The Differential Diagnosis of Chronic Ulcer of the Leg
By EDGAR A. HINES, JR., M.D.
CHRONIC ULCERS of the leg are one of
the main problems of any physician
especially interested in peripheral vascular
or cutaneous disease and they are not an un-
common problem in general medicine.
A discussion of chronic ulcers of the leg
is somewhat complicated by the fact that
about 40 diseases and conditions may be im-
portantly concerned in producing these ul-
cers. I will not attempt to list or to discuss
all of them.
The method of making a correct differen-
tial diagnosis of chronic ulcers of the leg is
essentially the same as that of making a dif-
ferential diagnosis in any other medical or
surgical condition.
Information from the History
A careful history is an important aid in
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making the differential diagnosis. Especially
detailed information should be obtained on
the following six points:
1. The Nature of the Lesion. A clear de-
scription of the complaint and the time that
it first appeared are important.
2. Initiating Factors. Information should
be elicited about factors that may have initi-
ated the lesion, such as local injury, strong
medication, infection, phlebitis, cold and fac-
titial (self-induced) injury.
3. Development of Lesion. A slowly devel-
oping lesion suggests that it is due to isehe-
mia or malignant lesion, whereas a rapidly
developing lesion may be due to stasis or in-
jury.
4. The Amount of Pain. An isehemic lesion
is usually more painful than one due to stasis
or exposure to cold.
5. The Effect of Posture on Pain. Informa-
tion about the effect of posture on pain may
suggest the type of ulcer. The severe pain of
From the Veterans Administration Hospital, Oteen,
North Carolina.
Circulation, Volumre XXVII, May 1963
an isehemic lesion may be relieved by placing
the leg in a dependent position. The mild
pain of a stasis lesion is usually relieved and
the stasis ulcer heals with elevation of the
extremity.
6. The Effect of Treatment. When previous
adequate treatment has resulted in extremely
slow healing, an ischemic lesion or a malig-
nant lesion should be suspected. When the
lesion is healing rapidly or when previous
similar lesions have healed rapidly, then the
ulcer is likely to be a stasis ulcer.
Helpful Points from the General Examination
During the physical examination of the
patient, the following should be noted:
1. Location of the Lesion. An unusual lo-
cation suggests an unusual cause of the ulcer,
such as a traumatic cause or a factitial (self-
induced) injury. Isehemic ulcers of ocelusive
arterial disease are more likely to occur on
the toes and foot than on the leg because this
is the most distant area supplied by the arte-
rial circulation. However, chronic ischemic
ulcers occasionally are seen on the leg and
when they occur they almost always have
been initiated by an injury of some kind.
Stasis ulcers occur usually on the inner side
of the leg in the area drained by the saphe-
nous venous system. The ulcers of erythema
induratum may develop on any part of the
leg but most commonly are on or near the
calf.
2. Topography of the Lesion. The irregu-
larity or regularity of outline should be
noted. The color will indicate, to some degree,
the blood supply. A pale color indicates poor
arterial blood supply; a red color, particu-
larly in the base of the ulcer, with good gran-
ulation tissue, indicates a good arterial blood
supply, like that seen in a stasis ulcer. The
presence or absence of any significant infec-
tion in the lesion should be noted.
989
 990
3. Condition of the Surrounding Skin. The
signs of stasis dermatitis that are usually
present around a stasis ulcer should be noted
particularly. The characteristic thin, trans-
parent skin of acrodermatitis atrophicans is
another example of the significance of the
condition of the skin in making a diagnosis.
4. State of the Venous and Arterial Circut-
lation. The physical signs of venous insuffi-
ciency are edema, eyanosis of the skin, and
varicose veins. The signs of occlusive arterial
disease are absence of arterial pulsation, pal-
lor of the extremity on elevation, a delay in
venous filling in the dependent position, and
persistent paleness and coldness of the skin.
5. Evidence of Other, Possibly Causative
Diseases. Special note should be taken of in-
dications of the following diseases that may
cause ulcers: (a) syphilis, (b) diabetes, the
ulcer of necrobiosis diabeticorum; (e) hyper-
tension, the hypertensive-ischemic ulcer; (d)
blood dyserasias, such as hemolytic anemia,
Mediterranean anemia, hypoganmaglobuline-
mia, and polycythemia; (e) tuberculosis, the
ulcer of erythema induratum, and (f) chronic
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ulcerative colitis, the ulcer of pyoderma
gangrenosa.
6. Neurologic Abnormalities. Certain neu-
rologic conditions produce the so-called
trophic ulcer. Examples are the perforating
ulcers associated with tabes dorsalis and the
trophic ulcers associated with syringonmyelia
and myelodysplasia. If no specific neurologic
diagnosis can be made but the ulcer resem-
bles a trophic lesion, suspect leprosy.
7. Presence of Bacterial Organtsms and
Fungi. Cultures of the ulcer for bacterial
organisms and fungi are needed in certain
cases, although bacterial organisms or fungi
are not often primary causative agents of
chronic ulcers of the leg. However, in some
conditions, such as tertiary syphilis with nod-
ular, ulcerated lesions, sporotrichosis, yaws
and other tropical conditions, specific organ-
isms are the cause of chronic leg ulcers.
8. Histologic Changes (Results of Biopsy).
It is always well to bear in mind that a
ehronic, nonhealing ulcer may be caused by
9HINES
malignant disease, such as (a) an epithelioma
of the skin, (b) the rare ulceration in the skin
of Kaposi's sarcoma, (e) the ulcerative lesion
in the skin of metastatic carcinonma, or (d)
lymphangiosarcoma, such as may be seen in
chronic lymphedema of long duration.
Causes of Ulcer
The causes of chronic leg ulcers may be
grouped generally under primarily vascular
causes and nonvascular causes. The primarily
vascular causes may be subdivided into those
due to diseases of the veins, those due to dis-
eases of the arteries, and those due to diseases
of the capillaries. Lymph vaseular diseases
are not considered, since chronic ulcer of the
leg is extremely rare in lymphedema of the
leg.
When disease of the veins is a cause of
chronic leg ulcer, inadequacy of the venous
return sufficient to produce chronic venous
insufficiency is always present. A distinetion
has been made by some authorities between
those ulcers that develop after deep throm-
bophlebitis (postphlebitic ulcers) and those
that occur in association with primary vari-
cose veins (varicose ulcers). Since the factors
that produce the ulcers and delay healing are
essentially the same in both types of venous
disease, a distinction is not justifiable. Gravi-
tational (postural) edema is almost always
present in both types of ulcer. The only dif-
ference clinically is that the ulcers that de-
velop after deep thrombophlebitis may occur
in atypical locations. But this is not consist-
ent enough to be of help in the differential
diagnosis.
The arterial disease associated with chronic
ulcers of the leg is always occlusive arterial
disease, and it may involve only the large
arteries or only the small arteries or arteri-
oles. The chronic leg ulcer, which occurs most
frequently in association with occlusion of
the large arteries, is that seen in arterioselero-
sis obliterans. Occlusive involvenment of small
arteries and arterioles in and beneath the skin
occurs in livedo reticularis, chronic pernio,
hypertensive isehemia, and rarely in periar-
teritis nodosa. In all these conditions infare-
Circulation, Volume XX VII, May 1963
 SYMPOSIUM PERIPHERAL VASCULAR DISORDERS 991

tion of the skin may lead to a chronic isehemic
ulcer.
The diseases of the capillaries in which
chronic leg ulcers may occur are those in
which primary hematologic diseases have not
been recognized. An example is idiopathic
thrombocytopenic purpura, in which chronic
ulcers of the leg occasionally oceur. These
ulcers are said to heal quickly after splenec-
tomy.
An increasing number of cases of chronic
leg ulcers is being reported in the literature
in association with a number of different non-
vascular diseases. Some of these have already
been mentioned in discussing the physical ex-
amination of the patient. In general, the non-
vaseular diseases that are associated with
chronic leg ulcers may be grouped into the
systemic diseases, such as diabetes and syph-
ilis, the blood dyserasias, the diseases due to
specific bacterial organisms and fungi, and a
group of diseases in which the cause has not
been determined and which may be generally
classified under collagen diseases, such as
systemic lupus erythematosus and chronic
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cm. in diameter within 2 or 3 weeks (fig. 1).
The fully developed lesion is superficial with
a pink or red base containing much granula-
tion tissue. When active infection is present,
the secretion and pus must be cleaned off in
order that the physician may look at the base
of the ulcer. The skin near the ulcer is often
pigmented and may be fibrotic if the sur-
rounding skin has been involved in recurring
episodes of low-grade cellulitis. Occasionally,
the ulcer may develop to an enormous size
and may encircle the entire leg. The ulcer
will almost always heal rapidly if the patient
is put to bed with the leg elevated and if irri-
tating ointments and solutions are not ap-
plied. Severe pain is not associated with
uncomplicated stasis ulcer.
Ulcer of Arteriovenous Fistula
The ulceration seen with arteriovenous fis-
tula is similar to the stasis ulcer of chronic
venous insufficiency. Since it occurs in a re-
gion in which the skin is warm or hot, these
ulcers are characteristically "hot ulcers."

ulcerative colitis.
Types of Ulcer
I will now discuss in more detail some types
of chronic ulcers of the leg.
Ulcer of Chronic Venous Insufficiency (Stasis Ulcer)
Ulceration due to chronic venous insuffi-
ciency seldom develops in the upper part of
the leg and never on the thigh. Occasionally,
an ulcer develops on the foot or toes, but this
occurs only when the patient has worn very
loose shoes or has gone without shoes and,
therefore, has allowed edema of the feet and
toes to develop. The common site is on the
lower inner part of the leg or over the inter-
nal malleolus. The initial lesion may appear
as a circumscribed area of erosion of the skin
or as a red, scaly area. Frequently, the lesion
is initiated by local injury or by infection
and occasionally by applying too strong med- Figure 1
icationi to the skin. If the patient remains Stasis ulcer resulting from chronic venous insuf-
on his feet, the lesion may develop rather ficiency. There is pigmentation in the surrounding
rapidly, sometimes reaching a size of 2 or 3 skin and some fibrosis.
Circulation, Volume XXVII, May 1963
 992
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Figure 2
Ischemic ulcer of arteriosclerosis obliteraus. The
lesion was initiated by remov'al of a piece of
adhesive from the skin which took some of the
skin with it.
HINES
Ulcer of Chronic Arterial Insufficiency (Ischemic
Ulcer)
As already mentioned, the chronic ulcers
seen in arterial disease with isehemia usually
occur on the toes or the feet. When they de-
velop on the leg, as they do occasionally, they
almost always are initiated by injury. Since
any part of the leg may be injured, there is
no typical location for the ischemic ulcer asso-
ciated with occlusive arterial disease. How-
ever, many of them are on the front of the
leg, as injury is most likely to occur in this
site. The initial injury is usually a crack or
a break in the skin like an abrasion or a con-
tusion which does not heal normally. The
surface of the ulcer will appear to have a
poor blood supply, that is, the ulcer will be
relatively pale in color without granulation
tissue.
Isehemic ulcers develop slowly and may
continue to enlarge over a period of weeks
or months. The surrounding skin shows no
signs of congestion or chronic venous insuffi-
ciency. The base of the ulcer eventually may
become covered with a yellowish or gray mem-
brane that is difficult to remove from the sur-
face of the ulcer (fig. 2). Unless diabetic
peripheral neuropathy is present, pain in the
ulcer, which often is severe, is a prominent
feature. Other signs of arterial insufficiency
such as absence of pulsations in the large
arteries of the leg and postural color ehanges
indicating isehemia will be found on exam-
ination.
Chronic Pernio and Livedo Reticularis
In both of these conditions, ulceration re-
sults from occlusion of the small arteries and
arterioles with infaretion of the skin. The
individual lesion is similar in the two condi-
tions, and it is always isehemic. The clinical
characteristics, however, are sufficiently dif-
ferent to establish the two conditions as sep-
arate entities. In both conditions, lesions may
be initiated by exposure to cold. The differ-
ential diagnosis of the two conditions must
be made on a clinical basis. Chronic pernio
affects mostly young women, whereas livedo
reticularis affects both men and women of
Circulation, Volume XXVII, May 1963
 SYMPOSIUM PERIPHERALI VASCULAR DISORDERS 993

any age. Ulcerative lesions always occur in

chronic pernio but appear much less often in
livedo reticularis.
In chronic pernio, the ulcers are usually
small and multiple and are located low on
the legs and around the ankles and seldom on
the feet or toes (fig. 3). There is more or less
simultaneous symmetrical involvement of
both legs. The initial spontaneous lesion is a
tender, red or purplish nodule in the skin,
which has appeared after exposure of the
legs to cold. Within a few days, a blister
appears on the surface of the erythematous Figure 4
nodule and the color changes to blue or even Livedo reticularis. Large ischemic ulcer around
violet. The blister then breaks down and internal malUeolus. Except for some purpuric color-
leaves a superficial ulcer. The surface of the ation, the surrounding skin is normal.
ulcer has an ischemic appearance. The sur-
rounding skin usually is not changed unless weeks, the lesions will heal spontaneously,
there is a residual fibrosis from old healed leaving a pigmented area which may remain
ulcers in the area. When the ulcer is develop-
permanently. All of the lesions go through
ing, it is usually painful, but as the ulcera- this cycle, and at any certain time lesions in
tion progresses, the pain tends to subside. various stages will be present.
After a variable period, usually from 3 to 5 In livedo reticularis, the distinguishing
feature is the livid netlike pattern of mottling
of the skin. When ulceration occurs, the ini-
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tial lesion may be a tender nodule in the skin,

but more often it is a circumscribed bluish or
purplish area in the skin. A blister may form
on the top of this area and later break down,
leaving a superficial ischemic-appearing ulcer
(fig. 4). The lesion in livedo reticularis has
no preferred site except that in more than
half of the cases it occurs in the lower part
of the leg or around the ankles.
The lesions of livedo reticularis do not ap-
pear in crops or go through the healing cycle
typical of chronic pernio, nor is the onset of
the ulcers of livedo reticularis as likely to be
closely associated with changes of the season
as in chronic pernio. The ulcer may gradu-
ally enlarge to 2 to 4 cm. in diameter over a
period of several weeks or months. Wher. the
lesion is well developed, moderate to severe
pain is a prominent feature. The lesion of
livedo reticularis is usually persistent and
Figure 3
difficult to heal, whereas the ulcerated lesions
Typical superficial ulcers of chronic pernio at of chronic pernio heal spontaneously, espe-
their usual site on the posterior aspect of the leg. cially if the patient is removed from a eold
Circulation, Volume XXVII, May 1963
 994
Figure 5
Hypertensive-ischemic ulcer over the external mal-
leous. Three weeks after formation of initiaZ lesion
showing purpuric discoloration and ischemnic ap-
pearance of ulcer.
environment. In both conditions, pulsations
in large arteries usually are not affected.
Hypertensive-Ischemic Ulcer
Most of the patients affected are women in
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the fifth and sixth decades of life with long-
standing essential hypertension. Organie
changes in the arterioles adjacent to the skin
lead to occlusion of the lumen and infaretion
of the skin. The area of infaretion in the skin
breaks down to form a superficial ischemic
ulcer. The individual ulcer has many features
similar to the ulcers seen in chronic pernio
and livedo reticularis, since in all three con-
ditions the pathologic lesion is similar. The
ulcers are usually located on the lateral sur-
face of the ankle but may occur low on the
posterior and lateral surface of the leg. The
initial lesion when it has developed sponta-
neously is a painful, red plaque in the skin
which, within a week or 10 days, becomes blue
and purpuric. If a plaque is not present, the
initial lesion is a small flat area of bluish dis-
coloration of a purpuric nature in the skin.
A hemorrhagic bleb forms on the surface of
the original lesion and breaks down into a
superficial ulcer (fig. 5). The ulcer appears
isehemnie with a pale surface with little or no
HINES
granulation tissue. The surface of the ulcer
is sensitive and very painful. Severe pain is
a prominent feature of the condition in the
active phase of the ulcer.
The ulcer may enlarge by a process of ex-
tension of the purpuric hemorrhagic portion
into the normal skin around the edges of the
ulcer with a subsequent breaking down of
the skin, leaving an ischemnic surface. Usually
the ulcer develops slowly over a period of
weeks or months, but when the ulcer is initi-
ated by injury, it may develop more rapidly.
Most lesions are eventually covered by a
thick, membranous esehar. The fully devel-
oped lesions range in size from 1 to 11 em.
in diameter. Minor local injury is an initiat-
ing factor in nmany cases. If irritating oint-
ments and solutions are not applied, the ulcer
usually heals within 6 to 9 nmonths even with-
out treatment.
Erythema Induratum
Erythema induratum, an ulcerating tuber-
culid, may develop on any part of the leg
but most often it is on the posterior surface.
The lesionis are usually bilateral and more or
less symmetrical. The initial lesion is a pain-
less, or only slightly painful, bluish-red sub-
cutaneous nodule. The nodule often persists
for weeks and then may resolve sponta-
nieously, leaving a depressed sear. Usually
the lesion breaks through the surface of the
skin and then undergoes necrosis, producing
a deep ulcer that may persist for months (fig.
6). After several lesions have been present
for months or years, the surrounding skin is
fibrotic and thickened and may beconme
brownish in color. Erythema induratum usu-
ally affects young women.
If there is any serious question about dif-
ferentiating this clinical picture from other
chronic ulcers affecting the backs of the legs,
such as with chronic pernio, biopsy usually
is helpful.
Ulcer of Chronic Hemolytic Anemia
Chronic hemolytic anemia is one of the
blood dyserasias in which chronic leg ulcers
may occur. The lesions usually appear around
the ankles. The initial lesion usually begins
Cireclation, Volume XXVII, May 1963
 SYMPOSIUM-PERIPHERAL VASCULAR DISORDERS 995
in an area of purpuric discoloration or in an
area of residual brownish pigmentation from
previous purpura. There is no typical initial
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rigure 6
Erythema induration. Deep p,unched-out ulcer on
calf of leg and smaller more superficial ulcer on
lower posterior surface of other leg.

Figure 8
Ulcerating epithelioma. Biopsy showed this lesion
to be squamous-cell carcinoma.

lesion, but it may start as a localized area of

Figure 7
Ulcer of chronic hemnolytic anemia. Area of pig-
.mentation over internal malleolus with small,
superficial ischemic-appearing ulcer in it.
Circulation, Volume XXVII, May 1963
scaling in the center of a purpuric area that
breaks down forming a superficial ulcer. The
surface of the ulcer is not as isehemic appear-
ing as in those ulcers that occur in occlusive
arterial disease nor is it as hyperemic ap-
pearing as a typical stasis ulcer. The appear-
anee of the lesion suggests involvement of
both small veins and small arteries. The
 996 HINES

ulcer enlarges gradually but usually does not
become much larger than 1 cm. in diameter
(fig. 7). Pain is not a prorninent feature of
the ulcer associated with blood dyserasias. It
is probable that injury is often an initiating
factor.but not enough cases of this type have
accumulated to know the real incidence of
initiation by injury. The ulcers are extremely
resistant to treatment, but most of them will
heal eventually.
Ulcerating Neoplasms (Epithelioma)
Epitheliomas of the leg are rare, and it is
probably because of this that the ulcers are
so often mistaken for stasis ulcers that occur
frequently on the leg. Ulcerating epithelio-
mas usually develop at the site of an old
injury but especially in scars from old radia-
tion burns, in healed lacerations, and in areas
of senile keratosis. Occasionally one will de-
velop in an area of apparently previously
normal skin. There is no typical or usual site.
The initial lesion may be a discrete, pea-sized
white nodule or an area of red, scaly skin.
A characteristic feature is the slow enlarge-
ment of the initial lesion and in some cases
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The lesion that has been present for several
months may be of any size, but, in the leg,
i4 is usually 2 or 3 cm. in diameter. Pain
is not a prominent feature, and some ulcers
are entirely painless. They do not respond to
conventional treatment for the usual type
of leg ulcer although some may undergo in-
complete, spontaneous healing and involution
in the center. The diagnosis may be established
by biopsy.
Relevant References
1. ESTES, J. E., FARBER, E. M., AND STICKNEY,
J. M.: Ulcers of the leg in Mediterranean
disease. Blood 3: 302, 1948.
2. FARBER, E. M., AND THAYER, J. M.: Cutaneous
manifestations of some common peripheral vas-
cular diseases. M. Clin. North America 35:
355, 1951.
3. FELDAKER, M., HINEs, E. A., JR., AND KIERLAND,
R. R.: Livedo reticularis with ulceration.
Circulation 13: 196, 1956.
4. HINEs, E. A., JR., AND FARBER, E. M.: Ulcer of
the leg due to arterioloselerosis and isehemia,
occurring in the presence of hypertensive
disease (hypertensive-ischemic ulcers): A pre-
liminary report. Proc. Staff Meet., Mayo Clin.
21: 337, 1946.
5. MARTORELL, F.: Hypertensive ulcer of the leg.

a gradual progression to a superficial ulcer. Angiology 1: 133, 1950.

The ulcer may become deep, eventually in-
volving the bone. A typical ulcer has a telan-
giectatic border and in the leg, where gravi-
tational factors are important, some purpuric
reaction in the surrounding skin (fig. 8). The
edges usually are rolled, shiny and white, or
pale. A brown crust may cover the center.
6. MCGOVERN, T., AND WRIGHT, I. S.: Pernio: A
vascular disease. Am. Heart J. 22: 583, 1941.
7. MONTGOMERY, H., O 'LEARY, P. A., AND BARKER,
N. W.: Nodular vascular diseases of the legs:
Erythema induratum and allied conditions.
J.A.M.A. 128: 335, 1945.
8. WILLIAMS, K. R., AND BUTCHER, H. R., JR.:
Cutaneous carcinoma mistaken for stasis ulcer
of the leg. Am. Surgeon 27: 1, 1961.

Kt2
The Power of Prophesy
No man is a true prophet otherwise than through the possession of such intimate
knowledge of a subject that he is able to say, "Thus matters must develop." Such was
Claude Bernard's prophecy of the future of his own science. His understanding of
physiology had become so perfect that the future could not be wholly doubtful. He
knew where the path must lead.-L. J. HENDERSON. Introduction. CLAUDE BERNARD, M.D.
The Introduction to the Study of Experimental Medicine. New York, The Macmillan
Company, 1927, p. ix.

Circulation, Volume XXVII, May 1963