VASCULITIS

Philip E. LeBoit, M.D.

Depts. of Pathology and Dermatology
University of California, San Francisco
What is vasculitis, and what it is not
asc!litis literally means inflammation of "lood vessels. Beca!se all inflammatory cells
enter the s#in via "lood or lymphatic vessels, and initially are seen near"y, the loosest possi"le
definition $o!ld incl!de all perivasc!lar inflammatory infiltrates. %n almost every inflammatory
s#in disease, endothelial cells are s$ollen, and e&press activation antigens. 'o$ever, a definition
"ased on $hether these nonspecific changes are present entirely lac#s predictive val!e( descri"ing
the lymphocytes fo!nd arro!nd the s!perficial ple&!s in a spongiotic dermatitis as s!perficial
lymphocytic vasc!litis $o!ld mislead the clinician, and $o!ld falsely imply a ris# of internal organ
involvement.
)o !se the term vasc!lititis in a meaningf!l $ay in dermatopathology *% $ill pass over the
!se of the term in general pathology( "eca!se inflammatory diseases in viscera are not as
n!mero!s as in the s#in, general pathologists can get a$ay $ith calling many inflammatory
conditions a vasc!litis+, it m!st reflect damage to vessel $alls and not merely the pro&imity of
inflammatory cells to them. )his definition varies some$hat depending on the si,e of the vessel in
-!estion, and the type of inflammatory cell seen in con.!nction $ith it. / s!rvey of the leading
dermatopathologists of the 0123s sho$s a near !nanimity regarding the definition of small vessel
vasc!litis $hen ne!trophils are the predominant cell type, "!t !tter conf!sion regarding
lymphocytic vasc!litis 4*0+4.
%n the case of "oth large and small vessels, the s!rest sign of in.!ry is necrosis of the vessel
$all. )he term 5necroti,ing vasc!litis5 reflects this, "!t is $ildly over!sed, as very fe$
vasc!litides res!lt in s!"stantial necrosis of vessels. Ultrastr!ct!ral e&amination sometimes sho$s
necrosis of occasional endothelial cells in some vasc!litides, "!t more often there are s!ch
findings as cytoplasmic s$elling as cells respond to in.!ry. 6hat most so(called necroti,ing
vasc!litides do sho$ is fi"rin deposition in vessel $alls or l!mens. Fi"rin deposits are a relatively
certain sign of vasc!lar in.!ry, and their presence in the conte&t of a infiltrate of inflammatory cells
$ithin and arro!nd vessel $alls signifies vasc!lititis. Le!#ocytoclasis alone is not indicative of
vasc!litis, e&cept that it can "e the earliest sign of small vessel le!#ocytoclastic vasc!litis. %n this
conte&t, n!clear d!st is seen alongside a sparse infiltrate of ne!trophils and eosinophils, !s!ally
involving "oth the s!perficial and the deep vasc!lar ple&!s. )here is a"!ndant n!clear d!st in
s!ch conditions as S$eet7s syndrome, gran!loma gl!teale infant!m, and 8i#!chi7s disease, "!t
none of these are $idely accepted as forms of vasc!litis.
Small c!taneo!s vessels *capillaries and ven!les+ can "e the sites of ne!trophilic,
lymphocytic, or gran!lomato!s vasc!lititis. Fi"rin deposition can "e fo!nd in any of these forms,
"!t in the case of lymphocytic and of gran!lomatos! vasc!litis, other r!les apply.
Disproportionate n!m"ers of lymphocytes $ithin the $all of a ven!le *rather than arro!nd it+ or
concentric lamination of a ven!lar $all are often fo!nd in the same sections as lymphocytic
vasc!litis mar#ed "y fi"rin depositis, and seem to "e e-!ally valid indicators of its presence. %n
the case of gran!lomato!s vasc!litis of small vessels, histiocytes $ithin the $alls of ven!les
0
indicate vasc!litis. 6hile monocytes e&it ven!les "y diapedesis, their conversion to tiss!e
histiocytes does not occ!r $ithin ven!lar $alls in conventional gran!lomato!s dermatitides.
M!sc!lar vessels *arterioles, small arteries and veins+ in the s#in can "e said to sho$
vasc!litis $hen inflammatory cells are present $ithin their $alls, as diapedesis does not occ!r in
thic# $alled vessels.
Primary v. secondary vasculitis
)he concept of primary v. secondary vasc!litis is diffic!lt to grasp and apply, "!t helps to
#eep clinicopathologic correlation acc!rate. %n a primary vasc!liitis the ins!lt to vessel $alls is an
essential part of the condition( le!#ocytoclastic vasc!litis is a clear c!t e&ample. %n secondary
vasc!litis the essential part of the condition *e.g. an insect "ite, or herpetic infection of
#eratinocytes+ resides o!tside vessel $alls, "!t the inflammatory cells that respond to the ins!lt in
t!rn involve vessels. )he determination of $hether a vasc!litis is primary or secondary t!rns on
$hether a pathologist can recogni,e the changes of the first in.!ry, $hich can "e s!"tle *as in a
specimen in $hich the p!nct!m of an insect "ite lies in another plane of section+.
)he most important e&ample of ho$ this distinction can "e of great clinical importance is
in regard to the changes seen in vessels "eneath !lcers. Fi"rin is often present in the $alls of
ven!les immediately "eneath an !lcer, and ne!trophils $ith a small ammo!nt of n!clear d!st can
also "e present in this conte&t. %f a pathologist ma#es the diagnosis of le!#ocytoclastic vasc!litis
"ased on s!ch changes, the clinician $ill "e misled. 9nly "y e&amining ven!les far a$ay from the
!lcer "ed for the changes of le!#ocytoclastic vasc!litis can the pathologist #no$ that they are not
loo#ing at secondary changes.
The dynamic composition o inlammatory cell iniltrates in cutaneous vasculitis
%t is critically important in any approach to inflammatory s#in disease to reali,e that the
histopathologic pict!re often changes over time, and that an appropriate !se of criteria("ased
diagnosis m!st ta#e this into acco!nt, i.e. different criteria may apply to the diagnosis of early,
f!lly developed, and $aning lesions. %n the case of the sle$ of conditions in $hich the initial
changes may consist of small vessel le!#ocytoclastic vasc!litis, there are divergent path$ays of
evol!tion( fi"rosis in the case of erythema elevat!m di!tin!m and gran!loma faciale,
gran!lomato!s inflammation in 6egener7s gran!lomatosis, etc. Polyarteritis nodosa "egins $ith
ne!trophilic infltrates in the $alls of arteries "!t can resolve $ith giant cells replacing them. Even
in some conditions s!ch as gran!loma ann!lare and necro"iosis lipoidica, $hich are not ordinarily
considered to "e vac!litides, there is some evidence "oth from light microscopy and from direct
imm!nofl!orescent e&amination that a transient le!#ocytoclastic vasc!litis might "e the inciting
even for more pesistent changes in connective tiss!e $hich elicit a gran!lomato!s reaction 4*:+4.
;elia"le information as to the age of a lesion, or failing that, an assessment "y the clinician as to
the stage of a lesion in its life cycle can "e inval!a"le.
An al!orithmic approach to cutaneous vasculitis
)he host of conditions that res!lt in c!taneo!s vasc!lititis can "e comprehended "y first
determining the si,e of the vessels affected, and then "y analy,ing the composition of the
inflammatory cell infiltrates arro!nd vessel $alls 4*<+4. Some conditions typically have distinctive
:
findings in the interstitial dermis, $hile other diseases and many early lesions even of the same
condition can lac# s!ch 5e&travasc!lar5 changes. Sometimes, as is the case $ith other
inflammatory s#in diseases, a specific diagnosis cannot "e determined, "!t !sef!l information can
still "e imparted to the clinician simply "y an acc!rate description of histologic morphology. /n
algorithm for the diagnosis of c!taneo!s vasc!litis is sho$n in )a"le 0.
Speciic types o cutaneous vasculitis
%. asc!litis affecting small vessels *ven!litis+
/. =e!trophils predominate
0. Le!#ocytoclastic vasc!litis, $ith no distinctive e&travasc!lar changes
Le!#ocytoclastic vasc!litis *allergic vasc!litis, necroti,ing vasc!litis+ is the most familiar
small vessel vasc!litis to general pathologists. %t is an e&ample of an inflammatory reaction
pattern, in that it is the res!lt of a variety of different disease processes that generate antigen(
anti"ody comple&es and res!lt in their deposition in vessel $alls. Li#e erythema nodos!m,
erythema ann!lare centrif!g!m, spongiotic dermatitis, or erythema m!ltiforme, its occ!rence does
not point to a specific ca!se. )he imm!ne comple&es that res!lt in le!#ocytoclastic vasc!litis may
"e the res!lt of infection, collagen vasc!lar disease, malignancy, or dr!g ingestion 4*>+4. /s $ith
many of the other inflammatory reaction patterns, a specific ca!se is sometiems not fo!nd. )here
are several specific clinicopatholgic forms of le!#ocytoclastic vasc!litis $ith $hich pathologists
sho!ld "e familiar. )hese incl!de Finkelstein's acute hemorrhagic edema of the skin, in $hich
ecchymotic coc#ade(li#e *i.e. $ith concentric rings of p!rp!ra+ lesions are seen in infants,
especially on the s#in of the head 4*?, @+4. %n Henoch-Schoenlein purpura, a"dominal and .oint
pain are co!pled $ith glomer!lonephritis. P!rp!ric lesions occ!r a"ove the $aistline in some
cases, a finding that is associated $ith renal involvement4*A+4. %n "oth conditions, %g/ may "e
fo!nd in c!taneo!s ven!les $itho!t other imm!noreactants. Hepatitis C has "een recogni,ed as a
ca!se of le!#ocytoclastic vasc!litis, in $hich it is often a factor in the generation of antigen
anti"ody comple&es that f!nction as mi&ed cryoglo"!lins 4*2+4. Most of the patients $ith this
association also have a positive test for rhe!matoid factor. Microscopic polyarteritis nodosa or
microscopic polyangiitis is a small vessel le!#ocytoclastic vasc!litis occ!ring in ad!lts, $ho often
s!ffer from p!lomary vasc!litis and glomer!lonephritis 4*1+4. Direct imm!nofl!orescent
microscopy is reportedly negative in many cases, leading to the s!pposition that imm!ne comple&
deposition occ!rs "!t is scant. /ntimyelopero&idase anti"odies leading to a postive p(/=C/ test
are a serologic mar#er for this disorder.
)he clinical lesions of le!#ocytoclastic vasc!litis "egin as pin# edemato!s pap!les, and
"ecome p!rp!ric over a fe$ days to a $ee# d!e to the e&travasation of erythrocytes. /s the
process resolves, and siderophages develop d!e to ingestion of r"cs, the pap!les can "ecome
"ro$n. %f the process res!lts in vasc!lar occl!sion, ischemic necrosis of the epidermis can
transpire, res!lting in a gray center.
'istologic feat!resB
Early lesionsB 0. =e!trophils and n!clear d!st in and arro!nd the $alls
of ven!les
<
:, E&travasated erythrocytes in varia"le n!m"ers
<. Eosinophils in varia"le n!m"ersC
F!lly developed
lesionsB 0. =e!trophils and n!clear d!st in and arro!nd the
$alls of ven!les
:. E&travasated erythrocytes in varia"le n!m"ers
<. Fi"rin in the $alls and sometimes l!mens of ven!les
>. EosinophilsC, CC
?. Papillary dermal edemaC
@. =ecrosis of the epidermis or of adne&al epitheli!mC
;esolving lesions
0. Fi"rin disappears from the $alls of vessels
:. =e!trophils diminish, monon!clear cells increase 4*03+4
<. =!clear d!st $ithin macrophages *#aryophagocytosis+
>. Siderophages
C varia"le feat!res
CC some claim that eosinophils are the predominant cell
type in the entity that they term 5eosinophilic
vasc!litis54*00+4
Urticarial vasculitis- an important clinicopathologic variant?
%n so(called !rticarial vasc!litis, lesions that resem"le hives clinically *i.e. pin# or s#in
colored, not p!rp!ric pap!les $ith smooth s!rfaces+ p!rportedly sho$ le!#ocytoclastic vasc!litis
histologically. Pin# pa!les of le!#ocytoclastic vasc!litis that have the histologic changes of early
lesions, as descri"ed a"ove are sometimes mista#en clinically for !rticaria, and do not resolve in
:>(>2 ho!rs as !rticaria do. 6hether !rticarial vasc!litis is tr!ly a form of le!#ocytoclastic
vasc!litis, $hether st!dies of the condition incl!de "oth ne!trophilic !rticaria and early evolving
pap!les of le!#ocytoclastic vasc!litis, $hether the condition is an a!thentic one, and $hether it is
disproportionately associated $ith collagen vasc!lar disease is !ncertain. Some a!thors have not
fo!nd hypocomplementemia in their patients 4*0:+4. Most standard te&t"oo#s posit its e&istence
as dogma, and state that it is associated $ith hypocomplementemia and collagen vasc!lar disease.
Many of the p!"lished photomicrographs of 5le!#ocytoclastic vasc!lits5 in $hat is p!rported to
"e !rticarial vasc!litis are shot at lo$ po$er, are o!t of foc!s, or are of thic#ly c!t sections
ma#ing it diffic!lt to tell $hether or not diagnostic changes of vasc!litis are act!ally present. )his
also holds tr!e for claims that vasc!litis sometimes occ!rs in !rticaria 4*0<+4. Some papers also
claim that imm!noglo"!lin and complement can "e present at the dermoepidermal .!nction in
!rticarial vasc!litis 4*0>+4. 6hat seems to "e certain is that some patients $ith !rticarial lesions
clinically and dermal infiltrates that contain ne!trophils have a systemic condition 4*0?+4.
Does immunofluorescent microscopy have a role in making the diagnosis of leukocytoclastic
vasculitis?
)he demonstration that imm!noglo"!lin and complement $ere present in the $alls of
vessels in le!#ocytoclastic vasc!litis $as a ma.or step in el!cidating its pathogenesis. 'o$ever,
>
the presence of imm!noreactants in the $alls of ven!les is transient. Lesions over a day old may
no longer contain imm!noreactants, pres!ma"ly "eca!se ne!trophilic en,ymes act to denat!re
them. )h!s, the predictive val!e of a negative res!lt depends on the age of the lesion. /lso, other
forms of in.!ry to vessel $alls can res!lt in the nonspecific deposition of imm!noreactants. % do
not ro!tinely recommend the !se of direct imm!nofl!orescence for the diagnosis of
le!#ocytoclastic vasc!litis for these reasons. %n the case of 'enoch(Schonlein p!rp!ra, %g/
deposits are present in the ven!lar $alls of !nivolved s#in, a finding that can "e a !sef!l
diagnostic ad.!nct. ;emem"er that %g/ can also "e seen in the s#in of patients $ith cirrhosis of
the liver in $eighing this finding.
hat can !e inferred !y scrutiny of a section of leukocytoclastic vasculitis re the presence of
visceral disease?
/ltho!gh many st!dies have attempted to correlate the histologic findings in "iopsy
specimens of le!#ocytoclastic vasc!litis $ith the ris# of internal organ involvement, s!ch feat!res
as the presence or a"sence of eosinophils, involvement of the vasc!lar ple&!s arro!nd eccrine
coils, and necrosis of follic!lar or eccrine epitheli!m do not predict in a given patient $hether
viscera are involved or $hether the disease is limited to the s#in, altho!gh there may "e a trend
to$ard systemic disease in patients $hose "iopsies sho$ stri#ing histopathologic findings 4*0:,
0@+4.
:. Le!#ocytoclastic vasc!ltis, $ith e&travasc!lar fi"rosis
)here t$o forms of le!#ocytoclastic vasc!litis are persistent, involve only the s#in, and
res!lt in fi"rosis. Both are diffic!lt to treat.
a. Erythema elevat!m di!tin!m
Erythema elevat!m di!tin!m *EED+ is a rare condition, even in tertiary referral centers,
"!t is pro"a"ly !nderrecogni,ed. )he clinical presentation of erythema elevat!m di!tin!m is of
hemorrhagic mac!les that evolve into pla-!es, and finally into fi"rotic pla-!es or prot!"erant
nod!les. )he lesions of EED are symmetrically distri"!ted over the dorsal s!rfaces of the acra
especially over .oints. )here are several important associations $ith systemic disease, incl!ding
streptococcal infection, '% infection, le!#emia, and connective tiss!e disease 4*0A+4.
'istopathologic feat!res 4*02+4B
Early lesionsB =e!trophils and ne!trophilic d!st arro!nd ven!les, fe$ e&travasated
erythrocytes
F!lly developed lesionsB Dense diff!se ne!trophilic infiiltrates, fi"rin in the $alls of some
ven!les, papillary dermal edema *sometimes+
Late lesionsB Large "!l#y pap!les, nod!les and pla-!es, $ith concentric fi"rosis arro!nd
ven!les, storiform fi"rosis, infiltrates of ne!trophils and le!#ocytoclasis. )his form can resem"le
fi"ro!s pse!dot!mor, and can even "e misdiagnosed as a lo$ grade sarcomaD Some e&amples of
the late stage of EED have many histiocytes, and can resem"le histiocytoma(rich dermatofi"roma.
?
;ecognition of this condition is important as early intervention can prevent fi"rotic
nod!les, $hich are large, prot!"erant and deforming. Dapsone is an effective therapy, "!t m!st "e
maintained for years.
". Eran!loma faciale
Eran!loma faciale is not a gran!lomato!s condtion at any stage in its development, "!t
rather a form of vasc!litis that affects facial, and rarely e&trafacial sites. %t differs in several $ays
from erythema elevat!m di!tin!m, "oth clinically and pathologically.
)he lesions of gran!loma faciale are !s!ally solitary or fe$, occ!ring on the faces of ad!lts
as oval tan or pin# to r!st colored pla-!es. Pat!lo!s follic!lar ostia are a hallmar#.
Early lesions of gran!loma faciale feat!re fi"rin in the $alls of ven!les, s!rro!nded "y
ne!trophils and ne!trophilic n!clear d!st, lymphocytes and eosinophils. /s lesions mat!re,
fi"ro"lasts and collagen "!ndles are arranged concentrically arro!nd ven!les, and plasma cells
appear. /ltho!gh there can "e a component of solitary macrophages, collections of them are not
fo!nd in gran!loma faciale. )he process often spares the papillary and perifollic!lar adventitial
dermis, a distri"!tion that corresponds to the dilated acrotrichia noted clinically.
)he lesions of gran!loma faciale are .!st as st!""orn as those of erythema elevat!m
di!tin!m $ith respect to treatment. )hey are sometimes mista#en clinically for s-!amo!s cell or
"asal cell carcioma, and e&cised. )hey often rec!r arro!nd the scar in s!ch cases.
/ltho!gh their nat!re as fi"rosing vasc!litides has led some a!thors to concl!de that
erythema elevat!m di!tin!m and gran!loma faciale are t$o e&pressions of the same disease, one
on facial and one on acral s#in, there are a n!m"er of significant differences that $arrant their
"eing considered separately. )he lesions of erythema elevat!m di!tin!m are stri#ingly
symmetrical in their clinical distri"!tion, $hile those of gran!loma faciale are assymetrically
distri"!ted. 6hen lesions of gran!loma faciale on the face are accompanied "y e&trafacial
occ!rences, those lesions have no propensity to develop over the dorsal s!rfaces of .oints, as do
those of erythema elevat!m di!tin!m. Erythema elevat!m di!tin!m has a n!m"er of associated
systemic diseases, $hile gran!loma faciale does not.
Solitary or oligolesional presentations of $hat appears to "e chronic fi"rosing
le!#ocytoclastic vasc!litis can occ!r in the s#in or s!"c!tis. )hese presentations lie o!tside of the
classic clincal pict!res of erythema elevat!m di!tin!m or gran!loma faciale, "!t can "e
histopathologically indisting!isha"le from either of these diseases. Some of the cases reported as
solitary fi"ro!s pse!dot!mor of the s#in are pro"a"ly "!rned o!t e&amples of this process.
<. Le!#ocytoclastic vasc!litis $ith e&travasc!lar gran!lomas
a. 6egener7s gran!lomatosis
6egener7s gran!lomatosis is a systemic condition often affecting the l!ngs, #idneys and
nasal m!cosa and that of the sin!ses. %t has a variety of histopathological manifestations,
incl!ding ne!trophilic and gran!lomato!s vasc!litis, and e&travasc!lar gran!lomas 4*01+4. )he
advent of serologic st!dies for c(/=C/ *serine protease+ no$ s!pplement the traditional methods
@
of ma#ing the diagnosis. Some no$ ma#e the diagnosis of 6egener7s syndrome for cases in
$hich gran!lomato!s infiltrates cannot "e proven "y "iopsy.
)he c!taneo!s manifestations of 6egener7s gran!lomatosis incl!de !m"illicated pap!les,
hemorrhagic pla-!es and !lcerated pla-!es. Beca!se some of the c!taneo!s findings can "e
relatively specific, a s#in "iopsy can ena"le early diagnosis of the condition.
Small vessel le!#ocytoclastic vasc!litis is integral to the pathologic process of 6egener7s
gran!lomatosis. %n its early stages, or in some lesions, there may "e no other findings that ena"le
a specific diganosis or even s!spicion of the condition. 5E&tavasc!lar gran!lomas5 are said to "e
characteristic of 6egener7s, "!t there is a considera"le range in the appearance of these str!ct!res,
$hich are entirely a"sent in many cases. %n some specimens there are only patchy infiltrates of
histiocytes, $hile in others there are palisaded infiltrates of them s!rro!nding degerated
ne!trophils and ne!trophilic de"ris, an appearance also termed 5Ch!rg(Stra!ss gran!loma5 or
e&travasc!lar palisaded ne!trophilic and gran!lomato!s dermatitis. %n some lesions of 6egener7s
gran!lomatosis, the ne!trophilic infiltrates arro!nd ven!les are replaced "y histiocytes.
". Palisaded ne!trophilic and gran!lomato!s dermatitis *rhe!matoid pap!les,
Ch!rg(Stra!ss gran!loma, e&travasc!lar necroti,ing gran!loma+
)his condition $ith many names is in some respects an s!perfial analog!e of rhe!matoid
nod!les 4*:3+4. Unli#e that more familiar complication of rhe!matoid arthritis, the pathologic
process in palisaded ne!trophilic and gran!lomato!s dermatitis is centered in the dermis rather
than s!"c!tis. %ts lesions are small !m"illicated pap!les, often symmetrically distri"!ted on the
e&tensor s!rfaces of .oints, "!t also in areas in $hich rhe!matoid nod!les are rarely fo!nd, s!ch as
the face . Early lesions sho$ a le!#ocytoclastic vasc!ltitis affecting small vessels that has a
distinctive palisaded pattern, $ith "road eosinophilic c!ffs of fi"rin that separate the $alls of
ven!les from dense masses of "asophilic material derived from ne!trophilic n!clear d!st. Later
lesions resem"le the palisaded pattern of gran!loma ann!lare, e&cept that n!clear d!st and
ne!trophils are present in the centers of gran!lomas rather than m!cin and the degenerated
"!ndles of collagen are thic# and eosinophilic rather than pale and $ispy. )hese palisaded
gran!lomas th!s have the appearance at scanning magnification of a ,one of dar# "l!e material
s!rro!nded "y a c!ff of pale staining cells4*:0+4. %dentical histologic findings have "een seen in
!lcerating pla-!es resem"ling those of necro"iosis lipoidica termed 7s!perficial !lcereating
rhe!matoid necro"iosis7.
)he importance of recogni,ing this condition at any stage in its evol!tion or devol!tion is
that this form of vasc!litis correlates highly $ith the presence of a systemic disease, s!ch as l!p!s
erythematos!s, rhe!matoid arthritis,
6egener7s gran!lomatosis, )a#ayas!7s arteritis, le!#emia, lymphoma, or endocarditis 4*::+4.
>, Le!#ocytoclastic vasc!litis $ith dense ne!trophilic infiltrates
)he so(called ne!trophilic dermatoses, the prototypical e&ample of $hich is S$eet7s
syndrome are characteri,ed "y dense, diff!se infiltrates of ne!trophils and ne!trophilic n!clear
d!st, !s!ally $itho!t discerna"le deposits of fi"rin in the $alls of ven!les. %n mat!re lesions of
S$eet7s syndrome ne!trophils are not typically fo!nd in the $alls of ven!les either.
/ case can "e made that some of the ne!trophilic dermatoses, and perhaps even S$eet7s
A
syndrome itself "egins $ith a transient small vessel le!#ocytoclastic vasc!litis. %n the "o$el
"ypass syndrome, and in many lesions of Bechet7s syndrome, small vessel vasc!litis affects
scattered ven!les.
a. Bechet7s syndrome
Bechet7s syndrome is rare in =orth /merica and E!rope in comparison to /sia and the
Middle East. %t characteristically affects yo!ng men, $ho develop acneiform facial lesions, and a
condition that sim!lates erythema nodos!m on the legs. %t is accompanied "y aptho!s !lcers in
the mo!th and genital m!cosae. Phle"itis, ne!rologic signs, arthritis, and m!coc!taneo!s
involvement can also "e present. Unli#e the case in erythema nodos!m, the 5erythema nodos!m(
li#e5 lesions of Bechet7s syndrome can !lcerate.
C!taneo!s lesions of the pannic!litis that occ!rs in Bechet7s syndrome are typically a
melange of small vessel le!#ocytoclastic vasc!litis affecting "oth ven!les and large vessels
*arterioles and small veins+ $ith fi"rin throm"i in some of the affected ven!les, ne!trophilic
infiltrates in the interstitial dermis and s!"c!taneo!s lo"!les, and changes d!e to in.!ry to
lipocytes s!ch as fatty microcysts and macrophages that have a foamy "asophilic appearance. %n
some e&amples, lymphocytic rather than ne!trophilic le!#ocytoclastic vasc!litis is present.
6hether there is an evol!tion from ne!trophils to lymphocytes in and arro!nd ven!les is
!ncertain. )he epidermis can s!ffer ischemia, res!lting in "allooning, retic!lar alteration, intra( or
s!"epidermal vesic!lation, and necrosis 4*:<+4. %n older lesions the s!pp!rative pannic!litis can
"ecome gran!lomato!s 4*:>+4.
". Bo$el(associated dermatitis(arthritis syndrome
%n the "o$el(associated dermatitis(arthritis syndrome *formerly called the "o$el("ypass
syndrome+ an overgro$th of "acteria in the g!t leads to the generation of anitgen(anti"ody
comple&es and their deposition in vessel $alls. %mm!ne comple&es are also tho!ght to "e the
ca!se of the arthritis that affects these patients. )he condition $as first noted in patients $ho
!nder$ent "o$el "ypass s!rgery for o"esity, res!lting in "lind loops that fostered the overgro$th
of "acteria. )he lesions of the condition are pap!les and nod!les, sometimes s!rmo!nted "y
p!st!les or vesicles. Later on, similar lesions $ere identified in patients $ho s!ffered from
inflammatory "o$el disease. /s "o$el("ypass s!rgery is seldom performed at the c!rrent time,
patients $ith !lcerative colitis or Crohn7s disease are no$ almost the only patients in $hom this
condition occ!rs. %ts distinction from S$eet7s syndrome, $hich can also affect this pop!lation is
concept!ally pro"lematic.
Biopsies of pap!les demonstrate perivasc!lar and intersitial, and later nod!lar and diff!se
infiltrates of ne!trophils and n!clear d!st, edema of the papillary dermis, and sometimes
s!"epidermal ne!trophilic p!st!les. Episodically, there are deposits of fi"rin in the $alls of
ven!les, along $ith ne!trophils and n!clear d!st.
?. Septic vasc!litis
Septic vasc!litis has t$o polar e&pressions, an ac!te, f!lminant form res!lting in a rapid
death in many cases if !ntreated *and sometimes despite treatment+, and a chronic form that can
last for months. Eonococcemia and meningococcemia are fre-!ently chronic, $hile
2
staphylococc!s, pse!domonas and several of the ric#ettsiae are often pathogens in the ac!te form.
)he lesions of "oth ac!te and chronic septic vasc!litis "egin as p!rp!ric mac!les that can
evolve into eschars or !lcers. %n chronic gonococcemia and in s!"ac!te "acterial endocarditis, the
lesions are often distri"!ted acarally, and are vesicop!st!les in the case of gonococcemia. Unli#e
the case in le!#ocytoclastic vasc!litis, many lesions are present a"ove the thighs. %n chronic
septic vasc!litis there is often .oint pain, and in the case of chronic meningococcemia, symptoms
refera"le to meningitis.
)he lesions of chronic septic vasc!litis "egin $ith throm"i in the l!mens of ven!les of "oth
ple&!s, s!rro!nded "y sparse infiltrates of ne!trophils. 6hile some d!st from ne!trophils can "e
present *there is al$ays some d!st $hen ne!trophils are a"o!t, as they are short(lived cells+, there
is only a fraction of that seen in le!#ocytoclastic vasc!litis. Later lesions can have edema of the
papillary dermis, and necrosis of the epidermis, follicles, or eccrine glands and d!cts.
S!"epidermal ne!trophilic p!st!les are often present in the vesicop!st!lar lesions of chronic
gonococcemia. Bacteria are fe$, and are generally not seen even in specially stained sections.
9ther important feat!res aside from the presence or near a"sence of n!clear d!st in disting!ishing
"et$een chronic septic vasc!litis and le!#ocytoclastic vasc!litis incl!de the distri"!tion of fi"rin
*mostly in l!mens in septic vasc!litis, mostly in ven!lar $alls in le!#ocytoclastic vasc!litis+, no
eosinophils in septic vasc!litis in contrast to their presence in a"o!t half of cases of
le!#ocytoclastic vasc!litis, irrespective of the specific ca!se.
%n contrast, in ac!te septic vasc!litis, especially in the form ca!sed "y pse!domonas
*ecthyma gangrenos!m+, there are a"!ndant "acteria in the $alls of ven!les. )hey can "e so
n!mero!s as to "e visa"le in ro!tine sections at scanning magnification. %n ac!te septic vasc!litis
d!e to ;ic#ettsiae, those organisms cannot "e seen even $ith silver stains in most cases, and their
demonstration re-!ires imm!nopero&idase staining. )his proced!re is only performed in a
handf!l of centers.
@. Livedo vac!litis *livedo vasc!lopathy+
)his condition affects the an#les of middle aged or older $omen, "eginning $ith a
retic!lated pattern of erythemato!s mac!les, and event!ting in small painf!l !lcers and in the
formation of atrophic $hite scars. )he latter stage is #no$n as atrophie "lanche.
Several credi"le investigators de"ate $hether or not the condition is inflammatory in
genesis *livedo vac!litis+ or d!e to defective fi"rinolysis *livedo vasc!lopathy+ 4*:?+4. )here are
often inflammatory cells in addition to fi"rin deposits in vessel $alls and l!mens in some st!dies,
and inflammatory cells appear to "e nearly a"sent in others. Fi"rin is often deposited in the
ma.ority of ven!les in a section, and "eca!se the an#les of affected patients are often affected "y
stasis, there are increased n!m"ers of ven!lar cross sections in many slides. )hese changes are
accompanied "y sparse perivasc!lar infiltrates of lymphocytes or ne!trophils. %n one recent st!dy,
lymphocytes $ere implicated as the earliest inflammatory cells on the scene. /s ischemic necrosis
of ven!les s!pervenes, ne!trophils arrive, and can "e seen either arro!nd ven!les or interstitially.
Ballooning of #eratinocytes from ischemia, epidermal necrosis, !lceration, and fi"rosis of the
papillary dermis $ith epidermal atrophy are vario!sly seen in older e&amples.
)he most common distinction that pathologists are called !pon to ma#e $ith respect to
1
livedo vasc!litis is to tell it apart from vasc!lar stasis changes or a stasis !lcer. )his is especially
diffic!lt as almost every patient $ith livedo vasc!litis has some stasis changes microscopically. %n
patients $ith stasis, "!t $itho!t livedo vasc!litis, there are cl!sters of thic# $alled ven!les in the
s!perficial dermis, "!t fi"rin is present only in the $alls of the most s!perficial ones, and
oftentimes is present only in the o!ter portion of the ven!lar $all. =e!trophils can "e present in
the s#in "eneath or arro!nd stasis !lcers, "!t are not fo!nd at a distance from the !lcer. %n a
timid "iopsy, the distinction can "e impossi"le.
B. Lymphocytic vasc!litis
)o have any predictive val!e, lymphocytic vasc!litis m!st "e defined in a restrictive
manner. Lymphocytes s!rro!nd ven!les in so many inflammatory conditions that one has to "e
e&ceedingly caref!l to not overdiagnose this finding. Lymphocytes s!rro!nd ven!les that have
fi"rin in their $alls and l!mens in a n!m"er of conditons( far many more than are mentioned in
most te&t"oo#s. )he pro"lem that arises $hen a lymphocytic vasc!litis is evident pathologically is
that many of these conditions only sho$ lymphocytic vasc!litis in a small minority of cases.
Diseases in $hich tr!e lymphocytic vasc!litis occ!rs can "e gro!ped into conditions in
$hich it occ!rs in the a"sence of other changes, or is accompanied "y interface dermatitis,
psoriasiform epidermal hyperplasia, gran!lomato!s dermatitis, or pannic!litis. /dditionally , the
lymphocytes need not "e typical( atypical lymphocytes s!rro!nd and infiltrate the $alls of ven!les
in several lymphoproliferative conditions. % $rote a leangthy consideration of this topic $ith a
long list of condtions in $hich lymphocytic vasc!litis can occ!r, "!t % am st!mped in my efforts to
arrive at a specific diagnosis in many cases.
/n e&ha!stive analysis of lymphocytic vasc!litis is "eyond the scope of this co!rse, "!t is
availa"le to the intrepid 4*:@+4. 6hether lymphocytic vasc!litis is a valid pathological mechanism
that e&plains the evol!tion of lesions in s#in diseases as diverse as pityriasis lichenoides et
varioliformis ac!ta and Sneddon7s syndrome, or is simply a secondary phenomenon, $itho!t
meaning as inferred "y other a!thors has not yet "een settled. %t is also !n#no$n $hether or not
le!#ocytoclastic vasc!ltiis evolves into lymphocytic vasc!litis in s!"stantial n!m"ers of cases. %
$ill "riefly revie$ one inflammatory condition in $hich lymphocytic vasc!litis is fo!nd in a"o!t
half of cases *perniosis+ and a lymphoma in $hich vasc!litis is ro!tinely fo!nd *nat!ral #iller cell
lymphoma+.
0. Perniosis
)his condition in pro"a"ly the most fre-!ent one in $hich a pathologist repeatedly
enco!nteres lymphocytic vasc!litis. Perniosis, or chil"lains, consists of pin# to p!rplish mac!les
and pap!les on the fingers, toes and sometimes legs. )hese arise in response to a"ove free,ing,
h!mid conditions s!ch as are fo!nd in the San Francisco Bay area *"!t not here in 'a$aii+.
Beca!se the lesions have a delayed onset after cold e&pos!re, some patients cannot relate them to
their ca!se. )he clinical differential diagnosis often incl!des vasc!litis, cryoglo"!linemia, or
erythema m!ltiforme.
Lesions of perniosis can sho$ a range of microscopic feat!res, the common denominator
of $hich is a s!perficial and deep perivasc!lar lymphocytic infiltrate 4*:A+4. aria"le feat!res
incl!de edema of the papillary dermis, infiltration of the lo$er half of the epidermis "y
03
lymphocytes, single apoptotic #eratinocytes, and lymphocytic vasc!litis. )he later can "e a
partic!larly val!a"le aid in disting!ishing perniosis from erythema m!ltiforme, as "oth can have
lymphocytes in the "asal ,one of the epidermis along $ith necrotic #eratinocytes.
:. /ngiocentric lymphoma, nat!ral #iller cell type
Several forms of lymphoma manifest themselves in the s#in $ith peri( and intravasc!lar
infiltrates of atypical lymphocytes. )hese incl!de angiocentric )(cell lymphoma, lymphomatoid
gran!lomatosis *B(cell lymphoma $ith dense reactive )(cell infiltrates+, nat!ral #iller cell
lymphoma, mycosis f!ngoides $ith angiocentric infltrates, and lymphomatoid pap!losis.
)he most distinctive of these condtions is nat!ral #iller cell lymphoma. )his disease has a
propensity to affect yo!ng /sian ad!lts, and presents in many cases $ith nasopharyngeal masses.
)he c!taneo!s lesions incl!de pla-!es that often !lcerate. Many cases have a f!lminant co!rse,
$ith death ens!ing in less than a year. )he changes in s#in "iopsy can "e pro"lematic( some
lesions appear to sho$ only s!perficial and deep perivasc!lar lymphocytic infiltrates, "!t the
n!clei of lymphocytes are slightly larger or more irreg!lar than in most inflammatory diseases.
ac!olar change, single necrotic #eratinocytes in the "asal ,one of the epidermis, and dense
infiltrates of lymphocytes in s!"c!taneo!s lo"!les, often accompanied "y necrosis are important
ancillary findings. )he diagnosis is more o"vio!s if some of the lymphocytes have large and
hyperchromatic n!clei. /d.!nctive tests are no$ availa"le to sec!re the diagnosis. )o!ch
imprints on fresh material stained $ith 6right(Eiemsa sho$ cytoplasmic gran!les, corresponding
to the finding that the circ!lating cells of nat!ral #iller cell lymphoma are large gran!lar
lymphocytes. CD?@ staining, $hich identifies the type of nat!ral #iller cell most often implicated
in this disease can no$ "e performed relia"ly on paraffin em"edded tiss!e, as can staining "y in
sit! hy"ridi,ation for Epstein(Barr vir!s. )he vir!s is clonally integrated into the genomes of
many cases of the condition, especially in patients from /sia or Latin /merica. /s most
lymphocytic infiltrates have only a fe$ Epstein(Barr vir!s positive cells, even a small cr!shed
specimen that sho$s a"!ndant viral genome can "e s!spected to "e nat!ral #iller cell lymphoma.
C. Eran!lomato!s vasc!litis
Eran!lomato!s vasc!litis of small vessels can "e inferred $hen histiocytes are fo!nd
$ithin the $all of a ven!le $ith or $itho!t fi"rin deposition. Eran!lomato!s vasc!litis can "e
fo!nd alone, $itho!t other changes, or in con.!nction $ith e&travasc!lar gran!lomato!s
infiltrates.
6hen fo!nd in isolation, the pathologist can ma#e a descriptive diagnosis of
gran!lomato!s vasc!litis, and sho!ld list the !nderlying diseases that can "e associated $ith it.
)hese incl!de inflammatory "o$el disease, 6egener7s gran!lomatosis, dr!g ingestion, and
a!toimm!ne disease. 9ne large series of patients $ith c!taneo!s gran!lomato!s vasc!litis that
fo!nd a high association $ith lymphoproliferative diseases and le!#emia is in need of re(
e&amination, as it $as performed prior to the advent of imm!nohistochemical mar#ers that $o!ld
ena"le the identification in ro!tinely processed tiss!e of nat!ral #iller cell angiocentric lymphoma
*CD?@+, or of the cells of lympho"lastic lymphoma *)d)+ 4*:2+4. Some of the cases in this st!dy
are li#ely to "e manifestations of specific lymphomato!s infiltrates, and consideration of this
possi"ility, close scr!tiny of the cytologic feat!res of the infiltrate, and imm!nohistochemistry *if
appropriate+ sho!ld "e performed. 'erpes simple& or ,oster infection commonly res!lts in a
00
secondary le!#ocytoclastic vasc!litisF this can even!tate in a gran!lomato!s one, a se-!ence that
can res!lt in the emergence of pap!les in an affected dermatome of herpes ,oster after the "listers
of that condition resolve. E&travasc!lar gran!lomato!s inflammation is accompanied "y
gran!lomato!s vasc!litis commonly in 6egener7s gran!lomatosis, and less commonly in
necro"iosis lipoidica or necro"iotic &anthogran!loma $ith paraproteinemia. /ltho!gh Crohn7s
disease only rarely affects the s#in, gran!lomato!s vasc!litis is commonly fo!nd alongside its
gran!lomato!s infiltrates.
0. 5Metastatic5 Crohn7s disease
/mong the conditions in $hich gran!lomato!s vasc!litis is accompanied "y e&travasc!lar
gran!lomata is the rare occ!rence of lesions of Crohn7s disease o!tside of the gastrointestinal
tract. So(called metastatic lesions of Crohn7s disease are pap!les that are fo!nd in the s#in or the
perine!m, or sometimes at some distance from it. )hey are practically never the presenting sign
of inflammatory "o$el disease.
Lesions of Crohn7s disease have a pathologic spectr!m that ranges from small sarcoidal
gran!lomata to palisaded infiltrates that can resem"le those of necro"iosis lipoidica. )he
palisaded macrophages occ!r arro!nd arease of degenerated collagen and fi"rosis. 6hile the
process may $ell "egin as a transient ne!trophilic le!#ocytoclastic vasc!litits, histiocytes are
typically fo!nd in and arro!nd the $alls of ven!les. 9ccl!sion of ven!lar l!mens co!ld res!lt in
in.!ry to connective tiss!e and a palisaded gran!lomato!s reaction. Macrophages in and arro!nd
the $alls of ven!les occ!r in c!taneo!s lesions of Crohn7s disease, "!t different pathologists have
interpreted them in vario!s $ays( some posit that they indicate an a!thentic gran!lomato!s
vasc!litis, $hile others "elieve that the macrophages are simply attracted to the peripheries of
ven!les 4*:1+4. )he finding on serial sections that gran!lomas apparently form $ithin the $alls of
ven!les s!pports the vasc!litic theory. )he antine!trophil cytoplasmic anti"ody test */=C/+ is
positive in a minority of cases of Crohn7s disease, !s!ally $ith a nongran!lar perin!clear pattern
and no reaction $ith myelopero&idase. )his is different from the res!lt in 6egener7s
gran!lomatosis in $hich a peripheral pattern of /=C/ occ!rs.
%%. /rteriolar vasc!litis *arteriolitis+
/rterioles are occasionally affected "y some of the conditions that ca!se ven!litis. )he
conditions considered herein are those in $hich arterioles are repeatedly affected. %n the first of
these, the mechanism is clearly le!#ocytoclastic vasc!litisF in the second t$o considered "elo$, a
lymphocytic vasc!litis follo$ed "y throm"osis appears to "e operative. Beca!se the occl!sion of
ven!les can "e compensated for "y collateral circ!lation, many ven!les m!st "e "loc#ed for
infarction to occ!r. %n contrast, arteriolar occl!sion often res!lts in infarction of the s#in and
!lceration.
Beca!se arterioles are located in the deep retic!lar dermis or s!perficial s!"c!tis, any
"iopsy performed on a patient s!spected of having an arteriolar vasc!litis has a high chance of
"eing an e&ercise in f!tility !nless the proced!re capt!res some s!"c!taneo!s fat( preferentially a
s!"stantial ammo!nt.
0. /rteriolar le!#ocytoclastic vasc!litis
0:
;hematoid vasc!litis is generally fo!nd in patients $ith high titres of rhe!matoid factor,
and can involve arterioles as $ell as ven!les and hence can ca!se s!ch maladies as digital infaction
and gangrene, and c!taneo!s !lcers. Biopsies often sho$ le!#ocytoclastic vasc!litis involving
arterioles in the deep dermis and s!"c!tis, sparing the s!perficial and sometimes the s!perficial
and deep ple&!ses.
:. Degos7 disease
)his condition, the complete name of $hich is sometimes given as 8ohlmeier(Degos7
disesae, is also called malignant atrophic pap!losis d!e to its sometimes fatal co!rse. Go!ng men
are the most commonly affected gro!p. Small, sharply marginated porcelain($hite mac!les
representing areas of infarcted s#in appear on the s#in of the tr!n# or that of the pro&imal lim"s.
)hese lesions are accompanied "y systemic symptoms *from "o$el or "rain infarction+ in some
patients or occ!r alone in others. )he term malignant atrophic pap!losis refers to the sometimes
fatal o!tcome of the condition.
)he mechanism of disease appears to "e a lymphocytic arteriolitis that rapidly leads to
throm"osis, and thence to infarction of a $edge shaped ,one of the s#in, incl!ding "oth the
epidermis and dermis, along $ith its adne&al str!ct!res. Biopsies of longstanding lesions
demonstrate sclerosis of the infarcted area $ith interstitial acid m!copolysaccharide deposition,
diminished n!m"ers of dermal fi"ro"lasts, and an atrophic epidermis.
<. Sneddon7s syndrome
Sneddon7s syndrome is a than#f!lly rare condition, in $hich arterioles and small arteries
have their l!mens occl!ded "y an intimal proliferation of fi"ro"lasts. )he c!taneo!s res!lt of this
process is a pattern of hypo( and hyperemia termed livedo racemosa. )his netli#e pattern of
erythema is similar to livedo retic!laris, "!t the polygonal ,ones of mottled s#in o!tlined "y livid
strea#s is m!ch larger *!pto several centimeters+ in livedo racemosa. Unli#e livedo retic!laris, the
erythemato!s pattern in livedo racemosa affects the tr!n# as $ell as the legs, and persists $hen
the s#in is $armed. )he reason that it is important to disting!ish the t$o conditions is that livedo
racemosa is associated in patients $ith Sneddon7s syndrome $ith a range of ne!rological and
psychiatric symptoms that res!lt from cere"ral ischemia, incl!ding ma.or stro#es.
Painsta#ing histologic st!dies have demonstrated that the earliest ins!lt to arterioles in
Sneddon7s syndrome is an 5endothelialitis5, i.e. the infiltration of lymphocytes "eneath arteriolar
endothelial cells, co!pled $ith the formation of s!"endothelial vac!oles and fi"rin deposition
4*<3+4. Progressive encroachment on the l!mens of arterioles "y a proliferation of fi"ro"lasts and
collagen deposition, and fragmentation of the internal elastic lamina are hallmar#s of the late
stages of Sneddon7s syndrome. / deep incisional "iopsy is essential for ma#ing the diagnosis.
Management of this condition is not yet satisfactory, "!t the discovery that it is inflammatory in
nat!re and has a throm"otic phase may lead to an effective treatment.
%%%. /rterial vasc!litis
S!"c!taneo!s arteries are only involved in a fe$ forms of vasc!litis. )he most important
of these are polyarteritis nodosa and nod!lar vasc!litis. Polyarteritis nodosa is a systemic disease,
affecting many internal organs via the formation of occl!sive nod!les at the sites at $hich arteries
0<
"ranch. M!ch more commonly enco!ntered "y dermatologists in clinical practice, and "y
dermatopathologists is the condition #no$n as s!"c!taneo!s or "enign c!taneo!s polyarteritis
nodosa, in $hich only s!"c!taneo!s vessels are affected. =od!lar vasc!litis is can also "e
considered as a pannic!litis, as arterial inflammation and occl!sion res!lt in e&tensive s!pp!ration
of nea"y fatty lo"!les. )he relationship "et$een nod!lar vasc!litis and a condition #no$n as
erythema ind!rat!m, $hich is no$ $ell esta"lished to "e a hypersensitivity reaction to t!"erc!lo!s
infection, has "een de"ated for almost ?3 years. Eiant cell or temporal arteritis also sho!ld "e
considered in the case of arteritis on the scalp. %t is only rarely enco!ntered "y dermatologists,
"!t can sometimes have !n!s!al manifestations s!ch as necrosis of the scalp 4*<0+4.
/s is the case $ith any m!sc!lar vessel, the presence of inflammatory cells in the $all of
an artery s!ffices to esta"lish the presence of vasc!litis. %nflammatory cells do not e&it arteries via
diapedesisF their presence in the $alls of arteries or veins implies vasc!litis. /s is also the case
$ith arteriolar vasc!litis, a "iopsy specimen sho!ld "e deep eno!gh to incl!de a s!"stantial
portion of s!"c!tis is any of these conditions are !nder consideration.
0. Polyarteritis nodosa
)he typical clinical presentation of this condition is $ith firm, painf!l, p!rplish
s!"c!taneo!s nod!les, distri"!ted assymetrically on the s#in of "oth legs. %n some patients the
nod!les are set in a "ac#gro!nd of livedo retic!laris, a net(li#e pattern of erythema. =e$ pap!les
may form rosettes arro!nd older ones, res!lting in a 5star"!rst5 pattern. Ulcers, typically stellate,
complicate the pict!re in a minority of cases. 6ith the e&ception of !lceration, $hich seems to "e
more commonly fo!nd more often in patients $ith systemic polyarteritis, the clinical appearance
of the c!taneo!s lesions does not help to predict the presence or a"sence of visceral involvement.
Patients $ith systemic polyarteritis do have a variety of symptoms, s!ch as fever, malaise and
myalgia. )hey may have hypertension of recent onset, protein!ria, or le!#ocytotosis. C!taneo!s
involvement only occ!rs in a"o!t :3H of patients $ith systemic polyarteritis.
Polyarteritis nodosa, $hether systemic or limited to s!"c!taneo!s vessels, "egins $ith
infiltrates of ne!trophils in the $alls of arteries, follo$ed "y le!#ocytoclasia, disr!ption of the
internal elastic lamina and in some arteries, throm"osis. =e!trophils commonly are fo!nd in the
fat immediately s!rro!nding the affected artery, "!t do not e&tend for a long distance into
s!"c!taneo!s lo"!les, i.e. there is only a limited degree of s!pp!rative pannic!litis. Small vessel
le!#ocytoclastic vasc!litis can also "e present alongside arteritis, or sometimes in specimens from
p!rp!ric lesions that lac# nod!larity. Direct imm!nofl!orescence is almost never performed for
diagnostic reasons, "!t the presence of %gM and C7< in arterial $alls indicates that antigen(
anti"ody comple&es have a ma.or pathogenic role, as in small vessel le!#ocytoclastic vasc!litis.
/s lesions age, eosinophils can .oin the infiltrate, and sometimes histiocytes or even giant cells are
present in older lesions. )he contention that systemic polyarteritis nodosa is manifested in the
s#in "y small vessel le!#ocytoclastic vasc!iltis, $hile the "enign c!taneo!s form sho$s arteritis
*as proposed in some papers 4*<:+4, and editions of Lever7s te&t"oo# !p !ntil 0113, "!t not in the
011A edition+ does not hold $ith the e&perience of most dermatopathologists and has little
s!pport in the literat!re.
%t $as recogni,ed in the 01A3s that polyarteritis nodosa co!ld "e limited to s!"c!taneo!s
arteries, sparing the viscera. 6hile the gro!p associated $ith the Mayo Clinic has p!shed the
concept that c!taneo!s polyarteritis and systemic polyarteritis are distinct, others regard
0>
polyarteritis as a disease that has a spectr!m of systemic involvement 4*<<+4 . 9ne st!dy in the
0123s esta"lished that many patients $ho initially seemed to have disease limited to the s#in later
proved to have systemic illnesses, incl!ding hepatitis B, /%DS, or cryoglo"!linemia, and the at
internal organs co!ld later "ecome involved 4*<>+4.
)he ma.or differential diagnosis is $ith nod!lar vasc!litis, and is disc!ssed "elo$.
:. =od!lar vasc!litis
=od!lar vasc!litis is, li#e polyarteritis nodosa, a ne!trophilic arteritis. %t typically occ!rs
on the calves of yo!ng ad!lt or middle aged $omen, $ith "ilaterally distri"!ted nod!les or
pla-!es that !lcerate, and heal $ith s!n#en stellate scars. )he condition $as separated in the
01>37s from erythema ind!rat!m "y 'amilton Montgomery. Erythema ind!rat!m $as considered
at that time to "e a t!"erc!lid( a hypersensitivity reaction to remote t!"erc!lo!s infection. By the
01A3s most /merican dermatopathologists ceased to "elieve that erythema ind!rat!m $as an
a!thentic condition, and regarded all patients $ith s!pp!rative arteritis and pannic!litis occ!ring
together as having nod!lar vasc!litis. By the late 0123s the pend!l!m "egan to s$ing the other
$ayF it "ecame clear that erythema ind!rat!m $as in fact an a!thentic condition, related to
myco"acterial infection *see "elo$+.
)he arteritis of nod!lar vasc!litis is seldom "iopsied in the first fe$ days or even $ee#s of
its e&istence. By the time of sampling, there is almost al$ays a s!pp!rative pannic!litis greater in
e&tent than the narro$ collar of s!pp!ration seen arro!nd arteries in polyarteritis nodosa. )he
ammo!nt of ne!trophilic n!clear d!st is less than in polyarteritis nodosa, altho!gh as is the case
$ith any ne!trophilic infiltrate, there is some, as ne!trophils only live for ho!rs to a day or so in a
c!taneo!s infiltrate. / n!m"er of secondary changes occ!r in lesions of nod!lar vasc!litis. )he
arteritis can res!lt in throm"osis. )he s!pp!rative pannic!litis can lead to fi"rosis and thic#ening
of septa, and damaged adipocytes can lea# fat, $hich in t!rn is phagocyti,ed "y histiocytes.
Coag!lation necrosis of adipocytes, and fi"rosis "et$een adiopocytes can also complicate the
pict!re.
=od!lar vasc!litis is most easily told apart from polyarteritis nodosa at scanning
magnification, "y the e&tent of involvement of s!"c!taneo!s lo"!les( a narro$ corona of
inflammation in polyarteritis, in contrast to e&tensive s!pp!ration and sometimes necrosis of
lo"!les in nod!lar vasc!litis. ;esolving lesions of nod!lar vasc!litis can "e pro"lematic, if s!ch
changes as fi"rosis of septa are not noted. Beca!se nod!lar vasc!litis and erythema ind!rat!m are
clinically indisting!isha"le, a t!"erc!lin s#in test sho!ld "e placed on any patient s!spected of
having nod!lar vasc!litis.
<. Erythema ind!rat!m
% noted a"ove that erythema ind!rat!m is no$ regarded as an a!thentic condition( one of
the tr!e t!"erc!lids. )he t!"erc!lids originally conceived as s#in diseases ten!o!sly related to
t!"erc!lo!s infection, early in the t$entieth cent!ry $hen many diseases that $e no$ #no$ have
no relationship to )B $ere so regarded. )he modern definition of a t!"erc!lid is that lesional
tiss!e does not contain myco"acteria "y special stains or c!lt!re, and that a t!"erc!lin s#in test is
positive, indicating a high degree of sensiti,ation to myco"acterial antigens. )he condion sho!ld
also respond to antit!"erc!lo!s therapy. Many patients $ith t!"erc!lids have histories of treated
0?
t!"erc!losis, and some even have active disease. Many investigators conisider erythema
ind!rat!m, pap!lonod!lar t!"erc!lid and lichen scrof!losor!m to "e a!thentic t!"erc!lids.
Myco"acterial transcipts are present in lesional tiss!e st!died !sing the polymerase chain reaction.
/nother former t!"erc!lid, rosacea(li#e t!"erc!lid of Le$andos#y to "e a form of rosacea,
!nrelated to t!"erc!losis. / memora"le concept regarding erythema ind!rat!m is that nod!lar
vasc!litis I a positive PPDJ erythema ind!rat!m 4*<?+4.
)he lesions of erythema ind!rat!m are tender p!rple nod!les or pla-!es, occ!ring on the
legs, "!ttoc#s and arms. Unli#e erythema nodos!m, lesions are commonly present on the calves
as $ell as on the shins. )hey resolve over a fe$ months, leaving depressed scars. Crops of ne$
lesions tend to arise in !ntreated patients or in patients $ho stop their treatment
premat!rely4*<@+4.
)he histopathology of erythema ind!rat!m can mirror that of nod!lar vasc!litis, $ith a
s!pp!rative arteritis and lo"!lar pannic!litis. )he spectr!m also incl!des mi&ed septal and lo"!lar
pannic!litis $ith small or large vessel le!#ocytoclastic ven!litis andKor arteritis. Caseation
necrosis *necrosis of histiocytes+ is sometimes present. )he presence of a"sence of vasc!litis in
the conte&t of a lo"!lar gran!lomato!s pannic!litis seems to have limited predictive val!e for the
presence of myco"acterial transcripts as detected "y PC;.

;EFE;E=CES
40. Lones ;E. M!estions to the editorial "oard and other a!thorities. /m L Dermatopathol
012?FA*:+B020(02A.
:. Dahl M. %mm!nofl!orescence, necro"iosis lipoidica, and "lood vessels. Fl!orescent
lights in the t!nnels. /rch Dermatol 0122F0:>*1+B0>0A(1.
<. Smoller B;, Mc=!tt =S, Contreras F. )he nat!ral history of vasc!litis. 6hat the histology
tells !s a"o!t pathogenesis. /rch Dermatol 0113F0:@*0+B2>(1.
>. E#enstam E, Callen LP. C!taneo!s le!#ocytoclastic vasc!litis. Clinical and la"oratory
feat!res of 2: patients seen in private practice. /rch Dermatol 012>F0:3*>+B>2>(1.
?. Legrain , Le.ean S, )aie" /, E!illard LM, Battin L, Maleville L. %nfantile ac!te
hemorrhagic edema of the s#inB st!dy of ten cases Nsee commentsO. L /m /cad Dermatol
0110F:>*0+B0A(::.
@. D!"in B/, Bronson DM, Eng /M. /c!te hemorrhagic edema of childhoodB an !n!s!al
variant of le!#ocytoclastic vasc!litis. L /m /cad Dermatol 0113F:<*: Pt :+B<>A(?3.
A. )ancrede(Bohin E, 9chonis#y S, ignon(Pennamen M(D, Flage!l B, Morel P, ;y"o.ad M.
Schonlein('enoch p!rp!ra in ad!lt patientsB ><2 predictive factors for %g/ glomer!lonephritis in a
retrospective st!dy of ?A cases. /rch Dermatol. 011AF0<<*>+B><2(>>:.
2. 8arls"erg PL, Lee 6M, Casey DL, Coc#erell CL, Cr!, PD, Lr. C!taneo!s vasc!litis and
rhe!matoid factor positivity as presenting signs of hepatitis C vir!s(ind!ced mi&ed
cryoglo"!linemia. /rch Dermatol 011?F0<0*03+B0001(:<.
1. %rvine /D, Br!ce %=, 6alsh MG, Bingham E/. Microscopic polyangiitisB Delineation of a
c!taneo!s(limited variant associated $ith antimyelopero&idase a!toanti"ody. /rch Dermatol.
011AF0<<*>+B>A>(>AA.
03. Pa& ;', 'odge SL, Callen LP. C!taneo!s le!#ocytoclastic vasc!litis. Serial
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0@
0113F0:@*0+B@1(A:.
00. Chen 8;, S! 6P, Pittel#o$ M;, Conn DL, Eeorge ), Leiferman 8M. Eosinophilic
vasc!litis in connective tiss!e disease. L /m /cad Dermatol 011@F<?*: Pt 0+B0A<(2:.
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0<. Peteiro C, )ori"io L. %ncidence of le!#ocytoclastic vasc!litis in chronic idiopathic !rticaria.
St!dy of 033 cases. /m L Dermatopathol 0121F00*@+B?:2(<<.
0>. Sanche, =P, 6in#elmann ;8, Schroeter /L, Dic#en C'. )he clinical and histopathologic
spectr!ms of !rticarial vasc!litisB st!dy of forty cases. L /m /cad Dermatol 012:FA*?+B?11(@3?.
0?. Mehregan D;, 'all ML, Ei"son LE. Urticarial vasc!litisB a histopathologic and clinical
revie$ of A: cases. L /m /cad Dermatol 011:F:@*< Pt :+B>>0(2.
0@. Sanche, =P, an 'ale 'M, S! 6P. Clinical and histopathologic spectr!m of necroti,ing
vasc!litis. ;eport of findings in 030 cases. /rch Dermatol 012?F0:0*:+B::3(>.
0A. LeBoit PE, Coc#erell CL. =od!lar lesions of erythema elevat!m di!tin!m in patients
infected $ith the h!man imm!nodeficiency vir!s. L /m /cad Dermatol 011<F:2*@+B101(::.
02. LeBoit PE, Gen )S, 6intro!" B. )he evol!tion of lesions in erythema elevat!m di!tin!m.
/m L Dermatopathol 012@F2*?+B<1:(>3:.
01. '! C', 97Lo!ghlin S, 6in#elmann ;8. C!taneo!s manifestations of 6egener
gran!lomatosis. /rch Dermatol 01AAF00<*:+B0A?(2:.
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Stra!ss gran!loma+ and systemic diseaseB a revie$ of :A cases. Medicine *Baltimore+
012<F@:*<+B0>:(?2.
:0. Ch! P, Connolly M8, LeBoit PE. )he histopathologic spectr!m of palisaded ne!trophilic
and gran!lomato!s dermatitis in patients $ith collagen vasc!lar disease. /rch Dermatol
011>F0<3*03+B0:A2(2<.
::. 6ilmoth EL, Perniciaro C. C!taneo!s e&travasc!lar necroti,ing gran!loma *6in#elmann
gran!loma+B confirmation of the association $ith systemic disease. L /m /cad Dermatol
011@F<>*? Pt 0+BA?<(1.
:<. Lee S', Ch!ng 8G, Lee 6S, Lee S. Behcet7s syndrome associated $ith "!llo!s
necroti,ing vasc!litis. L /m /cad Dermatol 0121F:0*: Pt :+B<:A(<3.
:>. Ch!n S%, S! 6P, Lee S, ;ogers ;Sd. Erythema nodos!m(li#e lesions in Behcet7s
syndromeB a histopathologic st!dy of <3 cases. L C!tan Pathol 0121F0@*?+B:?1(@?.
:?. McCalmont CS, McCalmont )', Lori,,o LL, 6hite 6L, Leshin B, ;oth"erger '. Livedo
vasc!litisB vasc!litis or throm"otic vasc!lopathyQ Clin E&p Dermatol 011:F0A*0+B>(2.
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:A. 'erman E6, 8e,is LS, Silvers D=. / distinctive variant of pernio. Clinical and
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systemic disease. L /m /cad Dermatol 012@F0>*<+B>1:(?30.
:1. 'ac#,ell(Bradley M, 'ed"lad M/, Stephansson E/. Metastatic Crohn7s disease. ;eport
of < cases $ith special reference to histopathologic findings. /rch Dermatol 011@F0<:*2+B1:2(<:.
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01A>F003*<+B>3A(0>.
0A
<<. )homas ;', Blac# MM. )he $ide clinical spectr!m of polyarteritis nodosa $ith
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0110F0:A*03+B0?:3(<.
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011@F<?*00+B23:(2.4
02