therapy

Optimal Therapeutic Approach for this Disease

The treatment for both macular amyloidosis and lichen amyloidosis tends to be grouped together in the literature with no uniformly effective therapy for these patients. Patient education is important in breaking the itch-scratch-itch cycle. In mild cases, topical corticosteroids have been beneficial.

In one study, betamethasone 17-valerate ointment (0.1%) was topically applied twice daily for 12 weeks with improvement. Topical calcineurin inhibitors (0.1% tacrolimus) and intralesional corticosteroids (triamcinolone) have been reported as alternative treatments for mild cases but there are no current recommendations in the literature for dosing regimens. There are a small number of cases involving the daily use of topical dimethyl sulfoxide (concentration ranging from 10% to 100%) with significant improvement achieved within 1 week.

Systemic therapies such as retinoids, cyclophosphamide, and cyclosporine have been shown to reduce pruritus and promote clearance of lesions but have more associated side effects. In one study, acitretin (0.7mg/kg per day) was given for 4.5 months with significant improvement noted after 6 weeks of treatment. In another study, nine patients were given cyclophosphamide (50mg per day) for at least 6 months with 4 patients showing at least 50% improvement after 6 months of treatment.

Additionally, there is some evidence in the literature promoting the use of phototherapy for primary localized cutaneous amyloidosis. In one study, patients who were initially treated with either BB UVB or PUVA phototheratients who were treated with either BB UVB or PUVA phototherapy (three times a week) showed noticeable improvement after 8 weeks of treatment. Another report involving a patient who was treated with NB UVB (three times per week) showed marked improvement after 5 months of treatment. Dermabrasion, CO2 laser, and pulse dye laser provide alternative options for patients unresponsive to other treatments.

Patient Management

Laboratory testing is not recommended for macular amyloidosis because there are no specific laboratory abnormalities associated with the condition. There are no clear guidelines for monitoring therapy for patients with macular amyloidosis. The timing of follow-up care is based on the individual’s response to a chosen treatment. More studies are needed to compare different treatments and maintenance regimens. Patients and family members should be informed about the chronicity of the disease and the potential for trying multiple therapies before resolution of symptoms.

Unusual Clinical Scenarios to Consider in Patient Management

There is an unclear link between primary localized cutaneous amyloidoses and a variety of immune disorders including systemic sclerosis, CREST syndrome, rheumatoid arhritis, systemic lupus erythematosus, primary biliary cirrhosis, autoimmune cholangitis, Kimura disease, ankylosing spondylitis, autoimmune thyroiditis, IgA nephropathy, and sarcoidosis. An association between macular amyloidosis and multiple endocrine neoplasia (MEN) type 2A has also been established for families presenting with hereditary forms of primary localized cutaneous amyloidosis. Appropriate referral to other specialists should be considered if any of these diseases are suspected.

What is the Evidence?

Borowicz, J, Gillespie, M, Miller, R. “Cutaneous amyloidosis”. Skinmed. vol. 2. 2011. pp. 96-100. (This manuscript provides a brief and current summary of the different cutaneous amyloidoses including primary systemic amyloidosis and primary cutaneous amyloidosis.)

Breathnach, S. “Amyloid and amyloidosis”. J Am Acad Dermatol. vol. 18. 1988. pp. 1-16. (This manuscript provides a decent overview of primary localized cutaneous amyloidosis but most of the text is dedicated to primary systemic amyloidosis.)

Dahdah, M, Kurban, M, Kibbi, A, Ghosn, S. “Primary localized cutaneous amyloidosis: a sign of immune dysregulation?”. Int J Dermatol. vol. 48. 2009. pp. 419-21. (This article discusses the possible pathogenesis and associated immune disorders for primary localized cutaneous amyloidosis.

de Argila, D, Ortiz-Romero, P, Ortiz-Frutos, J, Rodriguez-Peralto, J, Iglesias, L. “Cutaneous macular amyloidosis associated with multiple endocrine neoplasia 2A”. Clin Exp Dermatol. vol. 21. 1996. pp. 313-4. (This article discusses the association of macular amyloidosis with multiple endocrine neoplasia (MEN) type 2A.)

Jin, A, Por, A, Wee, L, Kai, C, Keok, G. “Comparative study of phototherapy (UVB) vs”. photochemotherapy (PUVA) vs. topical steroids in the treatment of primary cutanenous lichen amyloidosis. Photodermatol Photoimmunol Photomed. vol. 17. 2001. pp. 42-43. (In this small study, patients with lichen amyloidosis received BB UVB, PUVA or topical corticosteroids. Although the results were not statistically significant, both BB UVB and PUVA were determined to be better therapies in comparison to topical corticosteroids.)

Ratz, J, Bailin, P. “Cutaneous amyloidosis. A case report of the tumefactive variant and a review of the spectrum of clinical presentations”. J Am Acad Dermatol. vol. 4. 1981. pp. 21-26. (This 1981 article provides a good summary of the differences among the amyloidoses with cutaneous manifestations.)

Rasi, A, Khatami, A, Javaheri, S. “Macular amyloidosis: an assessment of prevalence, sex, and age”. Int J Dermatol. vol. 43. 2004. pp. 898-9. (This article nicely summarizes the epidemiological data for macular amyloidosis.).

Steciuk, A, Dompmartin, A, Troussard, X, Verneuil, L, Macro, M, Comoz, F. “Cutaneous amyloidosis and possible association with systemic amyloidosis”. Int J Dermatol. vol. 41. 2002. pp. 127-32. (This article provides an overview of the different types of amyloidosis with cutaneous manifestations.)

Tanaka, A, Arita, K, Lai-Cheong, J, Palisson, F, Hide, M, McGrath, J. “New insight into mechanisms of pruritus from molecular studies on familial primary localized cuteneous amyloidosis”. Br J Dermatol. vol. 161. 2009. pp. 1217-24. (This article provides general information about macular and lichen amyloidosis with a focus on the possible mechanism underlying familial primary localized cutaneous amyloidosis.)

Touart, D, Sau, P. “Cutaneous deposit diseases. Part I.”. J Am Acad Dermatol. vol. 39. 1998. pp. 149-71. (This article provides general information about macular and lichen amyloidosis with a focus on the possible mechanism underlying familial primary localized cutaneous amyloidosis.)