ARTICLE
The amyloidoses represent a heterogenous group of rare diseases characterized
by extracellular fibrillar protein deposits which have in common a typical
green birefringence in polarized light after congo red staining [1, 2].
Immunohistology allows the discrimination of various forms of amyloid
which are designated with regard to the major biochemical component by
acronyms (Table I) [3-9].
Alzheimer's disease as well as the spectrum of transmissible spongiform
encephalopathies, such as Creutzfeldt-Jakob-disease, also belong to the
amyloid syndromes, but are not known to involve the skin. We present the
rare observation of a patient affected by a multiple myeloma of the IgGlambda-type
and a systemic amyloidosis of the amyloid A subtype with haemorrhagic-bullous
skin involvement due to dermal deposits, which showed a positive diagnostic
reaction with anti-amyloid A but not anti-IgLlambda antibodies.
Case report
An 86-year-old female patient was admitted to our clinic suffering from
painful skin lesions of an increasing intensity for more than one year.
Physical examination revealed substantial macroglossia and generalized
skin ecchymoses predominantly in a periocular location, at the lateral
aspect of the neck, on the trunk, arms, thighs as well as the mucous membranes
(Fig. 1a
and b). Yellowish-white, firm, milium-like papules were
observed in a disseminated localization pattern, especially in the lateral
neck (Fig. 1b) and epigastric
areas (Fig. 2). Moreover
there were bullous, erosive and superficially scaring lesions which were
provoked by minor traumas such as the removal of tape bandages, due to
substantial skin fragility. Non-scaring alopecia manifested in a diffuse
pattern at the capillitium (Fig.
1b) accompanied by a complete loss of axillary and genital hairs.
Significant dermatochalasis was evident in the gluteal body location.
Laboratory examinations showed an ESR of 49/90 (Westergren), a relative
and absolute gammaglobulin increase with 29.6% (normal range 13.1-27.1%,
serum-protein-electrophoresis) and 27.1 g/l (7-16 g/l, nephelometry),
respectively, as well as an IgG and IgLlambda peak (immunofixation). In
the urine Bence-Jones proteins were detected, i.e. IgLlambda with
792 mg/l (< 20 mg/l) and IgLkappa with 100 mg/l (< 20 mg/l). Elevation
of serum uric acid by 465 kappamumol/l (< 420 kappamumol/l). Positive
detection of cryofibrinogen. Decreased platelet spreading by 14% (45-80%).
beta2-microglobulin and blood plasma viscosity were in the normal range.
Bone marrow examination revealed a diffuse infiltration of predominantly
small to middle-sized atypical plasma cells. Only few lytic bone lesions
were detected by radiography of the skeleton. Histopathological evaluation
of a biopsy from the rectum mucosa demonstrated amyloid deposition.
Dermatohistological investigation of skin biopsies showed beneath an
atrophic epidermis large amounts of an amorphous material deposited in
the upper and middle dermis (Fig.
3). The material stained light red by hematoxylin-eosin and proved
to be positive in the congo red staining (Fig.
4). The congo-red-positive depositions surrounded the significantly
congested dermal capillaries in a cuff-like manner and showed crack-like
blister formations filled with erythrocytes (Figs.
3 and 4). Immunohistologically
the dermal deposits reacted positively with a monoclonal murine anti-human
amyloid A antibody (clone mc1, code no. M 0759, DAKO) employing a peroxidase/AEC
chromogen detection system (Fig.
5). The deposits did not react with antibodies directed against
cytokeratins, immunoglobulin heavy nor light chains (IgG, IgM, IgA, kappa,
lambda).
Given the facts that the multiple myeloma was still at an initial stage
and that the aged patient was not threatened vitally by the myeloma nor
the amyloidosis, we decided not to treat by chemotherapy or plasmapheresis,
respectively. Instead a palliative regimen was chosen, i.e. a high
dose steroid pulse-interval monotherapy with dexamethasone 40 mg per day
over 4 days, every 4 weeks. Three treatment cycles led to a stabilization
of the disease process over an observation period of more than one and
a half years.
Discussion
There is no overall accepted clinical classification of amyloidoses.
Various forms of presentation have been described which may be generally
divided into systemic (generalized), and organ-limited, such as skin-limited
types (Table II). Among
the systemic forms of amyloidosis the hereditary, idiopathic and secondary
subforms have to be distinguished. The latter arise in coincidence with
chronic infections, non-infectious inflammatory diseases and tumor diseases
[12]. Skin manifestations of systemic amyloidosis are rare and known to
occur mostly in conjunction with an idiopathic subform or in association
with B cell neoplasias characterized by dermal AA- or AL-deposits [5,
10].
In our patient the immunohistological examination demonstrated substantial
dermal deposits of amyloid A, but we emphasize that there was no deposition
of immunoglobulins in the skin, although myeloma-derived IgGlambda paraproteins
were detectable in high pathological amounts in the blood circulation.
Thus, the skin was not directly affected by the myeloma-dependent paraproteins
themselves. Taken together, we found the noteworthily rare pathogenetic
constellation of a multiple myeloma of the type IgGlambda which we considered
as having been causative for the secondary development of a systemic amyloidosis
of the AA-type, with manifestation as macroglossia and amyloid deposition
in the rectum mucosa and skin. By thorough examination of the patient
we could rule out any other of those diseases known for their potential
to precipitate AA-type amyloidosis beside multiple myeloma (Table
3).
The precursor of the AA protein, which is unrelated to any immunoglobulin,
is known as the serum amyloid A (SAA) protein. In humans the SAA protein
is increased during the acute-phase reaction in response to cytokines
secreted by activated monocytes/macrophages. SAA may reach plasma levels
of up to 1,000-fold greater than that found in the non-inflammatory state
(2-3 mug/ml), thus also representing a very relevant diagnostic marker
for the clinical monitoring of inflammation activity [11, 12]. In amyloidosis,
SAA (104 amino acids, 12 kDa) is cleaved by proteolysis between residues
76 and 77, and the amino-terminal fragment, i.e. the amyloid A
protein, is deposited in the connective tissue in the form of fibrils
displaying a beta sheet folding pattern implying protease resistance [13].
With respect to our dermatohistological findings we explained the paramount
hemorrhagic aspect of the skin involvement by a highly increased fragility
of the capillaries which were congested and deflexibilized by the excessive
perivascular AA depositions. Concomittant cryoglobulinemia as well as
a possibly paraprotein-dependent impairment of thrombocyte spreading capacity,
which were both detected in our patient, may have additionally contributed
to this process of capillary rupture and erythrocyte extravasation. These
phenomena were most prominent in mechanically stressed body locations
such as the skin folds.
Treatment of skin involvement by systemic amyloidosis is a major challenge.
The fundamental problem for any treatment attempt is the characteristic
insolubility of amyloid deposits. Therefore therapy should primarily address
the underlying disease processes when they are identifiable, in order
to diminish any further amyloid deposition. Theoretical alternatives include
the use of melphalan, colchicin and thymosin. A marked improvement in
systemic amyloidosis has been reported following long-term symptomatic
treatment by dimethyl sulphoxide [14] or iododoxorubicin [15]. In our
case of an highly aged patient, we performed a palliative glucocorticoid
pulse interval therapy targeting the relatively asymptomatic multiple
myeloma as well as the macrophage-dependent dermal amyloid deposition,
which led to a beneficial stabilization of both interconnected disease
processes.
Article accepted on 25/10/99
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