ARTICLE
Systemic
amyloidosis is characterized by amyloid deposition in various tissues. Systemic
amyloidosis could be classified as primary amyloidosis, multiple myeloma-associated
amyloidosis, secondary systemic amyloidosis, and familial amyloidosis. Cutaneous
lesions of multiple myeloma-associated amyloidosis are of variable morphology
including periorbital ecchymoses (racoon syndrome), waxy papules or plaques
clustered in the face and neck, macroglossia and skin sclerosis, and occur
in 31-40% of cases [1]. The amyloid fibrils of multiple myeloma-associated
amyloidosis are composed of immunoglobulin light chain and deposit in the
upper dermis [2]. Abnormal light chain is always present in the serum or
urine and can be demonstrated in tissue culture of bone marrow cells from
affected patients [3]. The mechanism by which immunoglobulin light chain
deposits in the tissue is unknown.
Chronic exposure to ultraviolet rays causes degenerative alterations
in the skin, characterized by wrinkles and atrophy. The major histological
change in actinically damaged skin is the accumulation of basophilic fibers
in the upper dermis, referred to as basophilic degeneration of actinic
elastosis. Immunohistochemical and biochemical studies on the nature of
the accumulated fibers have demonstrated that altered elastin is the primary
component of the formation of actinic elastosis [4]. The mechanism of
the formation of actinic elastosis in photo-damaged skin is still unclear.
In the present study, we show that in a patient with both multiple myeloma-associated
amyloidosis and actinic elastosis, amyloid and elastotic material of actinic
elastosis never colocalize in the upper dermis. We discuss the possible
mechanism of this phenomenon.
Case report
A 65-year-old Japanese man with a one-year history of multiple myeloma
visited our department in November 2000 because of asymptomatic periorbital
papules for three months. Clinically, he had many irregular-shaped purpuric
lesions which he first noticed one and a half years previously. Many discrete
waxy papules of 2-3 mm in size were seen on the periorbital area (Fig.
1). He also had multiple bean-size nodules on the postauricular region,
macroglossia, scratch purpura on the chest and extremities. Laboratory
studies showed anemia (Hb 8.9 g/dl), thrombocytopenia (Plt 7.2 x 104/mm3),
and low serum total protein 5.1 mg/dl (normal, 6.5-8.2 mg/dl). The level
of IgG and serum creatinine were within normal limits. Urinalysis showed
proteinuria (4.4 g/day) and microscopic hematuria. Serum protein and urinary
protein electrophoresis showed a M-protein, monoclonal lambda light chain.
Echocardiography showed thickness of left and right ventricular walls
and granular sparkling, which was compatible with amyloid heart. The patient
received chemotherapy with a combination of vincristine, adriamycin and
dexamethasone (VAD) for multiple myeloma. His blood data was mildly improved,
but skin lesions remained unchanged.
Histology and immunohistochemistry
A skin biopsy specimen was taken from one of the periorbital papules.
It showed eosinophilic deposit which was positive with Congo red stain
just beneath the epidermis (Fig.
2a). Marked extravasation of erythrocytes was seen in the upper dermis.
In the mid dermis, there were thickened basophilic fibers of actinic elastosis
which were confirmed by Elastica van Gieson stain (Fig.
2b). There were very few elastic fibers in the amyloid deposit, and
amyloid deposit was not seen in the area of actinic elastosis. Amyloid
deposit and elastotic materials were clearly bordered in the upper dermis.
Immunohistochemically the deposit was positively stained with monoclonal
antibody for immunoglobulin lambda light chain, but negative for keratin
(not shown).
Discussion
Interaction of cutaneous amyloid with intact elastic fibers has been
implicated. Normal elastic fibers were found in the amyloid islands of
primary systemic amyloidosis, hereditary-familial amyloid neuropathy,
macular amyloidosis and amyloidosis cutis nodularis atrophicans [5, 6].
In a case of unique systemic amyloidosis, elastic fibers in the skin were
coated with an amyloid-staining material [7]. It is also reported that
amyloid fibers deposit in the peripheral microfibrils of elastic fibers,
but not in the central amorphous elastin on an electron microscopic observation
[5]. These previous reports suggest that amyloid fibrils may deposit interacting
with microfibrillar proteins of intact elastic fibers.
Recent biochemical studies have identified several microfibrillar proteins,
fibrillins, microfibril-associated glycoproteins (MAGPs) or microfibril-associated
proteins (MFAPs). Fibrillins are major constituents of microfibrils and
considered to play an essential role in the maturation of elastic fibers
[8]. It has been previously demonstrated that in the papillary dermis
of normal skin, elastin and fibrillin form candelabra-like structures
and project perpendicularly to the basal lamina of the dermo-epidermal
junction [9].
The major histological change in actinically
damaged skin is the accumulation of curled and tangled elastic fibers
in the upper dermis referred to as actinic elastosis. The mechanism of
accumulation of altered elastic fibers in sun-damaged skin is not clear
at present. Immunohistochemical or electron microscopic studies of elastic
fibers of sun-damaged skin revealed that immunoreactivity of fibrillin
is decreased, or increased [10, 11]. It has been also reported that elastic
fibers in actinic elastosis are modified by advanced glycation end product
(AGE) and become resistant to degradation leading to the accumulation
of AGE-modified elastic fibers in the skin [12].
Although it has been reported that normal elastic fibers interact with
amyloid deposit [5-7], we found that amyloid fibrils and disintegrated
elastic fibers of actinic elastosis did not interact, but localized separately
in the upper dermis in the present case. This is probably because amyloid
deposit fails to interact with elastic fibers containing abnormal amount
of fibrillin or structurally abnormal AGE-modified elastotic fibers.
Article accepted on 20/8/02
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