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Skin disorders in association with monoclonal gammopathies

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Monoclonal gammopathy represents a condition characterized by clonal proliferation and accumulation of immunoglobulin producing B-cells. A variety of skin disorders are associated with an increased level of monoclonal immunoglobulin proteins. These skin disorders can be divided into two groups. The first group represents a direct consequence of plasma cell proliferation. The colonization of the plasma cell clone in the dermis expressed as a deposition of proteins related to the M component belongs to this group for which the pathogenesis is well identified, as is the case for example with AL amyloidosis and cryoglobulins. The second group represents skin disorders such as scleromyxedema and Schnitzler syndrome that are highly associated with an M component, or diseases such as pyoderma gangrenosum and leukocytoclastic vasculitis that are more weakly associated with increased levels of monoclonal immunoglobulins. In some other dermatoses such as pemphigus, bullous pemphigoid, epidermolysis bullosa aquisita, Sezary syndrome, lymphomatoid papulosis, urticaria pigmentosa, and acquired ichthyosis, only presumptions exist regarding associations with monoclonal gammopathies. In this the pathogenesis, therapy and prognosis of the most relevant dermatoses shall be described in order of their degree of association with monoclonal gammopathies, which shall also be discussed.
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EUROPEAN JOURNAL OF MEDICAL RESEARCH 93
Abstract: Monoclonal gammopathy represents a condi-
tion characterized by clonal proliferation and accumu-
lation of immunoglobulin producing B-cells. A variety
of skin disorders are associated with an increased level
of monoclonal immunoglobulin proteins. These skin
disorders can be divided into two groups. The first
group represents a direct consequence of plasma cell
proliferation. The colonization of the plasma cell
clone in the dermis expressed as a deposition of pro-
teins related to the M component belongs to this
group for which the pathogenesis is well identified, as
is the case for example with AL amyloidosis and cryo-
globulins. The second group represents skin disorders
such as scleromyxedema and Schnitzler syndrome that
are highly associated with an M component, or dis-
eases such as pyoderma gangrenosum and leukocyto-
clastic vasculitis that are more weakly associated with
increased levels of monoclonal immunoglobulins. In
some other dermatoses such as pemphigus, bullous
pemphigoid, epidermolysis bullosa aquisita, Sézary
syndrome, lymphomatoid papulosis, urticaria pigmen-
tosa, and acquired ichthyosis, only presumptions exist
regarding associations with monoclonal gam-
mopathies. In this the pathogenesis, therapy and prog-
nosis of the most relevant dermatoses shall be de-
scribed in order of their degree of association with
monoclonal gammopathies, which shall also be dis-
cussed.
INTRODUCTION
Monoclonal gammopathies represent a spectrum of
diseases characterized by clonal proliferation and accu-
mulation of immunoglobulin-producing cells derived
from the B-cell lineage. Five major classes of im-
munoglobulins exist that are synthesized by normal
plasma cells (IgG, IgM, IgA, IgE, IgD). Normally, im-
munoglobulin production is heterogeneous polyclonal,
with each plasma cell clone secreting only one heavy
chain (γ, µ, α, δ, or ε) and one light chain (κ or λ) dur-
ing its life span. Dysfunctional clonal plasma cells pro-
duce one type of immunoglobulin, or in some in-
stances only the κor λlight chain molecules. Dispro-
portionate proliferation of one clone results in a corre-
sponding serum increase of its secreted molecular
product, the monoclonal immunoglobulin protein (M
component). The M component is readily detected as
a sharp symmetric spike (M spike) with α2, β, or γmo-
bility on electrophoresis of serum or urine. Im-
munofixation or immunoelectrophoresis is required to
identify the heavy and light chain class of the protein.
The magnitude of the M spike is related to the number
of cells producing the M component (Alexanian et al.
1999, Kyle 1999, Barosi et al. 2004). Monoclonal gam-
mopathy of unknown significance (MGUS) represents
a common manifestation of multiple disorders and
normal variants. MGUS occurs in 1 percent of healthy
people over the age of 50 and in 3 percent of people
over the age of 70. In about 80 percent of cases, the
abnormal protein does not cause any clinical symp-
toms (Varterasian 1995, Herrinton 1996, Brigden
1999). However, over time, 25 percent of people will
experience an increase in the amount of abnormal pro-
tein in their blood, which may progress to a B-cell ma-
lignancy or multiple myeloma (MM) (Bergsagel 1995).
MGUS might be associated with a variety of diseases
(Table 1). The M component is not only present in
plasma cell disorders such as MM, Waldenstrom’s
macroglobulinemia (WM), and various rare heavy chain
diseases (Table 2). M components are also detectable in
other lymphoid and non-lymphoid neoplasm’s such as
acute myeloid leukemia (AML), breast and colon can-
cer and even in a variety of non-neoplastic conditions
such as liver cirrhosis, sarcoidosis and rheumatoid
arthritis (Alexanian et al. 1999, Kyle and Greipp 1998)
(Table 1 and 2).
MONOCLONAL GAMMOPATHIES AND SKIN
DISORDERS
A variety of skin disorders have been reported to be
associated with an increased level of monoclonal im-
munoglobulin proteins in the serum. They can be di-
vided into two main groups. The first group repre-
sents disorders that are a direct consequence of the
usually malignant process. They result from plasma
cell proliferation and consecutively high levels of mon-
oclonal immunoglobulins in the serum. As such they
can also be further subdivided. On the one hand, there
is a direct infiltration of proliferative plasma cells into
the skin, especially in malignant conditions such as
MM and WM (Dimopoulos et al. 2000). On the other,
there are disorders related to the deposition of pro-
teins associated with the M component, as is seen for
example with AL amyloidosis and cryoglobulins
(Mussini et al. 1993, Daoud et al. 1999, Siami and Sia-
mi 1999, Piette 1986). The second main group repre-
sents skin disorders in which an M component is de-
tectable. There are diseases highly associated with an
M component such as scleromyxedema and Schnitzler
syndrome. Other disorders such as pyoderma gan-
grenosum occur in some malignant and inflammatory
March 29, 2005
Eur J Med Res (2005) 10: 93-104 © I. Holzapfel Publishers 2005
SKIN DISORDERS IN ASSOCIATION WITH MONOCLONAL GAMMOPATHIES
A. Harati, N. H. Brockmeyer, P. Altmeyer, A. Kreuter
Department of Dermatology and Allergology, Ruhr-University Bochum, Germany
EUROPEAN JOURNAL OF MEDICAL RESEARCH94 March 29, 2005
Table 2. Diagnostic criteria for multiple myeloma, myeloma variants and MGUS. Multiple myeloma: I+b, I+c, I+d, II+b, II+c,
II+d, III+a, III+c, III+d, a+b+c, a+b+d. MGUS: presence of a serum M-protein value less than 3 g/dL, fewer than 15% plas-
ma cells in the bone marrow, no or only small amounts of Bence-Jones protein in the urine, absence of lytic bone lesions, no re-
lated anemia, hypercalcemia, or renal failure (Barosi et al. 2004, Kyle and Rajkumar 2004).
Major criteria
IPlasmacytoma in tissue biopsy
II Bone marrow with more than 30% plasma cells
III Monoclonal globulin spike in serum protein electrophoresis, with an immunoglobulin G (IgG) peak of greater than
3.5 g/dL or an immunoglobulin A (IgA) peak of greater than 2 g/dL, or urine protein electrophoresis (in the pres-
ence of amyloidosis) greater than 1 g/24 h
Minor criteria
aBone marrow with 10-30% plasma cells
bMonoclonal globulin spike present but less than category III
cLytic bone lesions
dResidual normal immunoglobulin M (IgM) level of less than 50 mg/dL, IgA level of less than 100 mg/dL, or IgG
level of less than 600 mg/dL
Table 1. Monoclonal gammopathies and associated diseases (Duggan and Schattner 1986, Alexanian et al. 1999, Kyle and
Greipp 1998).
Category Associations Examples
MGUS Associated with plasma cell dyscrasias Progression to multiple myeloma and other plasma cell
dyscrasias in 25 % after 2 decades
Associated with other lymphoid and Carcinomas of the breast, gastrointestinal tract, kidney,
non-lymphoreticular neoplasms Hodgkin’s lymphomas, chronic myeloic leukemia
Associated with chronic inflammatory Rheumatoid arthritis, sarcoidosis, tuberculosis, osteomyelitis,
diseases pernicious anemia, etc.
Asymptomatic and non-progressive Age-related incidence, occurs in apparently healthy persons
(majority)
Transient plasma cell dyscrasias Virus infections, heart surgery, drug hypersensitivity
Malignant plasma cell Symptomatic and progressive Multiple myeloma, Waldenstrom`s macroglobulinemia, heavy
dyscrasias chain disease, AL amyloidosis
Table 3. Skin disorders in monoclonal gammopathies; a classification depending on thedegree of association (Daoud et al. 1999).
Group I: direct correlation
Cutaneous plasmacytoma
Hyperviscosity syndrome
Cryoglobulinemia
Amyloidosis
POEMS syndrome
Group IIa: high association
Scleromyxedema, lichen myxedematosus, papular muci-
nosis
Scleredema
Plane xanthomas
Necrobiotic xanthogranuloma
Schnitzler syndrome
Erythema elevatum diutinum
Subcorneal pustular dermatosis
Group IIb: low association
Pyoderma gangrenosum
Sweet syndrome
Leukocytoclastic vasculitis
Group III: association sporadically reported
Pemphigus
Bullous pemphigoid
Epidermolysis bullosa aquisita
Sézary syndrome
Lymphomatoid papulosis
Acquired ichthyosis
Urticaria pigmentosa
Reticular erythematous mucinosis
Xanthoma disseminatum
Lupus erythematosus
conditions, but the association is much weaker. The
pathophysiological pathway and the relevance of the
M component in the second disease group are still un-
clear. Epidemiological studies are warranted to assess
the relevance of dermatoses occurring with an M-
component. Because of immunological aspects and
growth factors, further examinations are required to
understand whether a dermatosis represents a parane-
oplastic disorder of a malignant plasma cell process or
whether the M-component is a parameter arising from
the dermatological disorder. In a large number of oth-
er dermatoses including pemphigus, bullous pem-
phigoid, epidermolysis bullosa aquisita, Sézary syn-
drome and lymphomatoid papulosis, an association
with MGUS is merely presumed. Table 3 summarizes
the most relevant skin disorders in MGUS, classified
according to the degree of association. Pruritus, pur-
pura, infections due to decreased immunoglobulin
production and a variety of drug reactions represent
other dermatologic manifestations of monoclonal
gammopathies (Daoud et al. 1999, Piette 1986).
GROUP I: DIRECT CORRELATION
CUTANEOUS PLASMACYTOMA
Cutaneous plasmacytoma (CP) of the skin presents as
non-tender, smooth, cutaneous or subcutaneous nod-
ules of 1-5 cm in diameter. The lesions are flesh or
plum-colored with a tendency to become crusted or
ulcerated. They are mostly distributed on the extremi-
ties, trunk, and face. Frequently, skin lesions present as
secondary CP in the setting of MM. Lesions may de-
velop as a direct expansion of underlying bone lesions
or they present as metastatic foci. Primary cutaneous
plasmacytomas with no evidence of involvement of
other tissues are exceedingly rare. Histologically, both
the dermis and the subcutaneous tissues are infiltrated
by plasma cells that vary in maturity. The so-called cu-
taneous plasmacytosis is based on monoclonality with
the presence of only kappa or lambda light chains. Im-
munoglobulins produced may be of any type, but IgA
appears to be frequently found (Daoud et al. 1999,
Collet et al. 1991). Therapy for CP in the setting of
MM includes chemotherapy and local radiation thera-
py. Surgical excision has a role in lesions restricted to
the skin, which are unresponsive to radiation therapy.
HYPERVISCOSITY SYNDROME
Hyperviscosity syndrome (HS) is caused by a significant
increase in whole blood viscosity, whichmay result from
increased cellular blood elements, such as in myelopro-
liferative disorders, orfrom a large amount (>3 g/dL) of
monoclonal proteins, mostly of the IgM type. Clinically,
HS may present as mucous membrane bleeding, retino-
pathy, cardiac failure, and neurological disturbances. If
HS is present together with cryoglobulins, Raynaud’s
syndrome might be observed. Blood viscosity must in-
crease by at least 4-fold for clinical symptoms to ap-
pear. A bleeding tendency can also be explained by the
presence of clotting factor antibodies and/or platelet
dysfunction because of surface coating by immunoglo-
bulins (Siami and Siami 1999, Kumar et al. 2003).
CRYOGLOBULINEMIA
Cryoglobulins are serum immunoglobulins complexed
with other immunoglobulins or proteins that re-
versibly precipitate in cold temperatures. Cryoglobu-
linemia is associated with a range of clinical findings,
including purpura in parts of the body exposed to cold
temperatures, Raynaud’s syndrome, acral hemorrhagic
necrosis, arthralgia, neurological manifestations, and
glomerulonephritis. The classification of cryoglobu-
linemia follows the initial description by Brouet et al.
in 1974 and is based on the immunoglobulin involved.
Type I cryoglobulins are monoclonal immunoglobu-
lins (Mussini et al. 1993), usually IgG or IgM. Type II
cryoglobulins are mixed cryoglobulins with a mono-
clonal and a polyclonal component. Type II cryoglob-
ulins can be associated either with B-cell malignancies
or with autoimmune disorders (Siami and Siami 1999,
Cuellar et al. 1995, Bulfoni 1995, Dammacco and San-
sonno 1997). Type III cryoglobulins are polyclonal im-
munoglobulins that form a cryoprecipitate with poly-
clonal IgG or a non-immunoglobulin serum compo-
nent. Patients with this type of cryoglobulin are affect-
ed by an autoimmune process or infection. After
serum is separated, it is stored at 4 °C. After approxi-
mately 24 hours, cryoprecipitates may be observed.
The severity of symptoms reflects the serum concen-
tration and the temperature at which cryoglobulins
precipitate. Purpura is the most typical clinical presen-
tation of cryoglobulinemia. Cold sensitivity is present
in fewer than 50% of patients with cryoglobulinemia.
Type I cryoglobulins are typically associated with Ray-
naud’s syndrome, acrocyanosis, retinal hemorrhage,
and arterial thrombosis. Type II and III cryoglobulins
are associated with arthralgias and vascular purpura.
Treatment of cryoglobulinemia is based on the severity
of clinical presentation. Mild cutaneous symptoms
may only call for avoidance of exposure to cold tem-
peratures. NSAID can alleviate more bothersome der-
matologic and articular manifestations. Renal involve-
ment may require corticosteroids and/or cytotoxic
agents. Plasmapheresis has been used in progressive
refractory disease, but it needs to be combined with
cytotoxic agents to avoid postpheresis rebound
(Iwasaki and Kakishita 1995).
AMYLOIDOSIS
Amyloidosis consists of a group of disorders in which
amyloid fibrils are extracellularly deposited in internal
organs and skin. Amyloid fibers in x-ray diffraction
studies demonstrate a beta-pleated structure, unlike
that of most human proteins. The proteins serving as
precursors for fibrils can be either light chain mono-
clonal proteins or serum protein A. This distinction
serves as a basis for classification into amyloid light
chain amyloidosis (AL) and serum protein A amyloi-
dosis (AA). AA-type amyloidosis is usually associated
with a chronic inflammatory process, such as rheuma-
toid arthritis, chronic osteomyelitis, tuberculosis, or
leprosy. Although the deposition of amyloid in the
skin is common in AA, it rarely leads to clinically ap-
parent skin lesions. AL-type amyloidosis is associated
with MM, MGUS and WM (Wong 1990). It common-
EUROPEAN JOURNAL OF MEDICAL RESEARCHMarch 29, 2005 95
ly affects the skin, with a reported incidence of 21 -
40%. The most characteristic features are non-prurit-
ic, non-tender, shiny, waxy papules, commonly located
on the eyelids. However, lesions can also be present in
the skin folds, the retroauricular folds, the anogenital
region, or the oral mucosa. Purpura is the type of le-
sion encountered most often because of the frequent
deposition of amyloid in blood vessel walls, resulting
EUROPEAN JOURNAL OF MEDICAL RESEARCH96 March 29, 2005
12
34
5
7
6
Fig. 1. Scleromyxedema.
Fig. 2. Scleredema.
Fig. 3. Plane Xanthomas.
Fig. 4. Necrobiotic xanthogranuloma.
Fig. 5. Schnitzler syndrome.
Fig. 6. Erythema elevatum et diutinum.
Fig. 7. Subcorneal pustular dermatosis.
in extreme fragility of the skin vessels. The deposition
of amyloid in the blood vessel walls is also responsible
for pinch purpura, which is frequently found on the
eyelids of patients with AL-type amyloidosis (Wong
1990). AL amyloid deposition is also responsible for
peripheral neuropathy, carpal tunnel syndrome and
orthostatic hypotension. Approximately 10% of pa-
tients with AL amyloidosis develop macroglossia,
which can produce dysphonia and dysphagia (Christi-
aens et al. 1999). Another manifestation of oral amy-
loidosis may be xerostomia, resulting from salivary
gland infiltration by amyloid. Primary cutaneous amy-
loidosis does not appear to be related to systemic dis-
ease. The papular type, often referred to as lichen
amyloidosis, presents with extremely pruritic, hyper-
keratotic, brownish papules. These papules are most
commonly the size of a pinhead, but they can reach 6-
8 mm in diameter and usually occur on the shins.
Macular amyloidosis is probably a variant of lichen
amyloidosis, presenting as pruritic, oval, grayish
brown macules on the lower extremities or back. De-
finitive diagnosis of systemic amyloidosis requires the
confirmation of amyloid deposits in the tissue. The
most commonly suggested sites include the rectum
and the tongue. However, several reports recently
published state that a skin biopsy is a sensitive, safer,
and less complicated procedure (Lee et al. 1998).
Evaluation of the patient with biopsy-proven cuta-
neous amyloid deposition depends on the clinical
scenario. Vessel wall infiltration and epidermal atro-
phy in a biopsy sample obtained from a patient
with waxy eyelid nodules should raise suspicion of
an AL-type amyloidosis (Lee et al. 1998), and a
search for underlying MM or WM is warranted. If
all clinical and pathologic features appear to suggest
lichen amyloidosis, no further search is necessary and
local measures should be undertaken. Effective thera-
py for AL- and AA-type amyloidosis is not yet avail-
able, with treatment being symptomatic most of the
time.
POEMS SYNDROME
Polyneuropathy, organomegaly, endocrinopathy, M
protein, and skin changes (POEMS syndrome) was de-
scribed as a separate pathologic entity in Japan based
on a series of 102 patients. However, since 1968 a
number of cases have also been reported in the United
States (Takatsuki 1994). Of the originally reported pa-
tients, 75% had a serum and occasionally an urinary
monoclonal spike, and in 95% of these patients the
monoclonal protein had a lambda light chain restric-
tion (Soubrier et al. 1994, Costa et al. 1990). In the
Japanese series, men were affected twice as often as
women, with a mean age of 46 years. Polyneuropathy
was present in all patients and was usually sensorimo-
tor. Organomegaly usually manifested itself as he-
patomegaly (82%), lymphadenopathy (65%), and
splenomegaly (39%). Endocrinopathy presented as im-
potence (78%) and gynecomastia (68%) in men as well
as amenorrhea (68%) in women (Cuellar et al. 1995).
Other reported endocrine abnormalities included glu-
cose intolerance, hyperthyroidism, hyperprolactinemia,
and adrenal insufficiency. In contrast to MM, no ane-
mia, no renal insufficiency, and only rare cases of hy-
percalcemia were reported. Bone marrow infiltration
by plasma cells was unusual. Patients reported bony le-
sions, but unlike those in MM, these lesions were
mostly osteosclerotic. Skin changes are commonly ob-
served in patients with POEMS syndrome, with 93 -
98% having diffuse hyperpigmentation and 92% hav-
ing peripheral edema. Ascites and pleural effusions
were occasionally reported. Hypertrichosis, digital
clubbing, white fingernails, sicca syndrome, and Ray-
naud’s syndrome have also been described (Goldstein
and Bandyopadhyay 2004, Lagueny et al. 2004).
EUROPEAN JOURNAL OF MEDICAL RESEARCHMarch 29, 2005 97
Fig. 8. Pyoderma gangrenosum. Fig. 9. Sweet syndrome. Fig. 10. Leukocytoclastic vasculitis.
89 10
GROUP IIA: HIGH ASSOCIATION
SCLEROMYXEDEMA, LICHEN MYXEDEMATOSUS,
PAPULAR MUCINOSIS
The terms lichen myxedematosus (LM), papular muci-
nosis (PM), and scleromyxedema (SM) are used inter-
changeably to describe the same disorder. A spectrum
of disease appears to exist, with the more localized,
less severe forms, which are generally called LM or
PM, and the more sclerotic, diffuse form, which is re-
ferred to as SM. LM is a rare skin disorder character-
ized by fibroblast proliferation and mucin deposition
in the dermis without any thyroid disease. The etiolo-
gy is unknown. However, LM is commonly associated
with plasma cell dyscrasia (Dinneen and Dicken 1995).
The basic defect is hypothesized to be a fibroblast dis-
order that causes the increased mucin deposition in
the skin. Most patients have a monoclonal paraprotein
band, usually of the IgG type. The association be-
tween this paraprotein and mucin deposition is not
clear, and the protein does not directly stimulate fi-
broblast proliferation. Most individuals with LM are
aged 30-70 years. LM is usually a chronic disease (Din-
neen and Dicken 1995). Although a majority of pa-
tients have MGUS, they rarely have associated MM.
However, when MM is present, the patient generally
has a poor prognosis. Patients with cardiac or pul-
monary involvement also have poor prognoses. In LM
or PM, the primary lesion is a 2-4 mm dome-shaped
and flesh-coloured or erythematous papule. Regarding
the distribution, lesions may coalesce into grouped
lichenoid papules and are found on the dorsal hands,
face, or extensor surfaces of the arms and legs.
Papules often have a striking pattern of parallel ridges.
In patients with the generalized lichenoid form, facial
ridges and facial folds may be distorted. This condi-
tion is called leonine faces. Patients with leonine faces
may have difficulty opening the mouth. In SM the pri-
mary lesions may involve widespread erythematous,
indurated skin resembling scleroderma, and diffuse
tightness of the skin (Fig. 1). The range of motion of
the face, fingers, and extremities is decreased. Systemic
manifestations include restrictive and obstructive pul-
monary dysfunction, cardiovascular abnormalities, and
polyarthritis. Obstructive and restrictive lung disease is
often manifested by dyspnea on exertion. Gastroin-
testinal symptoms, most commonly dysphagia, are re-
lated to esophageal aperistalsis. Severe proximal mus-
cle weakness, polyarthritis, and symptoms resembling
those of organic brain disease might appear. Inflam-
matory myopathy is also reported. Ophthalmologic
symptoms include ectropion and corneal opacities.
Cardiovascular abnormalities occur in 10% of cases.
Lesions feature large depositions of mucin in the der-
mis. Numerous plump stellate fibroblasts develop
throughout the dermis. The mucin stains with periodic
acid-Schiff and Alcian blue at pH 2.5, and it metachro-
matically stains with toluidine blue at pH 3.0. It has
been identified as hyaluronic acid, a non-sulfated acid
mucopolysaccharide. Treatment of LM is difficult and
often ineffective. Many therapeutic approaches have
been reported including retinoids, orthovoltage radia-
tion, electron beams, corticosteroids, PUVA, plasma-
pheresis, extracorporeal photophoresis, dermabrasion,
and carbon dioxide laser excision (Durani et al. 2001,
Harris et al. 1979, Dinneen and Dickson 1995, Lister
RK et al. 2000). For LM, the prognosis is a chronic
course with little tendency for spontaneous resolution.
SM usually has a poorer prognosis. Typical causes of
death include complications from systemic therapeutic
agents such as melphalan or systemic disease such as
cardiovascular involvement.
SCLEREDEMA
Scleredema is an uncommon condition of unknown
etiology. It is characterized by a non-pitting induration
of the skin with occasional erythema (Fig. 2). Sclerede-
ma can be categorized into 3 clinical subgroups, each
having a different history, course, and prognosis.
Group 1 accounts for most cases. Patients in group 1
have a history of preceding febrile illness, particularly
an upper respiratory tract streptococcal infection
(Cron and Swetter 1994). The onset of skin lesions is
rapid and usually clears within 6 months to 2 years.
The duration is not affected by the use of antibiotics.
Most pediatric patients fall into this group. Patients in
groups 2 and 3 generally have no prior history of
febrile illness. The onset of skin lesions in these pa-
tients is insidious. Patients in group 2 may have no pri-
or history of medical problems, but they appear to be
at a certain risk of developing MGUS or MM (Hodak
et al. 1988). Patients in group 3 have a prior history of
diabetes mellitus, usually with an adult onset and in-
sulin dependent, and they tend to have an unremitting
course. Although regarded as a benign, self-limited
skin disease, scleredema may be persistent and involve
the viscera. Rarely, it may result in death. The term
scleredema is a misnomer because neither sclerosis
nor edema is found upon microscopic examination.
Histological findings of scleredema include a thick-
ened dermis with deposition of mucin between thick-
ened collagen bundles (Ulmer et al. 1998). Fibroblast
cultures of affected skin have shown increased procol-
lagen synthesis. Likewise, serum from patients with
scleredema has been shown to stimulate collagen pro-
duction in normal skin fibroblasts. The morbidity of
skin changes in scleredema depends on the area of the
body involved. Involvement of the skin over the joints
may cause a limited range of motion. Scleredema on
the face can result in difficulties in opening the eyes
and mouth. Although rare, extensive truncal involve-
ment may cause restrictive lung disease. The tongue
may be involved in scleredema, resulting in dysarthria
and difficulty with mastication and tongue protrusion.
Other organs that may be affected in scleredema in-
clude the skeletal muscles, ocular muscles, pharynx,
liver, parotid glands, pleurae, peritoneum, and spleen.
Initial skin changes in scleredema usually occur on the
face, neck, and upper part of the back. Affected skin
may be flesh-coloured, erythematous, or hyperpig-
mented. Hands and feet are typically spared. No thera-
py is consistently effective for scleredema. A number
of therapies, including systemic steroids, cyclosporine,
methotrexate, PUVA, penicillamine, electron beam,
and glycemic control with prostaglandin E1 have been
tried with varying degrees of success (Bowen et al.
EUROPEAN JOURNAL OF MEDICAL RESEARCH98 March 29, 2005
2003, Pujol et al. 1995). Patients with long-standing
scleredema should be periodically monitored using the
results of electrophoresis to detect the development of
paraproteinemia or MM. Blood dyscrasias may occur
several years after the onset of scleredema. Although
the course of scleredema is unpredictable, patients in
groups 2 and 3 typically have a slowly progressive or
unremitting course over many years (Ulmer et al.
1998).
PLANE XANTHOMAS
Plane xanthomas (PX) are mostly yellow-coloured mac-
ules and rarely form elevated lesions (Fig. 3). They can
occur at any site. Involvement of the palmar creases is
characteristic for type III dysbetalipoproteinemia. They
can also be associated with secondary hyperlipidemias,
especially in cholestasis. Generalized PX can cover large
areas of the face, the neck, and the thorax, and the flex-
ures can also be involved. They may be associated with
hyperlipidemia, particularly hypertriglyceridemia (Hidal-
go Calleja et al. 1993). IgG gammopathy is most com-
mon in PX, however, the role of paraproteins in the ini-
tiation of PX is still unknown (Daoud et al. 1999).
NECROBIOTIC XANTHOGRANULOMA
Necrobiotic xanthogranuloma (NX) is a rare destruc-
tive cutaneous and subcutaneous disorder that most
frequently involves the face, especially the periorbital
region (Fig. 4). Twelve years after the original descrip-
tion, Mehregan and Winkelmann 1992 reported on 32
cases from their own patient circle and 16 from the lit-
erature. Since then, other cases have occasionally been
reported. MGUS is common in NX. IgG-kappa was
found in 23 cases and IgG-lambda in nine cases, while
cryoglobulins have also been reported (Roth et al.
2002). Bone marrow examination usually shows plas-
ma cell proliferation and, rarely, true myeloma. The
clinical feature is a xanthogranuloma with focal necro-
sis, presenting as multiple large, sometimes ulcerated,
red to yellow granulomatous nodules. Histologically,
these xanthomatous lesions are different from xan-
thomata typically associated with primary hyper-
lipoproteinemia. The anticipated Touton-type foamy
macrophages are present, but in addition there is colla-
gen necrosis, which is not generally seen in other xan-
thomata. The clinical course is chronic and often pro-
gressive. Low-dose chlorambucil treatment is safe and
effective, but individual patients have responded to
treatment with corticosteroids, melphalan, local radia-
tion, and plasma exchange (Machado et al. 2001).
SCHNITZLER SYNDROME
Schnitzler syndrome (SS), first reported in 1974, is
characterized by chronic, non-pruritic urticaria in asso-
ciation with recurrent fever, bone pain, and mono-
clonal IgM gammopathy at a concentration that is usu-
ally less than 10 g/dL (Fig. 5). Deposition of the IgM
paraprotein, leading to formation of immune com-
plexes and activation of the complement cascade,
might be responsible for cutaneous manifestations.
Another proposed mechanism involves the uncon-
trolled activation of interleukin-10. Most patients with
SS have a benign course. Approximately 10 - 15% of
patients eventually develop a lymphoplasmacytic ma-
lignancy, such as WM, lymphoplasmacytoid lym-
phoma, or IgM myeloma. Patients with SS present a
chronic, recurrent, urticarial eruption that is classically
non-pruritic. Rarely, mild pruritus may occur. Skin
eruption is usually the first symptom to occur, primar-
ily affecting the trunk and the extremities, sparing the
palms, the soles, and the face. Approximately 75% of
patients experience recurrent fevers in association with
urticarial eruptions. Each febrile episode usually re-
solves within a few hours, however, fever can persist
for up to 24 - 48 hours. Concurrent with fever, pa-
tients may complain of relapsing arthralgias (60%),
bone pain (50%), and myalgias. The bone pain typical-
ly involves the tibia, the femur, the ileum, and the ver-
tebral columns, but other sites can also be affected.
Fatigue and weight loss is present in a high percentage
of patients. The pathogenesis of SS is still unclear. In
1980, using anti-idiotype antibodies, Olsen et al.
demonstrated that IgM monoclonal antibodies reacted
with epidermal antigens. Saurat et al. in 1991 found
that the monoclonal IgM targeted 50-kd, 31-kd, and
17-kd proteins within epidermal extracts. These find-
ings suggest that IgM deposits may be involved in the
pathogenesis of SS, perhaps via formation of immune
complexes and activation of the complement system.
IL-10 is a known mediator of inflammation, and its
injection into the skin causes persistent erythema. In
1991, Saurat et al. found that the serum from 6 out of
9 patients with SS contained polyclonal IgG–type au-
toantibodies directed against IL-10. These autoanti-
bodies have been shown to prolong the half-life of IL-
10, to change its tissue distribution, and to enhance its
effects. As such, this increase in IL-10 activity could
account for the symptoms of urticaria and fever found
in SS. All cases of SS are associated with an IgM mono-
clonal gammopathy, which is demonstrated by serum
immunoelectrophoresis. Most cases are of the IgM-
kappa isotype. In 51% of cases, serum protein elec-
trophoresis may not detect the IgM gammopathy be-
cause levels can be very low. Both low serum comple-
ment levels and low serum C1 inhibitor levels are seen
in nearly 10% of patients. Cryoglobulin, antinuclear an-
tibody, and rheumatoid factor test results are positive
in a small percentage, 3%, 7%, and 7%, respectively.
Abnormal lymphoid proliferation is present in 10% of
bone marrow biopsy samples and 10% of lymph node
biopsy samples (de Castro et al. 1996). A recent review
of the pathology of SS showed that the histopathologi-
cal findings were not consistent. Features in some in-
cluded a superficial dermal and perivascular infiltrate
of polymorphonuclear cells, mostly neutrophils, sug-
gestive of neutrophilic urticaria. A small percentage
demonstrated a superficial perivascular mononuclear
infiltrate suggestive of chronic urticaria and lympho-
cytic inflammation. Vessels were intact, and dilatation
of dermal lymphatics with mild superficial edema was
present. Rare cases show fibrin deposition, extravasa-
tion of erythrocytes, or leukocytoclastic vasculitis. De-
posits of IgM and complement in the upper dermis
and/or at the dermoepidermal junction were seen in
45% of cases. IgM deposits were rarely found within
EUROPEAN JOURNAL OF MEDICAL RESEARCHMarch 29, 2005 99
vessel walls (de Castro et al. 1996). The urticarial erup-
tion of SS is typically resistant to treatment. Non-
steroidal anti-inflammatory drugs (NSAID), corticos-
teroids, and immunosuppressive agents have been re-
ported to provide variable relief from symptoms of
bone pain and arthralgias. However, no treatment is
consistently effective. Skin and extracutaneous mani-
festations respond poorly to H1 and H2 antihistamines.
Colchicine and dapsone have been tried with variable
success. Chloroquine, chlorambucil, cyclophosphamide,
azathioprine, plasmapheresis, and high-dose intra-
venous immunoglobulin usually have a poor response.
Prednisone, at doses of approximately 50 mg/d, is
often effective in controlling cutaneous eruptions. Re-
lapses are common in attempts to taper the dose of
prednisone. NSAID have proved to be of some benefit
for bone pain and fever but not for the urticaria. Of-
ten, a combination of low-dose prednisone and an
NSAID, with or without another immunosuppressive
agent, may be needed to control symptoms (Lipsker
2002).
ERYTHEMA ELEVATUM ET DIUTINUM
Erythema elevatum et diutinum (EED) is a rare type
of leukocytoclastic vasculitis characterized by red, pur-
ple, brown, or yellow papules, plaques, and nodules
(Fig. 6). Lesions are usually distributed on the extensor
surfaces of the body. The pathophysiology of EED
still remains uncertain. According to Gibson and Su,
lesions are caused by the deposition of immune com-
plexes in small blood vessels inducing an inflammatory
cascade with consecutive damage to the vessels (Gib-
son and Su 1995). This repetitive damage causes fibro-
sis and the appearance of cholesterol crystals and
myelin figures. Direct immunofluorescence shows de-
posits of complement as well as IgG, IgM, IgA, and
fibrin around the damaged vessels. Although first de-
scribed in 1888, the largest study of EED was pub-
lished in 1992 and included only 13 patients. Patients
usually present with persistent, firm lesions on the ex-
tensor surfaces of their skin, especially over the joints
(Yiannias et al. 1992). Lesions mostly consist of nod-
ules and oval plaques. However, on rare occasions,
blisters and ulcers may appear. The colour of the le-
sions progresses over time from yellow or pinkish to
red, purple, or brown. They can be completely asymp-
tomatic, painful, or cause a sensation of burning or
itching. The general health of the patient may be oth-
erwise good, although a history of arthralgia is often
found in EED. Disorders that have been associated
with EED include recurrent bacterial infections, viral
infections such as hepatitis B or HIV, and rheumato-
logic disease (Sachdev et al. 2002). In recent years, sev-
eral reports, including the two largest clinical studies
completed on EED, have suggested hematologic dis-
eases as the most common associated factor (Gibson
and El-Azhary 2000). Direct immunofluorescence
study results demonstrated changes consistent with
vasculitis, including deposits of complement, im-
munoglobulins (IgG, IgA, IgM), and fibrin (Wayte et
al. 1995). Yiannias et al. advocate routine immunoelec-
trophoresis testing for patients with EED. The grow-
ing number of studies showing that MGUS might play
a causal role in EED supports the use of this tech-
nique. A skin biopsy is the most useful examination
for diagnosing EED. No specific histological finding
can be used to single out the diagnosis of EED from
other leukocytoclastic diseases. However, the simulta-
neous presence of several histological findings can
help distinguish this disease from others. Early lesions
show vasculitis in small vessels of the upper and mid
dermis. Furthermore, a perivascular infiltrate consist-
ing of mainly polymorphonuclear neutrophils, frag-
mented nuclei, and to a lesser extent macrophages,
lymphocytes, and eosinophils is present throughout
the dermis. The epidermis can be affected and show
signs of edema, acanthosis, and even necrosis. Granu-
lation tissue and fibrosis in the dermis characterize
older lesions. Toxic hyaline is less apparent, but extra-
cellular cholesterol (EC) deposits may be observed in
the fibrotic tissue. This has been termed EC and was
thought at first to have a different etiology to EED
(Sachdev et al. 2002). Today, EC is known to be a
manifestation of EED. Furthermore, the use of the
term extracellular cholesterosis tends to be restricted,
since it is now believed that the main lipid deposits are
intracellular and that they are formed from cholesterol
esters produced by damaged tissue. Several studies and
clinical experience have shown a good response to
dapsone, whereas systemic steroids have not been
found to be effective generally. Sulfapyridine has simi-
lar effects to dapsone. Intermittent plasma exchange
was shown to control IgA paraproteinemia in associa-
tion with EED. The IgA levels responded to intermit-
tent plasma exchange treatment followed by consol-
idative doses of cyclophosphamide. This treatment
might be promising for severe EED that cannot be
controlled by dapsone. EED is a chronic disease that
usually evolves over a 5- to 10-year period, at which
point it may resolve. Lesions tend not to leave scars,
but areas of hyperpigmentation or hypopigmentation
might occur (Gibson and el-Azhary 2000).
SUBCORNEAL PUSTULAR DERMATOSIS
Subcorneal pustular dermatosis (SPD) is a rare, be-
nign, chronic relapsing pustular eruption of unknown
etiology (Fig. 7). This condition characteristically af-
fects the flexural sites of the trunk. SPD has common-
ly been reported in middle-aged and elderly women.
Sneddon and Wilkinson first described it as a separate
entity in 1956 (Sneddon and Wilkinson 1979, Sneddon
1977). The exact pathophysiology remains unknown.
Subcorneal accumulation of neutrophils suggests the
presence of potent chemoattractants in the upper part
of the epidermis. Neutrophil chemoattractants, such as
interleukin-8, leukotriene B4, and complement frag-
ments have been found at increased levels in scale ex-
tracts compared with controls. A possible etiologic
pathogen has not been identified. Patients typically
present with a chronic relapsing, pustular, erythema-
tous eruption that affects the trunk, particularly the
axillae, the groin, and the submammary region. The
rash can cause irritation, but this is not a prominent
feature. Systemic and toxic symptoms are not a fea-
ture, although skin lesions can become secondarily in-
fected. A background history of MGUS, MM, pyoder-
EUROPEAN JOURNAL OF MEDICAL RESEARCH100 March 29, 2005
ma gangrenosum, inflammatory bowel disease, or
rheumatoid arthritis may be present (Bolcskei et al.
1992). The association of paraproteinemia with SPD is
well recognized. Most reports include the presence of
IgA MGUS of either the kappa or the lambda light
chain type, but IgG gammopathies are also recognized
(Takata et al. 1994, Atukorala et al. 1993). A recent se-
ries showed that 4 of 10 patients showed a detectable
paraprotein level. Serum protein electrophoresis
should be repeated at appropriate intervals because
paraproteinemia has developed as late as 27 years after
presentation. Additionally, lymphoproliferative disease,
in particular MM, is known to develop in 17% of pa-
tients who have had MGUS for over 10 years (Stone
and Lyckholm 1996). A skeletal survey and bone mar-
row aspiration should be undertaken if MM is suspect-
ed, particularly since this is a recognized association
(Bolcskei et al. 1992). The hallmark sign is a sub-
corneal pustule that is filled with neutrophils and oc-
casional eosinophils. This finding is not pathogno-
monic and it may be found in a number of other con-
ditions, including pustular psoriasis, acute generalized
exanthematous pustulosis, pemphigus foliaceus, bacte-
rial impetigo, and dermatophytosis (Hensley and
Caughman 2000). However, pustules are exclusively
subcorneal, and they classically sit on top of a relative-
ly undisturbed epidermis with minimal spongiosis.
This feature differs from pustular psoriasis where the
pustule indents and disrupts the epidermis with
spongiform changes, and it may be associated with
spongiform pustules of Kogoj or Munro microab-
scesses visible elsewhere in the epidermis. In SPD,
neutrophils may be seen migrating up through the epi-
dermis with minimal associated spongiosis. The un-
derlying dermis shows a perivascular infiltrate of neu-
trophils and, occasionally, monocytes and eosinophils
(Vignon-Pennamen and Wallach 1995). Acantholysis is
not a prominent feature, although minor degrees may
be seen in older lesions. Direct and indirect immuno-
fluorescence results are typically negative, but repeated
investigation at suitable intervals is recommended to
detect late-onset intercellular IgA staining within the
epidermis, which is referred to as IgA pemphigus or
intercellular IgA dermatosis. The relationship between
SPD and IgA pemphigus is still being elucidated, but a
subgroup referred to as SPD type IgA pemphigus is
clinically indistinguishable from classic SPD (Vaccaro
et al. 1999). SPD responds to dapsone, but the re-
sponse is not necessarily complete (Roger et al. 1990).
Sulfapyridine and sulfamethoxypyridazine can be used
as alternatives, but they are regarded as being less ef-
fective. Oral corticosteroids are usually ineffective but
they have successfully been used in combination with
dapsone. Etretinate, and more recently acitretin, have
been reported as therapeutic alternatives. Narrowband
(TL-01) UV-B, broadband UV-B, psoralen ultraviolet
A (PUVA), and re-PUVA have all been reported as be-
ing of value in controlling SPD, but relapse may rapid-
ly occur, necessitating maintenance therapy or repeat-
ed courses (Todd et al. 1991). Combination chemother-
apy for underlying MM has been associated with clini-
cal improvement. Other therapeutic modalities anec-
dotally recommended include colchicine, ketocona-
zole, and minocycline.
GROUP IIB: LOW ASSOCIATION
PYODERMA GANGRENOSUM
Pyoderma gangrenosum (PG) is an inflammatory skin
disease that occurs in association with systemic disor-
ders in 50 - 80% of cases. Its most common associa-
tion is ulcerative colitis (Callen 1998). Approximately
1% of cases of PG occur in association with hemato-
logic disorders, including MM and other monoclonal
gammopathies. IgA gammopathy is most commonly
observed in patients with PG (Kohl et al. 1991, Mi-
juskovic et al. 2004). PG is characterized by painful
nodules or pustules, which open to form enlarging ul-
cers with tender raised borders that are frequently
vesicular or bullous (Fig. 8). Lesions are most often
solitary, but if multiple they may coalesce. They are
usually distributed on the lower extremities, although
they can also appear on the trunk, the abdomen, and
rarely the head and neck (Callen 1998). Systemic
symptoms of fatigue and fever may accompany skin
lesions. The pathogenesis of PG is unclear, and aber-
rations of cellular immunity and neutrophilic function
have been discussed. Histopathological findings are
non-specific and include ulceration and necrosis of the
epidermis and dermis, chronic inflammatory cells in
the centre of the lesions, and a dense infiltration of
neutrophils at the margins. The diagnosis is strictly
clinical. Lesions are typically sterile, unless secondary
infection occurs. PG should be differentiated from
bacterial cellulites, herpes simplex virus infection,
atypical mycobacterial infection, and deep fungal my-
coses. Excluding an infection is critical before treat-
ment is instituted (Callen 1998). Corticosteroids re-
main the treatment of choice. In patients with underly-
ing hematological malignancies, topical treatment is
generally ineffective. Systemic doses of up to 60-80 mg
daily may be administered. Intravenous pulse methyl-
prednisolone remains an option in refractory cases.
Regression of PG upon treatment of the underlying
disease has been reported. Other systemic treatments
include dapsone, sulfasalazine, and clofazimine. Of
importance, immunosuppressive agents such as 6-mer-
captopurine, azathioprine, cyclosporine, chlorambucil,
and cyclophosphamide alone or in combination with
steroids have been reported (Burruss et al. 1996, Pow-
ell et al. 1996, August and Wells 1974). The optimal se-
quence of therapy including both chemotherapy and
PG treatment should be tailored to the patient. On the
one hand, extensive loss of skin integrity causes pa-
tients with PG to be more prone to sepsis at the time
of chemotherapy-induced neutropenia. On the other,
immunosuppression with steroids remains an issue
(Callen 1998).
SWEET SYNDROME
In 1964, Robert Sweet described a syndrome involving
an acute onset of febrile neutrophilic dermatosis. It is
manifested by fever, neutrophilia, and erythematous
plaques or nodules that respond to steroid therapy
(von den Driesch 1994). Skin lesions most commonly
involve the upper extremities and face and begin as
tender erythematous plaques or nodules (Fig. 9). They
EUROPEAN JOURNAL OF MEDICAL RESEARCHMarch 29, 2005 101
may evolve into vesicles, bullae, or pustules. Extracuta-
neous manifestations are not infrequent and common-
ly affect the eyes, lungs, liver, kidneys, and bones. Lab-
oratory features include neutrophilia, anemia, and an
elevated erythrocyte sedimentation rate (von den Dri-
esch 1994). The diagnosis is based on clinical presen-
tation and characteristic findings at skin biopsy (Su
and Liu 1986). Histological evaluation reveals a neu-
trophilic infiltrate in the dermis, without evidence of
infection, vasculitis, or malignant cells (Bourke et al.
1997). Clinical syndromes can mimic several other en-
tities and differential diagnoses including erythema
multiforme and cellulitis. Patients are often initially
treated for an infectious process before the proper di-
agnosis is realized. In cases associated with malignan-
cy, SS typically appears shortly before or coincident
with the diagnosis. Lesions may wax and wane, but
they typically persist until therapy is administered.
Symptoms resolve with systemic steroids and/or suc-
cessful cancer-directed therapy. Naproxen, colchicine,
indomethacin and potassium iodide have been used in
alternative approaches (Jeanfils et al. 1997, Maillard et
al. 1999, von den Driesch 1994). Recurrent disease is
reported and may be a result of an underlying malig-
nancy. SS is associated with an underlying neoplasia in
20% of cases. Approximately 80% of these cases in-
volve hematological malignancies including acute
myeloid leukemia and MGUS (Nocente et al. 2002,
Bourke et al. 1997). However, non-malignant condi-
tions, including certain drug exposures, autoimmune
diseases, and infections have been linked to SS. The
exact mechanism for the development of SS is unclear,
and several theories have been proposed, including ab-
normalities in neutrophil chemotaxis, autoantibodies
directed against neutrophils, and alteration in cytokine
levels including interleukin-6 and granulocyte colony-
stimulating factor. The use of subcutaneous G-CSF in-
jections has been implicated as the inciting event in
several cases of SS (Arbetter et al. 1999). Although this
syndrome is often linked to acute myeloid leukemia as
a paraneoplastic process, skin lesions do not directly
involve malignant cells. Abnormalities in cytokine pro-
duction or response in the presence of leukemia are
believed to underlie the neutrophilic invasion of the
dermis (Reuss-Borst et al. 1993). On the other hand,
dermal infiltration with leukemic cells is a separate en-
tity referred to as leukemia cutis.
LEUKOCYTOCLASTIC VASCULITIS
Leukocytoclastic vasculitis (LV) is a histopathologic
term commonly used to denote a small-vessel vasculi-
tis (Fig. 10). Many possible causes exist for this condi-
tion, but a cause is not found in as many as 50% of pa-
tients. The disorder may be localized to the skin, or it
may manifest in other organs. The internal organs
most commonly affected include the gastrointestinal
tract or the kidneys. Joints are also commonly affected.
The prognosis is good when no internal involvement
is present. In the past, circulating immune complexes
were believed to cause LV (Lotti et al. 1998). Although
immune complexes are involved in the pathogenesis of
LV, other autoantibodies cause disease manifestations,
such as antineutrophil cytoplasmic antibody (ANCA),
other inflammatory mediators, and local factors that
involve the endothelial cells and other adhesion mole-
cules. The exact mechanisms remain to be elucidated.
Patients with LV may complain of itching, burning
sensation, and pain. Vasculitis of the skin may also oc-
cur in the absence of any systemic disease. Retiform
lesions were associated with IgA related immune com-
plex disease in one study. However, this result has not
been validated in subsequent studies (Claudy 1998).
Palpable purpura is most frequently observed on the
legs, but any surface can be involved. Purpuric lesions
are sometimes barely palpable. Urticarial lesions are of
a different character than routine urticaria, tending to
be of longer duration and tending to resolve with
some residual pigmentation or ecchymosis. The pic-
ture of LV is a pattern that can occur in any vasculitic
syndrome but may also occur in non-vasculitic dis-
eases such as neutrophilic dermatoses, at the base of a
biopsy sample of a leg ulceration, or in some insect
bite reactions. A skin biopsy sample reveals the pres-
ence of vascular and perivascular infiltration of poly-
morphonuclear leukocytes with formation of frag-
mented nuclei, extravasation of erythrocytes, and fibri-
noid necrosis of the vessel walls. This process is dy-
namic, a biopsy sample of a lesion too early or too late
in its development may not reveal these findings. Be-
tween one third and one half of cutaneous vasculitis
cases are idiopathic, the remainder have a variety of
causes. Antibiotics are the most common drugs that
can cause LV, particularly beta-lactams. NSAID and
diuretics also frequently cause LV. However, almost all
drugs are potential causes. Various infections can be
associated with LV. Upper respiratory tract infections
and viral hepatitis is most often implicated. Hepatitis
C is a regularly recognized cause of LV, probably
through the presence of cryoglobulins. Collagen vas-
cular diseases account for 10-15% of cases of LV. In-
flammatory bowel disease, ulcerative colitis, or Crohn
colitis, even Sjörgren syndrome and other autoimmune
disorders may be associated with cutaneous vasculitis
(Claudy 1998). The presence of vasculitis often de-
notes active disease and possibly a poorer prognosis.
Malignancy accounts for less than 1% of cases of cuta-
neous vasculitis. Lymphoproliferative diseases are
common, but any type of tumor at any site may be re-
lated to LV. Out of 135 patients with LV, only one had
MM. Cryoglobulinemia, infectious and medication hy-
persensitivity may also be relevant in the development
of LV in patients with MM. Up to now no study has
proven the incidence of LV in MGUS. Although LA is
a rare manifestation of plasma cell dyscrasias, serum
protein electrophoresis is useful for identifying a
MGUS amongst patients without otherwise identified
disease (Bayer-Garner and Smoller 2003). Serological
studies including antinuclear antibody, ANCA,
rheumatoid factor, complement levels, cryoglobulins,
and hepatitis C antibody should also be obtained
(Kaufmann et al. 2003).
GROUP III: ASSOCIATION SPORADICALLY
REPORTED
Numerous skin diseases have been reported in pa-
tients with MGUS. Nevertheless, it can be presumed
EUROPEAN JOURNAL OF MEDICAL RESEARCH102 March 29, 2005
that the presence of MGUS in such cases tends to be
coincidental since an underlying pathogenic mecha-
nism is absent. Furthermore, larger collectives of these
dermatoses have not been able to confirm any hypoth-
esized association. Table 3 summarizes the most rele-
vant skin diseases that have been sporadically reported
in patients with MGUS.
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Received: December 10, 2004 / Accepted: February 28, 2005
Address for correspondence:
Alexander Kreuter, MD
Department of Dermatology
Ruhr-University Bochum
Gudrunstrasse 56
D-44791 Bochum, Germany
Tel: +49-234-509-3439
Fax: +49-234-509-3409
E-mail: a.kreuter@derma.de
EUROPEAN JOURNAL OF MEDICAL RESEARCH104 March 29, 2005
... Por fim, as lesões cutâneas no MM podem surgir por toxicidade secundária a agentes terapêuticos usados no tratamento da doença. [2][3][4][5] Descrevemos dois casos clínicos com o diagnóstico de MM de cadeias leves kappa: o primeiro apresentando-se como depósitos de substância amilóide nos canais auditivos externos, e o segundo sob forma de XPD. ...
... Está descrita uma associação forte nos casos de XPD, xantogranuloma, escleromixedema e escleredema, síndrome de Schnitzler e síndrome de POEMS, enquanto outras condições, como a síndrome de Sweet, pioderma gangrenoso e vasculite leucocitoclástica apresentam associação menos específica com o MM; 4) efeitos adversos do tratamento do MM, como toxidermias ou doença de enxerto contra o hospedeiro, como complicação de transplante da médula óssea. [3][4][5][7][8][9] A amiloidose engloba um conjunto de doenças causadas pela deposição de fibrilhas proteicas insolúveis nos tecidos e órgãos. Cerca de 5 a 7% dos doentes com MM apresenta disfunção orgânica resultante de infiltração dos tecidos por amiloide. ...
... Revista SPDV 75 (4) surge em aproximadamente um quarto dos casos. 2,10 As lesões cutâneas podem apresentar-se sob forma de pápulas e placas translúcidas, fragilidade cutânea com formação de bolhas, lesões purpúricas e equimoses nas áreas de maior fricção, devido a angiopatia amilóide. ...
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O mieloma múltiplo é uma doença clonal caracterizada pela proliferação de plasmócitos. A apresentação clínica é variável. Manifesta-se, mais frequentemente, sob forma de infeções recorrentes, anemia, insuficiência renal ou dor óssea resultante das lesões osteolíticas. As manifestações cutâneas no mieloma múltiplo são raras e, na maioria dos casos, inespecíficas. Os autores descrevem dois doentes com lesões cutâneas distintas – depósitos nodulares de substância amiloide no canal auditivo externo e xantoma plano difuso - que possibilitaram o diagnóstico desta neoplasia hematológica.
... Unanswered questions about plasma cell dyscrasias remain but some clarifications have emerged. Often considered a low grade, innocuous process, MGUS, characterized by laboratory evidence of a monoclonal immunoglobulin in the serum or urine of an asymptomatic patient, is observed in approximately 3% of older adults 53,54 . Experience has shown that the underlying plasma cell clone can evolve to frank malignancy, culminating in multiple myeloma in approximately 1% of cases. ...
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We review the spectrum of cutaneous disorders associated with inflammatory and neoplastic plasmacytic pathology. Because plasma cells are derived from B‐lymphocytes our overview includes discussion of certain lymphoplasmacytic proliferations. It is structured along histopathological lines, addressing conditions characterized by (i) cutaneous plasma cell infiltrates, (ii) deposits of plasma cell products or their derivatives in the skin, and (iii) miscellaneous, poorly understood cutaneous complications of plasmacytic disorders. Lesions arising primarily in the skin and those due to cutaneous involvement by multisystem disorders are addressed. The range includes a spectrum of tumefactive and circulatory manifestations. We highlight key clinical and pathological features of the different conditions and outline recent advances in our understanding of these entities. By emphasizing the dermatopathological characteristics of this spectrum of disorders we hope to hone the diagnostic accuracy of practitioners in the field. This article is protected by copyright. All rights reserved.
... Several inflammatory diseases, including skin diseases, have been associated with the high binding and activation capacity of neutrophils and other defense cells, as well as with the expression of Ig kappa chain (P37) and heavy chain (Ig gamma chain) immunoglobulins [63,64]. Thus, the association between clinical compressive therapy and Ig kappa chain immunoglobulins is feasible from the point of view that failure of therapy promotes the differential expression of this protein in inflammatory exudate. ...
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Objective/background: Cutaneous immunoglobulin (Ig) amyloid light-chain (AL) amyloidosis associated with overt multiple myeloma (MM) is rare and optimal treatment is not well defined. The recently developed highly efficacious MM therapy has brought on a new set of challenges to this field for consideration. The goal of this paper is to describe the characteristics of cutaneous manifestations of systemic AL amyloidosis associated with MM according to age, sex, race, Ig type, plasma cell percentage, and cytogenetic and fluorescent in situ hybridization studies along with their outcomes. Methods: An electronic search of the PubMed database was performed to obtain key literature in AL amyloidosis and MM, using the following search terms: multiple myeloma, immunoglobulin light chain amyloidosis, and cutaneous amyloidosis. The search results were narrowed by selecting studies in English. Results were confined to the following articles types: case reports, case series, and systematic reviews. Results: We identified 32 cases from the PubMed database search and examined their potential relevance. We found the following: (a) higher prevalence in women (two-thirds) and white population; (b) IgG and IgA were equally distributed with lambda (λ) light chain occurring in 53-66% of cases; (c) majority of cases (56%) presented as hemorrhagic bullous lesions, followed by purpura/ecchymosis in 25% of cases; and (d) majority (64%) died within 6 months since diagnosis. Conclusions: We reviewed the constellation of the cutaneous manifestations of AL amyloidosis with concurrent MM. We found a female predominance, and more than half presented as hemorrhagic bullous lesions. There is a preponderance of λ light chains over kappa (κ) light chains, both as a free light chain (15% vs. 4%) and as an intact Ig (38% vs. 24%; absolute number of 14 vs. 7 patients, respectively). In the subgroup of patients with bullous skin lesions, λ light chain was present in eight cases and κ light chain in seven cases. All κ light chain subtypes presented with bullous lesions and no other cutaneous types of lesions. They carried very poor prognosis with majority of cases surviving only 6 months, much worse than overall patients with AL amyloidosis without myeloma or myeloma without amyloidosis.
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Background: Pyoderma gangrenosum (PG) is a devastating neutrophilic dermatosis that may be associated with trauma or systemic diseases. The associations, characteristics, and temporal relationship of PG with hematologic malignancies are not well understood. Objective: To perform a systematic review of PG associated with hematologic malignancies using data from case reports, case series, and retrospective studies. Methods: We searched MEDLINE, EBASE, Scopus, and Web of Science from each database's inception to 12 December 2018. Two reviewers independently selected studies and extracted data. Results: Two hundred seventy-nine publications met inclusion criteria (340 cases). Myelodysplastic syndrome (MDS) was the most commonly reported hematologic malignancy associated with PG, followed by monoclonal gammopathy of undetermined significance (MGUS) and acute myeloid leukemia. Mean age of patients was 56.5 years with males being more common. There was a predominance of the ulcerative PG subtype and multifocal distributions across all hematologic malignancies. The majority of MDS cases preceded PG which was reversed for MGUS. Limitations: The data were limited by reporting bias, as the PG subtypes rely on the rendered diagnosis reported. Additionally, the classification for hematologic malignancies has evolved since 1978. Conclusion: Patients with PG should be evaluated for hematologic malignancies with MDS being the most common.
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The present report deals with a case of subcorneal pustular dermatosis (SCPD) associated with IgA lambda myeloma and reviews the literature for similar cases. Three relevant points arise from this case: the association of the dermatosis with an IgA lambda myeloma that, as far as we know, has been described only three times previously; the longest period of time between the onset of the dermatosis and that of the myelopathy observed up to now; the good therapeutic response to etretinate, useful in the management of severe recalcitrant forms of SCPD.
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Sweet's syndrome, pyoderma gangrenosum, subcorneal pustular dermatosis, erythema elevatum diutinum form part of the clinical spectrum of neutrophilic dermatoses. These conditions share common features, such as the association with systemic diseases, i.e. myeloproliferative disorders, monoclonal gammopathies, rheumatoid arthritis, inflammatory bowel diseases. In addition, extra-cutaneous neutrophilic infiltrates may occur in patients with a neutrophilic dermatosis, thus defining neutrophilic disease. We review here the literature on cases of patients with neutrophilic dermatoses and well-documented, culture-negative, extra-cutaneous, neutrophilic lesions. Sites of involvement include the lungs, bones, joints, liver, central nervous system, lymph nodes, spleen, digestive tract, blood vessels and eyes. The awareness of these systemic manifestations allows the dermatologist to accurately evaluate these patients and to avoid unnecessary, aggresive investigations.
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A 46-year-old man with a 3-year history of pyoderma gangrenosum was admitted with ulceration (6 x 5 cm), on the right leg. Previously he had been treated with tapering doses of prednisone (maximum dose 1 mg / kg per day); however, he had had a few exacerbations following each taper of prednisone dose. Immunoelectrophoresis demonstrated monoclonal IgA gammopathy of lambda light chains. Abdominal echography and abdominal computed tomographic scan revealed multiple splenic abscesses. Treatment was started with oral prednisone (1 mg / kg per day) and cyclosporin (5 mg / kg per day) and 6 weeks later complete remission was achieved. Systemic involvement in pyoderma gangrenosum is very rare, and according to our knowledge there are only a few cases with spleen involvement.
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Introduction. – Necrobiotic xanthogranuloma is a rare cutaneous disorder usually associated with monoclonal gammapathy. We describe two new cases.Exegesis. – A 70-year-old patient was affected by a monoclonal gammopathy. She presented with a diplopia related to a retro-orbital tumor. The biopsy showed inflammatory lesions. Five years later, inflammatory xanthomatous skin lesions appeared. Biopsy specimens gave the diagnosis of necrobiotic xanthogranuloma. A 70-year-old woman was referred for inflammatory cutaneous lesions. Clinical, biological investigations and skin biopsies led to the diagnosis of cutaneous sarcoidosis associated with monoclonal gammopathy. Four years later, she developed a nephrotic syndrome. New skin biopsy specimens showed a necrobiotic xanthogranuloma.Conclusion. – Necrobiotic xanthogranuloma is a systemic disease. It is a rare non-Langerhans cell histiocytosis characterized by frequent cutaneous and ophthalmologic lesions and associated with monoclonal gammopathy. To our knowledge, retro-orbital involvement has never been reported in necrobiotic xanthogranuloma. Treatment is difficult.
Article
objective: To determine whether there are peculiarities of the POEMS syndrome (a multisystemic disorder associated with polyneuropathy, organomegaly, endocrinopathy of various forms, production of a monoclonal [M] component, and skin changes) in Caucasian patients, especially signs and symptoms absent in other series; and to attempt a reappraisal of the neuropathy and endocrinopathy to find a unifying mechanism.design: A retrospective, cooperative study compared 25 cases, observed over a 15-year period, with two published series of patients, one of Japanese patients and one of American patients, and with a review of the literature on non-Asian cases. Details were obtained of patients' medical history, physical examination, immunochemical and hormonal testing, roentgenographic examination, computed tomography imaging, and electromyography.results: The main features of the syndrome found in these patients were those first described in Japan: polyneuropathy, enlargement of the lymph nodes, liver, and spleen, endocrine disturbances, low concentration of the monoclonal component, hyperpigmentation, and hypertrichosis. Three other symptoms were found more frequently than previously reported: skin angiomas, scleroderma changes of the hands, and thrombocytosis. Electromyography and nerve biopsy showed a variety of abnormalities ranging from demyelination to axonal degeneration. Nerve deposits of immunoglobulin were absent. Organomegaly seemed to be heterogeneous. Pathologic findings in the enlarged lymph nodes and spleen were compatible with Castleman's disease. Liver biopsies were usually normal. The endocrine changes were surprisingly diverse, with some observations combining unrelated primary and secondary insufficiencies. No single hypothesis emerged regarding their mechanism. All M components had a λ-light chain. An IgG M component was found more frequently in solitary lesions. An IgA M component was found more frequently in patients without bone lesions. Sedimentation rate was usually normal. Radiotherapy of solitary plasmacytomas was followed by dramatic improvement of extramedullary signs and symptoms in all cases.conclusions: The symptoms, clinical course, and management of the patients reported here were similar to those observed in the literature. This study confirms the existence of a close link between symptoms and λ-light-chain production. There are indications that a plasma cell growth factor that does not cross-react with interleukin-6 (IL-6) may be involved.
Article
Pyoderma gangrenosum has been reported in association with ulcerative colitis (d'Sluis, 1966), Crohn's disease, rheumatoid disease and myeloma (Rockl, et al., 1964). It is disturbing that one of the myeloma patients reported by Jablonska, et al. (1967) Institute pyoderma which antedated detection of paraproteinaemia by 4 yr. It may, therefore, be a difficult matter to be certain that pyoderma gangrenosum is idiopathic. The use of azathioprine in pyoderma gangrenosum was reported on unfavourably by Corley in 1964 but Schoepf, et al. (1969) found it to be of value. Mercaptopurine, which is a metabolite of azathioprine, was reported as causing a dramatic remission of pyoderma gangrenosum in a child with acute leukaemia (Maldonedo et al., 1968). Other investigators have used cyclophosphamide (Crawford, et al., 1967) and corticosteroids (Hofstad, 1959; Holt & Waddington, 1973) although they did not help this patient. The use of radiotherapy does not seem to have been reported recently. In the case reported, a combination of moderately high doses of steroids and azathioprine was essential. High dose steroids, however, were ineffective and once control was achieved a reduction of steroid dosage was followed by relapse.
Article
A 33-year-old male was referred with a two-week history of fevers to 40°C and painful, erythematous skin and oral mucosal eruptions that had failed to respond to multiple anti-infectious agents. He had a recent diagnosis of a “myeloproliferative disorder with myelodysplastic features” on bone marrow biopsy, with associated pancytopenia. Two weeks before admission, he had been treated with a course of granulocyte colony-stimulating factor (G-CSF) at a dose of 300 μg/day in an attempt to improve his neutropenia. After four days of treatment, the fever and lesions developed. Infectious evaluation was negative; however, biopsies of the skin and oral mucosal lesions revealed histology consistent with Sweet's syndrome. Intravenous methylprednisolone (30 mg/day) was started with prompt defervescence and resolution of the lesions within days. With the increasing use of G-CSF, Sweet's syndrome is becoming more commonly recognized as an adverse effect. This is the first case of G-CSF–induced Sweet's syndrome to demonstrate gingival involvement. Am. J. Hematol. 61:126–129, 1999. © 1999 Wiley-Liss, Inc.
Article
Background: Cutaneous manifestations of myeloid leukemia can be specific or nonspecific. The study was designed to determine the prevalence and histologic appearance of cutaneous lesions in patients with myeloid leukemia and various myeloproliferative disorders. Methods: The histologic changes of cutaneous lesions in 52 patients with myelodysplastic syndrome, polycythemia vera, and myeloid, myelomonocytic, or monocytic leukemia are presented in this study. Results: Two types of cellular infiltrates were identified. In the first group, the most common pattern was a diffuse involvement by the leukemic cells through the entire dermis with preservation of a "grenz zone" in the superficial dermis. Two cases exhibited a Kaposi's sarcoma-like pattern, with prominent slit-like blood-filled spaces lined by myeloblasts against a fibrocellular stroma. The second group of lesions was characterized by dense, neutrophilic dermal infiltrates resembling acute neutrophilic dermatosis (Sweet's syndrome) or pyoderma gangrenosum. In two of these cases, scattered immature blast cells admixed with the mature neutrophilic elements were identified. Conclusions: Awareness of these different morphologic features and application of special stains are of value in the evaluation of suspicious cutaneous infiltrates in patients with myeloid leukemia and various myeloproliferative disorders.
Article
Scleredema adultorum of Buschke is a rare disorder of unknown aetiology. It is characterized by diffuse, non-pitting swelling and induration of the skin. Skin biopsies reveal marked thickening of the dermis due to collagenous replacement of the subcutis and deposition of hyaluronic acid between the collagen fibers. The disease classically only affects the skin. In 24 cases an associated monoclonal gammopathy has been detected. A 75-year old patient had a 19 year history of scleredema adultorum. In addition to a monoclonal gammopathy the patient suffered from involvement of the tongue, pharynx and upper esophagus. Furthermore a polyneuropathy, ocular involvement with restricted eye movements and a sicca syndrome were present. The simultaneous occurrence of cutaneous scleredema with any one of the above mentioned symptoms has been reported before. The wide variety of extracutaneous manifestations of scleredema as found in our patient is amazing and has not been previously described