VASCULITIS
Philip E. LeBoit, M.D.
Depts. of Pathology and Dermatology
University of California, San Francisco
What is vasculitis, and what it is not
Vasculitis literally means inflammation of blood vessels. Because all inflammatory cells
enter the skin via blood or lymphatic vessels, and initially are seen nearby, the loosest possible
definition would include all perivascular inflammatory infiltrates. In almost every inflammatory
skin disease, endothelial cells are swollen, and express activation antigens. However, a
definition based on whether these nonspecific changes are present entirely lacks predictive valuedescribing the lymphocytes found arround the superficial plexus in a spongiotic dermatitis as
superficial lymphocytic vasculitis would mislead the clinician, and would falsely imply a risk of
internal organ involvement.
To use the term vasculititis in a meaningful way in dermatopathology (I will pass over the
use of the term in general pathology- because inflammatory diseases in viscera are not as
numerous as in the skin, general pathologists can get away with calling many inflammatory
conditions a vasculitis), it must reflect damage to vessel walls and not merely the proximity of
inflammatory cells to them. This definition varies somewhat depending on the size of the vessel
in question, and the type of inflammatory cell seen in conjunction with it. A survey of the
leading dermatopathologists of the 1980s shows a near unanimity regarding the definition of
small vessel vasculitis when neutrophils are the predominant cell type, but utter confusion
regarding lymphocytic vasculitis §(1)§.
In the case of both large and small vessels, the surest sign of injury is necrosis of the
vessel wall. The term "necrotizing vasculitis" reflects this, but is wildly overused, as very few
vasculitides result in substantial necrosis of vessels. Ultrastructural examination sometimes
shows necrosis of occasional endothelial cells in some vasculitides, but more often there are such
findings as cytoplasmic swelling as cells respond to injury. What most so-called necrotizing
vasculitides do show is fibrin deposition in vessel walls or lumens. Fibrin deposits are a
relatively certain sign of vascular injury, and their presence in the context of a infiltrate of
inflammatory cells within and arround vessel walls signifies vasculititis. Leukocytoclasis alone
is not indicative of vasculitis, except that it can be the earliest sign of small vessel
leukocytoclastic vasculitis. In this context, nuclear dust is seen alongside a sparse infiltrate of
neutrophils and eosinophils, usually involving both the superficial and the deep vascular plexus.
There is abundant nuclear dust in such conditions as Sweet's syndrome, granuloma gluteale
infantum, and Kikuchi's disease, but none of these are widely accepted as forms of vasculitis.
Small cutaneous vessels (capillaries and venules) can be the sites of neutrophilic,
lymphocytic, or granulomatous vasculititis. Fibrin deposition can be found in any of these forms,
but in the case of lymphocytic and of granulomatosu vasculitis, other rules apply.
Disproportionate numbers of lymphocytes within the wall of a venule (rather than arround it) or
1
concentric lamination of a venular wall are often found in the same sections as lymphocytic
vasculitis marked by fibrin depositis, and seem to be equally valid indicators of its presence. In
the case of granulomatous vasculitis of small vessels, histiocytes within the walls of venules
indicate vasculitis. While monocytes exit venules by diapedesis, their conversion to tissue
histiocytes does not occur within venular walls in conventional granulomatous dermatitides.
Muscular vessels (arterioles, small arteries and veins) in the skin can be said to show
vasculitis when inflammatory cells are present within their walls, as diapedesis does not occur in
thick walled vessels.
Primary v. secondary vasculitis
The concept of primary v. secondary vasculitis is difficult to grasp and apply, but helps to
keep clinicopathologic correlation accurate. In a primary vasculiitis the insult to vessel walls is
an essential part of the condition- leukocytoclastic vasculitis is a clear cut example. In secondary
vasculitis the essential part of the condition (e.g. an insect bite, or herpetic infection of
keratinocytes) resides outside vessel walls, but the inflammatory cells that respond to the insult in
turn involve vessels. The determination of whether a vasculitis is primary or secondary turns on
whether a pathologist can recognize the changes of the first injury, which can be subtle (as in a
specimen in which the punctum of an insect bite lies in another plane of section).
The most important example of how this distinction can be of great clinical importance is
in regard to the changes seen in vessels beneath ulcers. Fibrin is often present in the walls of
venules immediately beneath an ulcer, and neutrophils with a small ammount of nuclear dust can
also be present in this context. If a pathologist makes the diagnosis of leukocytoclastic vasculitis
based on such changes, the clinician will be misled. Only by examining venules far away from
the ulcer bed for the changes of leukocytoclastic vasculitis can the pathologist know that they are
not looking at secondary changes.
The dynamic composition of inflammatory cell infiltrates in cutaneous vasculitis
It is critically important in any approach to inflammatory skin disease to realize that the
histopathologic picture often changes over time, and that an appropriate use of criteria-based
diagnosis must take this into account, i.e. different criteria may apply to the diagnosis of early,
fully developed, and waning lesions. In the case of the slew of conditions in which the initial
changes may consist of small vessel leukocytoclastic vasculitis, there are divergent pathways of
evolution- fibrosis in the case of erythema elevatum diutinum and granuloma faciale,
granulomatous inflammation in Wegener's granulomatosis, etc. Polyarteritis nodosa begins with
neutrophilic infltrates in the walls of arteries but can resolve with giant cells replacing them.
Even in some conditions such as granuloma annulare and necrobiosis lipoidica, which are not
ordinarily considered to be vaculitides, there is some evidence both from light microscopy and
from direct immunofluorescent examination that a transient leukocytoclastic vasculitis might be
the inciting even for more pesistent changes in connective tissue which elicit a granulomatous
reaction §(2)§. Reliable information as to the age of a lesion, or failing that, an assessment by
the clinician as to the stage of a lesion in its life cycle can be invaluable.
2
An algorithmic approach to cutaneous vasculitis
The host of conditions that result in cutaneous vasculititis can be comprehended by first
determining the size of the vessels affected, and then by analyzing the composition of the
inflammatory cell infiltrates arround vessel walls §(3)§. Some conditions typically have
distinctive findings in the interstitial dermis, while other diseases and many early lesions even of
the same condition can lack such "extravascular" changes. Sometimes, as is the case with other
inflammatory skin diseases, a specific diagnosis cannot be determined, but useful information
can still be imparted to the clinician simply by an accurate description of histologic morphology.
An algorithm for the diagnosis of cutaneous vasculitis is shown in Table 1.
Specific types of cutaneous vasculitis
I. Vasculitis affecting small vessels (venulitis)
A. Neutrophils predominate
1. Leukocytoclastic vasculitis, with no distinctive extravascular changes
Leukocytoclastic vasculitis (allergic vasculitis, necrotizing vasculitis) is the most familiar
small vessel vasculitis to general pathologists. It is an example of an inflammatory reaction
pattern, in that it is the result of a variety of different disease processes that generate antigenantibody complexes and result in their deposition in vessel walls. Like erythema nodosum,
erythema annulare centrifugum, spongiotic dermatitis, or erythema multiforme, its occurence
does not point to a specific cause. The immune complexes that result in leukocytoclastic
vasculitis may be the result of infection, collagen vascular disease, malignancy, or drug ingestion
§(4)§. As with many of the other inflammatory reaction patterns, a specific cause is sometiems
not found. There are several specific clinicopatholgic forms of leukocytoclastic vasculitis with
which pathologists should be familiar. These include Finkelstein's acute hemorrhagic edema of
the skin, in which ecchymotic cockade-like (i.e. with concentric rings of purpura) lesions are seen
in infants, especially on the skin of the head §(5, 6)§. In Henoch-Schoenlein purpura, abdominal
and joint pain are coupled with glomerulonephritis. Purpuric lesions occur above the waistline in
some cases, a finding that is associated with renal involvement§(7)§. In both conditions, IgA
may be found in cutaneous venules without other immunoreactants. Hepatitis C has been
recognized as a cause of leukocytoclastic vasculitis, in which it is often a factor in the generation
of antigen antibody complexes that function as mixed cryoglobulins §(8)§. Most of the patients
with this association also have a positive test for rheumatoid factor. Microscopic polyarteritis
nodosa or microscopic polyangiitis is a small vessel leukocytoclastic vasculitis occuring in
adults, who often suffer from pulomary vasculitis and glomerulonephritis §(9)§. Direct
immunofluorescent microscopy is reportedly negative in many cases, leading to the supposition
that immune complex deposition occurs but is scant. Antimyeloperoxidase antibodies leading to
a postive p-ANCA test are a serologic marker for this disorder.
The clinical lesions of leukocytoclastic vasculitis begin as pink edematous papules, and
3
become purpuric over a few days to a week due to the extravasation of erythrocytes. As the
process resolves, and siderophages develop due to ingestion of rbcs, the papules can become
brown. If the process results in vascular occlusion, ischemic necrosis of the epidermis can
transpire, resulting in a gray center.
Histologic features:
Early lesions: 1. Neutrophils and nuclear dust in and arround the walls
of venules
2, Extravasated erythrocytes in variable numbers
3. Eosinophils in variable numbers*
Fully developed
lesions:
walls of venules
1. Neutrophils and nuclear dust in and arround the
2. Extravasated erythrocytes in variable numbers
3. Fibrin in the walls and sometimes lumens of venules
4. Eosinophils*, **
5. Papillary dermal edema*
6. Necrosis of the epidermis or of adnexal epithelium*
Resolving lesions
1. Fibrin disappears from the walls of vessels
2. Neutrophils diminish, mononuclear cells increase §(10)§
3. Nuclear dust within macrophages (karyophagocytosis)
4. Siderophages
* variable features
** some claim that eosinophils are the predominant cell
type in the entity that they term "eosinophilic
vasculitis"§(11)§
Urticarial vasculitis- an important clinicopathologic variant?
In so-called urticarial vasculitis, lesions that resemble hives clinically (i.e. pink or skin
colored, not purpuric papules with smooth surfaces) purportedly show leukocytoclastic vasculitis
histologically. Pink paules of leukocytoclastic vasculitis that have the histologic changes of early
lesions, as described above are sometimes mistaken clinically for urticaria, and do not resolve in
24-48 hours as urticaria do. Whether urticarial vasculitis is truly a form of leukocytoclastic
vasculitis, whether studies of the condition include both neutrophilic urticaria and early evolving
papules of leukocytoclastic vasculitis, whether the condition is an authentic one, and whether it is
disproportionately associated with collagen vascular disease is uncertain. Some authors have not
found hypocomplementemia in their patients §(12)§. Most standard textbooks posit its existence
as dogma, and state that it is associated with hypocomplementemia and collagen vascular
disease. Many of the published photomicrographs of "leukocytoclastic vasculits" in what is
4
purported to be urticarial vasculitis are shot at low power, are out of focus, or are of thickly cut
sections making it difficult to tell whether or not diagnostic changes of vasculitis are actually
present. This also holds true for claims that vasculitis sometimes occurs in urticaria §(13)§.
Some papers also claim that immunoglobulin and complement can be present at the
dermoepidermal junction in urticarial vasculitis §(14)§. What seems to be certain is that some
patients with urticarial lesions clinically and dermal infiltrates that contain neutrophils have a
systemic condition §(15)§.
Does immunofluorescent microscopy have a role in making the diagnosis of leukocytoclastic
vasculitis?
The demonstration that immunoglobulin and complement were present in the walls of
vessels in leukocytoclastic vasculitis was a major step in elucidating its pathogenesis. However,
the presence of immunoreactants in the walls of venules is transient. Lesions over a day old may
no longer contain immunoreactants, presumably because neutrophilic enzymes act to denature
them. Thus, the predictive value of a negative result depends on the age of the lesion. Also,
other forms of injury to vessel walls can result in the nonspecific deposition of immunoreactants.
I do not routinely recommend the use of direct immunofluorescence for the diagnosis of
leukocytoclastic vasculitis for these reasons. In the case of Henoch-Schonlein purpura, IgA
deposits are present in the venular walls of univolved skin, a finding that can be a useful
diagnostic adjunct. Remember that IgA can also be seen in the skin of patients with cirrhosis of
the liver in weighing this finding.
What can be inferred by scrutiny of a section of leukocytoclastic vasculitis re the presence of
visceral disease?
Although many studies have attempted to correlate the histologic findings in biopsy
specimens of leukocytoclastic vasculitis with the risk of internal organ involvement, such
features as the presence or absence of eosinophils, involvement of the vascular plexus arround
eccrine coils, and necrosis of follicular or eccrine epithelium do not predict in a given patient
whether viscera are involved or whether the disease is limited to the skin, although there may be
a trend toward systemic disease in patients whose biopsies show striking histopathologic findings
§(12, 16)§.
2. Leukocytoclastic vascultis, with extravascular fibrosis
There two forms of leukocytoclastic vasculitis are persistent, involve only the skin, and
result in fibrosis. Both are difficult to treat.
a. Erythema elevatum diutinum
Erythema elevatum diutinum (EED) is a rare condition, even in tertiary referral centers,
but is probably underrecognized. The clinical presentation of erythema elevatum diutinum is of
hemorrhagic macules that evolve into plaques, and finally into fibrotic plaques or protuberant
nodules. The lesions of EED are symmetrically distributed over the dorsal surfaces of the acra
5
especially over joints. There are several important associations with systemic disease, including
streptococcal infection, HIV infection, leukemia, and connective tissue disease §(17)§.
Histopathologic features §(18)§:
Early lesions: Neutrophils and neutrophilic dust arround venules, few extravasated
erythrocytes
Fully developed lesions: Dense diffuse neutrophilic infiiltrates, fibrin in the walls of
some venules, papillary dermal edema (sometimes)
Late lesions: Large bulky papules, nodules and plaques, with concentric fibrosis arround
venules, storiform fibrosis, infiltrates of neutrophils and leukocytoclasis. This form can resemble
fibrous pseudotumor, and can even be misdiagnosed as a low grade sarcoma! Some examples of
the late stage of EED have many histiocytes, and can resemble histiocytoma-rich
dermatofibroma.
Recognition of this condition is important as early intervention can prevent fibrotic
nodules, which are large, protuberant and deforming. Dapsone is an effective therapy, but must
be maintained for years.
b. Granuloma faciale
Granuloma faciale is not a granulomatous condtion at any stage in its development, but
rather a form of vasculitis that affects facial, and rarely extrafacial sites. It differs in several ways
from erythema elevatum diutinum, both clinically and pathologically.
The lesions of granuloma faciale are usually solitary or few, occuring on the faces of
adults as oval tan or pink to rust colored plaques. Patulous follicular ostia are a hallmark.
Early lesions of granuloma faciale feature fibrin in the walls of venules, surrounded by
neutrophils and neutrophilic nuclear dust, lymphocytes and eosinophils. As lesions mature,
fibroblasts and collagen bundles are arranged concentrically arround venules, and plasma cells
appear. Although there can be a component of solitary macrophages, collections of them are not
found in granuloma faciale. The process often spares the papillary and perifollicular adventitial
dermis, a distribution that corresponds to the dilated acrotrichia noted clinically.
The lesions of granuloma faciale are just as stubborn as those of erythema elevatum
diutinum with respect to treatment. They are sometimes mistaken clinically for squamous cell or
basal cell carcioma, and excised. They often recur arround the scar in such cases.
Although their nature as fibrosing vasculitides has led some authors to conclude that
erythema elevatum diutinum and granuloma faciale are two expressions of the same disease, one
on facial and one on acral skin, there are a number of significant differences that warrant their
being considered separately. The lesions of erythema elevatum diutinum are strikingly
6
symmetrical in their clinical distribution, while those of granuloma faciale are assymetrically
distributed. When lesions of granuloma faciale on the face are accompanied by extrafacial
occurences, those lesions have no propensity to develop over the dorsal surfaces of joints, as do
those of erythema elevatum diutinum. Erythema elevatum diutinum has a number of associated
systemic diseases, while granuloma faciale does not.
Solitary or oligolesional presentations of what appears to be chronic fibrosing
leukocytoclastic vasculitis can occur in the skin or subcutis. These presentations lie outside of
the classic clincal pictures of erythema elevatum diutinum or granuloma faciale, but can be
histopathologically indistinguishable from either of these diseases. Some of the cases reported as
solitary fibrous pseudotumor of the skin are probably burned out examples of this process.
3. Leukocytoclastic vasculitis with extravascular granulomas
a. Wegener's granulomatosis
Wegener's granulomatosis is a systemic condition often affecting the lungs, kidneys and
nasal mucosa and that of the sinuses. It has a variety of histopathological manifestations,
including neutrophilic and granulomatous vasculitis, and extravascular granulomas §(19)§. The
advent of serologic studies for c-ANCA (serine protease) now supplement the traditional
methods of making the diagnosis. Some now make the diagnosis of Wegener's syndrome for
cases in which granulomatous infiltrates cannot be proven by biopsy.
The cutaneous manifestations of Wegener's granulomatosis include umbillicated papules,
hemorrhagic plaques and ulcerated plaques. Because some of the cutaneous findings can be
relatively specific, a skin biopsy can enable early diagnosis of the condition.
Small vessel leukocytoclastic vasculitis is integral to the pathologic process of Wegener's
granulomatosis. In its early stages, or in some lesions, there may be no other findings that enable
a specific diganosis or even suspicion of the condition. "Extavascular granulomas" are said to be
characteristic of Wegener's, but there is a considerable range in the appearance of these
structures, which are entirely absent in many cases. In some specimens there are only patchy
infiltrates of histiocytes, while in others there are palisaded infiltrates of them surrounding
degerated neutrophils and neutrophilic debris, an appearance also termed "Churg-Strauss
granuloma" or extravascular palisaded neutrophilic and granulomatous dermatitis. In some
lesions of Wegener's granulomatosis, the neutrophilic infiltrates arround venules are replaced by
histiocytes.
b. Palisaded neutrophilic and granulomatous dermatitis (rheumatoid papules,
Churg-Strauss granuloma, extravascular necrotizing granuloma)
This condition with many names is in some respects an superfial analogue of rheumatoid
nodules §(20)§. Unlike that more familiar complication of rheumatoid arthritis, the pathologic
process in palisaded neutrophilic and granulomatous dermatitis is centered in the dermis rather
than subcutis. Its lesions are small umbillicated papules, often symmetrically distributed on the
7
extensor surfaces of joints, but also in areas in which rheumatoid nodules are rarely found, such
as the face . Early lesions show a leukocytoclastic vascultitis affecting small vessels that has a
distinctive palisaded pattern, with broad eosinophilic cuffs of fibrin that separate the walls of
venules from dense masses of basophilic material derived from neutrophilic nuclear dust. Later
lesions resemble the palisaded pattern of granuloma annulare, except that nuclear dust and
neutrophils are present in the centers of granulomas rather than mucin and the degenerated
bundles of collagen are thick and eosinophilic rather than pale and wispy. These palisaded
granulomas thus have the appearance at scanning magnification of a zone of dark blue material
surrounded by a cuff of pale staining cells§(21)§. Identical histologic findings have been seen in
ulcerating plaques resembling those of necrobiosis lipoidica termed 'superficial ulcereating
rheumatoid necrobiosis'.
The importance of recognizing this condition at any stage in its evolution or devolution is
that this form of vasculitis correlates highly with the presence of a systemic disease, such as
lupus erythematosus, rheumatoid arthritis,
Wegener's granulomatosis, Takayasu's arteritis, leukemia, lymphoma, or endocarditis §(22)§.
4, Leukocytoclastic vasculitis with dense neutrophilic infiltrates
The so-called neutrophilic dermatoses, the prototypical example of which is Sweet's
syndrome are characterized by dense, diffuse infiltrates of neutrophils and neutrophilic nuclear
dust, usually without discernable deposits of fibrin in the walls of venules. In mature lesions of
Sweet's syndrome neutrophils are not typically found in the walls of venules either.
A case can be made that some of the neutrophilic dermatoses, and perhaps even Sweet's
syndrome itself begins with a transient small vessel leukocytoclastic vasculitis. In the bowel
bypass syndrome, and in many lesions of Bechet's syndrome, small vessel vasculitis affects
scattered venules.
a. Bechet's syndrome
Bechet's syndrome is rare in North America and Europe in comparison to Asia and the
Middle East. It characteristically affects young men, who develop acneiform facial lesions, and a
condition that simulates erythema nodosum on the legs. It is accompanied by apthous ulcers in
the mouth and genital mucosae. Phlebitis, neurologic signs, arthritis, and mucocutaneous
involvement can also be present. Unlike the case in erythema nodosum, the "erythema nodosumlike" lesions of Bechet's syndrome can ulcerate.
Cutaneous lesions of the panniculitis that occurs in Bechet's syndrome are typically a
melange of small vessel leukocytoclastic vasculitis affecting both venules and large vessels
(arterioles and small veins) with fibrin thrombi in some of the affected venules, neutrophilic
infiltrates in the interstitial dermis and subcutaneous lobules, and changes due to injury to
lipocytes such as fatty microcysts and macrophages that have a foamy basophilic appearance. In
some examples, lymphocytic rather than neutrophilic leukocytoclastic vasculitis is present.
Whether there is an evolution from neutrophils to lymphocytes in and arround venules is
uncertain. The epidermis can suffer ischemia, resulting in ballooning, reticular alteration, intra8
or subepidermal vesiculation, and necrosis §(23)§. In older lesions the suppurative panniculitis
can become granulomatous §(24)§.
b. Bowel-associated dermatitis-arthritis syndrome
In the bowel-associated dermatitis-arthritis syndrome (formerly called the bowel-bypass
syndrome) an overgrowth of bacteria in the gut leads to the generation of anitgen-antibody
complexes and their deposition in vessel walls. Immune complexes are also thought to be the
cause of the arthritis that affects these patients. The condition was first noted in patients who
underwent bowel bypass surgery for obesity, resulting in blind loops that fostered the overgrowth
of bacteria. The lesions of the condition are papules and nodules, sometimes surmounted by
pustules or vesicles. Later on, similar lesions were identified in patients who suffered from
inflammatory bowel disease. As bowel-bypass surgery is seldom performed at the current time,
patients with ulcerative colitis or Crohn's disease are now almost the only patients in whom this
condition occurs. Its distinction from Sweet's syndrome, which can also affect this population is
conceptually problematic.
Biopsies of papules demonstrate perivascular and intersitial, and later nodular and diffuse
infiltrates of neutrophils and nuclear dust, edema of the papillary dermis, and sometimes
subepidermal neutrophilic pustules. Episodically, there are deposits of fibrin in the walls of
venules, along with neutrophils and nuclear dust.
5. Septic vasculitis
Septic vasculitis has two polar expressions, an acute, fulminant form resulting in a rapid
death in many cases if untreated (and sometimes despite treatment), and a chronic form that can
last for months. Gonococcemia and meningococcemia are frequently chronic, while
staphylococcus, pseudomonas and several of the rickettsiae are often pathogens in the acute
form.
The lesions of both acute and chronic septic vasculitis begin as purpuric macules that can
evolve into eschars or ulcers. In chronic gonococcemia and in subacute bacterial endocarditis,
the lesions are often distributed acarally, and are vesicopustules in the case of gonococcemia.
Unlike the case in leukocytoclastic vasculitis, many lesions are present above the thighs. In
chronic septic vasculitis there is often joint pain, and in the case of chronic meningococcemia,
symptoms referable to meningitis.
The lesions of chronic septic vasculitis begin with thrombi in the lumens of venules of
both plexus, surrounded by sparse infiltrates of neutrophils. While some dust from neutrophils
can be present (there is always some dust when neutrophils are about, as they are short-lived
cells), there is only a fraction of that seen in leukocytoclastic vasculitis. Later lesions can have
edema of the papillary dermis, and necrosis of the epidermis, follicles, or eccrine glands and
ducts. Subepidermal neutrophilic pustules are often present in the vesicopustular lesions of
chronic gonococcemia. Bacteria are few, and are generally not seen even in specially stained
sections. Other important features aside from the presence or near absence of nuclear dust in
9
distinguishing between chronic septic vasculitis and leukocytoclastic vasculitis include the
distribution of fibrin (mostly in lumens in septic vasculitis, mostly in venular walls in
leukocytoclastic vasculitis), no eosinophils in septic vasculitis in contrast to their presence in
about half of cases of leukocytoclastic vasculitis, irrespective of the specific cause.
In contrast, in acute septic vasculitis, especially in the form caused by pseudomonas
(ecthyma gangrenosum), there are abundant bacteria in the walls of venules. They can be so
numerous as to be visable in routine sections at scanning magnification. In acute septic vasculitis
due to Rickettsiae, those organisms cannot be seen even with silver stains in most cases, and their
demonstration requires immunoperoxidase staining. This procedure is only performed in a
handful of centers.
6. Livedo vaculitis (livedo vasculopathy)
This condition affects the ankles of middle aged or older women, beginning with a
reticulated pattern of erythematous macules, and eventuting in small painful ulcers and in the
formation of atrophic white scars. The latter stage is known as atrophie blanche.
Several credible investigators debate whether or not the condition is inflammatory in
genesis (livedo vaculitis) or due to defective fibrinolysis (livedo vasculopathy) §(25)§. There are
often inflammatory cells in addition to fibrin deposits in vessel walls and lumens in some studies,
and inflammatory cells appear to be nearly absent in others. Fibrin is often deposited in the
majority of venules in a section, and because the ankles of affected patients are often affected by
stasis, there are increased numbers of venular cross sections in many slides. These changes are
accompanied by sparse perivascular infiltrates of lymphocytes or neutrophils. In one recent
study, lymphocytes were implicated as the earliest inflammatory cells on the scene. As ischemic
necrosis of venules supervenes, neutrophils arrive, and can be seen either arround venules or
interstitially. Ballooning of keratinocytes from ischemia, epidermal necrosis, ulceration, and
fibrosis of the papillary dermis with epidermal atrophy are variously seen in older examples.
The most common distinction that pathologists are called upon to make with respect to
livedo vasculitis is to tell it apart from vascular stasis changes or a stasis ulcer. This is especially
difficult as almost every patient with livedo vasculitis has some stasis changes microscopically.
In patients with stasis, but without livedo vasculitis, there are clusters of thick walled venules in
the superficial dermis, but fibrin is present only in the walls of the most superficial ones, and
oftentimes is present only in the outer portion of the venular wall. Neutrophils can be present in
the skin beneath or arround stasis ulcers, but are not found at a distance from the ulcer. In a
timid biopsy, the distinction can be impossible.
B. Lymphocytic vasculitis
To have any predictive value, lymphocytic vasculitis must be defined in a restrictive
manner. Lymphocytes surround venules in so many inflammatory conditions that one has to be
exceedingly careful to not overdiagnose this finding. Lymphocytes surround venules that have
fibrin in their walls and lumens in a number of conditons- far many more than are mentioned in
10
most textbooks. The problem that arises when a lymphocytic vasculitis is evident pathologically
is that many of these conditions only show lymphocytic vasculitis in a small minority of cases.
Diseases in which true lymphocytic vasculitis occurs can be grouped into conditions in
which it occurs in the absence of other changes, or is accompanied by interface dermatitis,
psoriasiform epidermal hyperplasia, granulomatous dermatitis, or panniculitis. Additionally , the
lymphocytes need not be typical- atypical lymphocytes surround and infiltrate the walls of
venules in several lymphoproliferative conditions. I wrote a leangthy consideration of this topic
with a long list of condtions in which lymphocytic vasculitis can occur, but I am stumped in my
efforts to arrive at a specific diagnosis in many cases.
An exhaustive analysis of lymphocytic vasculitis is beyond the scope of this course, but is
available to the intrepid §(26)§. Whether lymphocytic vasculitis is a valid pathological
mechanism that explains the evolution of lesions in skin diseases as diverse as pityriasis
lichenoides et varioliformis acuta and Sneddon's syndrome, or is simply a secondary
phenomenon, without meaning as inferred by other authors has not yet been settled. It is also
unknown whether or not leukocytoclastic vascultiis evolves into lymphocytic vasculitis in
substantial numbers of cases. I will briefly review one inflammatory condition in which
lymphocytic vasculitis is found in about half of cases (perniosis) and a lymphoma in which
vasculitis is routinely found (natural killer cell lymphoma).
1. Perniosis
This condition in probably the most frequent one in which a pathologist repeatedly
encounteres lymphocytic vasculitis. Perniosis, or chilblains, consists of pink to purplish macules
and papules on the fingers, toes and sometimes legs. These arise in response to above freezing,
humid conditions such as are found in the San Francisco Bay area (but not here in Hawaii).
Because the lesions have a delayed onset after cold exposure, some patients cannot relate them to
their cause. The clinical differential diagnosis often includes vasculitis, cryoglobulinemia, or
erythema multiforme.
Lesions of perniosis can show a range of microscopic features, the common denominator
of which is a superficial and deep perivascular lymphocytic infiltrate §(27)§. Variable features
include edema of the papillary dermis, infiltration of the lower half of the epidermis by
lymphocytes, single apoptotic keratinocytes, and lymphocytic vasculitis. The later can be a
particularly valuable aid in distinguishing perniosis from erythema multiforme, as both can have
lymphocytes in the basal zone of the epidermis along with necrotic keratinocytes.
2. Angiocentric lymphoma, natural killer cell type
Several forms of lymphoma manifest themselves in the skin with peri- and intravascular
infiltrates of atypical lymphocytes. These include angiocentric T-cell lymphoma, lymphomatoid
granulomatosis (B-cell lymphoma with dense reactive T-cell infiltrates), natural killer cell
lymphoma, mycosis fungoides with angiocentric infltrates, and lymphomatoid papulosis.
11
The most distinctive of these condtions is natural killer cell lymphoma. This disease has
a propensity to affect young Asian adults, and presents in many cases with nasopharyngeal
masses. The cutaneous lesions include plaques that often ulcerate. Many cases have a fulminant
course, with death ensuing in less than a year. The changes in skin biopsy can be problematicsome lesions appear to show only superficial and deep perivascular lymphocytic infiltrates, but
the nuclei of lymphocytes are slightly larger or more irregular than in most inflammatory
diseases. Vacuolar change, single necrotic keratinocytes in the basal zone of the epidermis, and
dense infiltrates of lymphocytes in subcutaneous lobules, often accompanied by necrosis are
important ancillary findings. The diagnosis is more obvious if some of the lymphocytes have
large and hyperchromatic nuclei. Adjunctive tests are now available to secure the diagnosis.
Touch imprints on fresh material stained with Wright-Giemsa show cytoplasmic granules,
corresponding to the finding that the circulating cells of natural killer cell lymphoma are large
granular lymphocytes. CD56 staining, which identifies the type of natural killer cell most often
implicated in this disease can now be performed reliably on paraffin embedded tissue, as can
staining by in situ hybridization for Epstein-Barr virus. The virus is clonally integrated into the
genomes of many cases of the condition, especially in patients from Asia or Latin America. As
most lymphocytic infiltrates have only a few Epstein-Barr virus positive cells, even a small
crushed specimen that shows abundant viral genome can be suspected to be natural killer cell
lymphoma.
C. Granulomatous vasculitis
Granulomatous vasculitis of small vessels can be inferred when histiocytes are found
within the wall of a venule with or without fibrin deposition. Granulomatous vasculitis can be
found alone, without other changes, or in conjunction with extravascular granulomatous
infiltrates.
When found in isolation, the pathologist can make a descriptive diagnosis of
granulomatous vasculitis, and should list the underlying diseases that can be associated with it.
These include inflammatory bowel disease, Wegener's granulomatosis, drug ingestion, and
autoimmune disease. One large series of patients with cutaneous granulomatous vasculitis that
found a high association with lymphoproliferative diseases and leukemia is in need of reexamination, as it was performed prior to the advent of immunohistochemical markers that
would enable the identification in routinely processed tissue of natural killer cell angiocentric
lymphoma (CD56), or of the cells of lymphoblastic lymphoma (TdT) §(28)§. Some of the cases
in this study are likely to be manifestations of specific lymphomatous infiltrates, and
consideration of this possibility, close scrutiny of the cytologic features of the infiltrate, and
immunohistochemistry (if appropriate) should be performed. Herpes simplex or zoster infection
commonly results in a secondary leukocytoclastic vasculitis; this can evenutate in a
granulomatous one, a sequence that can result in the emergence of papules in an affected
dermatome of herpes zoster after the blisters of that condition resolve. Extravascular
granulomatous inflammation is accompanied by granulomatous vasculitis commonly in
Wegener's granulomatosis, and less commonly in necrobiosis lipoidica or necrobiotic
xanthogranuloma with paraproteinemia. Although Crohn's disease only rarely affects the skin,
granulomatous vasculitis is commonly found alongside its granulomatous infiltrates.
12
1. "Metastatic" Crohn's disease
Among the conditions in which granulomatous vasculitis is accompanied by
extravascular granulomata is the rare occurence of lesions of Crohn's disease outside of the
gastrointestinal tract. So-called metastatic lesions of Crohn's disease are papules that are found
in the skin or the perineum, or sometimes at some distance from it. They are practically never
the presenting sign of inflammatory bowel disease.
Lesions of Crohn's disease have a pathologic spectrum that ranges from small sarcoidal
granulomata to palisaded infiltrates that can resemble those of necrobiosis lipoidica. The
palisaded macrophages occur arround arease of degenerated collagen and fibrosis. While the
process may well begin as a transient neutrophilic leukocytoclastic vasculitits, histiocytes are
typically found in and arround the walls of venules. Occlusion of venular lumens could result in
injury to connective tissue and a palisaded granulomatous reaction. Macrophages in and arround
the walls of venules occur in cutaneous lesions of Crohn's disease, but different pathologists have
interpreted them in various ways- some posit that they indicate an authentic granulomatous
vasculitis, while others believe that the macrophages are simply attracted to the peripheries of
venules §(29)§. The finding on serial sections that granulomas apparently form within the walls
of venules supports the vasculitic theory. The antineutrophil cytoplasmic antibody test (ANCA)
is positive in a minority of cases of Crohn's disease, usually with a nongranular perinuclear
pattern and no reaction with myeloperoxidase. This is different from the result in Wegener's
granulomatosis in which a peripheral pattern of ANCA occurs.
II. Arteriolar vasculitis (arteriolitis)
Arterioles are occasionally affected by some of the conditions that cause venulitis. The
conditions considered herein are those in which arterioles are repeatedly affected. In the first of
these, the mechanism is clearly leukocytoclastic vasculitis; in the second two considered below, a
lymphocytic vasculitis followed by thrombosis appears to be operative. Because the occlusion of
venules can be compensated for by collateral circulation, many venules must be blocked for
infarction to occur. In contrast, arteriolar occlusion often results in infarction of the skin and
ulceration.
Because arterioles are located in the deep reticular dermis or superficial subcutis, any
biopsy performed on a patient suspected of having an arteriolar vasculitis has a high chance of
being an exercise in futility unless the procedure captures some subcutaneous fat- preferentially a
substantial ammount.
1. Arteriolar leukocytoclastic vasculitis
Rhematoid vasculitis is generally found in patients with high titres of rheumatoid factor,
and can involve arterioles as well as venules and hence can cause such maladies as digital
infaction and gangrene, and cutaneous ulcers. Biopsies often show leukocytoclastic vasculitis
involving arterioles in the deep dermis and subcutis, sparing the superficial and sometimes the
13
superficial and deep plexuses.
2. Degos' disease
This condition, the complete name of which is sometimes given as Kohlmeier-Degos'
disesae, is also called malignant atrophic papulosis due to its sometimes fatal course. Young
men are the most commonly affected group. Small, sharply marginated porcelain-white macules
representing areas of infarcted skin appear on the skin of the trunk or that of the proximal limbs.
These lesions are accompanied by systemic symptoms (from bowel or brain infarction) in some
patients or occur alone in others. The term malignant atrophic papulosis refers to the sometimes
fatal outcome of the condition.
The mechanism of disease appears to be a lymphocytic arteriolitis that rapidly leads to
thrombosis, and thence to infarction of a wedge shaped zone of the skin, including both the
epidermis and dermis, along with its adnexal structures. Biopsies of longstanding lesions
demonstrate sclerosis of the infarcted area with interstitial acid mucopolysaccharide deposition,
diminished numbers of dermal fibroblasts, and an atrophic epidermis.
3. Sneddon's syndrome
Sneddon's syndrome is a thankfully rare condition, in which arterioles and small arteries
have their lumens occluded by an intimal proliferation of fibroblasts. The cutaneous result of
this process is a pattern of hypo- and hyperemia termed livedo racemosa. This netlike pattern of
erythema is similar to livedo reticularis, but the polygonal zones of mottled skin outlined by livid
streaks is much larger (upto several centimeters) in livedo racemosa. Unlike livedo reticularis,
the erythematous pattern in livedo racemosa affects the trunk as well as the legs, and persists
when the skin is warmed. The reason that it is important to distinguish the two conditions is that
livedo racemosa is associated in patients with Sneddon's syndrome with a range of neurological
and psychiatric symptoms that result from cerebral ischemia, including major strokes.
Painstaking histologic studies have demonstrated that the earliest insult to arterioles in
Sneddon's syndrome is an "endothelialitis", i.e. the infiltration of lymphocytes beneath arteriolar
endothelial cells, coupled with the formation of subendothelial vacuoles and fibrin deposition
§(30)§. Progressive encroachment on the lumens of arterioles by a proliferation of fibroblasts
and collagen deposition, and fragmentation of the internal elastic lamina are hallmarks of the late
stages of Sneddon's syndrome. A deep incisional biopsy is essential for making the diagnosis.
Management of this condition is not yet satisfactory, but the discovery that it is inflammatory in
nature and has a thrombotic phase may lead to an effective treatment.
III. Arterial vasculitis
Subcutaneous arteries are only involved in a few forms of vasculitis. The most important
of these are polyarteritis nodosa and nodular vasculitis. Polyarteritis nodosa is a systemic
disease, affecting many internal organs via the formation of occlusive nodules at the sites at
which arteries branch. Much more commonly encountered by dermatologists in clinical practice,
14
and by dermatopathologists is the condition known as subcutaneous or benign cutaneous
polyarteritis nodosa, in which only subcutaneous vessels are affected. Nodular vasculitis is can
also be considered as a panniculitis, as arterial inflammation and occlusion result in extensive
suppuration of neaby fatty lobules. The relationship between nodular vasculitis and a condition
known as erythema induratum, which is now well established to be a hypersensitivity reaction to
tuberculous infection, has been debated for almost 50 years. Giant cell or temporal arteritis also
should be considered in the case of arteritis on the scalp. It is only rarely encountered by
dermatologists, but can sometimes have unusual manifestations such as necrosis of the scalp
§(31)§.
As is the case with any muscular vessel, the presence of inflammatory cells in the wall of
an artery suffices to establish the presence of vasculitis. Inflammatory cells do not exit arteries
via diapedesis; their presence in the walls of arteries or veins implies vasculitis. As is also the
case with arteriolar vasculitis, a biopsy specimen should be deep enough to include a substantial
portion of subcutis is any of these conditions are under consideration.
1. Polyarteritis nodosa
The typical clinical presentation of this condition is with firm, painful, purplish
subcutaneous nodules, distributed assymetrically on the skin of both legs. In some patients the
nodules are set in a background of livedo reticularis, a net-like pattern of erythema. New papules
may form rosettes arround older ones, resulting in a "starburst" pattern. Ulcers, typically stellate,
complicate the picture in a minority of cases. With the exception of ulceration, which seems to
be more commonly found more often in patients with systemic polyarteritis, the clinical
appearance of the cutaneous lesions does not help to predict the presence or absence of visceral
involvement. Patients with systemic polyarteritis do have a variety of symptoms, such as fever,
malaise and myalgia. They may have hypertension of recent onset, proteinuria, or leukocytotosis.
Cutaneous involvement only occurs in about 20% of patients with systemic polyarteritis.
Polyarteritis nodosa, whether systemic or limited to subcutaneous vessels, begins with
infiltrates of neutrophils in the walls of arteries, followed by leukocytoclasia, disruption of the
internal elastic lamina and in some arteries, thrombosis. Neutrophils commonly are found in the
fat immediately surrounding the affected artery, but do not extend for a long distance into
subcutaneous lobules, i.e. there is only a limited degree of suppurative panniculitis. Small vessel
leukocytoclastic vasculitis can also be present alongside arteritis, or sometimes in specimens
from purpuric lesions that lack nodularity. Direct immunofluorescence is almost never
performed for diagnostic reasons, but the presence of IgM and C'3 in arterial walls indicates that
antigen-antibody complexes have a major pathogenic role, as in small vessel leukocytoclastic
vasculitis. As lesions age, eosinophils can join the infiltrate, and sometimes histiocytes or even
giant cells are present in older lesions. The contention that systemic polyarteritis nodosa is
manifested in the skin by small vessel leukocytoclastic vascuiltis, while the benign cutaneous
form shows arteritis (as proposed in some papers §(32)§, and editions of Lever's textbook up
until 1990, but not in the 1997 edition) does not hold with the experience of most
dermatopathologists and has little support in the literature.
15
It was recognized in the 1970s that polyarteritis nodosa could be limited to subcutaneous
arteries, sparing the viscera. While the group associated with the Mayo Clinic has pushed the
concept that cutaneous polyarteritis and systemic polyarteritis are distinct, others regard
polyarteritis as a disease that has a spectrum of systemic involvement §(33)§ . One study in the
1980s established that many patients who initially seemed to have disease limited to the skin later
proved to have systemic illnesses, including hepatitis B, AIDS, or cryoglobulinemia, and the at
internal organs could later become involved §(34)§.
The major differential diagnosis is with nodular vasculitis, and is discussed below.
2. Nodular vasculitis
Nodular vasculitis is, like polyarteritis nodosa, a neutrophilic arteritis. It typically occurs
on the calves of young adult or middle aged women, with bilaterally distributed nodules or
plaques that ulcerate, and heal with sunken stellate scars. The condition was separated in the
1940's from erythema induratum by Hamilton Montgomery. Erythema induratum was
considered at that time to be a tuberculid- a hypersensitivity reaction to remote tuberculous
infection. By the 1970s most American dermatopathologists ceased to believe that erythema
induratum was an authentic condition, and regarded all patients with suppurative arteritis and
panniculitis occuring together as having nodular vasculitis. By the late 1980s the pendulum
began to swing the other way; it became clear that erythema induratum was in fact an authentic
condition, related to mycobacterial infection (see below).
The arteritis of nodular vasculitis is seldom biopsied in the first few days or even weeks
of its existence. By the time of sampling, there is almost always a suppurative panniculitis
greater in extent than the narrow collar of suppuration seen arround arteries in polyarteritis
nodosa. The ammount of neutrophilic nuclear dust is less than in polyarteritis nodosa, although
as is the case with any neutrophilic infiltrate, there is some, as neutrophils only live for hours to a
day or so in a cutaneous infiltrate. A number of secondary changes occur in lesions of nodular
vasculitis. The arteritis can result in thrombosis. The suppurative panniculitis can lead to
fibrosis and thickening of septa, and damaged adipocytes can leak fat, which in turn is
phagocytized by histiocytes. Coagulation necrosis of adipocytes, and fibrosis between
adiopocytes can also complicate the picture.
Nodular vasculitis is most easily told apart from polyarteritis nodosa at scanning
magnification, by the extent of involvement of subcutaneous lobules- a narrow corona of
inflammation in polyarteritis, in contrast to extensive suppuration and sometimes necrosis of
lobules in nodular vasculitis. Resolving lesions of nodular vasculitis can be problematic, if such
changes as fibrosis of septa are not noted. Because nodular vasculitis and erythema induratum
are clinically indistinguishable, a tuberculin skin test should be placed on any patient suspected
of having nodular vasculitis.
3. Erythema induratum
I noted above that erythema induratum is now regarded as an authentic condition- one of
16
the true tuberculids. The tuberculids originally conceived as skin diseases tenuously related to
tuberculous infection, early in the twentieth century when many diseases that we now know have
no relationship to TB were so regarded. The modern definition of a tuberculid is that lesional
tissue does not contain mycobacteria by special stains or culture, and that a tuberculin skin test is
positive, indicating a high degree of sensitization to mycobacterial antigens. The condion should
also respond to antituberculous therapy. Many patients with tuberculids have histories of treated
tuberculosis, and some even have active disease. Many investigators conisider erythema
induratum, papulonodular tuberculid and lichen scrofulosorum to be authentic tuberculids.
Mycobacterial transcipts are present in lesional tissue studied using the polymerase chain
reaction. Another former tuberculid, rosacea-like tuberculid of Lewandosky to be a form of
rosacea, unrelated to tuberculosis. A memorable concept regarding erythema induratum is that
nodular vasculitis + a positive PPD= erythema induratum §(35)§.
The lesions of erythema induratum are tender purple nodules or plaques, occuring on the
legs, buttocks and arms. Unlike erythema nodosum, lesions are commonly present on the calves
as well as on the shins. They resolve over a few months, leaving depressed scars. Crops of new
lesions tend to arise in untreated patients or in patients who stop their treatment
prematurely§(36)§.
The histopathology of erythema induratum can mirror that of nodular vasculitis, with a
suppurative arteritis and lobular panniculitis. The spectrum also includes mixed septal and
lobular panniculitis with small or large vessel leukocytoclastic venulitis and/or arteritis.
Caseation necrosis (necrosis of histiocytes) is sometimes present. The presence of absence of
vasculitis in the context of a lobular granulomatous panniculitis seems to have limited predictive
value for the presence of mycobacterial transcripts as detected by PCR.
REFERENCES
§1.
Jones RE. Questions to the editorial board and other authorities. Am J Dermatopathol
1985;7(2):181-187.
2.
Dahl MV. Immunofluorescence, necrobiosis lipoidica, and blood vessels. Fluorescent
lights in the tunnels. Arch Dermatol 1988;124(9):1417-9.
3.
Smoller BR, McNutt NS, Contreras F. The natural history of vasculitis. What the
histology tells us about pathogenesis. Arch Dermatol 1990;126(1):84-9.
4.
Ekenstam E, Callen JP. Cutaneous leukocytoclastic vasculitis. Clinical and laboratory
features of 82 patients seen in private practice. Arch Dermatol 1984;120(4):484-9.
5.
Legrain V, Lejean S, Taieb A, Guillard JM, Battin J, Maleville J. Infantile acute
hemorrhagic edema of the skin: study of ten cases [see comments]. J Am Acad Dermatol
1991;24(1):17-22.
6.
Dubin BA, Bronson DM, Eng AM. Acute hemorrhagic edema of childhood: an unusual
variant of leukocytoclastic vasculitis. J Am Acad Dermatol 1990;23(2 Pt 2):347-50.
7.
Tancrede-Bohin E, Ochonisky S, Vignon-Pennamen M-D, Flageul B, Morel P, Rybojad
M. Schonlein-Henoch purpura in adult patients: 438 predictive factors for IgA
17
glomerulonephritis in a retrospective study of 57 cases. Arch Dermatol. 1997;133(4):438-442.
8.
Karlsberg PL, Lee WM, Casey DL, Cockerell CJ, Cruz PD, Jr. Cutaneous vasculitis and
rheumatoid factor positivity as presenting signs of hepatitis C virus-induced mixed
cryoglobulinemia. Arch Dermatol 1995;131(10):1119-23.
9.
Irvine AD, Bruce IN, Walsh MY, Bingham EA. Microscopic polyangiitis: Delineation of
a cutaneous-limited variant associated with antimyeloperoxidase autoantibody. Arch Dermatol.
1997;133(4):474-477.
10.
Zax RH, Hodge SJ, Callen JP. Cutaneous leukocytoclastic vasculitis. Serial
histopathologic evaluation demonstrates the dynamic nature of the infiltrate. Arch Dermatol
1990;126(1):69-72.
11.
Chen KR, Su WP, Pittelkow MR, Conn DL, George T, Leiferman KM. Eosinophilic
vasculitis in connective tissue disease. J Am Acad Dermatol 1996;35(2 Pt 1):173-82.
12.
Hodge SJ, Callen JP, Ekenstam E. Cutaneous leukocytoclastic vasculitis: correlation of
histopathological changes with clinical severity and course. J Cutan Pathol 1987;14(5):279-84.
13.
Peteiro C, Toribio J. Incidence of leukocytoclastic vasculitis in chronic idiopathic
urticaria. Study of 100 cases. Am J Dermatopathol 1989;11(6):528-33.
14.
Sanchez NP, Winkelmann RK, Schroeter AL, Dicken CH. The clinical and
histopathologic spectrums of urticarial vasculitis: study of forty cases. J Am Acad Dermatol
1982;7(5):599-605.
15.
Mehregan DR, Hall MJ, Gibson LE. Urticarial vasculitis: a histopathologic and clinical
review of 72 cases. J Am Acad Dermatol 1992;26(3 Pt 2):441-8.
16.
Sanchez NP, Van Hale HM, Su WP. Clinical and histopathologic spectrum of necrotizing
vasculitis. Report of findings in 101 cases. Arch Dermatol 1985;121(2):220-4.
17.
LeBoit PE, Cockerell CJ. Nodular lesions of erythema elevatum diutinum in patients
infected with the human immunodeficiency virus. J Am Acad Dermatol 1993;28(6):919-22.
18.
LeBoit PE, Yen TS, Wintroub B. The evolution of lesions in erythema elevatum
diutinum. Am J Dermatopathol 1986;8(5):392-402.
19.
Hu CH, O'Loughlin S, Winkelmann RK. Cutaneous manifestations of Wegener
granulomatosis. Arch Dermatol 1977;113(2):175-82.
20.
Finan MC, Winkelmann RK. The cutaneous extravascular necrotizing granuloma (ChurgStrauss granuloma) and systemic disease: a review of 27 cases. Medicine (Baltimore)
1983;62(3):142-58.
21.
Chu P, Connolly MK, LeBoit PE. The histopathologic spectrum of palisaded neutrophilic
and granulomatous dermatitis in patients with collagen vascular disease. Arch Dermatol
1994;130(10):1278-83.
22.
Wilmoth GJ, Perniciaro C. Cutaneous extravascular necrotizing granuloma (Winkelmann
granuloma): confirmation of the association with systemic disease. J Am Acad Dermatol
1996;34(5 Pt 1):753-9.
23.
Lee SH, Chung KY, Lee WS, Lee S. Behcet's syndrome associated with bullous
necrotizing vasculitis. J Am Acad Dermatol 1989;21(2 Pt 2):327-30.
24.
Chun SI, Su WP, Lee S, Rogers RSd. Erythema nodosum-like lesions in Behcet's
syndrome: a histopathologic study of 30 cases. J Cutan Pathol 1989;16(5):259-65.
25.
McCalmont CS, McCalmont TH, Jorizzo JL, White WL, Leshin B, Rothberger H. Livedo
vasculitis: vasculitis or thrombotic vasculopathy? Clin Exp Dermatol 1992;17(1):4-8.
26.
Carlson JA, Mihm MC, Jr., LeBoit PE. Cutaneous lymphocytic vasculitis: a definition, a
18
review, and a proposed classification. Semin Diagn Pathol 1996;13(1):72-90.
27.
Herman EW, Kezis JS, Silvers DN. A distinctive variant of pernio. Clinical and
histopathologic study of nine cases. Arch Dermatol 1981;117(1):26-8.
28.
Gibson LE, Winkelmann RK. Cutaneous granulomatous vasculitis: its relationship to
systemic disease. J Am Acad Dermatol 1986;14(3):492-501.
29.
Hackzell-Bradley M, Hedblad MA, Stephansson EA. Metastatic Crohn's disease. Report
of 3 cases with special reference to histopathologic findings. Arch Dermatol 1996;132(8):928-32.
30.
Zelger B, Sepp N, Schmid KW, Hintner H, Klein G, Fritsch PO. Life history of cutaneous
vascular lesions in Sneddon's syndrome [see comments]. Hum Pathol 1992;23(6):668-75.
31.
Baum EW, Sams WM, Jr., Payne RR. Giant cell arteritis: a systemic disease with rare
cutaneous manifestations. J Am Acad Dermatol 1982;6(6):1081-8.
32.
Diaz-Perez JL, Winkelmann RK. Cutaneous periarteritis nodosa. Arch Dermatol
1974;110(3):407-14.
33.
Thomas RH, Black MM. The wide clinical spectrum of polyarteritis nodosa with
cutaneous involvement. Clin Exp Dermatol 1983;8(1):47-59.
34.
Minkowitz G, Smoller BR, McNutt NS. Benign cutaneous polyarteritis nodosa.
Relationship to systemic polyarteritis nodosa and to hepatitis B infection. Arch Dermatol
1991;127(10):1520-3.
35.
White WL, Wieselthier JS, Hitchcock MG. Panniculitis: recent developments and
observations. Sem Cutan Med and Surg 1996;15(4):278-299.
36.
Cho KH, Lee DY, Kim CW. Erythema induratum of Bazin. Int J Dermatol
1996;35(11):802-8.§
19