CONTINUING MEDICAL EDUCATION

Wound healing and treating wounds

Differential diagnosis and evaluation of chronic wounds
Laurel M. Morton, MD,a and Tania J. Phillips, MDa,b
Chestnut Hill and Boston, Massachusetts

Learning objectives
After completing this learning activity, participants should be able to describe the physiologic steps of wound healing; generate a thorough differential for acute and chronic wounds;
and commence the appropriate work-up for accurate and expedient diagnosis.

Disclosures
Editors
The editors involved with this CME activity and all content validation/peer reviewers of the journal-based CME activity have reported no relevant financial relationships with
commercial interest(s).

Authors
The authors involved with this journal-based CME activity have reported no relevant financial relationships with commercial interest(s).

Planners
The planners involved with this journal-based CME activity have reported no relevant financial relationships with commercial interest(s). The editorial and education staff involved
with this journal-based CME activity have reported no relevant financial relationships with commercial interest(s).

Wounds are an excellent example of how the field of dermatology represents a cross-section of many
medical disciplines. For instance, wounds may be caused by trauma, vascular insufficiency, and underlying
medical conditions, such as diabetes, hypertension, and rheumatologic and inflammatory disease. This
continuing medical education article provides an overview of wound healing and the pathophysiology of
chronic wounds and reviews the broad differential diagnosis of chronic wounds. It also describes the initial
steps necessary in evaluating a chronic wound and determining its underlying etiology. ( J Am Acad
Dermatol 2016;74:589-605.)

Key words: chronic wounds; chronic wound differential diagnosis; chronic wound evaluation; chronic
wound work-up; wound healing; wound pathophysiology.

INTRODUCTION
Abbreviations used:
Wound management often falls within dermatol-
ogists’ scope of practice. We create acute surgical ABI: ankle brachial index
CVI: chronic venous insufficiency
wounds and frequently see poorly healing ulcers in DFU: diabetic foot ulcer
our clinics. In this article, we briefly discuss the MMP: matrix metalloproteinase
physiology of wound healing, the causes of poor MPA: microscopic polyangiitis
PAN: polyarteritis nodosa
wound healing, the broad differential diagnoses for PDGF: platelet-derived growth factor
chronic wounds, and the appropriate steps for PG: pyoderma gangrenosum
clinical evaluation of chronic wounds. PU: pressure ulcer
SCC: squamous cell carcinoma
TGF-b: transforming growth factorebeta
WOUND HEALING VLU: venous leg ulcer
Acute wounds undergo a well understood series
of steps as they heal. In chronic wounds, these steps

From SkinCare Physicians,a Chestnut Hill, and the Department of 0190-9622/$36.00

Dermatology,b Boston University School of Medicine, Boston. Ó 2015 by the American Academy of Dermatology, Inc.
Funding sources: None. http://dx.doi.org/10.1016/j.jaad.2015.08.068
Conflicts of interest: None declared. Date of release: April 2016
Accepted for publication August 14, 2015. Expiration date: April 2019
Correspondence to: Laurel M. Morton, MD, SkinCare Physicians,
1244 Boylston St, Ste 302, Chestnut Hill, MA 02467. E-mail:
laurel.m.morton@gmail.com.

589
590 Morton and Phillips
are disrupted. Researchers continue to work to
understand the pathophysiology of nonhealing
wounds, and several of the most important factors
will be discussed below.
NORMAL WOUND HEALING
Key points
d The 4 phases of normal wound healing
include hemostasis, inflammation, prolifer-
ation/repair, and remodeling
d Macrophages are the most important inflam-
matory cell in wound healingdthey phago-
cytose pathogenic organisms, degrade
debris, and stimulate granulation tissue
formation
d Fibroblasts are essential for proliferation
and lay down important structural elements,
including collagen, elastin, and extracellular
matrix proteins
d During the remodeling process, which can
take weeks to years, type III collagen is
converted to type I collagen
d Mature scar strength is about 80% of that of
unwounded skin
Wound healing occurs in 4 overlapping phases:
hemostasis, inflammation, proliferation, and
remodeling.
Hemostasis occurs via a fibrin and platelet plug,
which triggers the coagulation cascade. Damage to
endothelial cells exposes collagen that stimulates
platelets to undergo activation, adhesion, and aggre-
gation. Platelets produce chemotactic factors,
including platelet-derived growth factor (PDGF)
and transforming growth factor-b (TGF-b). These
growth factors attract macrophages, neutrophils,
fibroblasts, endothelial cells, and smooth muscle
cells,1 which are essential for the inflammatory and
proliferative phases. Fibrin, derived from platelet-
derived fibrinogen, acts as a matrix for incoming
macrophages and fibroblasts.2
The inflammatory phase begins as neutrophils
adhere to endothelium within minutes of trauma.3
Neutrophils use elastase and collagenase to facilitate
migration into the extracellular space, where they
phagocytose bacteria, degrade matrix proteins, and
attract additional neutrophils and macrophages.3
Macrophages are arguably the most important
inflammatory cell in the acute healing process,
dominating within 3 to 5 days.4 They phagocytose
pathogenic organisms, degrade wound debris,
and stimulate granulation tissue formation and
angiogenesis. Macrophage growth factors include
PDGF, TGF-b, fibroblast growth factor, interleukin-1,
interleukin-6, and tumor necrosis factorea.5 TGF-b
J AM ACAD DERMATOL
APRIL 2016
is particularly important, stimulating macrophages
and influencing fibroblast function, chemotaxis, and
collagen deposition.4
The proliferation phase encompasses fibroplasia,
granulation, epithelialization, and angiogenesis and
begins within 24 hours of wound infliction. An early
fibrin matrix allows keratinocytes, in part stimulated
by TGF-b, to migrate from the wound edge and hair
follicles and slide over keratinocytes already in the
wound bed in a ‘‘leap-frogging’’ action.1,5,6
Concurrently, vascular endothelial growth factor,
upregulated by low oxygen tension, promotes
angiogenesis.5,7 Nearby capillary endothelial cells
are recruited1 and stimulated to proliferate by
vascular endothelial growth factor, which also
induces smooth muscle cell migration.8
Fibroblasts, which migrate in between 48 and
72 hours postinjury, are important for dermal matrix
proliferation, regulated by PDGF, fibroblast
growth factor, and others.9 Fibroblasts produce
structural proteins, including collagen, elastin,
extracellular matrix proteins, and matrix metallopro-
teinases (MMPs). MMPs degrade the initial fibrin plug
and facilitate fibroblast movement.9 Collagen is
apparent 48 to 72 hours after the wound appears
and is maximally secreted between postinjury days 5
to 7. Type III collagen (fetal collagen) is initially more
dominant, stimulated by TGF-b.1 Glycosami-
noglycans and proteoglycans, components of the
extracellular matrix, provide strength, support, and
density.1
The remodeling process takes weeks to years.
Wound contraction begins by day 5 because of the
phenotypic change of fibroblasts into actin-laden
myofibroblasts.10 MMPs and tissue inhibitors of
metalloproteinases reorganize type III collagen
fibers into a stronger network of type I collagen.1
Collagen reaches ;20% of its tensile strength after
3 weeks and 80% strength at 12 months. The
maximum scar strength is 80% of that of unwounded
skin.
CHRONIC VERSUS ACUTE WOUNDS
Key points
d Wound healing time depends on multiple
factors, including wound size, depth, loca-
tion, patient age, and local and systemic
disease
d Acute wounds progress through the phases
of healing in a normal and timely manner
d Chronic wounds fail to progress through a
normal orderly and timely sequence of
repair or without restoring normal anatomy
and function
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VOLUME 74, NUMBER 4
Table I. Characteristics of acute versus chronic
wounds
Acute wounds Chronic wounds
Low levels of bacteria High levels of bacteria
(MRSA)
Low inflammatory cytokines High inflammatory cytokine
levels
Low protease and reactive High protease and reactive
oxygen species levels oxygen species levels
Intact functional matrix Degraded nonfunctional
matrix
High mitogenic activity Low mitogenic activity
Mitotically competent cells Senescent cells
MRSA, Methicillin-resistant Staphylococcus aureus.
Adapted from Mast and Schultz.11
d Normal healing is regulated by cytokines,
growth factors, and proteases
d Poor wound healing is characterized by
chronic inflammation, cellular senescence,
poor cytokine milieu, and critical bacterial
colonization
d Chronic wounds have elevated levels of
cytokines and proteases that destroy essen-
tial extracellular matrix components,
growth factors, and growth factor receptors
Macroscopically, wound healing depends on
multiple factors, including wound size, depth, and
location, patient age, and the presence of local or
systemic disease. At the molecular level, healing
wounds show low levels of bacteria, inflammatory
cytokines, proteases, and reactive oxygen species.
They exhibit intact functional matrix, high mitogenic
activity, and mitotically competent cells. Multiple
factors contribute to poor wound healing, including
reduced oxygenation, chronic inflammation, fibro-
blast senescence, impaired function, and levels of
critical cytokines, growth factors and their receptors,
abnormal MMP activity, and bacterial colonization
and infection11 (Table I).
In culture, fibroblasts from acute wounds are
mitotically competent with high mitogenic activity,
but chronic wound fibroblasts are senescent with
low mitogenic capacity.5,12,13
Wound fluid from acute wounds, such as
split-thickness skin graft donor sites, stimulates
fibroblast proliferation in culture, indicating a
growth-promoting molecular milieu.12 In contrast,
chronic wound fluid inhibits fibroblast and kerati-
nocyte proliferation.13-15 Cytokine and growth factor
receptors, such as type II TGF-b receptor, may also
be downregulated or improperly functioning in
chronic wounds.16,17
Morton and Phillips 591
Table II. Systemic and local factors contributing to
chronic wounds
Systemic
Age
Malnutrition
Medications (eg, corticosteroids and immunosuppressants)
Obesity
Chronic medical conditions (eg, cardiac failure,
connective tissue disease, hypoxia, endocrine
disorders, vascular disease, diabetes, cancer,
and immunosuppression)
Habits (eg, smoking and alcohol consumption)
Local
Vascular disease (venous and arterial)
Neuropathy or pressure
Infection
Necrotic tissue in the wound bed or excessive wound
tension
Unfavorable local environment (ie, inappropriate topical
products or dressings, contact dermatitis, or wound
that is too dry or too wet)
Inappropriate treatment (eg, debridement for pyoderma
gangrenosum)
Malignant wound
Repetitive trauma
Radiation
MMPs are overactive in chronic wounds, with
decreased levels of tissue inhibitors of metalloprotei-
nases.18-22 These high levels of proteases in chronic
wounds degrade the tissue matrix and impair healing.
Recent research does not support a clear correla-
tion between microbial load and wound healing,23
but we know that there is a continuum of wound
infection, ranging from contamination, where bacte-
ria do not multiply or cause clinical infection, to
systemic infection. Biofilms are a significant problem
in chronic wounds. They are composed of a
community of bacteria that secretes a matrix or
glycocalyx, which is protective against the host im-
mune response and difficult to eradicate. Bacteria
(both planktonic and biofilms) cause inflammation,
which leads to the release of proteases and reactive
oxygen species from inflammatory cells. Bacteria also
secrete exotoxins and proteases that degrade
proteins that are essential for healing. Biofilms have
been identified in 60% of biopsy specimens obtained
from chronic wounds but only 6% of biopsy
specimens obtained from acute wounds.24
DIFFERENTIAL DIAGNOSIS OF CHRONIC
WOUNDS
Chronic wounds can result from multiple systemic
and local factors (Table II), and the differential
592 Morton and Phillips J AM ACAD DERMATOL
APRIL 2016

Table III. Extended differential diagnosis for chronic wounds

Infection-related
Bacterial
Erysipelas bullosa, necrotizing fasciitis (Streptococcus haemolyticus), botryomycosis (commonly Staphylococcus aureus),
gas gangrene (Clostridium species), ecthyma gangrenosum (Pseudomonas aeruginosa), septic embolism, bacterial
endocarditis, anthrax (Bacillus anthracis), diphtheria (Corynebacterium diphteriae), meningococcemia (Neisseria
meningitides), bartonellosis (Bartonella bacilliformis), glanders (Burkholderia mallei), malakoplakia (commonly E. coli),
tularemia (Francisella tularensis), and yaws (Treponema pallidum pertenue)
Sexually transmitted anogenital ulceration: syphilis (Treponema pallidum), granuloma inguinale (Klebsiella granulomatis),
lymphogranuloma venereum (Chlamydia trachomatis), and chancroid (Haemophilus ducreyi)
Atypical mycobacterial
Leprosy (Mycobacterium leprae), buruli ulcer (M ulcerans), tuberculosis (M tuberculosis causing ulcerating cutaneous
tuberculosis, lupus vulgaris, and papulonecrotic tuberculid)
Viral: herpes simplex, varicella zoster, cytomegalovirus
Fungal: bullous tinea pedis, eumycotic mycetoma, chromoblastomycosis, coccidiomycosis, sporotrichosis, histoplas-
mosis, and blastomycosis
Protozoan: Leishmaniasis, amoebiasis (Entamoeba histolytica), and acanthamoeba
Medication-induced
Hydroxyurea
Methotrexate
Chemotherapeutics
Immunosuppressives
Bacillus Calmette-Guerin vaccination
Malignancy-related
Internal malignancy metastasis
Cutaneous malignancy
Squamous cell carcinoma (Marjolin ulcer)
Basal cell carcinoma
Melanoma (including acral and amelanotic types)
Merkel cell carcinoma
Kaposi sarcoma
Malignant fibrous histiocytoma
Lymphoproliferative malignancy
Medical conditions
Diabetes mellitus
Neuropathic conditions including tabes dorsalis, paraplegia, and multiple sclerosis
Klinefelter syndrome
Hypertension (Martorell ulcer)
Blood disorders
Polycythemia vera
Sickle cell anemia
Thrombocytopenia (including thrombotic thrombocytopenic purpura)
Paraproteinemia
Autoimmune conditions
Scleroderma
Rheumatoid arthritis
Cutaneous lupus erythematosus
Inflammatory bowel disease (including metastatic Crohn’s disease)
Nutrition (caloric, protein, vitamin, and mineral deficiencies)
Pressure
Primary skin conditions
Necrobiosis lipoidica
Sarcoidosis
Ulcerative pyoderma gangrenosum
Panniculitis (including erythema induratum)
Bullous diseases (including bullous pemphigoid, pemphigus, bullous lichen planus, and porphyria cutanea tarda)
StevenseJohnson syndrome and toxic epidermal necrolysis
Continued
J AM ACAD DERMATOL Morton and Phillips 593
VOLUME 74, NUMBER 4

Table III. Cont’d

Substance abuseerelated (Fig 1)
Skin-popping
Toxic and irritant properties of illicit drugs and adulterants
Vasoconstrictive cocaine
Bacterial embolism
Trauma (including burns, bites, and postsurgical injury)
Factitial (including dermatitis artefacta, malingering, and Munchausen by proxy)
Vascular
Venous leg ulcers
Chronic venous insufficiency
Congenital valvular insufficiency
Trauma-related valvular insufficiency
Thrombus-related valvular insufficiency (deep venous thrombosis)
Mixed venous-arterial or venous-lymphatic insufficiency
Arteriovenous malformation
Arterial leg ulcers
Atherosclerosis-related
Embolism-related
Thromboangiitis obliterans
Vasculitis
Small-vessel vasculitis: leukocytoclastic vasculitis, microscopic polyangiitis, granulomatosis with polyangiitis (formerly
Wegener granulomatosis), ChurgeStrauss, HenocheScho €nlein purpura, cryoagglutination (cryoglobulins, cryofibrino-
gen), and Behçet disease
Medium-sized vessel: polyarteritis nodosa
Vasculopathy
Hypercoagulopathic disorders (Table VI)
Disseminated intravascular coagulation and purpura fulminans
Sneddon syndrome (usually presenting as livedo reticularis)
Cholesterol emboli
Calciphylaxis
Warfarin-induced necrosis (and heparin necrosis)
Livedoid vasculopathy
Dego disease (malignant atrophic papulosis)

diagnosis for chronic, nonhealing ulcers is extensive

(Table III). Venous leg ulcers (VLUs), arterial ulcers,
and diabetic foot ulcers (DFUs) are the most
common wounds seen on the lower extremities
(Table IV).

COMMON LOWER EXTREMITY ULCERS

AND PRESSURE ULCERS
Key points
d The most common types of lower extremity
ulcers are venous leg ulcers, arterial ulcers,
and diabetic foot ulcers
d Venous leg ulcers occur in the gaiter
area (between the lower calf and
ankle), and are associated with edema,
hemosiderin pigment, venous eczema, and
lipodermatosclerosis Fig 1. Chronic ulcer caused by illicit drug use. Ulcer on
d Arterial ulcers are more common in smokers the shin of a man who used his wound as an access site for
and patients with diabetes mellitus, the injection of illicit drugs for many years. (Courtesy of
hyperlipidemia and hypertension; they are Jennifer Gloeckner-Powers, MD.)
594 Morton and Phillips J AM ACAD DERMATOL
APRIL 2016

Table IV. Comparison of venous leg ulcers, arterial ulcers, and diabetic foot ulcers
Ulcer type Location
Venous Gaiter region of the lower
leg ulcer leg (midcalf to 1 in inferior
to the malleolus)
Arterial ulcer Distal extremities and sites
of trauma, such as bony
prominences
Diabetic Plantar surfaces and sites
foot ulcer of repetitive trauma and
increased pressure
Clinical appearance Associated symptoms
Single or multiple lesions; irregularly Pain may or may not be present;
shaped and shallow; commonly aching in the legs after long
with granulation and fibrinous periods of standing; leg
tissue and rarely with necrotic heaviness and swelling
tissue; lower extremity edema;
venous eczema, hemosiderin
deposition, or lipodermatosclerosis;
inverted champagne bottle
appearance of the lower leg
Sharply demarcated borders; dry, Ulcer pain, often severe;
necrotic wound bed; sparse claudication (leg pain with
granulation tissue; signs of arterial exercise or at rest); pain that
insufficiency, such as cool extremities worsens with leg elevation and
and poor peripheral pulses, hair loss, improves with dependency
atrophic skin, and delayed capillary
refill time
Often with punched out borders; may Distal anesthesia or paraesthesia
be associated with callus, foot consistent with diabetic
deformity, or limited joint mobility; neuropathy; claudication
pink, warm, dry skin; signs of fissuring
and skin breakdown

painful, distal, and often dry or necrotic with
poor granulation tissue
d Diabetic foot ulcers are usually caused by
peripheral neuropathy or angiopathic
changes; they are most common at sites of
repetitive pressure, such as the soles of the
feet
d Pressure ulcers affect up to 5% of hospital-
ized patients and often occur over bony
prominences
Venous leg ulcers
VLUs, caused by chronic venous insufficiency
(CVI), comprise 50% to 70% of leg ulcers,25 with a
prevalence of 1% to 1.5%.26 Patients may report
swelling and lower extremity aching worsening
during the day and improving with elevation. The
history may include deep venous thrombosis,
trauma, or surgery to the lower leg.27
VLUs are often located in the gaiter region (Fig 2),
an area extending from midcalf to approximately 1 in
below the malleolus. They may be single or multiple
and are irregularly shaped but shallow. Red granu-
lation tissue or yellow fibrinous tissue is common;
black necrotic tissue is rare. Skin changes include
varicosities, pitting edema, dermatitis, hemosiderin
pigment, and lipodermatosclerosis28 (Fig 3).
The diagnosis of a VLU can often be made
clinically, but about 25% of patients with venous
reflux will not show typical clinical changes. Duplex
ultrasonography is helpful in assessing reflux and
obstruction.28,29 For superficial, deep femoral, and
deep calf veins, the cutoff value for length of reflux is
[500 ms. In the perforating veins, it is [350 ms; in
the common femoral, femoral, and popliteal veins it
is [1000 ms.30 Venography is rarely recommended
in postthrombotic disease.31 The ankleebrachial
index (ABI) should be performed to rule out
concurrent arterial disease.32,33
It has been shown that log healing rate, log
wound area ratio, and percentage change in wound
area can be used as surrogate markers to predict VLU
healing at the 12- or 24-week mark.34 For example, a
wound \10 cm2 in area and \12 months old has a
29% chance of not healing by week 24 of compres-
sion therapy. A wound [10 cm2 in area and
[12 months old has a 78% chance of not healing.35
Arterial leg ulcers
Arterial disease accounts for up to 25% of leg
ulcers.36 Atherosclerosis causes poor perfusion,
inadequate skin oxygenation, and tissue break-
down.36 Diabetes, smoking, hyperlipidemia,
hypertension, obesity, and increased age are
important risk factors.37 Patients may report
claudication and pain worsening with leg elevation
and improving with dependency.
Arterial ulcers frequently present over sites of
pressure or trauma, such as bony prominences, or at
J AM ACAD DERMATOL
VOLUME 74, NUMBER 4
Fig 2. Gaiter region. The gaiter region (located between
the 2 blue arrows) includes the lower leg from midcalf to
approximately 1 in inferior to the malleolus.
Fig 3. Venous leg ulcer. This ulcer is characterized by an
irregular shape, shallow depth, and a fibrinous base.
(Courtesy of Tania J. Phillips, MD.)
distal points, such as the toes. They appear punched
out with sharply demarcated borders and have dry,
necrotic wound beds. Granulation tissue is sparse.
Clinical findings include hair loss, atrophic skin, poor
peripheral pulses, and capillary refill time [3 to
4 seconds.38 Femoral bruits indicate proximal
atherosclerotic lesions, and delayed filling of veins
on dependency may result in bright pink or red
extremities.38 Confirmation tests include ABIs,
Doppler arterial waveform analysis, and transcuta-
neous oxygen pressure measurements.36 Peripheral
arterial disease (PAD) is diagnosed when the ABI is
#0.9. PAD is mild to moderate when the ABI is 0.4 to
Morton and Phillips 595
0.9 and severe when ABI is \0.4. An ABI [1.3 is
also abnormal and may represent noncompressible
vessels.39 Normal transcutaneous oxygen pressure
values depend on age and position (ie, higher for
younger patients and more proximal measure-
ments). Normal levels are approximately 60 mm
Hg, and levels #20 mm Hg suggest that revascular-
ization will improve wound healing.40 Arteriograms
and computed tomography or magnetic resonance
imaging scans may be useful to map any vascular
occlusion.
Diabetic foot ulcers
DFUs affect 4% to 10% of patients with diabetes
annually,41,42 and are the leading cause of hospital-
ization and amputation in these patients.41,42
Neuropathy and ischemia are the most common
causes, with infectious sequelae occurring
frequently.41,43,44 Between 50% and 60% of patients
with a DFU have signs of infection at the time of
hospital admission.45,46
In diabetes, autonomic deficits lead to deficient
sweating and altered blood flow regulation, resulting
in impaired distal extremity oxygenation and warm,
dry skin susceptible to fissuring and break
down.44,47,48 Up to 50% of ulcers are ischemic or
neuroischemic in origin,47 with poor glucose control
accelerating arterial disease.49
DFUs are commonly located on plantar surfaces at
sites of repetitive trauma. Calluses form at abnormal
pressure points because of neuropathy, deformities
(eg, Charcot foot), or limited joint mobility.50 Distal
extremities may be dry, pink, and warm. Sensation
with the nylon monofilament, Achilles tendon reflex,
and 128-Hz tuning fork testing may be abnormal.41,44
ABIs are indicated to evaluate for PAD, but can often
be falsely elevated because of vessel calcification.
Vascular imaging may be helpful, including duplex
ultrasonography, computed tomography angiog-
raphy, or magnetic resonance angiography.
Pressure ulcers
Pressure ulcers (PUs) are localized areas of tissue
necrosis that result from unrelieved pressure, leading
to localized tissue injury. They are commonly found
over bony prominences. PUs affect 1% to 5% of
hospitalized patients51,52 and up to 26.2% of patients
presenting to the emergency department from
nursing homes.53 The main etiologic factors include
pressure, shearing forces, friction, and moisture54,55
(Fig 4).
Risk factors include decreased level of conscious-
ness, malnutrition, impaired mobility, and fecal
incontinence.56 PUs are categorized from stage I to
IV, based on depth55 (Table V).
596 Morton and Phillips J AM ACAD DERMATOL
APRIL 2016

Fig 4. The distribution of common pressure ulcers. (Reproduced with permission from Phillips
TJ. Ulcers. Dermatology, vol 2. Philadelphia: Elsevier; 2008: p 1611.)

Table V. Pressure ulcer classification55

Stage I Nonblanchable erythema
Stage II Partial-thickness, shallow open ulcer with red pink wound bed without slough; may present as a blister
Stage III Full-thickness skin loss. Subcutaneous fat may be visible, but bone, tendon or muscle are not exposed;
slough may be present but does not obscure depth of tissue loss; may include undermining and tunneling
Stage IV Full-thickness tissue loss with exposed bone tendon or muscle; slough or eschar may be present; often
includes undermining and tunneling

RARER CAUSES OF ULCERS cryoglobulinemia has high rates of ulceration,

Key points
d Vasculitis can cause cutaneous nodules,
livedo, and deep wounds with scalloped
borders
d Vasculopathic ulcers are often small, painful,
and have a background of atrophie blanche
d Inflammatory cutaneous conditions, such as
pyoderma gangrenosum, may present with
ulceration
d Chronic ulcers may become malignant
d Squamous cell carcinoma can develop in
chronic pressure ulcers, venous ulcers, and
sites of previous burn injury (ie, Marjolin
ulcer).
ranging from 11% to 24%.59-61 In granulomatosis
with polyangiitisdformerly known as Wegener
diseasedulcers are pyoderma gangrenosum (PG)
elike and often form after minor trauma.62-64 Ulcers
are less common in ChurgeStrauss syndrome and
microscopic polyangiitis (MPA).62,63
Cutaneous medium-vessel vasculitis, such as
polyarteritis nodosa (PAN), manifests as painful
nodules on the lower extremities near the malleoli
with livedo reticularis and ulceration.62,63 A
420-patient study examining patients with PAN and
MPA revealed ulceration in 4% of patients with PAN
and 6% of patients with MPA.65 Ulceration may be
more common in purely cutaneous disease.66

Vasculitis
Small-vessel vasculitis may be associated with
superficial ulceration. Medium-vessel disease pre-
sents more commonly with nodules favoring the
lower extremities, livedo reticularis, and deep ulcers
with geographic or scalloped borders.57
In cryoglobulinemia, ulceration indicates larger
vessel involvement57 and poor prognosis.58 Mixed
Vasculopathy
Primary and secondary coagulopathies (Table VI)
can cause ulcers because of poor tissue perfusion.
The most common hypercoagulable disorder is fac-
tor V Leiden deficiency, which can be found in #25%
of patients with VLUs.67 Other important causes of
vasculopathic ulcers are discussed in Table VII.68-86
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VOLUME 74, NUMBER 4
Table VI. Primary and secondary coagulopathies
Causes of primary coagulopathy
Factor V Leiden
Prothrombin G20210A mutation
Methyltetrahydrofolate reductase mutation
Cystathione-beta-synthase mutation (homocysteinemia)
Antithrombin III deficiency
Protein C and S deficiency
Dysfibrinogenemia
Plasminogen deficiency
Elevated factors VIII, IX, or X
Tissue factor pathway inhibitor deficiency
IgA, Immunoglobulin A; IgG, immunoglobulin G; IgM, immunoglobulin M.
Necrobiosis lipoidica
Necrobiosis lipoidica is an idiopathic cutaneous
palisading granulomatous condition that is more
commonly seen in women and patients with
diabetes87,88 in the third or fourth decade87 of life.
It ulcerates 30% to 35% of the time.87,89
Well-circumscribed papules and nodules coalesce
into larger telangiectatic, violaceous plaques with
central red-brown to yellow-brown discoloration.
Central areas are atrophic, waxy, and may ulcerate.
Lesions are most often on the lower extremities and
can be painful90 (Fig 6).
Pyoderma gangrenosum
PG is a rare, ulcerating, neutrophilic dermatosis.
Inflammatory bowel disease is present in 20% to 30%
of patients with PG.91,92 Other associated conditions
include monoclonal gammopathy, hematologic
malignancy, paraproteinemia, Behçet disease,
Sweet syndrome, hepatitis, HIV, and systemic lupus
erythematosus.93 Lesions begin as tender nodules,
plaques, or pustules that become painful ulcers with
undermined, violaceous borders and friable wound
beds. Cribriform, atrophic scarring results. Ulcers are
typically multiple, demonstrate pathergy (induction
after trauma), and are usually located on the lower
extremities, though they may be peristomal.92
Malignancy-associated ulceration
Squamous cell carcinoma (SCC) can develop in
chronic wounds (ie, Marjolin ulcer).94 Suspicious
features include vegetative or nodular ulcers,
elevated or indurated margins, a tendency to bleed,
and failure to heal95 (Fig 7). In 66 patients with SCC
developing in burned or irradiated skin, the mean
time from injury to SCC diagnosis was 37 years, with
a high recurrence rate (58%) and a 5-year survival
rate of 52%.96 Malignancy may complicate ulcers of
Morton and Phillips 597
Causes of secondary coagulopathy
Hospitalization
Trauma
Surgery
Immobilization
Obesity
Malignancy
Medication
Smoking
Pregnancy
Antiphospholipid antibody syndrome (screen with
anticardiolipin antibodies [IgG, IgA, IgM], anti-beta2-
glycoprotein antibodies [IgG, IgM], and lupus anticoagulant)
Acquired hyperhomocysteinemia
other etiologies, including VLUs.97 Other skin
cancers that may present as nonhealing ulcers
include basal cell carcinoma, leiomyosarcoma,
malignant fibrous sarcoma, Kaposi sarcoma, Merkel
cell carcinoma, melanoma, large cell transformation
of mycosis fungoides, CD31 cutaneous large T-cell
lymphoma, and CD301 anaplastic large cell lym-
phoma.98-106
Hypertensive ulcers
Hypertensive ulcers were described by Martorell
in 1945.107 A later series described 40 patients with
ulcers ranging in size from \1 cm to 13 3 27 cm with
[50% initiated by trauma.108 Hypertensive ulcers are
painful, with a predilection for the anterolateral
lower two-thirds of the leg, and they occur when
blood pressure is poorly controlled. They may
involve the Achilles tendon109,110 and possess a
necrotic base with or without satellite lesions.108-110
Poor vasodilation109 and arteriosclerosis of small and
medium vessels are likely contributors. Occlusive
arterial disease must be ruled out. Clinically, they can
be difficult to distinguish from PG, but obtaining and
reviewing a deep biopsy specimen (including the
vessels) is diagnostic, and reveals arteriolosclerosis
with or without medial calcification.
CHRONIC ULCER WORK-UP
An adequate history and physical examination
may point to a diagnosis or guide a physician in
choosing the appropriate diagnostic protocol.
Key points
d The initial ulcer evaluation must include a
thorough history of present illness, medical
history, and a review of systems with a goal
of identifying complicating comorbid
conditions
 598 Morton and Phillips
Table VII. Important vasculopathic causes of ulceration
Vasculopathy Patient characterization Etiology Presentation
Cholesterol Patients are more commonly elderly men with Emboli are triggered by intravascular In addition to ulceration, cutaneous findings
emboli68,69 hypertension and atherosclerosis70; cholesterol radiologic intervention, vascular surgery, include livedo reticularis, gangrene, cyanosis,
emboli involve skin in 34-35% of cases,70,71 and anticoagulation72 nodules, and purpura71
with nearly 20% of cutaneous involvement
demonstrating ulceration70
Calciphylaxis 1-5% of patients on dialysis73,74; risk factors Demonstrates calcification of medium-sized Lesions begin as mottled, violaceous, indurated
include end stage renal disease, secondary arteries, leading to cutaneous necrosis75; plaques resembling livedo reticularis and
hyperparathyroidism, hypoalbuminemia, and etiology is poorly understood overall progress to ulcers with deep eschar formation
anticoagulation73-75; mortality is #80% when and refractory pain73
ulceration occurs76
Warfarin-induced Usually occurs in patients heterozygous for Paradoxical hypercoagulability because Produces petechiae and ecchymoses that progress
necrosis protein C or S mutations67,77; obese individuals of the vitamin Kedependence of proteins to hemorrhagic bullae and eventually eschar
are at higher risk C and S67,77; onset is usually 3-5 days after and ulceration77-79; commonly affects the
the initiation of warfarin, usually at high breasts, buttocks, abdomen, thighs and calves78,79
doses and without heparinization
Livedoid Female predominance of 3:180; mean age of onset Occlusive disease of superficial Classic triad of livedo racemosa, episodic and
vasculopathy is 45 years80 cutaneous vessels81; hypercoagulability painful purpuric macules and ulcers at the
likely plays a role,80,82 because ankles and posterior feet extending to the
anticoagulation has led to improvement posterior legs, and stellate porcelain white
in multiple cases83-85; poor peripheral scars (atrophie blanche)80-82; prodromal
vascular endothelial function may burning and lack of systemic findings is
contribute86 typical (Fig 5)

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J AM ACAD DERMATOL
VOLUME 74, NUMBER 4
Fig 5. Livedoid vasculopathy. This painful ulcer caused
by livedoid vasculopathy shows the classic finding
of stellate, porcelain white scars (atrophie blanche).
(Courtesy of Jennifer Gloekner-Powers, MD.)
Fig 6. Necrobiosis lipoidica. Note the large, well-defined
pink-brown plaque with multiple central areas that feature
atrophy and ulceration. (Courtesy of Lana Kashlan, MD.)
d The physical examination may reveal
identifying ulcer characteristics and associ-
ated skin changes that point to a specific
diagnosis
d Adjunctive diagnostic testing may be useful
and includes obtaining a biopsy specimen,
laboratory analysis, and imaging studies
History of present illness
A patient’s medical history can often give a clue as
to ulcer etiology. Evaluation of a chronic ulcer
Morton and Phillips 599
Fig 7. Squamous cell carcinoma. This woman in her 60s
presented with a nonhealing ulcer of [12 months’ dura-
tion. The biopsy specimen revealed invasive squamous
cell carcinoma. (Courtesy of Tania J. Phillips, MD.)
should include a thorough history, including time
of onset, presence of inciting trauma, progress of
healing, history of similar lesions, wound location,
and associated symptoms and signs, such as anes-
thesia, pain, or exudate. For example, ulcers caused
by PG often begin or worsen after trauma, starting as
a pustule, which rapidly enlarges. Wound care
practices and attempted treatments should be noted.
In many cases, poor healing is related to inadequate
wound care or a lack of compression.
Medical and medication history
A patient’s medical history is helpful in elucidating
the ulcer diagnosis. Current and previous medica-
tions should be carefully reviewed, including
chemotherapeutic agents and immunosuppressant
drugs. In addition to conditions listed in Table VIII,
malignancy should be considered as a primary or
secondary cause of ulceration, especially if the
wound is of long duration.
Family and social history
Family history of thromboses indicates the risk of
a hypercoagulable state; a rheumatologic family
history may suggest an autoimmune cause of an
ulcer. Occupations involving long hours of standing
worsen risk for CVI. Recent travel may point to an
infectious etiology. The use of alcohol or drugs
contributes to poor nutritional status. Intravenous
drug use increases the risk of hepatitis C, which is
commonly associated with mixed cryoglobulinemia.
Eating habits and a history of smoking raise
600 Morton and Phillips J AM ACAD DERMATOL
APRIL 2016

Table VIII. Relevant medical history and review of systems screening for chronic ulcer evaluation
Relevant medical history
Cardiovascular: hypertension (controlled or uncontrolled), atherosclerosis, intermittent claudication, congestive heart
failure, deep venous thrombosis, vascular malformation, lymphedema, and venous insufficiency
Respiratory: sarcoidosis
Gastrointestinal: inflammatory bowel disease
Hematologic/lymphatic: coagulopathy, recent anticoagulation therapy, blood disorders including: sickle cell anemia,
polycythemia vera, thalassemia, and thrombocytopenia
Renal: chronic kidney insufficiency or failure, hemodialysis
Neurologic: disease-causing neuropathy, multiple sclerosis
Musculoskeletal: history of lower extremity trauma or surgery
Pyschologic: substance abuse, neurodermatoses, dementia
Endocrinologic: diabetes mellitus and associated complications (retinopathy, nephropathy, neuropathy), corticosteroid
excess, thyroid disease
Skin: history of any chronic skin conditions, including vasculitis, necrobiosis lipoidica, sarcoidosis, PG, cutaneous
malignancy
Immunologic and rheumatologic: systemic lupus erythematosus, rheumatoid arthritis, Sjo €gren syndrome, scleroderma,
systemic and cutaneous vasculitis
Infection: chronic bacterial, viral, or fungal infections, including HIV, hepatitis, tuberculosis, or other atypical mycobacterial
infection
Surgical history: cardiovascular reperfusion interventions
Review of systems
Constitutional: fever, chills, sweats, weight loss or loss of appetite, recent hospitalization
Cardiovascular: chest pain, lower extremity pain with or without exertion, lower extremity pain exacerbated by long
periods of standing or worse at the end of the day, lower extremity edema, lower extremity pain worsened with leg
elevation
Respiratory: shortness of breath, cough (breathlessness may also indicate cardiac failure)
Gastrointestinal: abdominal pain, nausea, vomiting, diarrhea, bloody stool, constipation
Hematologic/lymphatic: slow healing, tendency to bleed or bruise
Neurological: headaches, lower extremity numbness, burning, tingling or pain
Musculoskeletal: myalgias, arthralgias, recent trauma
Skin: rashes, pruritus, unusual lesions or moles
Eyes: blurred or double vision, decreased visual acuity

awareness for nutritional deficiencies, arterial
ulcers, and thromboangiitis obliterans. The patient’s
living situation and support network can give
insight as to whether proper wound care is being
carried out.
area. Ulcers on the foot or high on the leg are
unlikely to be venous. Arterial ulcers tend to be
distal. Factitial ulcers often have an angular
shape, while vasculitic ulcers often have a
punched out appearance.

Review of systems 2. Wound edge, color, wound bed characteristics,

A review of systems is helpful in identifying
systemic conditions that may cause or exacerbate
an ulcer (Table VIII).
Physical examination
The patient’s general appearance, including
obesity, should be observed. A clinical examination
may reveal systemic disease associated with
cutaneous ulceration, such as connective tissue
disease or cutaneous malignancy. Helpful features
of a physical examination include the following:
1. What is the location, size, demarcation, and
shape of the ulcer, and is it singular or multiple?
Venous ulcers are commonly located in the gaiter
and the presence of undermining, satellites, or
nodularity should be noted. Ulcers in a linear
sporotrichoid distribution are suspicious for
deep fungal infection, while deeply undermined
ulcers with a violaceous border are classically
seen in patients with PG.
3. Fibrinous, granulation, and necrotic tissue
should be documented. Venous ulcers are not
necrotic unless arterial disease coexists.
4. Lymph nodes should be evaluated and lower
extremities examined for coolness or warmth.
5. Dorsalis pedis and posterior tibialis pulses must
be palpated and peripheral sensation evaluated.
J AM ACAD DERMATOL Morton and Phillips 601
VOLUME 74, NUMBER 4

Evaluation of Non-healing Leg

Ulcers

- History of presentIllness
- Past medical history and
medication history
- Family and social history
- Review of systems
- Physical Exam

Non-healing despite 4-6 weeks of

Venous Origin Arterial Origin Diabetic Origin Unusual Origin adequate wound care and
management

Evaluate for underlying medical

- Venous duplex ultrasound Incisional biopsy including wound
comorbidity with: complete blood
- Ankle-brachial index - Ankle-brachial index count, albumin, liver function tests, base and edge (consider biopsy of
- If unilateral lymphatic disease is Carefully rule out coincident normal skin for direct
- Consider CT or MRA to evaluate basic metabolic panel to include
suspected, consider imaging of the infection such as osteomyelitis, immunofluorescence if vasculitis is
for obstructive disease and creatinine, BUN and glucose
pelvis to rule out compression (i.e. which is best seen on MRI. suspected)
necessity of surgical intervention
malignant tumor or
lymphadenopathy)

Suspected vasculitis: C-reactive

protein, erythrocyte sedimentaion
rate, cytoplasmic-ANCA,
perinuclear-ANCA, total
complement, C3, C4, cryoglobulins,
cryofibrinogen, hepatitis C
antibody, serum protein
electrophoresis with
immunofixation

Suspected vasculopathy: PT,PTT,

INR,factor V Leiden, prothrombin
G20210A mutation,
methyltetrahydrofolate reducatase
mutation, cystathione-beta2-
synthase mutation, antithromibin
III, protein C, protein S,
plasminogen, anticardiolipin
antibodies, anti-beta2-glycoprotein,
lupus anticoagulant

Suspected infection: biopsy for

tissue analysis and culture for
bacterial, atypical mycobacterial
and fungal infections (may also
consider a PPD or serum
quantiferon gold to rule out
tuberculosis)

Suspected nutritional deficiency:

albumin, prealbumin, ferritin, zinc
levels

Suspected underlying medical

condition: autoimmune work up
(i.e. antinuclear antibodies, dsDNA,
rheumatoid factor), blood pressure
reading

Suspected pyoderma gangrenosum:

work up for underlying condition
such as inflammatory bowel
disease, autoimmune disorder,
hepatitis C

Suspected primary cutaneous

disorder (i.e. necrobiosis lipoidica,
malignancy): incisional biopsy

Fig 8. Flow chart for the evaluation of chronic ulcers after collecting a history of present illness,
medical history, review of systems, and physical examination.
602 Morton and Phillips
Where possible, the ABI should be measured at
the bedside.
6. Associated skin findings can be informative,
including purpura, papules, plaques, nodules,
callus, dermatitis, sclerotic or atrophic changes,
and scars, including cribriform scarring and
atrophie blanche.
7. Gross morphologic changes may include the
inverted champagne bottle appearance of
lipodermatosclerosis/chronic venous disease
and Charcot foot deformity of diabetes.
8. If wounds are purulent and feature spreading
erythema and warmth, or pain is out of
proportion to wound appearance, infection
should be considered. Deep infection, such as
osteomyelitis in the presence of DFUs, should
also be ruled out by probing the wound with a
metal probe to determine whether bone is
palpable.
Diagnostic tests
Diagnostic tests should be chosen based on the
history and physical examination and include
obtaining a tissue biopsy specimen, cultures,
hematologic laboratory analysis, vascular studies,
and imaging (Fig 8).
If an ulcer has been resistant to healing after 4 to
8 weeks of appropriate treatment, obtaining a biopsy
specimen should be strongly considered. Tissue
analysis may diagnose infection, vasculitis or
vasculopathy, inflammatory conditions, malignancy,
and hypertensive ulcers. An incisional biopsy
specimen is almost always more useful than a small
punch biopsy specimen. The sample should include
tissue from the wound bed and normal surrounding
tissue. A portion of tissue may be sent for bacterial,
atypical mycobacterial, and fungal cultures. If
vasculitis is suspected, lesional and perilesional
normal skin adjacent to the lesion should be sent
for immunofluorescent studies.
Useful laboratory studies include a complete
blood cell count to evaluate for anemia and serum
protein, albumin, prealbumin, zinc, and ferritin to
evaluate for nutritional deficiencies. A basic
metabolic panel and liver function tests may also
indicate underlying comorbidities.
In patients with suspected vasculitis, C-reactive
protein level, erythrocyte sedimentation rate,
cytoplasmic antineutrophilic cytoplasmic antibodies,
perinuclear antineutrophilic cytoplasmic antibodies,
total complement (CH100 or CH50), C3, C4,
blood urea nitrogen, and creatinine assessments
J AM ACAD DERMATOL
APRIL 2016
are informative. Consider cryoglobulins, cryofibri-
nogen, hepatitis C antibody, and serum protein
electrophoresis with immunofixation to assess for
paraproteinemia. When coagulopathy is suspected,
a thorough laboratory work-up is essential
(Table VI), including prothrombin time, partial
thromboplastin time, and international normalized
ratio. When an immunosuppressed state is sus-
pected, hepatitis work-up and an analysis for HIV
are important. Purified protein derivative or
QuantiFERON-Gold tests can be used when there
is suspicion for tuberculosis.
The ABI can be performed at the bedside to
exclude arterial disease in any patient who needs
compression therapy. Segmental pressures, pulse
volume recordings, or toeebrachial pressure indices
can be performed in the vascular laboratory where
bedside testing is not possible because of edema
or other factors. Venous duplex Doppler ultrasono-
graphic studies may confirm CVI. Computed
tomographic angiography or magnetic resonance
angiography can be considered if arteriovenous
malformation or obstructive arterial disease that
may require surgical revascularization are suspected.
If there is suspicion for lymphatic disease, a
computed tomography scan of the pelvis to rule
out lymphadenopathy or other obstructive
pathology may be necessary.
In conclusion, dermatologists may be presented
with difficult to heal chronic wounds of unclear
etiology. Understanding the pathophysiology of
wound healing and the broad differential diagnosis
for ulcers is invaluable in arriving at an appropriate
diagnosis.
REFERENCES
1. Kirsner RS. Wound iealing. In: Bolognia JL, Jorizzo JL,
Rapini RP, eds. Dermatology. 2nd ed. St Louis (MO): Elsevier
Health Sciences; 2008:2147-2158; Vol 2.
2. Budzynski AZ. Fibrinogen and fibrin: biochemistry and
pathophysiology. Crit Rev Oncol Hematol. 1986;6:97-146.
3. McDaniel JC, Roy S, Wilgus TA. Neutrophil activity in chronic
venous leg ulcersda target for therapy? Wound Repair Regen.
2013;21:339-351.
4. Mahdavian Delavary B, van der Veer WM, van Egmond M,
Niessen FB, Beelen RH. Macrophages in skin injury and repair.
Immunobiology. 2011;216:753-762.
5. Shah JM, Omar E, Pai DR, Sood S. Cellular events and
biomarkers of wound healing. Indian J Plast Surg. 2012;45:
220-228.
6. Zhang CP, Fu XB. Therapeutic potential of stem cells in
skin repair and regeneration. Chin J Traumatol. 2008;11:
209-221.
7. Przybylski M. A review of the current research on the role of
bFGF and VEGF in angiogenesis. J Wound Care. 2009;18:
516-519.
8. Grosskreutz CL, Anand-Apte B, Duplaa C, et al. Vascular
endothelial growth factor-induced migration of vascular
smooth muscle cells in vitro. Microvasc Res. 1999;58:128-136.
J AM ACAD DERMATOL
VOLUME 74, NUMBER 4
9. Bainbridge P. Wound healing and the role of fibroblasts. J
Wound Care. 2013;22:407-408, 410-412.
10. Baum CL, Arpey CJ. Normal cutaneous wound healing:
clinical correlation with cellular and molecular events.
Dermatol Surg. 2005;31:674-686; discussion 686.
11. Mast BA, Schultz GS. Interactions of cytokines, growth
factors, and proteases in acute and chronic wounds. Wound
Repair Regen. 1996;4:411-420.
12. Katz MH, Alvarez AF, Kirsner RS, Eaglstein WH, Falanga V.
Human wound fluid from acute wounds stimulates fibroblast
and endothelial cell growth. J Am Acad Dermatol. 1991;25:
1054-1058.
13. Trengove NJ, Bielefeldt-Ohmann H, Stacey MC. Mitogenic
activity and cytokine levels in non-healing and healing
chronic leg ulcers. Wound Repair Regen. 2000;8:13-25.
14. Mendez MV, Raffetto JD, Phillips T, Menzoian JO, Park HY. The
proliferative capacity of neonatal skin fibroblasts is reduced
after exposure to venous ulcer wound fluid: a potential
mechanism for senescence in venous ulcers. J Vasc Surg.
1999;30:734-743.
15. Bucalo B, Eaglstein WH, Falanga V. Inhibition of cell
proliferation by chronic wound fluid. Wound Repair Regen.
1993;1:181-186.
16. Harris IR, Yee KC, Walters CE, et al. Cytokine and protease
levels in healing and non-healing chronic venous leg ulcers.
Exp Dermatol. 1995;4:342-349.
17. Cowin AJ, Hatzirodos N, Holding CA, et al. Effect of healing
on the expression of transforming growth factor beta(s) and
their receptors in chronic venous leg ulcers. J Invest Dermatol.
2001;117:1282-1289.
18. Ladwig GP, Robson MC, Liu R, Kuhn MA, Muir DF, Schultz GS.
Ratios of activated matrix metalloproteinase-9 to tissue
inhibitor of matrix metalloproteinase-1 in wound fluids are
inversely correlated with healing of pressure ulcers. Wound
Repair Regen. 2002;10:26-37.
19. Yager DR, Zhang LY, Liang HX, Diegelmann RF, Cohen IK.
Wound fluids from human pressure ulcers contain elevated
matrix metalloproteinase levels and activity compared to
surgical wound fluids. J Invest Dermatol. 1996;107:743-748.
20. Mwaura B, Mahendran B, Hynes N, et al. The impact of
differential expression of extracellular matrix metalloprotei-
nase inducer, matrix metalloproteinase-2, tissue inhibitor of
matrix metalloproteinase-2 and PDGF-AA on the chronicity
of venous leg ulcers. Eur J Vasc Endovasc Surg. 2006;31:
306-310.
21. Utz ER, Elster EA, Tadaki DK, et al. Metalloproteinase
expression is associated with traumatic wound failure. J
Surg Res. 2010;159:633-639.
22. Moor AN, Vachon DJ, Gould LJ. Proteolytic activity in wound
fluids and tissues derived from chronic venous leg ulcers.
Wound Repair Regen. 2009;17:832-839.
23. Percival SL, Thomas JG, Williams DW. Biofilms and bacterial
imbalances in chronic wounds: anti-Koch. Int Wound J. 2010;
7:169-175.
24. James GA, Swogger E, Wolcott R, et al. Biofilms in chronic
wounds. Wound Repair Regen. 2008;16:37-44.
25. Gillespie DL, Kistner B, Glass C, et al. Venous ulcer diagnosis,
treatment, and prevention of recurrences. J Vasc Surg. 2010;
52(5 suppl):8S-14S.
26. van Gent WB, Wilschut ED, Wittens C. Management of
venous ulcer disease. BMJ (Clin Res Ed). 2010;341:c6045.
27. Etufugh CN, Phillips TJ. Venous ulcers. Clin Dermatol. 2007;25:
121-130.
28. Morton LM, Phillips TJ. Wound healing update. Semin Cutan
Med Surg. 2012;31:33-37.
Morton and Phillips 603
29. Labropoulos N, Leon LR Jr. Duplex evaluation of venous
insufficiency. Semin Vasc Surg. 2005;18:5-9.
30. Labropoulos N, Tiongson J, Pryor L, et al. Definition of
venous reflux in lower-extremity veins. J Vasc Surg. 2003;38:
793-798.
31. Raju S, Neglen P. Clinical practice. Chronic venous
insufficiency and varicose veins. N Engl J Med. 2009;360:
2319-2327.
32. Ueda T, Tanabe K, Morita M, Nakahara C, Katsuoka K.
Leg ulcer due to multiple arteriovenous malformations
in the lower extremity of an elderly patient. Int Wound J.
doi: 10.1111/iwj.12273. Published online April 10, 2014.
33. Lee SG, Ohtoshi E, Matsuyoshi N, Ohta K, Horiguchi Y,
Imamura S. Foot ulcer due to arteriovenous malformation:
report of a case. J Dermatol. 1997;24:255-257.
34. Gelfand JM, Hoffstad O, Margolis DJ. Surrogate endpoints for
the treatment of venous leg ulcers. J Invest Dermatol. 2002;
119:1420-1425.
35. Margolis DJ, Allen-Taylor L, Hoffstad O, Berlin JA. The
accuracy of venous leg ulcer prognostic models in a wound
care system. Wound Repair Regen. 2004;12:163-168.
36. Nelson EA, Bradley MD. Dressings and topical agents for
arterial leg ulcers. Cochrane Database Syst Rev. 2007;1:
CD001836.
37. Mekkes JR, Loots MA, Van Der Wal AC, Bos JD. Causes,
investigation and treatment of leg ulceration. Br J Dermatol.
2003;148:388-401.
38. Phillips TJ, Dover JS. Leg ulcers. J Am Acad Dermatol. 1991;
25(6 pt 1):965-987.
39. Khan TH, Farooqui FA, Niazi K. Critical review of the ankle
brachial index. Curr Cardiol Rev. 2008;4:101-106.
40. Cao P, Eckstein HH, De Rango P, et al. Chapter II: diagnostic
methods. Eur J Vasc Endovasc Surg. 2011;42(suppl 2):S13-S32.
41. Ricco JB, Thanh Phong L, Schneider F, et al. The diabetic foot:
a review. J Cardiovasc Surg. 2013;54:755-762.
42. Singh N, Armstrong DG, Lipsky BA. Preventing foot ulcers in
patients with diabetes. JAMA. 2005;293:217-228.
43. Bruhn-Olszewska B, Korzon-Burakowska A, Gabig-
Ciminska M, Olszewski P, Wegrzyn A, Jakobkiewicz-
Banecka J. Molecular factors involved in the development
of diabetic foot syndrome. Acta Biochimica Pol. 2012;59:
507-513.
44. Lepantalo M, Apelqvist J, Setacci C, et al. Chapter V: diabetic
foot. Eur J Vasc Endovas Surg. 2011;42(suppl 2):S60-S74.
45. Apelqvist J. The foot in perspective. Diabetes Metab Res Rev.
2008;24(suppl 1):S110-S115.
46. Prompers L, Huijberts M, Apelqvist J, et al. High prevalence of
ischaemia, infection and serious comorbidity in patients with
diabetic foot disease in Europe. Baseline results from the
Eurodiale study. Diabetologia. 2007;50:18-25.
47. Gershater MA, Londahl M, Nyberg P, et al. Complexity of
factors related to outcome of neuropathic and neuroischae-
mic/ischaemic diabetic foot ulcers: a cohort study. Diabeto-
logia. 2009;52:398-407.
48. Schaper NC, Huijberts M, Pickwell K. Neurovascular control
and neurogenic inflammation in diabetes. Diabetes Metab Res
Rev. 2008;24(suppl 1):S40-S44.
49. Selvin E, Marinopoulos S, Berkenblit G, et al. Meta-analysis:
glycosylated hemoglobin and cardiovascular disease in
diabetes mellitus. Ann Intern Med. 2004;141:421-431.
50. Alavi A, Sibbald RG, Mayer D, et al. Diabetic foot ulcers: Part I.
Pathophysiology and prevention. J Am Acad Dermatol. 2014;
70:1.e1-1.e18; quiz 19-20.
51. Schuurman JP, Schoonhoven L, Defloor T, van Engelshoven I,
van Ramshorst B, Buskens E. Economic evaluation of pressure
604 Morton and Phillips
ulcer care: a cost minimization analysis of preventive
strategies. Nurs Econ. 2009;27:390-400, 415.
52. Kroger K, Niebel W, Maier I, Stausberg J, Gerber V,
Schwarzkopf A. Prevalence of pressure ulcers in hospitalized
patients in Germany in 2005: data from the Federal Statistical
Office. Gerontology. 2009;55:281-287.
53. Keelaghan E, Margolis D, Zhan M, Baumgarten M. Prevalence
of pressure ulcers on hospital admission among nursing
home residents transferred to the hospital. Wound Repair
Regen. 2008;16:331-336.
54. Kanj LF, Wilking SV, Phillips TJ. Pressure ulcers. J Am Acad
Dermatol. 1998;38:517-536; quiz 537-8.
55. National Pressure Ulcer Advisory Panel website. NPUAP
pressure ulcer stages/categories. Available at: http://www.
npuap.org/resources/educational-and-clinical-resources/npuap-
pressure-ulcer-stagescategories/. Accessed May 12, 2014.
56. Maklebust J, Magnan MA. Risk factors associated with having
a pressure ulcer: a secondary data analysis. Adv Wound Care.
1994;7:25, 27-28, 31-34 passim.
57. Stone JH, Nousari HC. ‘‘Essential’’ cutaneous vasculitis: what
every rheumatologist should know about vasculitis of the
skin. Curr Opin Rheumatol. 2001;13:23-34.
58. Ramos-Casals M, Stone JH, Cid MC, Bosch X. The
cryoglobulinaemias. Lancet. 2012;379:348-360.
59. Ferri C, Sebastiani M, Giuggioli D, et al. Mixed
cryoglobulinemia: demographic, clinical, and serologic
features and survival in 231 patients. Semin Arthritis Rheum.
2004;33:355-374.
60. Della Rossa A, Tavoni A, D’Ascanio A, et al. Mortality
rate and outcome factors in mixed cryoglobulinaemia: the
impact of hepatitis C virus. Scand J Rheumatol. 2010;39:
167-170.
61. Bryce AH, Kyle RA, Dispenzieri A, Gertz MA. Natural history
and therapy of 66 patients with mixed cryoglobulinemia. Am
J Hematol. 2006;81:511-518.
62. Atzeni F, Carrabba M, Davin JC, et al. Skin manifestations in
vasculitis and erythema nodosum. Clin Exp Rheumatol. 2006;
24(1 suppl 40):S60-S66.
63. Fiorentino DF. Cutaneous vasculitis. J Am Acad Dermatol.
2003;48:311-340.
64. Daoud MS, Gibson LE, DeRemee RA, Specks U, el-Azhary RA,
Su WP. . Cutaneous Wegener’s granulomatosis: clinical,
histopathologic, and immunopathologic features of thirty
patients. J Am Acad Dermatol. 1994;31:605-612.
65. Kluger N, Pagnoux C, Guillevin L, Frances C. Comparison of
cutaneous manifestations in systemic polyarteritis nodosa
and microscopic polyangiitis. Br J Dermatol. 2008;159:
615-620.
66. Daoud MS, Hutton KP, Gibson LE. Cutaneous periarteritis
nodosa: a clinicopathological study of 79 cases. Br J Dermatol.
1997;136:706-713.
67. Thornsberry LA, LoSicco KI, English JC 3rd. The skin and
hypercoagulable states. J Am Acad Dermatol. 2013;69:
450-462.
68. Davies DJ, Thurasingham K. Intractable leg ulceration caused
by cutaneous cholesterol embolism. Med J Aust. 1992;157:
267-268.
69. Becker KA, Schwartz RA, Rothenberg J. Leg ulceration and
the cholesterol embolus. J Med. 1997;28:387-392.
70. Falanga V, Fine MJ, Kapoor WN. The cutaneous
manifestations of cholesterol crystal embolization. Arch
Dermatol. 1986;122:1194-1198.
71. Fine MJ, Kapoor W, Falanga V. Cholesterol crystal
embolization: a review of 221 cases in the English literature.
Angiology. 1987;38:769-784.
J AM ACAD DERMATOL
APRIL 2016
72. Motegi S, Abe M, Shimizu A, et al. Cholesterol crystal
embolization: skin manifestation, gastrointestinal and central
nervous symptom treated with corticosteroid. J Dermatol.
2005;32:295-298.
73. Hayashi M. Calciphylaxis: diagnosis and clinical features. Clin
Exp Nephrol. 2013;17:498-503.
74. Rogers NM, Coates PT. Calcific uraemic arteriolopathy: an
update. Curr Opin Nephrol Hypertens. 2008;17:629-634.
75. Zhou Q, Neubauer J, Kern JS, Grotz W, Walz G, Huber TB.
Calciphylaxis. Lancet. 2014;383:1067.
76. Fine A, Zacharias J. Calciphylaxis is usually non-ulcerating:
risk factors, outcome and therapy. Kidney Int. 2002;61:
2210-2217.
77. Miura Y, Ardenghy M, Ramasastry S, Kovach R, Hochberg J.
Coumadin necrosis of the skin: report of four patients. Ann
Plast Surg. 1996;37:332-337.
78. Kakagia DD, Papanas N, Karadimas E, Polychronidis A.
Warfarin-induced skin necrosis. Ann Dermatol. 2014;26:
96-98.
79. Nazarian RM, Van Cott EM, Zembowicz A, Duncan LM.
Warfarin-induced skin necrosis. J Am Acad Dermatol. 2009;
61:325-332.
80. Kerk N, Goerge T. Livedoid vasculopathy - current aspects of
diagnosis and treatment of cutaneous infarction. J Dtsch
Dermatol Ges. 2013;11:407-410.
81. Kerk N, Goerge T. Livedoid vasculopathy - a thrombotic
disease. Vasa. 2013;42:317-322.
82. Alavi A, Hafner J, Dutz JP, et al. Livedoid vasculopathy: an
in-depth analysis using a modified Delphi approach. J Am
Acad Dermatol. 2013;69:1033-1042.e1.
83. Browning CE, Callen JP. Warfarin therapy for livedoid
vasculopathy associated with cryofibrinogenemia and
hyperhomocysteinemia. Arch Dermatol. 2006;142:75-78.
84. Di Giacomo TB, Hussein TP, Souza DG, Criado PR. Frequency
of thrombophilia determinant factors in patients with
livedoid vasculopathy and treatment with anticoagulant
drugsda prospective study. J Eur Acad Dermatol Venereol.
2010;24:1340-1346.
85. Deng A, Gocke CD, Hess J, Heyman M, Paltiel M, Gaspari A.
Livedoid vasculopathy associated with plasminogen
activator inhibitor-1 promoter homozygosity (4G/4G) treated
successfully with tissue plasminogen activator. Arch
Dermatol. 2006;142:1466-1469.
86. Yang CH, Shen SC, Hui RC, Huang YH, Chu PH, Ho WJ.
Association between peripheral vascular endothelial
dysfunction and livedoid vasculopathy. J Am Acad Dermatol.
2012;67:107-112.
87. Muller SA, Winkelmann RK. Necrobiosis lipoidica
diabeticorum. A clinical and pathological investigation of
171 cases. Arch Dermatol. 1966;93:272-281.
88. Erfurt-Berge C, Seitz AT, Rehse C, Wollina U, Schwede K,
Renner R. Update on clinical and laboratory features in
necrobiosis lipoidica: a retrospective multicentre study of 52
patients. Eur J Dermatol. 2012;22:770-775.
89. Franklin C, Stoffels-Weindorf M, Hillen U, Dissemond J.
Ulcerated necrobiosis lipoidica as a rare cause for chronic
leg ulcers: case report series of ten patients. Int Wound J.
2015;12:548-554.
90. Reid SD, Ladizinski B, Lee K, Baibergenova A, Alavi A.
Update on necrobiosis lipoidica: a review of etiology,
diagnosis, and treatment options. J Am Acad Dermatol.
2013;69:783-791.
91. Thrash B, Patel M, Shah KR, Boland CR, Menter A. Cutaneous
manifestations of gastrointestinal disease: part II. J Am Acad
Dermatol. 2013;68:211.e1-211.e33; quiz 244-246.
J AM ACAD DERMATOL
VOLUME 74, NUMBER 4
92. Ahronowitz I, Harp J, Shinkai K. Etiology and management of
pyoderma gangrenosum: a comprehensive review. Am J Clin
Dermatol. 2012;13:191-211.
93. Miller J, Yentzer BA, Clark A, Jorizzo JL, Feldman SR.
Pyoderma gangrenosum: a review and update on new
therapies. J Am Acad Dermatol. 2010;62:646-654.
94. Phillips TJ, Salman SM, Bhawan J, Rogers GS. Burn scar
carcinoma. Diagnosis and management. Dermatol Surg. 1998;
24:561-565.
95. Chakrabarty A, Phillips T. Leg ulcers of unusual causes. Int J
Lower Extrem Wounds. 2003;2:207-216.
96. Edwards MJ, Hirsch RM, Broadwater JR, Netscher DT,
Ames FC. Squamous cell carcinoma arising in previously
burned or irradiated skin. Arch Surg. 1989;124:115-117.
97. Granel F, Barbaud A, Schmutz JL. Basal and squamous cell
carcinoma associated with chronic venous leg ulcer. Int J
Dermatol. 2001;40:539-540.
98. Schnirring-Judge M, Belpedio D. Malignant transformation
of a chronic venous stasis ulcer to basal cell carcinoma
in a diabetic patient: case study and review of the
pathophysiology. J Foot Ankle Surg. 2010;49:75-79.
99. Baldursson BT, Hedblad MA, Beitner H, Lindelof B. Squamous
cell carcinoma complicating chronic venous leg ulceration: a
study of the histopathology, course and survival in 25
patients. Br J Dermatol. 1999;140:1148-1152.
100. Yin NC, Miteva M, Covington DS, Romanelli P, Stojadinovic O.
The importance of wound biopsy in the accurate diagnosis of
acral malignant melanoma presenting as a foot ulcer. Int J
Lower Extrem Wounds. 2013;12:289-292.
Answers to CME examination
Identification No. JA0416
April 2016 issue of the Journal of the American Academy of Dermatology.
Morton LM, Phillips TJ. J Am Acad Dermatol 2016;74:589-605.
1. c
2. d
Morton and Phillips 605
101. Turk BG, Bozkurt A, Yaman B, Ozdemir F, Unal I. Melanoma
arising in chronic ulceration associated with lymphoedema. J
Wound Care. 2013;22:74-75.
102. Monteiro D, Horta R, Eloy C, Silva P, Silva A. Kaposi’s sarcoma
arising in a burn scar mimicking Marjolin’s ulcer. Burns. 2013;
39:e25-e28.
103. Lucandri G, Mazzocchi P, Bascone B, et al. Unusual ulcerated
Merkel cell carcinoma of the skin: report of a case. Tumori.
2006;92:555-558.
104. Herrmann JL, Hughey LC. Recognizing large-cell transforma-
tion of mycosis fungoides. J Am Acad Dermatol. 2012;67:
665-672.
105. Kolluri R, Kamel O. Images in vascular medicine.
Unusual etiology of painful leg ulcers. Vasc Med. 2007;12:
255-256.
106. Rao SD, Ravi R, Govindarajan M. Primary cutaneous CD 301
anaplastic large cell lymphoma. Indian J Surg. 2010;72(suppl
1):283-285.
107. Martorell F. Las ulceras supramaleolares por arteriolitis de las
grandes hipertensas. Actas del Instituto Policlinico de Barce-
lona. 1945;1:6-9.
108. Schnier BR, Sheps SG, Juergens JL. Hypertensive ischemic
ulcer. A review of 40 cases. Am J Cardiol. 1966;17:560-565.
109. Graves JW, Morris JC, Sheps SG. Martorell’s hypertensive leg
ulcer: case report and concise review of the literature. J Hum
Hypertens. 2001;15:279-283.
110. Alavi A, Mayer D, Hafner J, Sibbald RG. Martorell hypertensive
ischemic leg ulcer: an underdiagnosed EntityÓ. Adv Skin
Wound Care. 2012;25:563-572; quiz 573-574.
3. c
4. b