White : Diseases of the Skin - Cellular and Metabolic Cutaneous Infiltrates

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Gary M. White & Neil H. Cox

Diseases of the Skin

11	Cellular and Metabolic Cutaneous Infiltrates

AMYLOIDOSES

General aspects, etiology, and pathogenesis

Amyloid is a group of disorders characterized by deposition of abnormal tissue proteins in a ﬁbrillar form with b-pleated sheet conﬁguration.

The deposits also contain serum amyloid P, which is a globulin similar to C-reactive protein. The clinical pattern varies depending on the type of ﬁbrillar protein and its localization (Figs 11.59 – Figs 11.64).

Fig. 11.62 Systemic amyloid with massive periorbital deposits. (Courtesy of the Department of Dermatology, University of California, San Diego.)

Fig. 11.63 Systemic amyloidosis. Diffuse inﬁltration of amyloid along with lymphedema may lead to massive enlargement of tissue. In this case, the hand and ﬁngers on the left are massively enlarged compared with the normal hand on the right.

Fig. 11.64 Diffuse cutaneous involvement by amyloid, with extensive bruising and bullae.

The main types of amyloid proteins of dermatologic relevance are as follows.

•	Amyloid ﬁbrils derived from immunoglobulin light chains (mainly of l type), known as amyloid L (AL). This occurs in primary systemic amyloid or in systemic myeloma-associated amyloid. Less commonly, immunoglobulin heavy chains (AH) constitute the amyloid protein in these types of amyloid. Nodular amyloid (of the skin or at other internal sites) also contains AL.
•	Amyloid derived from serum amyloid A precursor protein, this type being termed amyloid A (AA). AA occurs secondary to a wide variety of chronic inflammatory disorders, such as tuberculosis, rheumatoid and other chronic arthritis, bronchiectasis, some lymphomas, and chronic venous ulceration. Of particular dermatologic relevance, as there are cutaneous as well as systemic features, AA occurs in familial Mediterranean fever and other periodic fevers, as well as in familial cold urticaria and Muckle–Wells’ syndrome (a familial disorder with urticaria and deafness).
•	Amyloid derived from altered keratin—this occurs in several skin tumors, such as basal cell carcinoma and Bowen disease, and in benign lesions, such as seborrheic keratoses and porokeratosis, but is rarely prominent clinically. It is probably also the amyloid type in macular amyloid and lichen amyloidosis, in which scratching may play a part in disrupting keratinocytes.

About 20 other proteins are implicated in amyloidosis of various internal organs.

Clinical features

Cutaneous involvement in different types of amyloidosis is listed in Table 11.9.

Systemic amyloid may present as malaise, edema (with proteinuria), arthritis, neuropathy, cardiomyopathy, and many other symptoms. The cutaneous presentation is typically as purpura, due to amyloid inﬁltration of walls of small blood vessels in the skin. Linear purpura after scratches, pinch purpura (especially at thin skin areas), and periorbital purpura are most typical, but widespread purpura, bullae, and waxy plaques may also occur. Macroglossia is a frequent feature.
Localized cutaneous amyloid occurs as several distinct forms.

•	Nodular amyloid occurs mainly in older patients, and consists of one or several reddish brown nodules that appear mainly on the face and extremities. Most nodular amyloid is probably due to a polyclonal reactive process of AL ﬁbrils, but some patients have a monoclonal gammopathy or urinary Bence Jones protein.
•	Lichen amyloidosis occurs mainly in patients of Chinese origin, and causes small, brown, keratotic papules on the shins.
•	Macular amyloidosis is most common in Asian and South American populations, but also occurs in white ones. It usually affects the upper back and presents as rippled brown lines. It may be associated with chronic itch and scratching or rubbing, for example in notalgia paresthetica (Ch. 9).

Differential diagnosis

This depends on the pattern.

•	Purpura in systemic disease—may resemble many causes of purpura or coagulopathy. Lesions around eyes may be felt to resemble simple bruising.
•	Waxy plaques in systemic disease—may resemble syringomas (eyelids) or multiple trichofolliculomas (paranasal and eyelids) in early stages; differential later might include histiocytoses, mucinoses, xanthomatoses, necrobiotic xanthogranuloma, and cutaneous metastases.
•	Nodular amyloidosis—differential includes primary skin tumors, such as basal cell carcinoma; granulomatous diseases, such as GA or sarcoidosis; xanthomas; granuloma faciale (a vasculitis); and skin lymphoma.
•	Lichen amyloidosis—most likely to be confused with simple licheniﬁcation; lichen planus and lichen myxedematosus (papular lesions) are possible differentials.
•	Macular amyloidosis—other causes of rippled hyperpigmentation include licheniﬁcation, nostalgia paresthetica, and the so-called atopic dirty neck. The last in particular has the same rippled pigmented appearance as in macular amyloidosis. Although it is not routinely detectable, amyloid has been observed in such lesions by electron microscopy, so it may be a similar process. Notalgia paresthetica may be a form of entrapment neuropathy but is often felt to overlap with macular amyloid.

Treatment

Systemic amyloidosis is treated with a variety of chemotherapeutic agents, particularly melphalan, to control the underlying plasma cell dyscrasia, together with symptomatic treatment of complications such as cardiac failure.

Table 11.9 CUTANEOUS INVOLVEMENT IN AMYLOIDOSIS

Clinical type Amyloid protein Skin ﬁndings

Primary cutaneous amyloidosis
Macular amyloidosis
Lichen amyloidosis
Nodular amyloidosis
fiKeratin
fiKeratin
Amyloid L (AL) Rippled pigmentation, usually trunk.
Lichenoid papules, usually legs.
Usually solitary, yellowish brown, sometimes rather translucent nodule

Secondary cutaneous amyloidosis
Related to localized lesions Keratin Amyloid may be present in numerous lesions, including basal cell carcinoma, nevi, seborrheic keratosis, porokeratosis.

Systemic amyloidosis
Primary systemic (AL) amyloidosis
and myeloma-associated
amyloidosisReactive amyloidosis
(amyloid A, AA).
Hereditary forms
Mainly AL/

AA
AA

Skin ﬁndings in about 30–40%. Also macroglossia. Skin features are as follows.Purpura: due to vascular wall infiltration, especially at areas of minor trauma (includes ‘pinch purpura’), or periorbital (raccoon sign) if increased vascular pressure by coughing etc.
Plaques: due to skin infiltration; waxy yellowish or purpuric, often papular or cobblestoned plaque morphology.
Others: bullae, sclerodermoid plaques, paronychia or nail dystrophy.

Skin findings are rare, although the diagnosis may often be made by subcutaneous fat
aspirate for histologic examination. There may be features of a chronic skin disorder that has led to reactive amyloidosis, for example psoriasis, scleroderma, lupus erythematosus, hidradenitis suppurativa.
Familial Mediterranean fever may cause urticaria-like skin lesions; Muckle–Wells’ syndrome is familial urticaria and deafness (note: there are many other hereditary amyloidoses in which other amyloid proteins are involved).

Localized nodular amyloid is generally treated surgically by excision, curettage, or laser.

Macular amyloid is generally treated with antipruritic measures.Amyloidoses

Clinical type	Amyloid protein	Skin ﬁndings
Primary cutaneous amyloidosis Macular amyloidosis Lichen amyloidosis Nodular amyloidosis	fiKeratin fiKeratin Amyloid L (AL)	Rippled pigmentation, usually trunk. Lichenoid papules, usually legs. Usually solitary, yellowish brown, sometimes rather translucent nodule
Secondary cutaneous amyloidosis Related to localized lesions	Keratin	Amyloid may be present in numerous lesions, including basal cell carcinoma, nevi, seborrheic keratosis, porokeratosis.
Systemic amyloidosis Primary systemic (AL) amyloidosis and myeloma-associated amyloidosisReactive amyloidosis (amyloid A, AA). Hereditary forms	Mainly AL/ AA AA	Skin ﬁndings in about 30–40%. Also macroglossia. Skin features are as follows.Purpura: due to vascular wall infiltration, especially at areas of minor trauma (includes ‘pinch purpura’), or periorbital (raccoon sign) if increased vascular pressure by coughing etc. Plaques: due to skin infiltration; waxy yellowish or purpuric, often papular or cobblestoned plaque morphology. Others: bullae, sclerodermoid plaques, paronychia or nail dystrophy. Skin findings are rare, although the diagnosis may often be made by subcutaneous fat aspirate for histologic examination. There may be features of a chronic skin disorder that has led to reactive amyloidosis, for example psoriasis, scleroderma, lupus erythematosus, hidradenitis suppurativa. Familial Mediterranean fever may cause urticaria-like skin lesions; Muckle–Wells’ syndrome is familial urticaria and deafness (note: there are many other hereditary amyloidoses in which other amyloid proteins are involved).