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Vascular Inflammation (Vasculitis) in Sweet Syndrome
A Clinicopathologic Study of 28 Biopsy Specimens From 21 Patients
Janine C. Malone, MD;
Stephen P. Slone, MD;
Lisa A. Wills-Frank, MD;
Paul K. Fearneyhough, MD;
Sheron C. Lear, HT(ASCP), HTL, QIHC;
L. Jane Goldsmith, PhD;
Antoinette F. Hood, MD;
Jeffrey P. Callen, MD
Arch Dermatol. 2002;138:345-349.
ABSTRACT
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Background Sweet syndrome is characterized by painful, erythematous plaques of
rapid onset accompanied by fever. Absence of vasculitis is a histologic criterion
for diagnosis. However, recent reports suggest that vasculitis should not
exclude the diagnosis. We hypothesized that vasculitis can occur in Sweet
syndrome and that it represents an epiphenomenon rather than a primary immune-mediated
process.
Design Skin biopsy specimens from patients with Sweet syndrome were reviewed
to determine the prevalence of vasculitis. The clinicopathologic features
of cases with vasculitis were evaluated for statistically significant associations.
Specimens with vasculitis underwent immunofluorescence staining.
Setting University department of dermatology, university hospital, and private
practice.
Patients Medical records and biopsy specimens of 21 patients meeting diagnostic
criteria for Sweet syndrome were reviewed.
Interventions None.
Results The prevalence of vasculitis was 29% (6 of 21 patients). There was a
significant association of vasculitis with lesions of longer duration (P = .02). Vascular immunoglobulin and complement could not
be demonstrated in cases of Sweet syndrome with vasculitis.
Conclusions Vasculitis is not a primary, immune-mediated process in Sweet syndrome
but occurs secondary to noxious products released from neutrophils. Blood
vessels in lesions of longer duration are more likely to develop vasculitis
than those of shorter duration because of prolonged exposure to noxious metabolites.
Vasculitis does not exclude a diagnosis of Sweet syndrome.
INTRODUCTION
ACUTE FEBRILE neutrophilic dermatosis (Sweet syndrome), first described
by Sweet in 1964,1 is a disease characterized
by painful, erythematous nodules and plaques of rapid onset accompanied by
fever and neutrophilia. In many cases the disease follows a viral infection,
especially of the upper respiratory tract, and it has also been reported in
association with hematologic and visceral malignancies, medication (most commonly
granulocyte colony-stimulating factor), autoimmune disease, inflammatory bowel
disease, and pregnancy.
Sweet syndrome is histologically categorized as a neutrophilic dermatosis.
A dense dermal infiltrate composed of neutrophils with leukocytoclasis and
prominent papillary dermal edema occasionally producing subepidermal vesiculation
or bullae are the usual findings. The clinicopathologic features of Sweet
syndrome are so characteristic as to have elicited diagnostic criteria for
the disease, proposed by Su and Liu2 and subsequently
modified by von den Driesch et al3 to include
abnormal laboratory values (elevated erythrocyte sedimentation rate, positive
C-reactive protein, and peripheral-blood leukocytosis with >70% neutrophils).
The histologic absence of vasculitis has been considered a defining
characteristic of the disease and a useful feature to differentiate Sweet
syndrome from other neutrophilic dermatoses in which vasculitis is commonly
seen, such as leukocytoclastic vasculitis and erythema elevatum diutinum.
However, a number of reports have described evidence of vessel wall damage
in patients with clinical signs and symptoms of the disease.4-5
We postulated that vasculitis may be present in Sweet syndrome and that it
represents an epiphenomenon rather than primary immune complex–mediated
disease. Using the diagnostic criteria as guidelines, we reviewed 28 biopsy
specimens from 21 patients with Sweet syndrome to determine the prevalence
of vasculitis and any association between vasculitis and patient age or sex,
lesion duration, and underlying disease process.
PATIENTS AND METHODS
The medical records of patients coded with the diagnosis of Sweet syndrome
were reviewed in a dermatology practice that examines both private and university-based
patients. Of 36 cases retrieved from the search (from January 1, 1989, through
December 21, 1999) and with materials available for review, 21 cases (28 biopsy
specimens) satisfied the diagnostic criteria for Sweet syndrome6
(Table 1) and were included in
the study. Of the 7 patients who underwent more than 1 biopsy, 6 had different
lesions sampled concurrently; 1 patient required biopsy on a later occasion
to establish the diagnosis.
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Table 1. Diagnostic Criteria for Sweet Syndrome*
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Standard hematoxylin-eosin–stained sections from archival paraffin-embedded
tissues were evaluated. Immunofluorescence staining was performed on paraffin-embedded
biopsy specimens showing evidence of vasculitis (fibrinoid necrosis and intramural
inflammation). Each case was examined for the presence of IgG, IgM, IgA, and
C3 by means of appropriate positive and negative paraffin-embedded control
tissues. Positive controls included skin biopsy specimens from 3 patients
with bullous pemphigoid that showed positive staining with antibody against
IgG, IgM, and C3. Biopsy specimens from 2 patients with pemphigus vulgaris
and IgA pemphigus demonstrated immunofluorescence reactivity with antibody
against IgG and IgA, respectively. Negative control tissues comprised sections
of patient tissues lacking antibody application. Sections 4 µm thick
were placed on sialinized slides (to improve tissue adhesion) after flotation
on a protein-free water bath and allowed to air-dry. After overnight drying
at 37°C, slides were deparaffinized in xylene and rehydrated successively
in 100%, 95%, and 50% alcohol baths. After distilled water and phosphate-buffered
saline rinses, sections were incubated in Streptomyces griseus (Pronase; CalBiochem, San Diego, Calif) and 75 µg/100 mL of
Tris buffer at 37°C for 75 minutes. Sections were then rinsed 3 times
for 10 minutes each in phosphate-buffered saline. Sections were incubated
in fluorescein isothiocyanate–labeled antibody at room temperature for
2 hours. All antisera were applied in 1:4 dilution. After incubation, slides
were washed in phosphate-buffered saline 6 times for 5 minutes each. Sections
were coverslipped with an aqueous mounting medium with fluorescence-preserving
properties (Aquamount; Lerner Laboratories, Pittsburgh, Pa) and examined within
6 hours using a fluorescent microscope (Olympus BX60; Olympus Corporation,
Lake Success, NY).
Ordered measures (age and lesion duration) were compared by means of
the nonparametric Mann-Whitney test. Categorical tables (disease association,
sex, lesion location, and inflammatory intensity and pattern) were analyzed
with the Fisher-Freeman-Halton exact test, which computes correct P values even in cases of sparse tables. The statistical software used
was SPSS, version 8.0 (SPSS Inc, Chicago, Ill), and StatXact, version 4.0
(CYTEL Software Corp, Cambridge, Mass).
RESULTS
CLINICAL FINDINGS
Clinical characteristics of patients are listed in Table 2. Two patients have been described previously.7-8
In our 21 cases (18 women and 3 men), the age ranged from 25 to 73 years (average
age, 49 years). Two of the men had hematologic malignancies. An associated
disease process was seen in 15 patients (71%): 6 (29%) had inflammatory disease,
5 (24%) had infectious disease, and 4 (19%) had hematologic malignancy. Three
of 6 patients with an inflammatory condition had rheumatoid arthritis, and
4 of 5 patients with a suspected infectious association described a recent
or ongoing viral upper respiratory tract infection. In the majority of patients
(68%), lesions involved the head and neck area and/or the upper extremity.
Most patients who had more than 1 lesion described a uniform eruption of multiple
lesions, although 6 (29%) described outbreaks at varying time intervals.
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Table 2. Clinicopathologic Features of 21 Patients With Sweet Syndrome*
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MICROSCOPIC FINDINGS
All biopsy specimens demonstrated a dermal infiltrate composed predominately
of neutrophils (Figure 1). The infiltrate
occurred in a diffuse pattern (16 [47%] of the 34 patterns seen), bandlike
pattern (8/34 [24%]), and a vaguely perivascular pattern (10/34 [29%]), although
overlap was occasionally seen within the same biopsy specimen (Table 3). The infiltrate was described as moderate in the majority
(54%) of cases.
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Figure 1. Diffuse basophilia of the dermis
resulting from a dense neutrophilic inflammatory cell infiltrate characteristic
of Sweet syndrome (hematoxylin-eosin, original magnification x100).
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Table 3. Degree and Pattern of Infiltrate in Biopsy Specimens of Sweet
Syndrome*
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Vasculitis was seen in 6 biopsy specimens (21%), although evidence of
vessel wall damage, including intramural inflammatory cells and/or extravasated
erythrocytes, was identified in most cases (21 specimens [79%]). Within individual
biopsy specimens, evidence of vessel wall damage was usually diffuse; however,
of the 6 biopsy specimens that met the criteria for vasculitis, often only
a single vessel demonstrated both fibrinoid change and intramural inflammation
(Figure 2). Of the 6 patients who
had multiple concurrent biopsies performed, only 1 (patient 7) demonstrated
vasculitis in 1 specimen. In the patient who underwent biopsy on separate
occasions (patient 19), neither of the 2 specimens showed evidence of vessel
wall damage (Figure 3). The presence
or absence of vasculitis did not show an association with the pattern or intensity
of the inflammatory infiltrate, although the majority of specimens demonstrating
vasculitis showed a moderate or extensive inflammatory infiltrate. The presence
of vasculitis was significantly associated with lesions that had been present
for a longer duration before their biopsy (P = .02).
The median duration of lesions with and without vasculitis was 17.5 and 6
days, respectively. Two of the 6 patients whose biopsy specimens demonstrated
vasculitis had had lesions present between 1 and 3 months before their biopsy,
and only 1 of the 15 patients whose specimens did not demonstrate vasculitis
described the lesion as having been present 3 months before biopsy. Only 1
biopsy specimen that demonstrated vasculitis came from a lesion that had been
present a week or less (3 days), whereas 14 specimens (50%) without evidence
of vasculitis had been present a week or less. Patient age did not show an
association with the presence or absence of vasculitis (P = .18), although specimens that showed vasculitis tended to occur
in older patients compared with specimens that lacked vasculitis (median age,
61 and 47 years, respectively). No significant association was found between
associated disease state and sex and the presence or absence of vasculitis.
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Figure 2. Dermal vessel displaying vasculitis
characterized by fibrinoid necrosis and a few intramural inflammatory cells
(hematoxylin-eosin, original magnification x1000).
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Figure 3. A dermal vessel from a biopsy
specimen lacking evidence of vasculitis. The vessel is surrounded by an intense
inflammatory infiltrate; however, there is no fibrinoid necrosis and no intramural
inflammatory infiltrate (hematoxylin-eosin; original magnification x400).
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Immunofluorescence staining of the 6 biopsy specimens demonstrating
vasculitis was negative for both immunoglobulin and complement within vessel
walls. Control skin biopsy specimens stained appropriately.
COMMENT
Since Sweet's original description of 8 female patients with acute onset
of fever, leukocytosis, and erythematous plaques demonstrating a neutrophilic
infiltrate, more than 500 cases of Sweet syndrome have been reported in the
literature. The clinical and pathologic findings of the disease were so distinctive
as to have been developed into diagnostic criteria. Of note, histologic evidence
of vasculitis strongly militated against a diagnosis of Sweet syndrome. The
absence of vasculitis has been considered a useful method to distinguish this
disease from other diseases presenting with predominantly neutrophilic infiltrates
with vasculitis. Several studies challenge this dictum. In his study of 54
biopsy specimens from 37 patients with Sweet syndrome, Jordaan4
found evidence of vessel wall damage with fibrinoid necrosis and extravasated
erythrocytes in 18% and 76% of biopsy specimens, respectively. In addition,
von den Driesch5 reported vasculitis-like changes
in 30% of cases of Sweet syndrome. Another study described 6 female patients
with lesions of the hands resembling Sweet syndrome and typical systemic manifestations
but with histologic evidence of vasculitis.9
Strictly adhering to the classic diagnostic criteria for Sweet syndrome, the
authors chose to classify this disease as a distinct entity termed pustular vasculitis of the hands.
We found unequivocal evidence of vasculitis in lesions from patients
who met the clinical criteria for Sweet syndrome. Microscopic evidence of
vasculitis is defined as the presence of inflammatory cells within blood vessel
walls in association with necrosis.10 Commonly
associated with vasculitis, but not essential for its diagnosis, are extravasated
erythrocytes and intraluminal thrombi. The cause of necrotizing vasculitis
in the dermatologic diseases leukocytoclastic vasculitis and Arthus reaction
has been well defined. Both are type III immune complex–mediated diseases.
Leukocytoclastic vasculitis results from the passive deposition of circulating
immune complexes in vessel walls, whereas the experimentally produced Arthus
reaction follows localized formation and precipitation of immune complexes
at the site of antigen entry in a host carrying circulating antibodies to
that antigen. Activation of the complement cascade and induction of macrophages
and neutrophils through their Fc receptors results in the production of chemotactic
factors, anaphylatoxins, and a variety of additional proinflammatory mediators
that produce vessel wall damage.
Unlike the Arthus reaction and leukocytoclastic vasculitis, the stimulus
for neutrophil diapedesis and activation in Sweet syndrome is unknown. A possible
role for bacterial, viral, or tumor antigens6;
circulating autoantibodies11; immune complexes12; or cytokines13-14
has been postulated. The drug most frequently implicated in the disease is
granulocyte colony-stimulating factor,15-16
further suggesting a role for cytokines in the pathogenesis. Antibodies to
neutrophil cytoplasmic antigens have been reported in Sweet syndrome.11 Three of our patients underwent testing for antibodies
to neutrophil cytoplasmic antigens, with a negative result. Immunofluorescence
evaluation of skin lesions in Sweet syndrome failed to yield consistent results.17-18 Perivascular C3 and fibrin have been
reported,6 probably representing nonspecific
leakage from damaged vessels.
Although the stimulus for transmigration of neutrophils across dermal
venules has not been elucidated, the final common pathway for vessel wall
damage is the release of toxic metabolites and proteases from activated neutrophils.
The longer that dermal blood vessels are exposed to toxic substances, the
more damage will be incurred. The varying pattern of dermal inflammatory infiltrate
seen in association with damaged blood vessels suggests a variety of mechanisms
responsible for the occurrence of secondary vasculitis. A perivascular infiltrate
was seen in approximately one third of biopsy specimens that demonstrated
vasculitis, suggesting a "de novo" epiphenomenon, ie, vasculitis resulting
from vascular wall transmigration of inflammatory cells. The remaining two
thirds of cases demonstrating vasculitis showed evidence of vessel wall damage
in areas involved by a diffuse or bandlike inflammatory infiltrate, suggesting
an "innocent bystander" epiphenomenon of vessel wall damage.
Our findings of unequivocal vasculitis in lesions of long duration and
absence of immunoglobulin and complement in vessel walls support the theory
of secondary vessel wall damage. Obviously, pathogenic factors other than
lesion duration are at play, since not all lesions of long duration contained
damaged vessel walls and one of the lesions of short duration (<7 days)
showed evidence of vasculitis. This apparent miscorrelation is magnified in
light of the fact that a single patient who underwent concurrent biopsy of
2 separate lesions, both of long duration, had evidence of vessel wall damage
in 1 biopsy specimen but not in the second biopsy specimen. Although supportive
of an absence of systemic vasculitis in this patient, varying evidence of
vasculitis may have resulted from the clinician's or pathologist's sampling
error.
We confirmed a female preponderance in the disease overall (6:1), as
well as the lack of sex bias in malignancy-associated Sweet syndrome. All
cases associated with neoplasia occurred in patients with hematologic malignancies.
None of our patients had unequivocal evidence of a drug-related cause. Patient
1 presented with disease approximately 6 weeks after starting isotretinoin
therapy for acne vulgaris, but an association could not be proved, as treatment
was provided at the same time the drug was withdrawn. She responded well to
oral prednisone therapy, with resolution of multiple facial lesions in 3 days.
A rechallenge with the drug was not attempted.
Patients with lesions demonstrating vasculitis tended to be older than
patients whose biopsy specimens did not demonstrate vasculitis, although this
difference was not statistically significant (P =
.18). This may have been the result of a delay in seeking medical attention,
which is known to occur more frequently in the elderly population, who frequently
suffer various social and financial restrictions. Patients' inability to remember
the duration of long-standing lesions may have imposed a source of error in
this study. For uniform statistical calculations, durations of lesions were
input as days, although the patients' reports of long-standing durations tended
to be on the order of months. In addition, patients who had multiple lesions
may have miscalculated the duration of the lesion or lesions that underwent
biopsy.
In summary, we found evidence of vasculitis (fibrinoid degeneration
of vessel walls and intramural inflammation) in 21% of biopsy specimens taken
from patients exhibiting clinical signs and symptoms diagnostic of Sweet syndrome.
Had we applied less stringent criteria for the diagnosis of vasculitis, this
percentage would have been greater, as many biopsy specimens demonstrated
intramural inflammation and perivascular hemorrhage without fibrinoid necrosis
of the vessel walls. Immunofluorescence microscopy failed to detect immune
complex deposition in vessel walls. We propose that the absence of vasculitis
is not an absolute criterion for lesions of Sweet syndrome; alternatively,
the presence of vasculitis does not rule out a diagnosis of Sweet syndrome.
We concur with the theory proposed by Jordaan4
and championed by others5, 13 that
vasculitis in Sweet syndrome is not a result of immune complex–mediated
injury but represents secondary vessel wall damage due to toxic metabolites
released by activated neutrophils.
AUTHOR INFORMATION
Accepted for publication June 20, 2001.
Information from this article was presented at the annual meeting of
the US and Canadian Academy of Pathology, Atlanta, Ga, March 5, 2001.
Corresponding author and reprints: Jeffrey P. Callen, MD, Division
of Dermatology, Department of Medicine, University of Louisville School of
Medicine, 310 E Broadway, Louisville, KY 40202 (e-mail: jefca{at}aol.com).
From the Department of Pathology and Laboratory Medicine (Drs Malone,
Slone, Wills-Frank, and Fearneyhough and Ms Lear), Division of Dermatology,
Department of Medicine (Drs Fearneyhough and Callen), and Department of Family
and Community Medicine (Dr Goldsmith), University of Louisville School of
Medicine, Louisville, Ky; and Division of Dermatopathology, Department of
Pathology, Indiana University School of Medicine, Indianapolis (Drs Malone
and Hood).
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