The Differential Diagnosis of Leg Ulcers

Background: Chronic wounds on the leg (below the knee) are called leg ulcers. They have many causes, and thus patients with leg ulcers are treated by many different kinds of medical specialist. Appproximately 80% of sufferers have chronic venous insufficiency (CVI) and/or peripheral arterial occlusive disease (PAOD). Knowledge of the relevant differential diagnoses is important for appropriate treatment, particularly for patients with atypical findings or an intractable course.

Methods: This article is based on publications retrieved by a selective search in PubMed, including current guidelines and expert recommendations.

Results: The diagnostic evaluation of a leg ulcer can be structured according to the ABCDE rule. This involves individualized, targeted history-taking (anamnesis); bacteriological testing; clinical examination; ancillary testing, particularly for perfusion (defective vascular system); and extras, such as biopsies. Specifically, we present in this article the main aspects of the complex diagnostic evaluation of venous leg ulcers, arterial leg ulcers, vasculitis, vasculopathy, calciphylaxis, pyoderma gangrenosum, necrobiosis lipoidica, ecthyma, and squamous cell carcinoma. There remain many unsolved problems, including interactions between the various areas of clinical treatment and the relative paucity of relevant high-quality research.

Conclusion: A timely differential-diagnostic evaluation for the many diseases that can cause leg ulcers, which require treatment from representatives of many different medical specialties and health professions, is a prerequisite for their effective individualized treatment.

Chronic wounds are a significant interdisciplinary challenge; the quality of life of affected individuals is considerably reduced by pain, often unpleasant odors, and limited mobility, as well as other factors (1). This leads to further problems, such as social isolation, sleep disorders or depression (2). In Germany, the prevalence of chronic wounds is approximately 1–2% (3). The most common manifestations are diabetic foot ulcer, pressure ulcer and leg ulcer (4).

An ulcer is a skin wound that extends at least into the dermis. “Leg” specifies the anatomical location of the lesions at the lower legs. Thus, the term leg ulcers merely describes a clinical sign as opposed to a diagnosis. Approximately 80% of patients with chronic leg ulcers suffer from chronic venous insufficiency (CVI) and/or peripheral arterial occlusive disease (PAOD). Knowledge of the differential diagnoses is important for appropriate treatment, particularly with regard to patients with atypical findings or an intractable course (Box, eBox) (5). In this review, we will discuss the most common causes of leg ulcers as well as the corresponding diagnostic work-up.

Box

Selection of potentially relevant factors and conditions which can cause leg ulcers

eBox

Extended selection of potentially relevant factors and conditions which can cause leg ulcers

Venous leg ulcers

Approximately 0.2% of the German population has active venous leg ulcers (VLUs) (6). The prevalence increases to about 3.6% after the age of 65 years (7). Risk factors include increasing age, female sex, elevated body mass index, arterial hypertension, and venous thrombosis (7). The five-year recurrence rate is approximately 70% (8). Venous disorders are categorized using the CEAP classification system (9) (Table 1, eTable):

• C – Clinic
• E – Etiology
• A – Anatomy
• P – Pathophysiology.

Table 1

List of the clinical findings (C) of the CEAP classification of venous disorders

eTable

CEAP Classification* of venous disorders

CVI is caused by impaired venous outflow due to incompetent venous valves. Hemodynamically relevant reflux leads to ambulatory venous hypertension and hypervolemia with decreased capillary perfusion and flow rate. Activated leukocytes trigger inflammation in venous vessel walls and the adjacent tissue. Local hypoxia is further aggravated by the formation of pericapillary fibrin cuffs (8). A venous leg ulcer is the most severe lesion resulting from trophic disorders of the skin organ. A growing number of functional venous disorders, such as obesity-associated dependency syndrome, have also been described (10). Patients with obesity-associated dependency syndrome can develop venous leg ulcers in the absence of venous incompetence or obstructions; these are caused by prolonged sitting and pressure on the leg’s venous system by hanging flaps of skin (11).

The predilection sites are superior or posterior to the medial malleolus (Figure 1 a). Symptoms of pain vary greatly in severity.

Figure 1

a) Venous leg ulcer, b) arterial leg ulcer, c) cutaneous leukocytoclastic angiitis, d) livedoid vasculopathy, e) calciphylaxis, f) pyoderma gangrenosum, g) necrobiosis lipoidica, h) ecthyma, i) squamous cell carcinoma.

The edematous tissue surrounding venous leg ulcers shows typical skin changes (eFigure 1). Corona phlebectatica paraplantaris (CPP) manifests below the malleoli. The initially red, later yellow-brown hyperpigmentation, which is caused by hemosiderin deposits, is referred to as purpura jaune d’ocre. The congestive dermatitis leads to poorly demarcated, itchy eczema on the lower legs. Hypodermitis (“pseudo-erysipelas“) refers to erythematous areas which are frequently noted bilaterally at the lower legs (12). Lipodermatosclerosis is caused by the chronic inflammation of dermis and subcutis. The typical, but non-specific atrophie blanche is a vasculopathy observed in advanced stages of CVI.

eFigure 1

Patient with a) a venous leg ulcer, b) corona phlebectatitica paraplantaris, c) lipodermatosclerosis, d) purpura jaune d’ocre, and e) stasis dermatitis

The gold standard in the diagnosis of venous disorders is color-coded duplex ultrasonography which visualizes both the morphology and the hemodynamics of the blood vessels. The Valsalva maneuver is used to assess venous valvular function (13).

Arterial leg ulcers

PAOD causes restrictions in blood flow in the arteries supplying the extremities and, more rarely, in the aorta. The flow can be partially restricted by stenoses or completely by an occlusion. All aspects promoting atherosclerosis are considered risk factors, including, in particular, smoking, disorders of fat metabolism and metabolic syndrome. The overall prevalence amounts to 3–10% and starts increasing to 15–20% from the age of 70 (14). The Fontaine classification is commonly used to grade the severity of PAOD (Table 2). In the advanced stage, blood supply to acral areas is reduced, leading to necrosis. However, an arterial leg ulcer can also develop as a result. Common triggers include injury to the anterior tibial crest, pressure on the area proximal to the lateral malleolus as well as excoriations. In most cases, PAOD is not the primary cause of the ulcer at the lower leg, but it prevents it from healing (14).

Table 2

Fontaine classification of peripheral arterial occlusive disease

Predilection sites are the areas at the lower leg that are exposed to pressure (Figure 1 b). A typical clinical observation is that necrosis initially develops in usually cool, dry skin.

The presence of palpable foot pulses does not rule out PAOD. The ankle-brachial index (ABI) is the gold standard for the basic clinical evaluation of the arterial system. The systolic blood pressure is measured at the brachial artery, tibial posterior artery and tibial anterior artery, using a Doppler probe, after the patient has been at rest on the treatment table for about 10 minutes. The lowest ankle arterial pressure is divided by the mean brachial arterial systolic pressure. A value below 0.9 is considered diagnostic of PAOD (15). PAOD with an ankle arterial pressure ≥ 70 mmHg in the presence of normal systemic pressure is considered compensated; in contrast, an ankle arterial pressure < 70 mmHg is associated with delayed wound healing (16). Additional tests include toe pressure measurement, oscillography, transcutaneous oxygen measurement, and color-coded duplex ultrasonography (17). The actual conclusion situation should be visualized using digital subtraction angiography (DSA), computed tomography angiography (CTA) or magnetic resonance angiography (MRA) (14).

Cutaneous vasculitides

Vasculitides are a heterogeneous group of inflammatory diseases that can affect any blood vessel of the body. Autoimmune processes trigger inflammation of the vessel walls with reactive stenosis and occlusion. The classification of the Chapel Hill Consensus Conference Nomenclature of Vasculitides is primarily based on the size and type of the vessels involved (18).

Painful areas of necrosis and ulcers with purple margins are most commonly associated with cutaneous leukocytoclastic angiitis, the clinical hallmark of which is palpable purpura. It is caused by deposits of circulating immune complexes in small vessels. Approximately 15 new cases/million population are diagnosed each year (19).

The predilection sites of cutaneous leukocytoclastic angiitis are the distal lower extremities (Figure 1 c). In most patients who develop ulcers, these are usually disseminated and located bilaterally.

The diagnostic gold standard is the histopathological examination of a biopsy specimen. Potential triggers include infectious diseases, drugs and neoplasms; these factors should be addressed during history-taking as well as by serological and, if required, ancillary testing (20).

Cutaneous vasculopathies

Cutaneous vasculopathies are occluding, primarily non-inflammatory vascular diseases. They are associated with a number of hematological or dermatological conditions (20). Potential triggers include drugs such as hydroxyurea. After a mean hydroxyurea therapy duration of two to five years, cumulative vascular damage leads to the development of a violaceous erythematous rash und very painful ulcers on the distal lower extremities (21).

Livedoid vasculopathy is associated with thromboembolic occlusion of the cutaneous vascular plexus. The prevalence is estimated to be approximately 1/100 000 population, with significant female preponderance. Local triggers include injuries and other mechanisms causing slower blood flow. Patients are frequently young adults without familial predisposition, experiencing recurrences. The non-specific cardinal symptoms include painful skin ulcers, livedo racemosa (eFigure 2) and atrophie blanche (22).

eFigure 2

Livedo racemosa refers to the reticular, erythematous purple skin changes that also belong to the triad of clinical symptoms of livedoid vasculopathy. However, it can also occur independent of these condition, for example associated with vasculitides.

The predilection sites of livedoid vasculopathy are the distal lower extremities (Figure 1 d).

The diagnostic gold standard is the histopathological examination of a biopsy specimen (22).

Calciphylaxis

Calciphylaxis is a calcific uremic arteriolopathy. The average age of patients at the time of onset was about 60 years; 80% of the affected individuals are women (23). The disease primarily occurs in patients with end-stage renal disease; the prevalence is 1% to 4% across all patients with dialysis-dependent renal failure. Calciphylaxis is caused by a disorder of the calcium-phosphate metabolism. Since coumarins lead to an inhibition of the matrix gla protein (MGP) and thus promote calcification, patients taking these substances should be switched to an anticoagulant of another class. The six-month survival rate is about 57% (23).

The predilection sites are the lower extremities where purple erythematous skin changes appear that develop into extremely painful necrotic lesions and ulcers (Figure 1 e).

The diagnostic gold standard is the histopathological examination of a biopsy specimen (23).

Pyoderma gangrenosum

Pyoderma gangrenosum is an ulcerative neutrophilic dermatosis of unclear etiology. The prevalence ranges from 0.3 to 1.0/100 000 population. It is commonly associated with comorbidities, such as inflammatory bowel disease, (hematological) neoplasms, diabetes mellitus, or rheumatoid arthritis (24).

In 70% of affected individuals, the predilection sites are the extensor aspects of the lower extremities (Figure 1 f). The pathergy phenomenon describes the development of the lesions after a (minimal) mechanical trauma. Clinically, pyoderma gangrenosum is characterized by erythematous nodules or sterile pustules which rapidly develop into very painful ulcers with dusky purple, partially undermined rim (24).

The diagnostic gold standard is the PARACELSUS score that summarizes the non-specific but typical signs and symptoms of the disease (Table 3) (25).

Table 3

PARACELSUS score for the diagnosis of pyoderma gangrenosum (25)*

Necrobiosis lipoidica

Necrobiosis lipoidica is an inflammatory granulomatous skin disease. In about 60% of patients, it is associated with diabetes mellitus. The incidence is 0.3% to 1.2% in people with diabetes. The pathophysiology of the disease is thought to involve a T-cell-mediated immune reaction with release of pro-inflammatory cytokines and lysosomal enzymes, triggering inflammation and local tissue destruction with dermal accumulation of lipids (26).

The predilection sites are the extensor aspects of the lower extremities. The clinical course is marked by the development of yellowish-brown plaques with erythematous rim and numerous scattered telangiectasias (Figure 1 g). Progressive atrophy can lead to very painful ulcers (26).

The diagnostic gold standard is the histopathological examination of a biopsy specimen. Even if the initial examinations were unremarkable, patients should be repeatedly tested for diabetes during follow-up.

Cutaneous infectious diseases

Leg ulcers can be caused by many infectious diseases, involving bacteria, viruses, fungi, or protozoa. Mycobacteriosis, such as Buruli ulcer, or leishmaniosis are common (sub-) tropical diseases presenting with leg ulcers (27). After swimming in open water, skin wounds can also become infected with vibrios or Corynebacterium diphtheriae (28).

In Europe, the most common type of ulcerative pyoderma is referred to as ecthyma. The prevalence is estimated to be 1.0/100 000 population. Predisposing factors include poor hygiene, malnutrition, diabetes mellitus, immunosuppression, and eczema (29). In most cases, β-hemolytic streptococci or Staphylococcus aureus cause the pustules which then develop into multiple, sharply demarcated, not very painful ulcers that are rarely larger than 3–5 cm in size (29).

The predilection sites of ecthyma are the distal lower extremities (Figure 1 h).

The diagnostic gold standard is clinical inspection. In cases complicated by concomitant soft-tissue infection, the patient’s vital signs should be monitored and serological markers of inflammation should be assessed; if necessary, bacterial swabs as well as biopsies should also be obtained.

Cutaneous neoplasms

Particularly with regard to leg ulcers that do not respond to treatment or show an atypical clinical course, it is important to rule out neoplasms, such as basal cell carcinoma, malignant melanoma, metastases, and squamous cell carcinoma (30).

On the one hand, leg ulcers can be a complication of squamous cell carcinoma and, on the other hand, squamous cell carcinoma can develop secondarily as a complication of leg ulcers (Marjolin’s ulcer). This skin cancer usually causes ulcers that are not very painful, sharply demarcated and slowly grow in size (Figure 1 i). According to an analysis of data of the German Marjolin Registry, the mean interval between the diagnosis of a venous leg ulcer and the diagnosis of a related squamous cell carcinoma was 16 years. Clinical features included pain, resistance to therapy, fetor, as well as atypical morphology with a nodular wound bed and hypergranulation tissue (31).

There are no predilection sites for squamous cell carcinoma lesions at the lower legs.

The diagnostic gold standard is the histopathological examination of ideally multiple biopsy specimens.

Structured diagnosis

The diagnostic evaluation of a chronic leg ulcer can be structured according to the ABCDE rule (32).

• A – History-taking (anamnesis) should address not only the current wound but also wounds that occurred in the past, as well as cofactors, comorbidities and family history.
• B – Bacteria, but they rarely cause leg ulcers. Bacteriological testing is mainly used to identify superinfection and/or the presence of multidrug-resistant organisms (MDROs), such as methicillin-resistant Staphylococcus aureus (MRSA). In patients with leg ulcers, it is generally sufficient for bacteriological testing to collect a swab of the surface of the ulcer. However, in patients with suspicion of mycobacteriosis biopsies should be obtained in addition (33).
• C – Clinical examinations often provide important clues to wound etiology and complications based on the location of the wound and the morphology of the wound edge and surrounding tissue.
• D – For the diagnostic evaluation of perfusion, clinical and ancillary testing of both the venous and arterial system are required.
• E – Extras include many additional diagnostic tests which are used for targeted evaluation. Blood count and acute-phase proteins are rather assessed as part of the work-up of bacterial superinfection (34). Biopsy is the method of greatest clinical importance; it is typically obtained from the edge of the wound. If an atypical cause is suspected, a biopsy should be taken without delay. If despite apparently appropriate treatment, no improvement is noted, a biopsy should be performed after twelve weeks at the latest. Since timing and earlier treatment often have a considerable effect on biopsy results, this information should be included when ordering a biopsy. Especially in patients with suspected vasculitis, direct immunofluorescence (DIF) testing should be performed (35).

Discussion

Many challenges in the diagnosis and management of patients with chronic leg ulcers have yet to be overcome in Germany. For example, with relevant causes often not being diagnosed, patient management focuses narrowly on treating the symptom “wound” (Figure 2). However, diagnosing the underlying cause(s) of leg ulcers and providing causal treatment are crucial to the long-term success of therapy (36).

Figure 2

Simplified flowchart of the diagnosis of chronic leg ulcers

Particularly with regard to patients with atypical findings or an intractable course, differential diagnoses, which are otherwise rarely included in the work-up, should be taken into account (5) (Table 4, eBox). Once a correct diagnosis has been established, causal treatment can be initiated. Additional supportive treatment with modern moist wound therapy is often beneficial (37). Since the majority of conditions presenting with leg ulcers are associated with edema, compression treatment should be started after any contraindications have been ruled out (38). Especially in patients with inflammatory and infectious diseases, additional treatment with systemic therapies is usually required (39).

Table 4

Overview of important aspects for various causes of leg ulcers

Worldwide, numerous projects have been launched with the aim of providing continuing education for treating healthcare professionals or telemedical consultations in order to improve the care structures for patients with leg ulcers. Despite these efforts, considerable deficits remain (40).

Conclusion for clinical practice

There are many different conditions that can cause leg ulcers. Therefore, it is important that patients with leg ulcers are diagnosed and treated by an interdisciplinary and interprofessional team as early as possible.

Conflict of interest statement
JD received lecture fees, consulting fees and/or fees for clinical studies from the following companies: 3M, Aurealis, Biomonde, Coloplast, Convatec, Curea, Flen Pharma. Integra, Juzo, Lohmann&Rauscher, medi, Mölnlycke, Novartis, Piomic, UCB, Urgo.

JMP received lecture fees, consulting fees and/or fees for clinical studies from the following companies: Bristol-Myers Squibb, Novartis, Sanofi, Pierre Fabre, Therakos.

MM received lecture fees, consulting fees and/or fees for clinical studies from the following companies: Adtec Heathcare, Mölnlycke, Reheacell, Urgo.

KK received lecture fees, consulting fees and/or fees for clinical studies from the following companies: BMS, Coloplast, Urgo.

Manuscript received on 2 February 2024; revised version accepted on 17 June 2024

Translated from the original German by Ralf Thoene, M.D.

Corresponding author
Prof. Dr. med. Joachim Dissemond

Universitätsklinikum Essen

Klinik und Poliklinik für Dermatologie,
Venerologie und Allergologie

Hufelandstraße 55
45122 Essen, Germany

Cite this as:
Dissemond J, Placke JM, Moelleken M, Kröger K: The differential diagnosis of leg ulcers. Dtsch Arztebl Int 2024; 121: 733–9. DOI: 10.3238/arztebl.m2024.0133

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