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Cutaneous amyloidoses and systemic amyloidoses with cutaneous

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Article  in  European journal of dermatology: EJD · March 2010

DOI: 10.1684/ejd.2010.0842 · Source: PubMed

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Review article Eur J Dermatol 2010; 20 (2): 152-60

Stephan SCHREML1 Cutaneous amyloidoses and systemic

Rolf-Markus SZEIMIES1
Thomas VOGT1 amyloidoses with cutaneous involvement
Michael LANDTHALER1
Josef SCHROEDER2
Philipp BABILAS1 Extracellular deposition of altered autologous protein (amyloid protein)
1
within the dermis is the hallmark of cutaneous amyloidoses and sys-
Department of Dermatology, temic amyloidoses with cutaneous involvement. Amyloidoses may be
University Hospital Regensburg,
Franz-Josef-Strauss-Allee 11, acquired or hereditary in nature and subclassification differentiates
93053 Regensburg, Germany
2
between primary amyloidosis (no obvious predisposing disease) and
Institute of Pathology, secondary amyloidosis (specific underlying disease). More than 26 dif-
University Hospital Regensburg,
Franz-Josef-Strauss-Allee 11, ferent proteins and peptides have been identified as amyloid precursors
93053 Regensburg, Germany and these proteins are used to subclassify this heterogenous group of
diseases. The amyloid proteins show an anti-parallel β-sheet conforma-
Reprints: S. Schreml tion and form non-branching linear filaments of variable lengths and
<stephan.schreml@klinik.uni-regens-
burg.de> diameters of approximately 7.5 to 10 nm. However, the exact etiopatho-
genesis of amyloid formation still remains unclear. Depending on histo-
anatomical distribution and amount, amyloid may cause progressive and
life-threatening organ dysfunction. Clinical presentation, histology,
electron microscopy, and biochemical-immunological differentiation
represent decisive tools for an accurate diagnosis.
Article accepted on 15/9/2009 Key words: amyloidosis, hereditary, non-hereditary

he term “amyloid”, which stands for starch-like

T
according to the amyloid subtype found. The amyloid
(lat. amylum), was introduced into science by P component – which seems to be structurally identical
Rudolf Virchow in 1854, who described extracel- with the serum amyloid P component (SAP) – can be
lular precipitates which turn brown after incubation with detected in almost all amyloid deposits [9] and amounts
iodine [1]. Even though these precipitates are proteins to approximately 15% of the total weight of the extracted
rather than carbohydrates, the terms “amyloid” and “amy- amyloid [2]. Furthermore, several different amyloid
loidosis” were coined for this heterogeneous group of dis- subtypes may be present in one clinical entity, which
eases. The key feature of all types of amyloidoses is the can be classified by biochemical and immunological
extracellular deposition of autologous proteins as charac- methods.
teristic amyloid fibrils [2, 3]. Amyloid can originate from
various precursor proteins, and this pathogenetic modifi-
cation of normal human proteins may be triggered by Biochemical and immunological aspects
chronic inflammation, malignancies, and mutations.
Cutaneous amyloidoses and cutaneous manifestations of Based on biochemical and immunological investigations, a
systemic amyloidoses are rare in Europe but far more fre- variety of different cutaneous amyloid subtypes can be dis-
quent in Southeast Asia, China, and South America [4, 5]. tinguished. Sometimes, more than one amyloid subtype can
Even though the clinical presentation varies, particular be found.
clinical features may point to amyloidosis. On the other (1) Amyloid A (AA) = fragments of serum amyloid associ-
hand, cutaneous signs are often the key finding for the ated protein (SAA);
initial diagnosis of underlying systemic amyloidosis. (2) Amyloid K (AK) = cytokeratin, keratin-associated
amyloid;
(3) Amyloid L (AL) = immunoglobulin light chain
Basic classification type/Bence-Jones amyloid (ALκ/ALλ-Ratio: 1:2);
(4) Amyloid β2 (Aβ2M) = β2-microglobulin deposition in
Amyloidoses can be subdivided in cutaneous amyloidoses hemodialysis patients;
and systemic amyloidoses with cutaneous involvement (5) Amyloid TTR (ATTR) = transthyretin precipitation with
doi: 10.1684/ejd.2010.0842

[2, 6]. In both groups, amyloid is precipitated in the extra- polyneuropathy;

cellular space of the dermis. In cutaneous amyloidoses, (6) Amyloid ApoA1 (AApoA1) = apolipoprotein A1 depo-
amyloid precipitates can be found in the papillary dermis sition with cardiomyopathy;
[7]. In contrast, in systemic amyloidoses with cutaneous (7) Amyloid ApoE4 (AApoE4) = apolipoprotein E4 in
involvement, subpapillary layers (Stratum reticulare, sub- some forms of primary cutaneous amyloidosis;
cutis), dermal appendages, and blood vessels may also be (8) Amyloid Cys C (ACys) = cystatin C deposition with
involved [8]. In addition, amyloidoses can be classified cerebral hemorrhages;

152 EJD, vol. 20, n° 2, March-April 2010

(9) Amyloid Gel (AGel) = gelsolin deposition in Meretoja-
syndrome with cutaneous symptoms (cutis laxa, petechiae, A
alopecia).
With respect to cytokeratins, it should be mentioned that
cytokeratin 5 is predominantly found in basal keratinocytes.
A cytokeratin profile of primary and secondary cutaneous
amyloidoses showed positivity for cytokeratin 5 in all inves-
tigated cases of both formalin-fixed paraffin-embedded
tissue sections and frozen tissue sections. In descending
order, other cytokeratins are also present in primary
(CK5 > 1 > 14 > 10) and secondary (CK5 > 1 > 10 > 14)
cutaneous amyloidoses [10]. Based on these results, antibo-
dies against cytokeratin 5 may be used for diagnosing
amyloidosis. Also pan-CK-antibodies and for instance
34βE12 are suitable for staining of CK5, CK1, CK10, and
CK14. These antibodies are preferentially used for the
immunological diagnosis of most organ-limited cutaneous
amyloidoses.

B
Clinical presentation
Clinical presentation (figure 1) of the different amyloi-
doses affecting the skin varies (tables 1, 2). Organ-
limited cutaneous amyloidoses often show yellowish or
brownish macules, papules, or plaques of varying config-
uration, whereas systemic amyloidoses often initially
present with petechiae, ecchymosis, and non-healing
ulcers. These differences in clinical presentation are due
to the amyloid deposition, which – in organ-limited
cutaneous amyloidoses – nearly exclusively occurs in
the papillary dermis but also affects deeper skin layers
in systemic amyloidoses. Perivascular amyloid deposition
makes blood vessels fragile, eventually causing intracuta-
neous micro- and macro-hemorrhages. For all types of
amyloidoses, pruritus is a typical symptom.

C
Diagnostics
Once cutaneous involvement has been assumed, the most
important diagnostic step is to take a punch biopsy in the
respective lesion or area. Biopsies taken from the rectal
submucosa or from abdominal subcutaneous adipose
tissue may also contribute to a definitive diagnosis. As
soon as a tissue sample has been acquired, histology and
electron microscopy are very important diagnostic tools.
Common histological criteria of biochemically heteroge-
neous amyloids are eosinophilia, often PAS positivity, affinity
to congo red [11, 12] and thioflavin T [8], as well as meta-
chromasia after staining with crystal violet or methyl violet.
Using congo red, amyloid shows characteristic (apple) green
birefringence when viewed under polarized light, a phenom-
enon also called dichroism [13, 14]. In lichenoid (papular)
and macular organ-limited cutaneous amyloidoses, amyloid Figure 1. Clinical presentation. Lichen amyloidosus of the lower
can be found in the papillary dermis directly below the basal limbs (A), macular cutaneous amyloidosis of the chest (B), peri-
epidermal layer. The overlying epidermis often shows orbital cutaneous bleedings in systemic amyloidosis (C).
acanthosis and hyperkeratosis (figure 2). Blood vessels
remain unaffected in lichenoid and macular amyloidoses. In
contrast, subcutis and vessels may be diffusely infiltrated in
nodular amyloidosis [2, 15, 16]. Sometimes, differentiation of Electron microscopy shows a loose network of unbranched
nodular amyloidosis and systemic variants may be extremely filaments [17-19] measuring 7.5 to 10 nm in diameter
difficult, and a sophisticated diagnostic approach is needed to (figure 3). The ultrastructural similarity of the different
diagnose other organs involved. amyloid precipitates is a fibrillary anti-parallel beta-sheet

EJD, vol. 20, n° 2, March-April 2010 153

Table 1. Organ-limited cutaneous amyloidoses

Type of amyloidosis Amyloid fibril Cutaneous findings - Important differentials Associated diseases and
(amyloid subtype) precursor frequent localisation variants
(other sites)
Non-hereditary organ-limited cutaneous amyloidosis (nh-cA)
Primary lichenoid Cytokeratin Soft or hyperkeratotic, Lichen ruber verrucosus, Association: multiple
(papular) amyloidosis = (CK 5 > 1 > 14 > 10) partially confluent papules lichen simplex chronicus, myeloma
lichen amyloidosus - lichen ruber planus Variants: biphasic (syn.
(AK) shin, (calf, forearm) hypertrophicus mixed or allotropic) cutaneous
amyloidosis
(= macular + lichenoid),
poikilodermatic variant
(= lichenoid papules, blisters,
poikilodermatic lesions)
Primary macular Cytokeratin Vaguely-demarcated, itchy, Atopic eczema, Association: MEN2a,
amyloidosis (CK 5 > 1 > 14 > 10) pigmented plaques, lesions postinflammatory primary biliary cirrhosis?
(AK) often associated with hyperpigmentation, lichen Variants: biphasic (syn.
friction (by scratching and simplex chronicus, fixed mixed or allotropic) cutaneous
itching; syn. friction or drug eruption amyloidosis
brush amyloidosis) (= macular + lichenoid),
- poikilodermatic variant
interscapular region, (macules, blisters,
(extremities, trunk) poikilodermatic lesions),
anosacral variant
(predominantly in Japan),
Papillomatosis confluens
et reticularis Gougerot-
Carteaud?
Secondary cutaneous Cytokeratin See associated diseases Depending on the clinical Association: skin tumors*,
amyloidosis (CK 5 > 1 > 10 > 14) presentation (see other discoid lupus erythematodes,
(AK) forms) post PUVA therapy
Primary nodular Solitary or multiple, waxy
Immunoglobulin light Dermatitis maculosa Association:
(tumefactive) chains nodules with atrophic atrophicans, atrophodermia paraproteinemia, diabetes
amyloidosis (ALκ:ALλ = 1:2) epidermis and/or idiopathica chronica mellitus, Sjögren’s syndrome,
(AL) teleangiectasia circumscripta, nevus CREST syndrome?
- lipomatosus, cutaneous
legs, trunk, (head, genitals) lymphomas
Hereditary organ-limited cutaneous amyloidosis (h-cA)
Familial primary e.g. Apolipoprotein E4 Papules, macules, puritus See differentials under Association: Oncostatin M
cutaneous amyloidosis - lichenoid (papular)/ receptor (OSMR) mutations,
(AApoE4 etc.) Localisation often like in macular amyloidosis associated gene locus
lichenoid (papular)/ 5p13.1-q11.2, lipid metabolic
macular amyloidosis disorders
A = amyloid; AK: cytokeratin; AL: immunoglobulin light chains; AApoE4: apolipoprotein E4; MEN2a: multiple endocrine neoplasia 2A; *Skin
tumors: nevi, sweat gland tumors, pilomatrixomas, actinic keratoses and seborrhoic warts, porokeratosis Mibelli, Morbus Bowen, basal cell carci-
noma, trichoepithelioma, etc.

structure. The filaments are composed of protofilaments, Subclassification

and filaments aggregate to fibrils. Fibrils are found in the
extracellular space, small amounts are phagocytosed by Organ-limited cutaneous amyloidosis (cA)
fibroblasts, and a so-called filamentous and pyknotic
degeneration of keratinocytes has been described in the In this form of amyloidosis, amyloid precipitates are lim-
literature [7-17]. Fibroblasts may also be directly involved ited to the skin, mostly to the papillary dermis. Hereditary
in the process of amyloid production [20], but no exact (h-cA) and non-hereditary cutaneous amyloidoses (nh-cA)
studies are yet available on this issue. In contrast to the can be differentiated. In addition, primary and secondary
respective amyloid protein, the amyloid P component is forms have been described as subclasses of non-hereditary
non-fibrillary and shows a pentagonal ultrastructure [21]. cutaneous amyloidoses (table 1).
In recent years, abdominal fat pad fine-needle aspiration
biopsy has become the most important diagnostic tool for Non-hereditary organ-limited cutaneous
diagnosing systemic amyloidosis, not least because of its amyloidoses (nh-cA)
practicability [22, 23] and high sensitivity in smear prepara- Most cutaneous amyloidoses can be attributed to this
tions. A definitive diagnosis (even though only minimal group. The most common entity of nh-cA is called (pri-
amounts of amyloid are present) can be achieved by scan- mary) lichenoid (syn. papular) amyloidosis (figure 1A),
ning subcutaneous tissue samples with an electron micro- which is far more common in South America [4] and
scope. Amyloid may even be subclassified by electron Asia [5] than in Europe or the United States. Data on
microscopy after immuno-gold labeling [24]. the exact prevalence of these rare diseases are unreliable

154 EJD, vol. 20, n° 2, March-April 2010

Table 2. Systemic amyloidoses with cutaneous involvement

Type of amyloidosis Amyloid fibril Cutaneous findings Extracutaneous findings Associated diseases and
(amyloid subtype) precursor variants
Non-hereditary systemic amyloidoses with cutaneous involvement (nh-sA)
Primary systemic and Immunoglobulin Petechiae, hemorrhages, nail Macroglossia, Association: acquired von
myeloma-associated light chains dystrophy, waxy papules/ nephropathy, Willebrand syndrome
amyloidosis nodules/plaques, tumorous cardiomyopathy, (avWS)
(AL) lesions, skleroderma-like neuropathy, intestinal Variants: bullous
infiltration, purpura, papules, involvement, CTS amyloidosis, oral mucosal
nodules, bullous lesions, bullous amyloidosis
alopecia, cutis laxa
Secondary systemic Serum amyloid Minor cutaneous Nephropathy, Association: chronic
amyloidosis associated A (SAA) involvement, sometimes hepatosplenomegaly, infections (e.g. osteomyelitis,
with inflammation/tumor petechiae, purpura and gastrointestinal disorders bronchiectasis), rheumatoid
(AA) alopecia (bleeding, motility diseases, neoplasia
disorders) (e.g. thyroid carcinoma,
Hodgkin’s disease)
Secondary hemodialysis- β2-microglobulin Soft plaques CTS, bone cysts, Association: nephropathy,
associated systemic destructive arthropathy diabetes mellitus
amyloidosis
(Aβ2M)
Hereditary systemic amyloidoses with cutaneous involvement (h-sA)
Hereditary transthyretin Transthyretin Atrophic scars, non-healing Peripheral and autonomic Mutations: predominantly
amyloidosis/familial (thyroxin-binding ulcers, petechiae neuropathy, CTS Val30Met
amyloid polyneuropathy prealbumin) (especially His 114
(ATTR) variant), cardiomyopathy,
nephropathy
Hereditary ApoA1 Apolipoprotein A1 Maculopapular lesions, Cardiomyopathy
amyloidosis petechiae
(AApoA1)
Hereditary cystatin C Cystatin C Clinically asymptomatic, but Multiple cerebral
amyloidosis positive histology hemorrhages
(ACys)
TNF-receptor 1 Serum amyloid Periorbital edema, migrating Prolonged episodic fever Mutations: extracellular
associated periodic fever A (SAA) cutaneous erythemas, periods, abdominal pain, domain of TNF-receptor 1
syndrome (TRAPS) conjunctivitis myalgia (about 40 distinct mutations)
(AA)
Hereditary gelsolin Gelsolin Cutis laxa, pruritus, petechiae, Corneal dystrophy, Variants: Danish type
amyloidosis (Meretoja’s ecchymoses, hypotrichosis, neuropathy often with (654G-T), Finnish type
syndrome) alopecia cranial nerve involvement, (654G-A) etc.
(AGel) CTS, minor nephropathies
Muckle-Wells-syndrome Serum amyloid Cold sensitivity, pruritus, cold Fever, chills, arthralgia,
(AA) A (SAA) urticaria-like lesions leukocytosis, lancinating
limb pain
A: amyloid; AA: serum amyloid A; Aβ2M: β2-microglobulin; AL: immunoglobulin light chain; AApoA1: apolipoprotein A1; ACys: cystatin C; AGel:
gelsolin; CTS: carpal tunnel syndrome; TRAPS: tumor necrosis factor receptor 1 associated periodic fever syndrome.

but it is known that mixed blood patients and Caucasians Nevertheless, the exact etiopathogenesis of the disease
are the mainly affected patient groups in South America remains unclear. A commonly accepted theory is that apo-
[4]. In this paper it has also been reported that in countries ptotic basal keratinocytes release cytokeratins, which are
closer to the equator the prevalence of primary cutaneous then covered with auto-antibodies, phagocytosed by
amyloidoses seems to be higher. In addition, women seem macrophages, and enzymatically degraded to amyloid K
to be more frequently affected by primary cutaneous amy- (cytokeratin). Amyloid K is therefore a key feature of
loidoses than men (f:m ratio approximately 2-3:1) [4]. organ-limited cutaneous amyloidoses [2, 10, 25, 26].
Macular (approx. 35%), papular (approx. 35%) and mixed Cytokeratin 5 (also 1, 10, and 14) is the major constituent
maculo-papular (approx. 15%) amyloidoses account for of amyloid in lichenoid and macular amyloidosis. In addi-
the vast majority of primary cutaneous amyloidoses, tion, the lipid transport protein apolipoprotein E4 (ApoE4)
whereas other types like nodular amyloidosis (approx. was found to be a component of amyloid deposits in
1.5%) are quite rare [4]. Anyway, the ethnic origin of a study of 14 Japanese patients suffering from either
patients seems to be of great importance as, in Asia, lichenoid or macular amyloidosis [27, 28]. The reason
papular amyloidosis (approx. 75%) is more frequent than for keratinocyte apoptosis in primary amyloidoses
the macular type (approx. 10%). Interestingly, biphasic remains unclear. Recent papers have claimed that a mech-
(= mixed, see below) amyloidosis seems to be more anism of apoptosis regulation involving transglutaminase
frequent (approx. 15%) in Asia than the macular type [5]. 2 may play a pivotal role in the pathogenesis of cutaneous

EJD, vol. 20, n° 2, March-April 2010 155

 A A B

C D

Figure 3. Electron microscopy. Fibrillary extracellular amyloid

deposition at 800-fold (A, bar: 10 μm), 5,000-fold (B, bar: 2 μm),
10,000-fold (C, bar 1 μm) and 20,000-fold (D, bar: 500 nm)
electron microscopic magnification. Black dots mark collagen
fibers and white dots show amyloid precipitates. D) Shows the
structure of an amyloid depot in detail.

additional cytokeratin (amyloid K precursor) release. In

this context, pruritus – which provokes scratching of the
skin – is thought to induce additional amyloid K deposi-
tion, which in turn leads to intensified pruritus: a vicious
Figure 2. Histology. Semi-thin tissue sections (plastic- circle. However, scratching of intact skin may also be the
embedded, double-staining with toluidin blue and alkalic
fuchsin) with amyloid deposition in the papillary dermis. Exten-
starting point for amyloid K deposition, which is also
sive amyloid depots are visible as light-blue precipitates within known as friction or brush amyloidosis. Therefore, friction
the papillae at 20-fold (A) and 40-fold (B) magnification. amyloidosis is sometimes also classified as one form of
secondary cutaneous amyloidosis [35]. However, there is
still controversy as regards the friction factor in macular
amyloidoses [29, 30]. Characteristic clinical correlates of and secondary amyloidosis. Often, secondary amyloid
amyloid precipitates are pruritus and a morphological deposition is found in association with skin tumors (basal
spectrum that ranges from well- or vaguely-demarcated, cell carcinoma, actinic keratoses, squamous cell carcinoma,
hyperpigmented, yellowish to brownish macules, to firm skin appendage tumors) and benign lesions (e.g. seborrhoic
papules with pink to brownish lichenoid glossiness. The warts), solar elastosis, collagenoses (e.g. lupus erythema-
localized macular variant is often considered a separate todes), and after PUVA therapy [31, 36-40]. In secondary
entity and called macular cutaneous amyloidosis. In cutaneous amyloidoses, cytokeratin 5 is also the predomi-
contrast to the lichenoid form, macular amyloidosis nant amyloid precursor [10].
more frequently occurs in women and is often located at As illustrated in table 1, associations of the lichenoid
the interscapular space or at the extremities. A rare variant form of cutaneous amyloidosis have been described
of lichenoid and macular amyloidosis is called biphasic with multiple myeloma as well as between macular var-
(better mixed or allotropic) cutaneous amyloidosis, in iants and multiple endocrine neoplasia MEN2a [41-43].
which lichenoid and macular lesions occur simultaneously A recent case report also described the possible associa-
[2, 31, 32]. In addition, a poikilodermatic form of cutane- tion of primary macular amyloidosis and primary biliary
ous amyloidosis exists, in which lichenoid or macular cirrhosis [44].
lesions occur in combination with blisters and poikiloder- A very rare form of primary nodular cutaneous amyloid-
matic skin lesions [33]. A recently published paper has osis is characterized by amyloid that is composed of
also reported a familial variant of poikilodermatic cutane- immunoglobulin light chains (amyloid L). Plasma cells
ous amyloidosis [34]. infiltrating the skin (e.g. in extramedullary plasmocytoma)
In macular amyloidosis (figure 1B), the pathogenetic factor produce monoclonal immunoglobulin light chains of κ- or
friction (itching and scratching which lead to friction amy- λ-type (ALκ:ALλ = 1:2) as amyloid precursors. Nodular
loidosis) may play a pivotal role as mechanical stimuli may cutaneous amyloidosis presents with solitary or multiple,
induce apoptosis of basal keratinocytes with subsequent mostly asymptomatic, brownish to red, firm plaques or

156 EJD, vol. 20, n° 2, March-April 2010

nodules, typically on the legs or the trunk. This entity Non-hereditary systemic amyloidoses with cutaneous
seems to be associated with diabetes mellitus and involvement (nh-sA)
Sjögren’s syndrome [15, 16]. One case report has also On a regular basis, primary non-hereditary systemic amy-
described the simultaneous appearance of CREST syn- loidoses are caused by monoclonal plasma-cell prolifera-
drome (calcinosis, Raynaud’s syndrome, esophageal tion. The underlying diseases comprise entities such as
involvement, sclerodactyly, teleangiectasia) and nodular multiple myeloma, Waldenström’s disease, Bence-Jones
amyloidosis [45]. plasmocytoma, heavy chain disease, malignant lympho-
mas, and others. The common feature of these diseases
Hereditary organ-limited cutaneous amyloidoses (h-cA) is the production of monoclonal immunoglobulins. Immu-
noglobulin light chains (isotypes κ and λ) serve as
The overwhelming majority of organ-limited cutaneous amyloid prescursors (amyloid L (AL) = light chain
amyloidoses occur sporadically. Case reports on familial type/Bence-Jones amyloid; ALκ/ALλ-ratio: 1:2). In spite
amyloidosis mainly originate from South America, Tai- of the clinical polymorphism of AL-type amyloidoses,
wan, and Southeast Asia. In Caucasians, hereditary cuta- petechiae and purpura of the face or intertriginous areas
neous amyloidoses are very rare and, up to now, only few (maybe due to friction) can be considered as cutaneous
family trees have been reported [46, 47]. The clinical indicators. Furthermore, confluent white to yellowish,
presentation of h-cA does not significantly differ from waxy, partially hemorrhagic papules or nodules can be
non-hereditary forms. Familial clustering as well as the found, predominantly occurring on the face, the eyelids
predominance in some ethnic groups has led to an inten- and the head. In severe cases, these lesions may lead to
sive search for susceptibility genes. In 2006, Lee and ulceration and scarring alopecia. If the dermis is exten-
co-workers reported on a genome-wide screening of Tai- sively infiltrated by amyloid, scleroderma-like skin altera-
wanese families and found evidence for a susceptibility tions (especially of the fingers) may occur, known as
locus on chromosome 5 (5p13.1-q11.2) [48]. Based on scleroderma amyloidosum Gottron. Also blisters and nail
this finding, Arita et al. detected two distinct mutations dystrophy have been reported as manifestations of
of the OSMR (oncostatin M receptor) gene (chromosome myeloma-associated amyloidosis [56]. An association of
5p13.1) in three families with amyloidosis [49]. A linkage acquired von Willbrand’s syndrome (avWS) and AL amy-
of familial cutaneous amyloidosis to a locus on 1q23 has loidosis has also been described [57]. Amyloid precipita-
also been previously published [50]. We have also tion within the oral cavity mucosa may present as papules
in the case of local deposition or as macroglossia in the
described a distinct OSMR gene mutation in a Caucasian
case of diffuse infiltration. As a clinical variant of light-
family with three cases of familial primary cutaneous
chain amyloidoses, bullous cutaneous manifestations [58]
amyloidosis [51]. Just recently, mutations have been (sometimes haemorrhagic) [59] or bullous manifestations
discovered in the IL-31 receptor A (IL-31RA) gene of of the mucosa [60] may occur.
Taiwanese families with primary familial cutaneous amy- In secondary systemic amyloidoses, an underlying disease
loidosis [52]. This is very interesting as (1) both OSMR leads to the deposition of amyloid in different tissues. The
and IL-31RA are encoded on chromosome 5p, (2) both primary disease determines the amyloid precursor struc-
are cytokine receptors and (2) OSMR-β and IL-31RA ture and thereby the type of amyloid, the most common
can form a heterodimeric receptor. variant being AA-type amyloidosis. Chronic inflammation
(infectious or non-infectious) or neoplastic diseases as
Systemic amyloidoses with cutaneous involvement (sA) well as sporadic gene defects lead to an enhanced produc-
tion of serum amyloid A (SAA, an acute phase protein).
Systemic amyloidoses are characterized by amyloid depo- Experimental cutaneous amyloidosis due to leishmania
sition in mesenchymal structures of internal organs (pref- infection has already been described [61]. Hepatic produc-
erably heart muscle, liver, kidneys), which may lead to a tion of SAA is stimulated by interleukin 1 (among others),
successive loss of function and eventually to death. In and macrophages degrade SAA to amyloid A. However,
addition, systemic amyloidoses show cutaneous involve- skin signs are very rare and manifest as purpura, plaques,
ment in about 50% of patients, which enables physicians or nodules. Also, clinically intact skin may show amyloid
to diagnose the underlying disease at an early stage [53]. A deposition. Secondary amyloidoses of the AA-type
In analogy to organ-limited cutaneous amyloidoses, sys- show a tendency to regression if the underlying disease
temic amyloidoses may be subclassified into hereditary is successfully treated.
(h-sA) and non-hereditary (nh-sA) forms as well as into Another secondary variant of systemic amyloidoses with
primary and secondary amyloidosis (table 2). The clinical cutaneous involvement occurs in hemodialysis patients
presentation of the cutaneous involvement in systemic and shows β2-microglobulin (beta-sheet structure) as amy-
amyloidoses is often characterized by petechiae, hemor- loid precursor (table 2) [2, 62].
rhages, ecchymosis, and pruritus. Bleedings are often
seen in the periorbital region [54, 55] (figure 1C), which Hereditary systemic amyloidoses with cutaneous
are due to the deposition of amyloid in and around vascu- involvement (h-sA)
lar structures – a deposition pattern that is rarely seen in Among the hereditary variants, the most common form is
organ-limited cutaneous amyloidoses. The only exception familial amyloid polyneuropathy due to the deposition of
to this rule is nodular amyloidosis, in which perivascular altered transthyretin (a protein of the prealbumin fraction)
amyloid deposition may also be encountered and in which [9, 63]. Mostly, this form is caused by a Val30Met mutation
the histology may bear a strong resemblance to systemic [64]. Other forms of hereditary amyloidoses are associated
amyloidosis with cutaneous involvement. with cardiomyopathy (apolipoprotein A1 amyloidosis),

EJD, vol. 20, n° 2, March-April 2010 157

multiple cerebral hemorrhages (cystatin C amyloidosis) [2] the use of oral acitretin in the treatment of biphasic
or carpal tunnel syndrome [65]. In contrast to apolipopro- (syn. mixed or allotropic) amyloidosis. Relief of pruritus,
tein A1 amyloidosis (AApoA1), cystatin C amyloidosis an improvement of the papules and discrete clearance
(ACys) is clinically asymptomatic with no skin signs, and of hyperpigmentation were observed after four months
only histology may show the typical amyloid deposition. treatment with 0.5 mg/kg per day oral acitretin [78]. As
The combination of prolonged fever episodes, abdominal lichen amyloidosus has also been reported to be partially
pain, myalgia, and migrating cutaneous erythema is charac- thermosensitive, maybe this phenomenon could be utilized
teristic for the rare TNF-receptor 1 associated periodic in potential treatment regimens [79]. With respect to pri-
fever syndrome TRAPS [66, 67]. Here, a mutation of the mary cutaneous lichen amyloidosus, there is one study
extracellular domain of the TNF-receptor 1 leads to inflam- reporting on significantly reduced pruritus, hyperpigmenta-
matory reactions with subsequent serum amyloid A precipi- tion and lesion size after 50 mg per day oral cyclophospha-
tation. Impressive clinical presentations with massive mide over 6 months [80]. Oftentimes, the same treatment
deforming cutis laxa, extensive petechiae, hemorrhages, modalities are used for macular amyloidosis.
as well as hypotrichosis or alopecia can be seen in gelsolin
amyloidoses (AGel), also known as Meretoja’s syndrome Surgical and laser treatment
[68, 69]. Different mutations result in an amino acid Surgical treatment strategies may be favourable when conser-
exchange [70]. Among others, a Danish (654G-T) and a vative treatments are of limited success (e.g. often in nodular
Finnish (654G-A) type can be differentiated [71]. Another cutaneous amyloidosis). Efficient surgical treatment strate-
rare syndrome also associated with amyloid deposition gies involve excision and split-thickness skin grafting [81],
(presumably amyloid A) and cutaneous signs is called
dermabrasion [82], shave excision [83] as well as currettage
Muckle-Wells-syndrome, which is characterized by cutane-
and cautery [84]. Other strategies like pulsed dye laser treat-
ous amyloid deposition, periodic urticaria-like skin lesions, ments [85] and carbon dioxide (CO2) laser evaporation [86]
lancinating limb pain, and the development of sensorineural have also been successfully used in some cases.
hearing loss [72, 73].
Treatment of systemic amyloidoses with cutaneous
Treatment strategies involvement
Of course, systemic amyloidoses with cutaneous involvement
To date the treatment of the different forms of cutaneous should always be treated by a team involving dermatologists,
amyloidosis remains a challenge for all medical disciplines internal medicine specialists (oncologists, rheumatologists,
involved. In all variants of amyloidoses pruritus is often a etc.) and plastic surgeons – in case there are functionally or
major problem, leading to further skin irritation and even to aesthetically deforming lesions. In case there is an identifiable
new amyloid deposits. Therefore, anti-pruritic treatment underlying disease leading to cutaneous amyloid deposition,
should be one component of the treatment regimen. Due all efforts should be made to slow down or stop the progress
to the low number of affected patients, only a few treatment of the disease [87]. For example, amyloidosis associated with
strategies have carefully been studied, so that most treat- myeloma should primarily be treated by treating the underly-
ment options are recommended based on studies with ing myeloma in cooperation with experienced oncologists.
small sample sizes or even case reports. Oftentimes, immunosuppression is a core component in
treating systemic amyloidoses which are based on inflam-
Topical treatment mation. For instance, AA-amyloidosis resulting from familial
Mediterranean fever (FMF) can be improved using colchicines
Topical administration of steroids (occlusive dressings) or [87]. Maybe, the addition of anakinra (interleukin-1 receptor
intralesional steroid injections are the classical treatments antagonist, IL-1Ra) [88] to colchicine is beneficial as well in
of choice [74]. Others have studied the effect of photo- the treatment of FMF associated amyloidosis as it tempers
therapy (narrow band UVB: nbUVB), photochemotherapy theunderlying inflammatory reactions. TNF-receptor associ-
(PUVA) and compared these strategies to topical steroid ated periodic fever syndrome (TRAPS) associated with amy-
applications [75]. The authors showed that these strategies loidoses may also be treated by TNF-blockade and IL-1
may be alternatives to topical steroids but admit that antagonists [87]. Other strategies like the administration of
larger prospective trials are needed to statistically prove intravenous immunoglobulins and plasma exchange have
the effects observed. Apart from that, dimethylsulfoxide also been successfully tried in the treatment of primary sys-
(DMSO) may be topically applied. However, Pandhi temic amyloidoses [89]. An increasing number of patients
et al. saw neither anti-pruritic effects nor any amyloid- with Aβ2-amyloidosis is expected as hemodialysis has per-
dissolving properties of DMSO [76]. mitted the long-term survival of patients with severe chronic
renal failure [90, 91]. Improvement of the renal function and
Systemic treatment subsequently the possibility of stopping hemodialysis are the
As mentioned, DMSO can be topically applied, but there keys to improving and possibly completely stopping
are also reports on the efficacy of oral DMSO in the Aβ2-amyloidosis.
treatment of systemic amyloidoses with cutaneous
involvement [77]. Furthermore, there is one review of
case reports discussing the effect of oral retinoids in Conclusion
the treatment of lichen amyloidosus [78]. This review
shows that oral retinoids administered over about half a Because of the varying clinical presentations and the rare
year may even lead to a complete remission of lichen occurrence of amyloidoses in Caucasians, cutaneous
amyloidosus. The case they also report on deals with amyloidoses and systemic amyloidoses with cutaneous

158 EJD, vol. 20, n° 2, March-April 2010

involvement are often disregarded as a possible differen- 19. Shirahama T, Cohen AS. High-resolution electron microscopic
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