Localized cutaneous amylodosis

 

Salient features

 

·       The three major forms of primary cutaneous amyloidosis are:

 

·       Macular amyloidosis: hyper pigmentated macules, often on the upper arm and back

 

·       lichen amyloidosis: hyper pigmented papules, favors the extensor surfaces of the extremities

 

·       both types are characterized by rippled pattern with parallel bands or ridges of hyperpigmentation

 

 

·       Biphasic amyloidosis has features of both macular amyloidosis and lichen amyloidosis

 

·       The amyloid deposits in macular amyloidosis and lichen amyloidosis are keratinocyte-derived.

 

 

Introduction

 

Primary localized cutaneous amyloidosis is associated with the deposition of amyloid in apparently normal skin without associated deposits in internal organs. The most common variants are macular amyloidosis, lichen amyloidosis and biphasic amyloidosis. Primary localized cutaneous amyloidosis can have a profound effect on quality of life due to the associated pruritus and visual appearance of the skin lesions.

 

 

Etiology

 

The etiology of PLCA remains unknown. The occurrence of rare familial cases suggests the importance of genetic factors. It has been proposed that focal epidermal damage and filamentous degeneration of keratinocytes is followed by apoptosis and conversion of filamentous masses (colloid bodies) into amyloid material in the papillary dermis.

 

 

Pathogenesis

 

The precise pathogenesis of primary cutaneous amyloidosis is not yet fully understood. Prolonged friction, genetic predisposition, Epstein-Barr virus and environmental factors have all been proposed as possible etiologic factors. The precursor protein involved has not been fully characterized; however, the amyloid of macular and lichenoid variants of primary cutaneous amyloidosis is thought to be keratinocyte-derived. This has been supported by ultra structural studies demonstrating transitional forms between viable keratinocytes and amyloid, as well as by positive reactions with monoclonal antibodies directed against keratins of basal keratinocytes. The fibrillar theory proposes that the tonofilaments of keratinocytes undergo filamentous degeneration and pass into the dermis, where, presumably, they are modified by histiocytes and fibroblasts into amyloid material.

 

Amyloid characteristics

 

In H&E-stained sections, amyloid appears as homogeneous, hyaline, eosinophilic masses. With Congo red staining, amyloid has an orange–red color by light microscopy, and it has a characteristic green birefringence under polarized light. Staining with antibodies directed against specific precursors (e.g. keratin).

 

By electron microscopy, amyloid appears as 7 to 10 nm wide, non-branching, non-anastomosing fibrils. X-ray crystallography and infrared spectroscopy reveal a characteristic cross-β-pleated sheet conformation. The cross-β-pleated sheet configuration of amyloid is believed to be responsible for the staining and birefringence with Congo red.

 

Clinical features

Because macular amyloid and lichen amyloidosus may coexist in an affected individual (biphasic amyloidosis), they are regarded as variants of a single pathological process.

Macular amyloidosis is often pruritic but pruritus may be absent in 18% of cases. The lesions of macular amyloidosis are small brownish macules, either in a confluent manner or a characteristic rippled pattern. The latter can be best appreciated by stretching the skin. The lesions may be confined to the interscapular area, but more commonly are extensively distributed over the upper back or chest. Lesions may also occur on the extensor surfaces of the extremities, and occasionally on the buttocks. Extensive involvement can be seen in an occasional patient. Macular amyloidosis usually presents in early adulthood, and women may be affected more often than men. In biphasic amyloidosis, fine papular lesions are superimposed upon a background of hyperpigmentation.

The term “friction amyloidosis” has been used to describe a subgroup of patients in whom local friction as a result of rubbing the skin vigorously with a nylon brushes, towels and other rough materials perhaps causing epidermal damage, contributes to the production of macular and lichenoid lesions. There is also significant clinical overlap between macular amyloidosis and the pigmented type of nostalgia paresthetica, where pruritus of the scapular areas leads to rubbing and scratching.

Lichen amyloidosis is the most common form of primary cutaneous amyloidosis and usually presents as persistent, pruritic plaques distributed principally on the shins. The calves and other extensor surfaces of the extremities such as ankles, dorsa of the feet, anterior thighs, arms, forearms and abdominal or chest wall, may also be involved. Initial lesions are discrete, firm, scaly, hyperkeratotic and skin-colored or hyper pigmented papules, which later coalesce into plaques that often have a rippled or ridged pattern. At the onset, lesions are usually unilateral, but over time a bilateral, symmetric distribution pattern can develop. The condition usually persists for many years with localized pruritus as the prominent symptom.

Primary cutaneous amyloidosis of the auricular concha, in which small papules are grouped on the concha of the ear, is also believed to be a variant of PLCA, and may coexist with lichen amyloidosus.

Primary cutaneous amyloidosis manifesting as pigmentation and lichenification of the anal and sacral regions has been described as an ano-sacral variant, but these patients often have lichen amyloidosis or biphasic amyloidosis elsewhere.

Dyschromic amyloidosis is a rare variant in which a guttate leukoderma is superimposed upon a background of hyperpigmentation and admixed with characteristic lesions of macular and lichen amyloidosis

 

Pathology

In macular and lichenoid forms of amyloidosis, amyloid deposits are restricted to the upper dermis, particularly the papillary dermis. In macular amyloidosis, the deposits of amyloid are composed of small, multifaceted, amorphous globules, similar in size to the hyaline bodies found in lichen planus. They may be so sparse that more than one biopsy is necessary to confirm the diagnosis, and are easily missed without the use of special stains. The epidermis is usually of normal thickness. In lichen amyloidosis, the deposits may expand the papillae and displace the elongated rete ridges laterally, and the overlying epidermis is often acanthotic and hyperkeratotic. Melanophages and a sparse perivascular lymphohistiocytic infiltrate can be seen in both forms. Antikeratin antibodies (such as LP34, MNF 116 and RCK 102) may be useful in identifying these two forms of primary cutaneous amyloidosis.

Photomicrograph of macular amyloidosis (H and E, ×400)

Photomicrograph showing apple-green birefringence (arrows) under polarized microscope (Congo red stain, ×100)

 

Differential diagnosis

The diagnosis of primary cutaneous amyloidosis is based upon the morphology of the lesions and on the histologic demonstration of the cutaneous amyloid deposits.

There is significant overlap in the appearance of macular amyloidosis and nostalgia paresthetica. The latter is also seen on the upper back and can have rippled hyperpigmentation. Histologically, nostalgia paresthetica contains scattered melanophages but no amyloid deposits.

The primary differential diagnosis for lichen amyloidosis includes lichen simplex chronicus (LSC) and hypertrophic lichen planus (LP). Both of these are characterized by chronic pruritic plaques, often on the shins. Histologically, both exhibit hyperkeratosis, acanthosis, and a mild to moderate lymphohistiocytic inflammatory infiltrate but no amyloid deposits. In LSC, lichenification is often prominent, while hypertrophic LP lesions may have a violaceous hue and, on histologic examination, a lichenoid infiltrate with vacuolar degeneration.

 

Treatment

To date, none of the treatment modalities has proven to be curative or uniformly effective in patients with macular and lichenoid amyloidosis. Treatment must be directed at breaking the itch–scratch–itch cycle usually present in these patients. Chronic friction, scratching and rubbing, for example with towels and nylon brushes, can serve as possible precipitating or aggravating factors, and patients should be advised of this. Potent topical corticosteroids are useful to some extent, especially in mild cases, and their use under occlusion or in combination with a mild keratolytic agent such as salicylic acid (particularly in lichen amyloidosis) may have added benefit. The involved sites can be protected from scratching by applying occlusive dressings such as hydrocolloids or gauze wraps impregnated with zinc oxide for a period of weeks to months, but recurrence rates may be high. A trial of topical dimethyl sulfoxide (DMSO; 50% or 100% solution) has been reported to have little beneficial effect. Based upon case reports, topical calcineurin inhibitors may play an adjunctive role.

Dermabrasion has been shown to be beneficial in lichen amyloidosis involving the limbs: the epidermis and part of the papillary dermis along with some of the amyloid is removed, permitting re-epithelialization to occur from the adnexal structures. After more than 5 years of follow-up, there was significant improvement in symptoms and appearance without recurrence. Post inflammatory hypo- and hyperpigmentation did occur but usually improved over time.

Acitretin (0.5 mg/kg/day) have been reported to improve pruritus and result in flattening of lesions with some clearance of the associated hyper pigmentation. Low-dose cyclophosphamide (50 mg daily) is reported to be effective in reducing pruritus and papules in lichen amyloidosis. Dexamethasone cyclophosphamide pulse therapy stopped itching after five sessions and lesions cleared after nine sessions with no relapse during 30 months of follow-up. However, the side effects of these systemic medications must be weighed against the possible benefits.

CO₂ or erbium:YAG laser therapy has also been shown to be of benefit in some patients with macular and lichen amyloidosis.

 

TREATMENT OF MACULAR AND LICHEN AMYLOIDOSIS

Potent topical corticosteroids, including under occlusion (2) Topical calcineurin inhibitors (3) Intralesional corticosteroids (3) Occlusive dressings (e.g. hydrocolloid) or wraps (e.g. zinc oxide-impregnated) (3) UVB phototherapy (2) PUVA phototherapy (2) Systemic retinoids (2) Dermabrasion (2) CO2 laser therapy (2) Low-dose cyclophosphamide (3) Cyclosporine (3)

Key to evidence-based support: (1) prospective controlled trial; (2) retrospective study or large case series; (3) small case series or individual case reports. PUVA, psoralen plus UVA; UVB, ultraviolet B.